Breast Cancer

CHICAGO – New data from the TAILORx trial are welcome news for women with HR-positive, HER2-negative, axillary node–negative early-stage breast cancer and their oncologists caught in the gray area surrounding the need for adjuvant chemotherapy.

Results of the noninferiority phase 3 trial—the largest adjuvant breast cancer treatment trial ever conducted—show that among the 6,711 women with an intermediate Oncotype DX Breast Recurrence Score (11-25), those who received only endocrine therapy and skipped adjuvant chemotherapy did not have worse invasive disease-free survival than counterparts who received both (hazard ratio, 1.08; P=.26).

The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy alone and 84.3% with both chemotherapy and endocrine therapy, and the pattern was essentially the same for freedom from any recurrence and distant recurrence, and overall survival.

The findings are practice changing, according to lead study author Joseph A. Sparano, MD, associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.

In a video interview at the annual meeting of the American Society of Clinical Oncology, he discussed implications of the new data for decision making, results of interaction analyses showing that one size does not fit all and certain women with intermediate recurrence scores do derive benefit from adjuvant chemotherapy, as well as plans to use the tumor samples for future analyses on those that do recur.

CHICAGO – New data from the TAILORx trial are welcome news for women with HR-positive, HER2-negative, axillary node–negative early-stage breast cancer and their oncologists caught in the gray area surrounding the need for adjuvant chemotherapy.

Results of the noninferiority phase 3 trial—the largest adjuvant breast cancer treatment trial ever conducted—show that among the 6,711 women with an intermediate Oncotype DX Breast Recurrence Score (11-25), those who received only endocrine therapy and skipped adjuvant chemotherapy did not have worse invasive disease-free survival than counterparts who received both (hazard ratio, 1.08; P=.26).

The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy alone and 84.3% with both chemotherapy and endocrine therapy, and the pattern was essentially the same for freedom from any recurrence and distant recurrence, and overall survival.

The findings are practice changing, according to lead study author Joseph A. Sparano, MD, associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.

In a video interview at the annual meeting of the American Society of Clinical Oncology, he discussed implications of the new data for decision making, results of interaction analyses showing that one size does not fit all and certain women with intermediate recurrence scores do derive benefit from adjuvant chemotherapy, as well as plans to use the tumor samples for future analyses on those that do recur.

CHICAGO – New data from the TAILORx trial are welcome news for women with HR-positive, HER2-negative, axillary node–negative early-stage breast cancer and their oncologists caught in the gray area surrounding the need for adjuvant chemotherapy.

Results of the noninferiority phase 3 trial—the largest adjuvant breast cancer treatment trial ever conducted—show that among the 6,711 women with an intermediate Oncotype DX Breast Recurrence Score (11-25), those who received only endocrine therapy and skipped adjuvant chemotherapy did not have worse invasive disease-free survival than counterparts who received both (hazard ratio, 1.08; P=.26).

The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy alone and 84.3% with both chemotherapy and endocrine therapy, and the pattern was essentially the same for freedom from any recurrence and distant recurrence, and overall survival.

The findings are practice changing, according to lead study author Joseph A. Sparano, MD, associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.

In a video interview at the annual meeting of the American Society of Clinical Oncology, he discussed implications of the new data for decision making, results of interaction analyses showing that one size does not fit all and certain women with intermediate recurrence scores do derive benefit from adjuvant chemotherapy, as well as plans to use the tumor samples for future analyses on those that do recur.

CHICAGO – In the SANDPIPER trial, the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) was associated with a small but significant progression-free survival (PFS) benefit, compared with fulvestrant alone in women with advanced estrogen-receptor positive, HER2-negative breast cancer.

That 2-month PFS benefit, described as “modest” by investigators, came at the cost of significant toxicities, with nearly 50% of patients treated with the combination having grade 3 or greater toxicities, compared with 16% of patients treated with fulvestrant alone.

In this video interview from the annual meeting of the American Society of Clinical Oncology, ASCO expert Harold Burstein, MD, PhD, from the Dana-Farber Cancer Institute in Boston, questions whether the PI3K pathway, shown to be targetable in hematologic malignancies, is worth continuing to pursue in breast cancer.

Dr. Burstein had no disclosures.

CHICAGO – In the SANDPIPER trial, the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) was associated with a small but significant progression-free survival (PFS) benefit, compared with fulvestrant alone in women with advanced estrogen-receptor positive, HER2-negative breast cancer.

