Breast Cancer

Ado-trastuzumab emtansine, a HER-2 targeted antibody-drug conjugate, has been approved by the Food and Drug Administration for treatment of women with HER2-positive, late-stage metastatic breast cancer, the agency announced Feb. 22.

Marketed as Kadcyla by Genentech, the treatment is a combination of an HER2-targeted antibody, trastuzumab, and DM1, a microtubule inhibitor, and is indicated as a single agent "for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination," according to the prescribing information. Patients should have either received previous therapy for metastatic disease, or had disease recurrence during or within 6 months of completing adjuvant therapy, according to the indication. The treatment is administered in an intravenous infusion every 3 weeks.

"Kadcyla is trastuzumab connected to a drug called DM1 that interferes with cancer cell growth," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Kadcyla delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," he added.

Kadcyla is the fourth FDA-approved breast cancer treatment that targets the HER2 protein. The other three drugs approved for treating HER2-positive breast cancer are trastuzumab (Herceptin), approved in 1998; lapatinib (Tykerb), approved in 2007; and pertuzumab (Perjeta), approved in 2012.

Approval of Kadcyla was based on a randomized, open label, phase III study of 991 patients with HER2-positive, locally-advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The median progression-free survival was 9.6 months among those treated with Kadcyla, compared with 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months among those treated with Kadcyla, compared with 25.1 months among those treated with lapatinib and capecitabine, according to statements from the FDA and Genentech. Overall survival and progression-free survival were the study’s primary endpoints.

The most common side effects associated with treatment (affecting more than 25% of patients) were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation.

This accelerated approval was completed in 6 months instead of the usual 12-month review period, which is used for drugs that may provide safer and effective treatment when there is no satisfactory alternative treatment or when the treatment provides significant improvements over available treatments. Ado-trastuzumab emtansine has been referred to as T-DM1 during clinical trials.

Kadcyla will be available within 2 weeks of approval, according to the statement from Genentech, a member of the Roche group. The agent is currently under review by the European Medicines Agency for the same indication.

Serious adverse events associated with Kadcyla should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch. The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf.

e.mechcatie@elsevier.com

Ado-trastuzumab emtansine, a HER-2 targeted antibody-drug conjugate, has been approved by the Food and Drug Administration for treatment of women with HER2-positive, late-stage metastatic breast cancer, the agency announced Feb. 22.

Marketed as Kadcyla by Genentech, the treatment is a combination of an HER2-targeted antibody, trastuzumab, and DM1, a microtubule inhibitor, and is indicated as a single agent "for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination," according to the prescribing information. Patients should have either received previous therapy for metastatic disease, or had disease recurrence during or within 6 months of completing adjuvant therapy, according to the indication. The treatment is administered in an intravenous infusion every 3 weeks.

"Kadcyla is trastuzumab connected to a drug called DM1 that interferes with cancer cell growth," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Kadcyla delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," he added.

Kadcyla is the fourth FDA-approved breast cancer treatment that targets the HER2 protein. The other three drugs approved for treating HER2-positive breast cancer are trastuzumab (Herceptin), approved in 1998; lapatinib (Tykerb), approved in 2007; and pertuzumab (Perjeta), approved in 2012.

Approval of Kadcyla was based on a randomized, open label, phase III study of 991 patients with HER2-positive, locally-advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The median progression-free survival was 9.6 months among those treated with Kadcyla, compared with 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months among those treated with Kadcyla, compared with 25.1 months among those treated with lapatinib and capecitabine, according to statements from the FDA and Genentech. Overall survival and progression-free survival were the study’s primary endpoints.

The most common side effects associated with treatment (affecting more than 25% of patients) were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation.

This accelerated approval was completed in 6 months instead of the usual 12-month review period, which is used for drugs that may provide safer and effective treatment when there is no satisfactory alternative treatment or when the treatment provides significant improvements over available treatments. Ado-trastuzumab emtansine has been referred to as T-DM1 during clinical trials.

Kadcyla will be available within 2 weeks of approval, according to the statement from Genentech, a member of the Roche group. The agent is currently under review by the European Medicines Agency for the same indication.

Serious adverse events associated with Kadcyla should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch. The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf.

e.mechcatie@elsevier.com

Ado-trastuzumab emtansine, a HER-2 targeted antibody-drug conjugate, has been approved by the Food and Drug Administration for treatment of women with HER2-positive, late-stage metastatic breast cancer, the agency announced Feb. 22.

