Advanced and Metastatic Breast Cancer

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Approximately one-third of the patients treated in the ASCENT clinical trial comparing the antibody-drug conjugate sacituzumab govitecan (Trodelvy, Gilead) with single-agent chemotherapy in patients with triple-negative breast cancer (TNBC) did not have an initial diagnosis of TNBC.

But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.

“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview

Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”

“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
 

Antibody-drug conjugate

Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.

In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).

The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.

In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.

At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.

The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
 

Progression-free survival, overall survival results

For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).

The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.

Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).

The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
 

Health-related quality of life

In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.

The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.

For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.

Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.

“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”

“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.

The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.

Approximately one-third of the patients treated in the ASCENT clinical trial comparing the antibody-drug conjugate sacituzumab govitecan (Trodelvy, Gilead) with single-agent chemotherapy in patients with triple-negative breast cancer (TNBC) did not have an initial diagnosis of TNBC.

But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.

“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview

Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”

“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
 

Antibody-drug conjugate

Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.

In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).

The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.

In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.

At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.

The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
 

Progression-free survival, overall survival results

For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).

The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.

Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).

The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
 

Health-related quality of life

In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.

The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.

For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.

Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.

“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”

“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.

The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.

Approximately one-third of the patients treated in the ASCENT clinical trial comparing the antibody-drug conjugate sacituzumab govitecan (Trodelvy, Gilead) with single-agent chemotherapy in patients with triple-negative breast cancer (TNBC) did not have an initial diagnosis of TNBC.

But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.

“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview

Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”

“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
 

Antibody-drug conjugate

Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.

In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).

The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.

In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.

At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.

The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
 

Progression-free survival, overall survival results

For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).

The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.

Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).

The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
 

Health-related quality of life

In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.

The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.

For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.

Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.

“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”

“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.

The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.

Long-term survival outcomes are better when postmenopausal women are on an aromatase inhibitor for 5 years, instead of the usual 2-3 years, following tamoxifen for hormone receptor–positive breast cancer, according to a randomized, open-label trial from Italy with over 2,000 women.

The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.

Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.

The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.

Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.

Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).

Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).

At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.

It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.

With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.

Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.

For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.

However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.

Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.

There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”

The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.

aotto@mdedge.com

Long-term survival outcomes are better when postmenopausal women are on an aromatase inhibitor for 5 years, instead of the usual 2-3 years, following tamoxifen for hormone receptor–positive breast cancer, according to a randomized, open-label trial from Italy with over 2,000 women.

The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.

Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.

The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.

Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.

Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).

Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).

At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.

It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.

With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.

Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.

For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.

However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.

Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.

There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”

The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.

aotto@mdedge.com

Long-term survival outcomes are better when postmenopausal women are on an aromatase inhibitor for 5 years, instead of the usual 2-3 years, following tamoxifen for hormone receptor–positive breast cancer, according to a randomized, open-label trial from Italy with over 2,000 women.

The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.

Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.

The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.

Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.

Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).

Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).

At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.

It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.

With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.

Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.

For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.

However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.

Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.

There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”

The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.

aotto@mdedge.com

Based on significant progression-free survival benefits in the phase III TULIP trial, trastuzumab duocarmazine may provide a new treatment option among pretreated HER2-positive metastatic breast cancer patients, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).

Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer progression-free survival with SYD985

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).

A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
 

Another option

“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”

“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”

Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”

The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

Based on significant progression-free survival benefits in the phase III TULIP trial, trastuzumab duocarmazine may provide a new treatment option among pretreated HER2-positive metastatic breast cancer patients, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).

Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer progression-free survival with SYD985

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).

A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
 

Another option

“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”

“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”

Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”

The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

Based on significant progression-free survival benefits in the phase III TULIP trial, trastuzumab duocarmazine may provide a new treatment option among pretreated HER2-positive metastatic breast cancer patients, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).

Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer progression-free survival with SYD985

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).