That 2-month PFS benefit, described as “modest” by investigators, came at the cost of significant toxicities, with nearly 50% of patients treated with the combination having grade 3 or greater toxicities, compared with 16% of patients treated with fulvestrant alone.

In this video interview from the annual meeting of the American Society of Clinical Oncology, ASCO expert Harold Burstein, MD, PhD, from the Dana-Farber Cancer Institute in Boston, questions whether the PI3K pathway, shown to be targetable in hematologic malignancies, is worth continuing to pursue in breast cancer.

Dr. Burstein had no disclosures.

CHICAGO – In the SANDPIPER trial, the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) was associated with a small but significant progression-free survival (PFS) benefit, compared with fulvestrant alone in women with advanced estrogen-receptor positive, HER2-negative breast cancer.

That 2-month PFS benefit, described as “modest” by investigators, came at the cost of significant toxicities, with nearly 50% of patients treated with the combination having grade 3 or greater toxicities, compared with 16% of patients treated with fulvestrant alone.

In this video interview from the annual meeting of the American Society of Clinical Oncology, ASCO expert Harold Burstein, MD, PhD, from the Dana-Farber Cancer Institute in Boston, questions whether the PI3K pathway, shown to be targetable in hematologic malignancies, is worth continuing to pursue in breast cancer.

Dr. Burstein had no disclosures.

Illustration: Kimberly Martens for OBG Management

Advances in cancer genetics are rapidly changing how clinicians assess an individual’s risk for breast cancer. ObGyns counsel many women with a personal or family history of the disease, many of whom can benefit from genetics counseling and testing. As patients with a hereditary predisposition to breast cancer are at higher risk and are younger at diagnosis, it is imperative to identify them early so they can benefit from enhanced surveillance, chemoprevention, and discussions regarding risk-reducing surgeries. ObGyns are uniquely poised to identify young women at risk for hereditary cancer syndromes, and they play a crucial role in screening and prevention over the life span.

CASE Patient with breast cancer history asks about screening for her daughters

A 52-year-old woman presents for her annual examination. She underwent breast cancer treatment 10 years earlier and has done well since then. When asked about family history of breast cancer and ethnicity, she reports her mother had breast cancer later in life, and her mother’s father was of Ashkenazi Jewish ancestry.In addition, a maternal uncle had metastatic prostate cancer. You recall that breast cancer diagnosed before age 50 years and Ashkenazi ancestry are “red flags” for a hereditary cancer syndrome. The patient wonders how her daughters should be screened. What do you do next?

Having a risk assessment plan is crucial

Given increasing demands, limited time, and the abundance of information to be discussed with patients, primary care physicians may find it challenging to assess breast cancer risk, consider genetics testing for appropriate individuals, and counsel patients about risk management options. The process has become even more complex since the expansion in genetics knowledge and the advent of multigene panel testing. Not only is risk assessment crucial for this woman and her daughters, and for other patients, but a delay in diagnosing and treating breast cancer in patients with hereditary and familial cancer risks may represent a worrisome new trend in medical litigation.^1,2 Clinicians must have a process in place for assessing risk in all patients and treating them appropriately.

The American Cancer Society (ACS) estimated that 252,710 cases of breast cancer would be diagnosed in 2017, leading to 40,610 deaths.³ Twelve percent to 14% of breast cancers are thought to be related to hereditary cancer predisposition syndromes.^4–8 This means that, every year, almost 35,000 cases of breast cancer are attributable to hereditary risk. These cases can be detected early with enhanced surveillance, which carries the highest chance for cure, or prevented with risk-reducing surgery in identified genetic mutation carriers. Each child of a person with a genetic mutation predisposing to breast cancer has a 50% chance of inheriting the mutation and having a very high risk of cancer.

In this patient’s case, basic information is collected about her cancer-related personal and family history.

Asking a few key questions can help in stratifying risk:

• Have you or anyone in your family had cancer? What type, and at what age?
• If breast cancer, did it involve both breasts, or was it triple-negative?
• Is there a family history of ovarian cancer?
• Is there a family history of male breast cancer?
• Is there a family history of metastatic prostate cancer?
• Are you of Ashkenazi Jewish ethnicity?
• Have you or anyone in your family ever had genetics testing for cancer?