Marketed as Kadcyla by Genentech, the treatment is a combination of an HER2-targeted antibody, trastuzumab, and DM1, a microtubule inhibitor, and is indicated as a single agent "for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination," according to the prescribing information. Patients should have either received previous therapy for metastatic disease, or had disease recurrence during or within 6 months of completing adjuvant therapy, according to the indication. The treatment is administered in an intravenous infusion every 3 weeks.

"Kadcyla is trastuzumab connected to a drug called DM1 that interferes with cancer cell growth," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Kadcyla delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," he added.

Kadcyla is the fourth FDA-approved breast cancer treatment that targets the HER2 protein. The other three drugs approved for treating HER2-positive breast cancer are trastuzumab (Herceptin), approved in 1998; lapatinib (Tykerb), approved in 2007; and pertuzumab (Perjeta), approved in 2012.

Approval of Kadcyla was based on a randomized, open label, phase III study of 991 patients with HER2-positive, locally-advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The median progression-free survival was 9.6 months among those treated with Kadcyla, compared with 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months among those treated with Kadcyla, compared with 25.1 months among those treated with lapatinib and capecitabine, according to statements from the FDA and Genentech. Overall survival and progression-free survival were the study’s primary endpoints.

The most common side effects associated with treatment (affecting more than 25% of patients) were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation.

This accelerated approval was completed in 6 months instead of the usual 12-month review period, which is used for drugs that may provide safer and effective treatment when there is no satisfactory alternative treatment or when the treatment provides significant improvements over available treatments. Ado-trastuzumab emtansine has been referred to as T-DM1 during clinical trials.

Kadcyla will be available within 2 weeks of approval, according to the statement from Genentech, a member of the Roche group. The agent is currently under review by the European Medicines Agency for the same indication.

Serious adverse events associated with Kadcyla should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch. The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf.

e.mechcatie@elsevier.com

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

michele.sullivan@elsevier.com

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

michele.sullivan@elsevier.com

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

michele.sullivan@elsevier.com

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

Women who have hormone-sensitive breast cancer and who have taken tamoxifen for 5 years as adjuvant therapy stand to benefit from an additional 5 years of the drug, according to preliminary findings from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial.¹

Tamoxifen is widely used to treat estrogen-receptor–positive (ER-positive) breast cancer and is generally prescribed for 5 years of daily use once the cancer has been excised. The drug substantially reduces the breast cancer mortality rate not only while treatment continues, but throughout the first 15 years after diagnosis.

Implications of the ATLAS findings for gynecologic care

Mindy Goldman, MD

“The results of this trial have been long-awaited and are very exciting,” said Mindy Goldman, MD, director of the Women’s Cancer Care Program in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco. “I think these results will be translated into changes in clinical care right away.”

Because breast cancer is very common, gynecologists need to be aware of the gynecologic effects of drugs like tamoxifen, Dr. Goldman said. Gynecologists “need to ask their patients how long they have been on tamoxifen and about side effects they may be having.”

Although menopausal symptoms such as hot flashes improve over time in women who take tamoxifen, some women may continue to experience bothersome symptoms longer with the extended therapy, Dr. Goldman said.

Among her recommendations:

• Be aware of nonhormonal treatments for menopausal symptoms for breast cancer patients. Among the options are low doses of a number of different antidepressants, the neuropathic pain reliever gabapentin, and the antihypertensive clonidine. Some agents, such as gabapentin, cause sedation as a side effect and can be used for women having sleep disturbances. Doses of gabapentin are much lower than those used for neuropathic pain, and start as low as 100 mg or 300 mg per night, typically not exceeding 1,200 mg per day.
• Know the uterine effects of tamoxifen, which include increased endometrial thickening, cystic changes, benign polyps—and, in postmenopausal women, rare risks of uterine cancer. “Most endometrial cancers will present with bleeding, so gynecologists need to make sure they are discussing any abnormal bleeding with their patients on tamoxifen.”
• Consider tamoxifen’s effects on bone. In the ATLAS trial, there were fewer bone fractures among women who extended treatment.
• Avoid overly aggressive scrutiny. “In my Women’s Cancer Care Program, I see many patients who come for consults on a gyn issue related to their breast cancer,” Dr. Goldman said. “What I have found is that, many times, their gynecologists are too aggressive. They know that tamoxifen can increase the risk of uterine cancer, but they are doing routine ultrasounds in asymptomatic women and taking action based on endometrial thickness, like doing D&Cs for women who don’t necessarily need them—sometimes even hysterectomies.” Guidelines from the American College of Obstetricians and Gynecologists clearly state that routine ultrasound imaging is not indicated merely because a woman takes tamoxifen. “What I hope doesn’t happen is that ObGyns see these data as justification for more interventions.”