A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
 

Another option

“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”

“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”

Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”

The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

There was over a 12-month improvement in median overall survival when the CDK 4/6 inhibitor ribociclib was added to the aromatase inhibitor letrozole for postmenopausal hormone receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer, according to phase 3 results (abstract LBA17_PR) presented at the European Society for Medical Oncology Congress 2021 on Sept. 19.

“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.

At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).

It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.

“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.

Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.

The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.

Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.

Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.

In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”

However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.

“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.

“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.

“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.

No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.

Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.

Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.

The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.

This article was updated 9/24/21.

aotto@mdedge.com

There was over a 12-month improvement in median overall survival when the CDK 4/6 inhibitor ribociclib was added to the aromatase inhibitor letrozole for postmenopausal hormone receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer, according to phase 3 results (abstract LBA17_PR) presented at the European Society for Medical Oncology Congress 2021 on Sept. 19.

“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.

At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).

It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.

“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.

Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.

The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.

Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.

Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.

In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”

However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.

“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.

“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.

“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.

No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.

Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.

Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.

The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.

This article was updated 9/24/21.

aotto@mdedge.com

There was over a 12-month improvement in median overall survival when the CDK 4/6 inhibitor ribociclib was added to the aromatase inhibitor letrozole for postmenopausal hormone receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer, according to phase 3 results (abstract LBA17_PR) presented at the European Society for Medical Oncology Congress 2021 on Sept. 19.

“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.

At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).

It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.

“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.

Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.

The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.

Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.

Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.

In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”

However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.

“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.

“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.

“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.

No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.

Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.

Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.

The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.

This article was updated 9/24/21.

aotto@mdedge.com

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

sworcester@mdedge.com

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

sworcester@mdedge.com

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

sworcester@mdedge.com

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.

Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.

While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.

Study underscores need for ethnically diverse datasets

In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.

The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.

After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.

PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.

In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.

The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.

“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.

First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.

“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.

In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”

Higher morality among African American women

While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.

Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”

Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.

Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
 

Potential PRS benefits underscore need to eliminate bias

The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.

For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.

A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.

Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.

Confluence project

Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.

Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.

“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.

Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.

“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.

NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.

Direct-to-consumer global PRS

In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”

The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.

A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.

In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.

However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).

According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.

“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”

“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.

“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”

Commercial PRSs may benefit research

While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.

“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”

In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.

“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”

Dr. Pederson disclosed that she is a consultant for Myriad Genetics.

The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.

Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.

While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.

Study underscores need for ethnically diverse datasets

In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.

The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.

After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.

PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.

In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.

The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.

“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.

First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.

“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.

In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”

Higher morality among African American women

While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.

Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”

Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.

Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
 

Potential PRS benefits underscore need to eliminate bias

The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.

For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.

A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.

Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.

Confluence project

Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.

Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.

“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.

Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.

“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.

NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.

Direct-to-consumer global PRS

In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”

The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.

A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.

In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.

However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).

According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.

“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”

“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.

“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”

Commercial PRSs may benefit research

While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.

“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”

In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.

“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”

Dr. Pederson disclosed that she is a consultant for Myriad Genetics.

The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.

Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.

While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.

Study underscores need for ethnically diverse datasets

In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.

The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.

After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.

PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.

In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.

The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.

“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.

First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.

“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.

In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”

Higher morality among African American women

While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.

Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”

Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.

Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
 

Potential PRS benefits underscore need to eliminate bias

The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.

For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.

A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.

Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.

Confluence project

Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.

Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.

“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.

Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.

“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.

NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.

Direct-to-consumer global PRS

In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”

The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.

A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.

In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.

However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).

According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.

“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”

“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.

“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”

Commercial PRSs may benefit research

While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.

“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”

In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.

“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”

Dr. Pederson disclosed that she is a consultant for Myriad Genetics.

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

A version of this article first appeared on Medscape.com.

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

A version of this article first appeared on Medscape.com.

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

A version of this article first appeared on Medscape.com.