The hallmarks of hereditary cancer are multiple cancers in an individual or family; young age at diagnosis; and ovarian, pancreatic, or another rare cancer. Metastatic prostate cancer was added as a red flag for hereditary risk after a recent large series found that 11.8% of men with metastatic prostate cancer harbor germline mutations.⁹

CASE Continued

On further questioning, the patient reports she had triple-negative (estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer, a feature of patients with germline BRCA1 (breast cancer susceptibility gene 1) mutations.¹⁰ In addition, her Ashkenazi ancestry is concerning, as there is a 1-in-40 chance of carrying 1 of the 3 Ashkenazi founder BRCA mutations.¹¹ Is a genetics consultation needed?

Read about guidelines for referral and testing.

Guidelines for genetics referral and testing

According to the TABLE, which summarizes national guidelines for genetics referral, maternal and paternal family histories are equally important. Our patient was under age 50 at diagnosis, has a history of triple-negative breast cancer, is of Ashkenazi ancestry, and has a family history of metastatic prostate cancer. She meets the criteria for genetics testing, and screening for her daughters most certainly will depend on the findings of that testing. If she carries a BRCA1 mutation, as might be anticipated, each daughter would have a 50% chance of having inherited the mutation. If they carry the mutation as well, they would begin breast magnetic resonance imaging (MRI) screening at age 25.¹² If they decide against genetics testing, they could still undergo MRI screening as untested first-degree relatives of a BRCA carrier, per ACS recommendations.¹³

Integrating evidence and experience

Over the past 10 to 20 years, other breast cancer susceptibility genes (eg, BRCA2, PALB2, CHEK2) have been identified. More recently, next-generation sequencing has become commercially available. Laboratories can use this newer method to sequence multiple genes rapidly and in parallel, and its cost is similar to that of single-syndrome testing.¹⁴ When more than 1 gene can explain an inherited cancer syndrome, multigene panel testing may be more efficient and cost-effective. Use of multigene panel testing is supported in guidelines issued by the National Comprehensive Cancer Network,¹² the American College of Obstetricians and Gynecologists,¹⁵ and other medical societies.

For our patient, the most logical strategy would be to test for the 3 mutations most common in the Ashkenazi population and then, if no mutation is found, perform multigene panel testing.

Formal genetics counseling can be very helpful for a patient, particularly in the era of multigene panel testing.^16,17 A detailed pedigree (family tree) is elicited, and a genetics specialist determines whether testing is indicated and which test is best for the patient. Possible test findings are explained. The patient may be found to have a pathogenic variant with associated increased cancer risk, a negative test result (informative or uninformative), or a variant of uncertain significance (VUS). VUS is a gene mutation identified with an unknown effect on protein function and an unclear association with cancer risk. A finding of VUS may make the patient anxious,¹⁸ create uncertainty in the treating physician,¹⁹ and lead to harmful overtreatment, excessive surveillance, or unnecessary use of a preventive measure.^19–21 Genetics counseling allows the patient, even the patient with VUS, to make appropriate decisions.²² Counseling may also help a patient or family process emotional responses, such as fear and guilt. In addition, counselors are familiar with relevant laws and regulations, such as the Genetic Information Nondiscrimination Act of 2008 (GINA), which protects patients from insurance and employment discrimination. Many professional guidelines recommend providing genetics counseling in conjunction with genetics testing,^12,23 and some insurance companies and some states require counseling for coverage of testing.

Cost of genetics counseling. If patients are concerned about the cost of genetics testing, they can be reassured with the following information^24–26:

• The Patient Protection and Affordable Care Act (ACA) identifies BRCA testing as a preventive service
• Medicare provides coverage for affected patients with a qualifying personal history
• 97% of commercial insurers and most state Medicaid programs provide coverage for hereditary cancer testing
• Most commercial laboratories have affordability programs that may provide additional support.

If a BRCA mutation is found: Many patients question the value of knowing whether they have a BRCA mutation. What our patient, her daughters, and others may not realize is that, if a BRCA mutation is found, breast MRI screening can begin at age 25. Although contrast-enhanced MRI screening is highly sensitive in detecting breast cancer,^27–29 it lacks specificity and commonly yields false positives.

Some patients also worry about overdiagnosis with this highly sensitive test. Many do not realize that preventively prescribed oral contraceptives can reduce the risk of ovarian cancer by 50%, and cosmetically acceptable risk-reducing breast surgeries can reduce the risk by 90%.