It was known that 5 years of tamoxifen are more effective than 2 years. Until now, however, it was unclear whether continuation beyond 5 years further reduces the 15-year breast cancer mortality rate.

Details of the trial

In the trial of 12,894 women, investigators randomly assigned those who had received tamoxifen for 5 years to another 5 years of therapy or to no additional therapy, regardless of ER status. For the analysis, however, they included only the 6,847 women known to have ER-positive disease. Of these women, 3,428 were randomly assigned to continue tamoxifen for another 5 years (10 years total), and 3,418 were allocated to stop the therapy immediately (5 years total).

Women who continued tamoxifen had a lower rate of recurrence and breast cancer mortality, but that benefit took several years to emerge. From the beginning of the ATLAS trial to year 15, the risk of recurrence was 21.4% among women who had continued tamoxifen to 10 years, and it was 25.1% among women who had only 5 years of therapy. Breast cancer mortality also declined significantly during years 5 to 15; it was 12.2% among women who continued tamoxifen to 10 years, and it was 15% among women who had only 5 years of therapy.

“Our results, taken together with results from previous trials of 5 years of tamoxifen versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis,” said Christina Davies, MBChB, lead investigator. “Good evidence now exists that 10 years of tamoxifen in ER- positive breast cancer produces substantial reductions in rates of recurrence and in breast cancer mortality, not only during the first decade, while treatment continues, but also during the second decade, long after it has ended.”

Side effects were more common among postmenopausal women

Although tamoxifen has some side effects, they had a relatively small net effect on survival. The most significant effect was an increased risk—among postmenopausal women—of endometrial cancer. However, the excess risk of dying of endometrial cancer by year 15 was only 0.2% (0.4% among women who continued tamoxifen to 10 years vs 0.2% in the control group).

Investigators found no evidence that tamoxifen increases the risk of stroke, despite the fact that the US Food and Drug Administration lists stroke as a possible side effect of the drug.

We want to hear from you!  Tell us what you think.

Women who have hormone-sensitive breast cancer and who have taken tamoxifen for 5 years as adjuvant therapy stand to benefit from an additional 5 years of the drug, according to preliminary findings from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial.¹

Tamoxifen is widely used to treat estrogen-receptor–positive (ER-positive) breast cancer and is generally prescribed for 5 years of daily use once the cancer has been excised. The drug substantially reduces the breast cancer mortality rate not only while treatment continues, but throughout the first 15 years after diagnosis.

Implications of the ATLAS findings for gynecologic care

Mindy Goldman, MD

“The results of this trial have been long-awaited and are very exciting,” said Mindy Goldman, MD, director of the Women’s Cancer Care Program in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco. “I think these results will be translated into changes in clinical care right away.”

Because breast cancer is very common, gynecologists need to be aware of the gynecologic effects of drugs like tamoxifen, Dr. Goldman said. Gynecologists “need to ask their patients how long they have been on tamoxifen and about side effects they may be having.”

Although menopausal symptoms such as hot flashes improve over time in women who take tamoxifen, some women may continue to experience bothersome symptoms longer with the extended therapy, Dr. Goldman said.

Among her recommendations:

• Be aware of nonhormonal treatments for menopausal symptoms for breast cancer patients. Among the options are low doses of a number of different antidepressants, the neuropathic pain reliever gabapentin, and the antihypertensive clonidine. Some agents, such as gabapentin, cause sedation as a side effect and can be used for women having sleep disturbances. Doses of gabapentin are much lower than those used for neuropathic pain, and start as low as 100 mg or 300 mg per night, typically not exceeding 1,200 mg per day.
• Know the uterine effects of tamoxifen, which include increased endometrial thickening, cystic changes, benign polyps—and, in postmenopausal women, rare risks of uterine cancer. “Most endometrial cancers will present with bleeding, so gynecologists need to make sure they are discussing any abnormal bleeding with their patients on tamoxifen.”
• Consider tamoxifen’s effects on bone. In the ATLAS trial, there were fewer bone fractures among women who extended treatment.
• Avoid overly aggressive scrutiny. “In my Women’s Cancer Care Program, I see many patients who come for consults on a gyn issue related to their breast cancer,” Dr. Goldman said. “What I have found is that, many times, their gynecologists are too aggressive. They know that tamoxifen can increase the risk of uterine cancer, but they are doing routine ultrasounds in asymptomatic women and taking action based on endometrial thickness, like doing D&Cs for women who don’t necessarily need them—sometimes even hysterectomies.” Guidelines from the American College of Obstetricians and Gynecologists clearly state that routine ultrasound imaging is not indicated merely because a woman takes tamoxifen. “What I hope doesn’t happen is that ObGyns see these data as justification for more interventions.”