Many are unaware of the associated risks with ovarian, prostate, pancreatic, and other cancers; of risk management options; and of assisted reproduction options, such as preimplantation genetics diagnosis, which can prevent the passing of a genetic mutation to future generations. The guidelines on risk management options are increasingly clear and helpful,^12,30–32 and women often turn to their ObGyns for advice about health and prevention.

ObGyns are often the first-line providers for women with a personal or family history of breast cancer. Identification of at-risk patients begins with taking a careful family history and becoming familiar with the rapidly evolving guidelines in this important field. Identification of appropriate candidates for breast cancer genetics testing is a key step toward prevention, value-based care, and avoidance of legal liability.

CASE Resolved

In this case, testing for the 3 common Ashkenazi BRCA founder mutations was negative, and multigene panel testing was also negative. Her husband is not of Ashkenazi Jewish descent and there is no significant family history of cancer on his side. The daughters are advised to begin high-risk screening at the age of 32, 10 years earlier than their mother was diagnosed, but no genetic testing is indicated for them.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

Advances in cancer genetics are rapidly changing how clinicians assess an individual’s risk for breast cancer. ObGyns counsel many women with a personal or family history of the disease, many of whom can benefit from genetics counseling and testing. As patients with a hereditary predisposition to breast cancer are at higher risk and are younger at diagnosis, it is imperative to identify them early so they can benefit from enhanced surveillance, chemoprevention, and discussions regarding risk-reducing surgeries. ObGyns are uniquely poised to identify young women at risk for hereditary cancer syndromes, and they play a crucial role in screening and prevention over the life span.

CASE Patient with breast cancer history asks about screening for her daughters

A 52-year-old woman presents for her annual examination. She underwent breast cancer treatment 10 years earlier and has done well since then. When asked about family history of breast cancer and ethnicity, she reports her mother had breast cancer later in life, and her mother’s father was of Ashkenazi Jewish ancestry.In addition, a maternal uncle had metastatic prostate cancer. You recall that breast cancer diagnosed before age 50 years and Ashkenazi ancestry are “red flags” for a hereditary cancer syndrome. The patient wonders how her daughters should be screened. What do you do next?

Having a risk assessment plan is crucial

Given increasing demands, limited time, and the abundance of information to be discussed with patients, primary care physicians may find it challenging to assess breast cancer risk, consider genetics testing for appropriate individuals, and counsel patients about risk management options. The process has become even more complex since the expansion in genetics knowledge and the advent of multigene panel testing. Not only is risk assessment crucial for this woman and her daughters, and for other patients, but a delay in diagnosing and treating breast cancer in patients with hereditary and familial cancer risks may represent a worrisome new trend in medical litigation.^1,2 Clinicians must have a process in place for assessing risk in all patients and treating them appropriately.

The American Cancer Society (ACS) estimated that 252,710 cases of breast cancer would be diagnosed in 2017, leading to 40,610 deaths.³ Twelve percent to 14% of breast cancers are thought to be related to hereditary cancer predisposition syndromes.^4–8 This means that, every year, almost 35,000 cases of breast cancer are attributable to hereditary risk. These cases can be detected early with enhanced surveillance, which carries the highest chance for cure, or prevented with risk-reducing surgery in identified genetic mutation carriers. Each child of a person with a genetic mutation predisposing to breast cancer has a 50% chance of inheriting the mutation and having a very high risk of cancer.

In this patient’s case, basic information is collected about her cancer-related personal and family history.

Asking a few key questions can help in stratifying risk:

• Have you or anyone in your family had cancer? What type, and at what age?
• If breast cancer, did it involve both breasts, or was it triple-negative?
• Is there a family history of ovarian cancer?
• Is there a family history of male breast cancer?
• Is there a family history of metastatic prostate cancer?
• Are you of Ashkenazi Jewish ethnicity?
• Have you or anyone in your family ever had genetics testing for cancer?

The hallmarks of hereditary cancer are multiple cancers in an individual or family; young age at diagnosis; and ovarian, pancreatic, or another rare cancer. Metastatic prostate cancer was added as a red flag for hereditary risk after a recent large series found that 11.8% of men with metastatic prostate cancer harbor germline mutations.⁹

CASE Continued

On further questioning, the patient reports she had triple-negative (estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer, a feature of patients with germline BRCA1 (breast cancer susceptibility gene 1) mutations.¹⁰ In addition, her Ashkenazi ancestry is concerning, as there is a 1-in-40 chance of carrying 1 of the 3 Ashkenazi founder BRCA mutations.¹¹ Is a genetics consultation needed?