It was known that 5 years of tamoxifen are more effective than 2 years. Until now, however, it was unclear whether continuation beyond 5 years further reduces the 15-year breast cancer mortality rate.

Details of the trial

In the trial of 12,894 women, investigators randomly assigned those who had received tamoxifen for 5 years to another 5 years of therapy or to no additional therapy, regardless of ER status. For the analysis, however, they included only the 6,847 women known to have ER-positive disease. Of these women, 3,428 were randomly assigned to continue tamoxifen for another 5 years (10 years total), and 3,418 were allocated to stop the therapy immediately (5 years total).

Women who continued tamoxifen had a lower rate of recurrence and breast cancer mortality, but that benefit took several years to emerge. From the beginning of the ATLAS trial to year 15, the risk of recurrence was 21.4% among women who had continued tamoxifen to 10 years, and it was 25.1% among women who had only 5 years of therapy. Breast cancer mortality also declined significantly during years 5 to 15; it was 12.2% among women who continued tamoxifen to 10 years, and it was 15% among women who had only 5 years of therapy.

“Our results, taken together with results from previous trials of 5 years of tamoxifen versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis,” said Christina Davies, MBChB, lead investigator. “Good evidence now exists that 10 years of tamoxifen in ER- positive breast cancer produces substantial reductions in rates of recurrence and in breast cancer mortality, not only during the first decade, while treatment continues, but also during the second decade, long after it has ended.”

Side effects were more common among postmenopausal women

Although tamoxifen has some side effects, they had a relatively small net effect on survival. The most significant effect was an increased risk—among postmenopausal women—of endometrial cancer. However, the excess risk of dying of endometrial cancer by year 15 was only 0.2% (0.4% among women who continued tamoxifen to 10 years vs 0.2% in the control group).

Investigators found no evidence that tamoxifen increases the risk of stroke, despite the fact that the US Food and Drug Administration lists stroke as a possible side effect of the drug.

We want to hear from you!  Tell us what you think.

Women who have hormone-sensitive breast cancer and who have taken tamoxifen for 5 years as adjuvant therapy stand to benefit from an additional 5 years of the drug, according to preliminary findings from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial.¹

Tamoxifen is widely used to treat estrogen-receptor–positive (ER-positive) breast cancer and is generally prescribed for 5 years of daily use once the cancer has been excised. The drug substantially reduces the breast cancer mortality rate not only while treatment continues, but throughout the first 15 years after diagnosis.

Implications of the ATLAS findings for gynecologic care

Mindy Goldman, MD

“The results of this trial have been long-awaited and are very exciting,” said Mindy Goldman, MD, director of the Women’s Cancer Care Program in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco. “I think these results will be translated into changes in clinical care right away.”

Because breast cancer is very common, gynecologists need to be aware of the gynecologic effects of drugs like tamoxifen, Dr. Goldman said. Gynecologists “need to ask their patients how long they have been on tamoxifen and about side effects they may be having.”

Although menopausal symptoms such as hot flashes improve over time in women who take tamoxifen, some women may continue to experience bothersome symptoms longer with the extended therapy, Dr. Goldman said.

Among her recommendations:

• Be aware of nonhormonal treatments for menopausal symptoms for breast cancer patients. Among the options are low doses of a number of different antidepressants, the neuropathic pain reliever gabapentin, and the antihypertensive clonidine. Some agents, such as gabapentin, cause sedation as a side effect and can be used for women having sleep disturbances. Doses of gabapentin are much lower than those used for neuropathic pain, and start as low as 100 mg or 300 mg per night, typically not exceeding 1,200 mg per day.
• Know the uterine effects of tamoxifen, which include increased endometrial thickening, cystic changes, benign polyps—and, in postmenopausal women, rare risks of uterine cancer. “Most endometrial cancers will present with bleeding, so gynecologists need to make sure they are discussing any abnormal bleeding with their patients on tamoxifen.”
• Consider tamoxifen’s effects on bone. In the ATLAS trial, there were fewer bone fractures among women who extended treatment.
• Avoid overly aggressive scrutiny. “In my Women’s Cancer Care Program, I see many patients who come for consults on a gyn issue related to their breast cancer,” Dr. Goldman said. “What I have found is that, many times, their gynecologists are too aggressive. They know that tamoxifen can increase the risk of uterine cancer, but they are doing routine ultrasounds in asymptomatic women and taking action based on endometrial thickness, like doing D&Cs for women who don’t necessarily need them—sometimes even hysterectomies.” Guidelines from the American College of Obstetricians and Gynecologists clearly state that routine ultrasound imaging is not indicated merely because a woman takes tamoxifen. “What I hope doesn’t happen is that ObGyns see these data as justification for more interventions.”

It was known that 5 years of tamoxifen are more effective than 2 years. Until now, however, it was unclear whether continuation beyond 5 years further reduces the 15-year breast cancer mortality rate.

Details of the trial

In the trial of 12,894 women, investigators randomly assigned those who had received tamoxifen for 5 years to another 5 years of therapy or to no additional therapy, regardless of ER status. For the analysis, however, they included only the 6,847 women known to have ER-positive disease. Of these women, 3,428 were randomly assigned to continue tamoxifen for another 5 years (10 years total), and 3,418 were allocated to stop the therapy immediately (5 years total).

Women who continued tamoxifen had a lower rate of recurrence and breast cancer mortality, but that benefit took several years to emerge. From the beginning of the ATLAS trial to year 15, the risk of recurrence was 21.4% among women who had continued tamoxifen to 10 years, and it was 25.1% among women who had only 5 years of therapy. Breast cancer mortality also declined significantly during years 5 to 15; it was 12.2% among women who continued tamoxifen to 10 years, and it was 15% among women who had only 5 years of therapy.

“Our results, taken together with results from previous trials of 5 years of tamoxifen versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis,” said Christina Davies, MBChB, lead investigator. “Good evidence now exists that 10 years of tamoxifen in ER- positive breast cancer produces substantial reductions in rates of recurrence and in breast cancer mortality, not only during the first decade, while treatment continues, but also during the second decade, long after it has ended.”

Side effects were more common among postmenopausal women

Although tamoxifen has some side effects, they had a relatively small net effect on survival. The most significant effect was an increased risk—among postmenopausal women—of endometrial cancer. However, the excess risk of dying of endometrial cancer by year 15 was only 0.2% (0.4% among women who continued tamoxifen to 10 years vs 0.2% in the control group).

Investigators found no evidence that tamoxifen increases the risk of stroke, despite the fact that the US Food and Drug Administration lists stroke as a possible side effect of the drug.

We want to hear from you!  Tell us what you think.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

PALM BEACH, FLA. – More than a fifth of women in Texas with image-detected breast abnormalities failed to undergo minimally invasive breast biopsy as recently as 2008, according to a review of statewide Medicare data, even though in 2005 a U.S. consensus panel declared the minimally invasive approach the procedure of choice and that few patients should have excisional biopsy as their initial procedure.

The analysis also revealed substantial disparities in use of minimally-invasive breast biopsy (MIBB) relative to open-surgical biopsy. In several rural health service areas (HSA) of Texas during 2005-2008, fewer than 40% of women undergoing biopsy of an image-detected breast abnormality had MIBB, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association. During 2005-2008, 5% of Texas HSAs had MIBB rates greater than 90%, the target set by U.S. cancer organizations. The researchers also identified low levels of MIBB use for Hispanic women, and women of low socioeconomic status.

"Our studies identify targets for interventions to improve MIBB rates, such as the Hispanic disparity and geographic variations in practice pattern," she said. "Our findings highlight that the strategies for intervention need to vary by geographic region and the underlying etiology of the failure to adopt this cost-effective practice," said Dr. Riall, a cancer surgeon at the University of Texas Medical Branch in Galveston.

"This is by far the most detailed study of MIBB [practice patterns] performed to date," commented Dr. Stephen Grobmyer, a surgical oncologist and director of breast services at the Cleveland Clinic.

The data documented that surgeons were an important contributor to MIBB underuse. Throughout the 9 years of data studied by Dr. Riall and her associates during 2001-2008, 70% of MIBB were performed by radiologists, while 26% were performed by surgeons. In contrast, surgeons performed 94% of open, excisional biopsies. When a woman’s breast mass was first identified by a surgeon, 44% of the women had MIBB; when first identified by a primary care physician, 58% had MIBB; when first identified by an oncologist, 59% had MIBB; and when first identified by a gynecologist, 67% had MIBB.