Read about guidelines for referral and testing.

Guidelines for genetics referral and testing

According to the TABLE, which summarizes national guidelines for genetics referral, maternal and paternal family histories are equally important. Our patient was under age 50 at diagnosis, has a history of triple-negative breast cancer, is of Ashkenazi ancestry, and has a family history of metastatic prostate cancer. She meets the criteria for genetics testing, and screening for her daughters most certainly will depend on the findings of that testing. If she carries a BRCA1 mutation, as might be anticipated, each daughter would have a 50% chance of having inherited the mutation. If they carry the mutation as well, they would begin breast magnetic resonance imaging (MRI) screening at age 25.¹² If they decide against genetics testing, they could still undergo MRI screening as untested first-degree relatives of a BRCA carrier, per ACS recommendations.¹³

Integrating evidence and experience

Over the past 10 to 20 years, other breast cancer susceptibility genes (eg, BRCA2, PALB2, CHEK2) have been identified. More recently, next-generation sequencing has become commercially available. Laboratories can use this newer method to sequence multiple genes rapidly and in parallel, and its cost is similar to that of single-syndrome testing.¹⁴ When more than 1 gene can explain an inherited cancer syndrome, multigene panel testing may be more efficient and cost-effective. Use of multigene panel testing is supported in guidelines issued by the National Comprehensive Cancer Network,¹² the American College of Obstetricians and Gynecologists,¹⁵ and other medical societies.

For our patient, the most logical strategy would be to test for the 3 mutations most common in the Ashkenazi population and then, if no mutation is found, perform multigene panel testing.

Formal genetics counseling can be very helpful for a patient, particularly in the era of multigene panel testing.^16,17 A detailed pedigree (family tree) is elicited, and a genetics specialist determines whether testing is indicated and which test is best for the patient. Possible test findings are explained. The patient may be found to have a pathogenic variant with associated increased cancer risk, a negative test result (informative or uninformative), or a variant of uncertain significance (VUS). VUS is a gene mutation identified with an unknown effect on protein function and an unclear association with cancer risk. A finding of VUS may make the patient anxious,¹⁸ create uncertainty in the treating physician,¹⁹ and lead to harmful overtreatment, excessive surveillance, or unnecessary use of a preventive measure.^19–21 Genetics counseling allows the patient, even the patient with VUS, to make appropriate decisions.²² Counseling may also help a patient or family process emotional responses, such as fear and guilt. In addition, counselors are familiar with relevant laws and regulations, such as the Genetic Information Nondiscrimination Act of 2008 (GINA), which protects patients from insurance and employment discrimination. Many professional guidelines recommend providing genetics counseling in conjunction with genetics testing,^12,23 and some insurance companies and some states require counseling for coverage of testing.

Cost of genetics counseling. If patients are concerned about the cost of genetics testing, they can be reassured with the following information^24–26:

• The Patient Protection and Affordable Care Act (ACA) identifies BRCA testing as a preventive service
• Medicare provides coverage for affected patients with a qualifying personal history
• 97% of commercial insurers and most state Medicaid programs provide coverage for hereditary cancer testing
• Most commercial laboratories have affordability programs that may provide additional support.

If a BRCA mutation is found: Many patients question the value of knowing whether they have a BRCA mutation. What our patient, her daughters, and others may not realize is that, if a BRCA mutation is found, breast MRI screening can begin at age 25. Although contrast-enhanced MRI screening is highly sensitive in detecting breast cancer,^27–29 it lacks specificity and commonly yields false positives.

Some patients also worry about overdiagnosis with this highly sensitive test. Many do not realize that preventively prescribed oral contraceptives can reduce the risk of ovarian cancer by 50%, and cosmetically acceptable risk-reducing breast surgeries can reduce the risk by 90%.

Many are unaware of the associated risks with ovarian, prostate, pancreatic, and other cancers; of risk management options; and of assisted reproduction options, such as preimplantation genetics diagnosis, which can prevent the passing of a genetic mutation to future generations. The guidelines on risk management options are increasingly clear and helpful,^12,30–32 and women often turn to their ObGyns for advice about health and prevention.