The low levels of MIBB use occurred despite increasingly strong recommendations during the period studied to move MIBB to the forefront of breast-abnormality assessment. In 2001, the first international consensus conference on image-detected breast cancer, organized by the University of Southern California, said that "percutaneous biopsy is the preferred initial diagnostic procedure in most patients with mammographically detected abnormalities"(J. Amer. Coll. Surg. 2001;193:297-302).

In 2005, the second international consensus conference on image-detected breast cancer racheted up the recommendation, saying "minimally invasive breast biopsy is the optimal tissue-acquisition method and the procedure of choice for image-detected breast abnormalities. It should be readily available to all patients with image-detected lesions" (J. Amer. Coll. Surg. 2005;201:586-597).

Although the third international consensus conference did not take place until 2009, the year after the end of the period studied by Dr. Riall, the statement at that time showed how MIBB had become the clear standard of care for biopsy of suspicious breast masses. The 2009 panel said that "percutaneous needle biopsy represents ‘best practice’ and should be the new ‘gold standard’ for initial diagnosis. It should essentially replace open biopsy in this role. The Panel called on the medical community to change their current practice if they are using open surgical breast biopsy as a standard diagnostic procedure. Surgeons should audit their practice and make adjustments to decrease their rate of open biopsy for initial diagnosis to less than 5% to 10%" (J. Amer. Coll. Surg. 2009;209:504-20).

"We need to get a message out to surgeons because they are the ones doing many of the open biopsies," Dr. Riall said in an interview. "Surgeons are a group to target, but we also need to target primary care physicians and other referring physicians so that they understand that MIBB is appropriate. The decision to do MIBB versus open biopsy should be made with the surgeon and with the oncologist who will ultimately treat the breast cancer; the decision should not be made just by a radiologist," who is usually the first person to see a mass when it is first detected by mammography.

Dr. Riall also stressed that the causes of MIBB underuse are multifactorial, and require multiple solutions.

"In very rural areas, the primary problem is access to mammography. In the cases where women cluster in primary care practices that don’t do MIBB, we need to provide better physician education. In regions where there is a high density of private practice surgeons, open biopsy is driven by reimbursement. I think there is an interaction of patient preference, surgeon preference, education and training, geographic region, and availability of radiologists and mammography facilities. Trying to dissect it is very hard."

Her study identified in Texas Medicare records 67,582 unique women aged 66 years or older who underwent 75,518 unique breast mass episodes during 2001-2008, including 49,653 (66%) of masses that underwent MIBB and 25,865 (34%) that underwent open surgical biopsy. Use of MIBB rose steadily during the period, starting at 44% of masses in 2001 and increasing to 79% by 2008.

Analysis of MIBB use by Medicare health service area showed stark geographic disparities, with MIBB use as low as 21% in one HSA. During 2005-2008, MIBB use remained at 40% or less in several HSA along the Rio Grande border and in East Texas, including the HSAs in the south Texas towns of McAllen and Harlingen. In contrast, the HSA immediately adjacent to these that includes Brownsville had a MIBB rate greater than 70%. The analysis also showed than many of the HSAs with the lowest rates of MIBB use were located in Texas regions with high Hispanic populations, Dr. Riall said.

Dr. Riall and Dr. Grobmyer had no disclosures.

PALM BEACH, FLA. – More than a fifth of women in Texas with image-detected breast abnormalities failed to undergo minimally invasive breast biopsy as recently as 2008, according to a review of statewide Medicare data, even though in 2005 a U.S. consensus panel declared the minimally invasive approach the procedure of choice and that few patients should have excisional biopsy as their initial procedure.

The analysis also revealed substantial disparities in use of minimally-invasive breast biopsy (MIBB) relative to open-surgical biopsy. In several rural health service areas (HSA) of Texas during 2005-2008, fewer than 40% of women undergoing biopsy of an image-detected breast abnormality had MIBB, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association. During 2005-2008, 5% of Texas HSAs had MIBB rates greater than 90%, the target set by U.S. cancer organizations. The researchers also identified low levels of MIBB use for Hispanic women, and women of low socioeconomic status.

"Our studies identify targets for interventions to improve MIBB rates, such as the Hispanic disparity and geographic variations in practice pattern," she said. "Our findings highlight that the strategies for intervention need to vary by geographic region and the underlying etiology of the failure to adopt this cost-effective practice," said Dr. Riall, a cancer surgeon at the University of Texas Medical Branch in Galveston.

"This is by far the most detailed study of MIBB [practice patterns] performed to date," commented Dr. Stephen Grobmyer, a surgical oncologist and director of breast services at the Cleveland Clinic.

The data documented that surgeons were an important contributor to MIBB underuse. Throughout the 9 years of data studied by Dr. Riall and her associates during 2001-2008, 70% of MIBB were performed by radiologists, while 26% were performed by surgeons. In contrast, surgeons performed 94% of open, excisional biopsies. When a woman’s breast mass was first identified by a surgeon, 44% of the women had MIBB; when first identified by a primary care physician, 58% had MIBB; when first identified by an oncologist, 59% had MIBB; and when first identified by a gynecologist, 67% had MIBB.

The low levels of MIBB use occurred despite increasingly strong recommendations during the period studied to move MIBB to the forefront of breast-abnormality assessment. In 2001, the first international consensus conference on image-detected breast cancer, organized by the University of Southern California, said that "percutaneous biopsy is the preferred initial diagnostic procedure in most patients with mammographically detected abnormalities"(J. Amer. Coll. Surg. 2001;193:297-302).

In 2005, the second international consensus conference on image-detected breast cancer racheted up the recommendation, saying "minimally invasive breast biopsy is the optimal tissue-acquisition method and the procedure of choice for image-detected breast abnormalities. It should be readily available to all patients with image-detected lesions" (J. Amer. Coll. Surg. 2005;201:586-597).

Although the third international consensus conference did not take place until 2009, the year after the end of the period studied by Dr. Riall, the statement at that time showed how MIBB had become the clear standard of care for biopsy of suspicious breast masses. The 2009 panel said that "percutaneous needle biopsy represents ‘best practice’ and should be the new ‘gold standard’ for initial diagnosis. It should essentially replace open biopsy in this role. The Panel called on the medical community to change their current practice if they are using open surgical breast biopsy as a standard diagnostic procedure. Surgeons should audit their practice and make adjustments to decrease their rate of open biopsy for initial diagnosis to less than 5% to 10%" (J. Amer. Coll. Surg. 2009;209:504-20).

"We need to get a message out to surgeons because they are the ones doing many of the open biopsies," Dr. Riall said in an interview. "Surgeons are a group to target, but we also need to target primary care physicians and other referring physicians so that they understand that MIBB is appropriate. The decision to do MIBB versus open biopsy should be made with the surgeon and with the oncologist who will ultimately treat the breast cancer; the decision should not be made just by a radiologist," who is usually the first person to see a mass when it is first detected by mammography.

Dr. Riall also stressed that the causes of MIBB underuse are multifactorial, and require multiple solutions.

"In very rural areas, the primary problem is access to mammography. In the cases where women cluster in primary care practices that don’t do MIBB, we need to provide better physician education. In regions where there is a high density of private practice surgeons, open biopsy is driven by reimbursement. I think there is an interaction of patient preference, surgeon preference, education and training, geographic region, and availability of radiologists and mammography facilities. Trying to dissect it is very hard."

Her study identified in Texas Medicare records 67,582 unique women aged 66 years or older who underwent 75,518 unique breast mass episodes during 2001-2008, including 49,653 (66%) of masses that underwent MIBB and 25,865 (34%) that underwent open surgical biopsy. Use of MIBB rose steadily during the period, starting at 44% of masses in 2001 and increasing to 79% by 2008.

Analysis of MIBB use by Medicare health service area showed stark geographic disparities, with MIBB use as low as 21% in one HSA. During 2005-2008, MIBB use remained at 40% or less in several HSA along the Rio Grande border and in East Texas, including the HSAs in the south Texas towns of McAllen and Harlingen. In contrast, the HSA immediately adjacent to these that includes Brownsville had a MIBB rate greater than 70%. The analysis also showed than many of the HSAs with the lowest rates of MIBB use were located in Texas regions with high Hispanic populations, Dr. Riall said.

Dr. Riall and Dr. Grobmyer had no disclosures.

PALM BEACH, FLA. – More than a fifth of women in Texas with image-detected breast abnormalities failed to undergo minimally invasive breast biopsy as recently as 2008, according to a review of statewide Medicare data, even though in 2005 a U.S. consensus panel declared the minimally invasive approach the procedure of choice and that few patients should have excisional biopsy as their initial procedure.

The analysis also revealed substantial disparities in use of minimally-invasive breast biopsy (MIBB) relative to open-surgical biopsy. In several rural health service areas (HSA) of Texas during 2005-2008, fewer than 40% of women undergoing biopsy of an image-detected breast abnormality had MIBB, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association. During 2005-2008, 5% of Texas HSAs had MIBB rates greater than 90%, the target set by U.S. cancer organizations. The researchers also identified low levels of MIBB use for Hispanic women, and women of low socioeconomic status.