ObGyns are often the first-line providers for women with a personal or family history of breast cancer. Identification of at-risk patients begins with taking a careful family history and becoming familiar with the rapidly evolving guidelines in this important field. Identification of appropriate candidates for breast cancer genetics testing is a key step toward prevention, value-based care, and avoidance of legal liability.

CASE Resolved

In this case, testing for the 3 common Ashkenazi BRCA founder mutations was negative, and multigene panel testing was also negative. Her husband is not of Ashkenazi Jewish descent and there is no significant family history of cancer on his side. The daughters are advised to begin high-risk screening at the age of 32, 10 years earlier than their mother was diagnosed, but no genetic testing is indicated for them.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

Advances in cancer genetics are rapidly changing how clinicians assess an individual’s risk for breast cancer. ObGyns counsel many women with a personal or family history of the disease, many of whom can benefit from genetics counseling and testing. As patients with a hereditary predisposition to breast cancer are at higher risk and are younger at diagnosis, it is imperative to identify them early so they can benefit from enhanced surveillance, chemoprevention, and discussions regarding risk-reducing surgeries. ObGyns are uniquely poised to identify young women at risk for hereditary cancer syndromes, and they play a crucial role in screening and prevention over the life span.

CASE Patient with breast cancer history asks about screening for her daughters

A 52-year-old woman presents for her annual examination. She underwent breast cancer treatment 10 years earlier and has done well since then. When asked about family history of breast cancer and ethnicity, she reports her mother had breast cancer later in life, and her mother’s father was of Ashkenazi Jewish ancestry.In addition, a maternal uncle had metastatic prostate cancer. You recall that breast cancer diagnosed before age 50 years and Ashkenazi ancestry are “red flags” for a hereditary cancer syndrome. The patient wonders how her daughters should be screened. What do you do next?

Having a risk assessment plan is crucial

Given increasing demands, limited time, and the abundance of information to be discussed with patients, primary care physicians may find it challenging to assess breast cancer risk, consider genetics testing for appropriate individuals, and counsel patients about risk management options. The process has become even more complex since the expansion in genetics knowledge and the advent of multigene panel testing. Not only is risk assessment crucial for this woman and her daughters, and for other patients, but a delay in diagnosing and treating breast cancer in patients with hereditary and familial cancer risks may represent a worrisome new trend in medical litigation.^1,2 Clinicians must have a process in place for assessing risk in all patients and treating them appropriately.

The American Cancer Society (ACS) estimated that 252,710 cases of breast cancer would be diagnosed in 2017, leading to 40,610 deaths.³ Twelve percent to 14% of breast cancers are thought to be related to hereditary cancer predisposition syndromes.^4–8 This means that, every year, almost 35,000 cases of breast cancer are attributable to hereditary risk. These cases can be detected early with enhanced surveillance, which carries the highest chance for cure, or prevented with risk-reducing surgery in identified genetic mutation carriers. Each child of a person with a genetic mutation predisposing to breast cancer has a 50% chance of inheriting the mutation and having a very high risk of cancer.

In this patient’s case, basic information is collected about her cancer-related personal and family history.

Asking a few key questions can help in stratifying risk:

• Have you or anyone in your family had cancer? What type, and at what age?
• If breast cancer, did it involve both breasts, or was it triple-negative?
• Is there a family history of ovarian cancer?
• Is there a family history of male breast cancer?
• Is there a family history of metastatic prostate cancer?
• Are you of Ashkenazi Jewish ethnicity?
• Have you or anyone in your family ever had genetics testing for cancer?

The hallmarks of hereditary cancer are multiple cancers in an individual or family; young age at diagnosis; and ovarian, pancreatic, or another rare cancer. Metastatic prostate cancer was added as a red flag for hereditary risk after a recent large series found that 11.8% of men with metastatic prostate cancer harbor germline mutations.⁹

CASE Continued

On further questioning, the patient reports she had triple-negative (estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer, a feature of patients with germline BRCA1 (breast cancer susceptibility gene 1) mutations.¹⁰ In addition, her Ashkenazi ancestry is concerning, as there is a 1-in-40 chance of carrying 1 of the 3 Ashkenazi founder BRCA mutations.¹¹ Is a genetics consultation needed?

Read about guidelines for referral and testing.