"Our studies identify targets for interventions to improve MIBB rates, such as the Hispanic disparity and geographic variations in practice pattern," she said. "Our findings highlight that the strategies for intervention need to vary by geographic region and the underlying etiology of the failure to adopt this cost-effective practice," said Dr. Riall, a cancer surgeon at the University of Texas Medical Branch in Galveston.

"This is by far the most detailed study of MIBB [practice patterns] performed to date," commented Dr. Stephen Grobmyer, a surgical oncologist and director of breast services at the Cleveland Clinic.

The data documented that surgeons were an important contributor to MIBB underuse. Throughout the 9 years of data studied by Dr. Riall and her associates during 2001-2008, 70% of MIBB were performed by radiologists, while 26% were performed by surgeons. In contrast, surgeons performed 94% of open, excisional biopsies. When a woman’s breast mass was first identified by a surgeon, 44% of the women had MIBB; when first identified by a primary care physician, 58% had MIBB; when first identified by an oncologist, 59% had MIBB; and when first identified by a gynecologist, 67% had MIBB.

The low levels of MIBB use occurred despite increasingly strong recommendations during the period studied to move MIBB to the forefront of breast-abnormality assessment. In 2001, the first international consensus conference on image-detected breast cancer, organized by the University of Southern California, said that "percutaneous biopsy is the preferred initial diagnostic procedure in most patients with mammographically detected abnormalities"(J. Amer. Coll. Surg. 2001;193:297-302).

In 2005, the second international consensus conference on image-detected breast cancer racheted up the recommendation, saying "minimally invasive breast biopsy is the optimal tissue-acquisition method and the procedure of choice for image-detected breast abnormalities. It should be readily available to all patients with image-detected lesions" (J. Amer. Coll. Surg. 2005;201:586-597).

Although the third international consensus conference did not take place until 2009, the year after the end of the period studied by Dr. Riall, the statement at that time showed how MIBB had become the clear standard of care for biopsy of suspicious breast masses. The 2009 panel said that "percutaneous needle biopsy represents ‘best practice’ and should be the new ‘gold standard’ for initial diagnosis. It should essentially replace open biopsy in this role. The Panel called on the medical community to change their current practice if they are using open surgical breast biopsy as a standard diagnostic procedure. Surgeons should audit their practice and make adjustments to decrease their rate of open biopsy for initial diagnosis to less than 5% to 10%" (J. Amer. Coll. Surg. 2009;209:504-20).

"We need to get a message out to surgeons because they are the ones doing many of the open biopsies," Dr. Riall said in an interview. "Surgeons are a group to target, but we also need to target primary care physicians and other referring physicians so that they understand that MIBB is appropriate. The decision to do MIBB versus open biopsy should be made with the surgeon and with the oncologist who will ultimately treat the breast cancer; the decision should not be made just by a radiologist," who is usually the first person to see a mass when it is first detected by mammography.

Dr. Riall also stressed that the causes of MIBB underuse are multifactorial, and require multiple solutions.

"In very rural areas, the primary problem is access to mammography. In the cases where women cluster in primary care practices that don’t do MIBB, we need to provide better physician education. In regions where there is a high density of private practice surgeons, open biopsy is driven by reimbursement. I think there is an interaction of patient preference, surgeon preference, education and training, geographic region, and availability of radiologists and mammography facilities. Trying to dissect it is very hard."

Her study identified in Texas Medicare records 67,582 unique women aged 66 years or older who underwent 75,518 unique breast mass episodes during 2001-2008, including 49,653 (66%) of masses that underwent MIBB and 25,865 (34%) that underwent open surgical biopsy. Use of MIBB rose steadily during the period, starting at 44% of masses in 2001 and increasing to 79% by 2008.

Analysis of MIBB use by Medicare health service area showed stark geographic disparities, with MIBB use as low as 21% in one HSA. During 2005-2008, MIBB use remained at 40% or less in several HSA along the Rio Grande border and in East Texas, including the HSAs in the south Texas towns of McAllen and Harlingen. In contrast, the HSA immediately adjacent to these that includes Brownsville had a MIBB rate greater than 70%. The analysis also showed than many of the HSAs with the lowest rates of MIBB use were located in Texas regions with high Hispanic populations, Dr. Riall said.

Dr. Riall and Dr. Grobmyer had no disclosures.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.