Guidelines for genetics referral and testing

According to the TABLE, which summarizes national guidelines for genetics referral, maternal and paternal family histories are equally important. Our patient was under age 50 at diagnosis, has a history of triple-negative breast cancer, is of Ashkenazi ancestry, and has a family history of metastatic prostate cancer. She meets the criteria for genetics testing, and screening for her daughters most certainly will depend on the findings of that testing. If she carries a BRCA1 mutation, as might be anticipated, each daughter would have a 50% chance of having inherited the mutation. If they carry the mutation as well, they would begin breast magnetic resonance imaging (MRI) screening at age 25.¹² If they decide against genetics testing, they could still undergo MRI screening as untested first-degree relatives of a BRCA carrier, per ACS recommendations.¹³

Integrating evidence and experience

Over the past 10 to 20 years, other breast cancer susceptibility genes (eg, BRCA2, PALB2, CHEK2) have been identified. More recently, next-generation sequencing has become commercially available. Laboratories can use this newer method to sequence multiple genes rapidly and in parallel, and its cost is similar to that of single-syndrome testing.¹⁴ When more than 1 gene can explain an inherited cancer syndrome, multigene panel testing may be more efficient and cost-effective. Use of multigene panel testing is supported in guidelines issued by the National Comprehensive Cancer Network,¹² the American College of Obstetricians and Gynecologists,¹⁵ and other medical societies.

For our patient, the most logical strategy would be to test for the 3 mutations most common in the Ashkenazi population and then, if no mutation is found, perform multigene panel testing.

Formal genetics counseling can be very helpful for a patient, particularly in the era of multigene panel testing.^16,17 A detailed pedigree (family tree) is elicited, and a genetics specialist determines whether testing is indicated and which test is best for the patient. Possible test findings are explained. The patient may be found to have a pathogenic variant with associated increased cancer risk, a negative test result (informative or uninformative), or a variant of uncertain significance (VUS). VUS is a gene mutation identified with an unknown effect on protein function and an unclear association with cancer risk. A finding of VUS may make the patient anxious,¹⁸ create uncertainty in the treating physician,¹⁹ and lead to harmful overtreatment, excessive surveillance, or unnecessary use of a preventive measure.^19–21 Genetics counseling allows the patient, even the patient with VUS, to make appropriate decisions.²² Counseling may also help a patient or family process emotional responses, such as fear and guilt. In addition, counselors are familiar with relevant laws and regulations, such as the Genetic Information Nondiscrimination Act of 2008 (GINA), which protects patients from insurance and employment discrimination. Many professional guidelines recommend providing genetics counseling in conjunction with genetics testing,^12,23 and some insurance companies and some states require counseling for coverage of testing.

Cost of genetics counseling. If patients are concerned about the cost of genetics testing, they can be reassured with the following information^24–26:

• The Patient Protection and Affordable Care Act (ACA) identifies BRCA testing as a preventive service
• Medicare provides coverage for affected patients with a qualifying personal history
• 97% of commercial insurers and most state Medicaid programs provide coverage for hereditary cancer testing
• Most commercial laboratories have affordability programs that may provide additional support.

If a BRCA mutation is found: Many patients question the value of knowing whether they have a BRCA mutation. What our patient, her daughters, and others may not realize is that, if a BRCA mutation is found, breast MRI screening can begin at age 25. Although contrast-enhanced MRI screening is highly sensitive in detecting breast cancer,^27–29 it lacks specificity and commonly yields false positives.

Some patients also worry about overdiagnosis with this highly sensitive test. Many do not realize that preventively prescribed oral contraceptives can reduce the risk of ovarian cancer by 50%, and cosmetically acceptable risk-reducing breast surgeries can reduce the risk by 90%.

Many are unaware of the associated risks with ovarian, prostate, pancreatic, and other cancers; of risk management options; and of assisted reproduction options, such as preimplantation genetics diagnosis, which can prevent the passing of a genetic mutation to future generations. The guidelines on risk management options are increasingly clear and helpful,^12,30–32 and women often turn to their ObGyns for advice about health and prevention.

ObGyns are often the first-line providers for women with a personal or family history of breast cancer. Identification of at-risk patients begins with taking a careful family history and becoming familiar with the rapidly evolving guidelines in this important field. Identification of appropriate candidates for breast cancer genetics testing is a key step toward prevention, value-based care, and avoidance of legal liability.

CASE Resolved

In this case, testing for the 3 common Ashkenazi BRCA founder mutations was negative, and multigene panel testing was also negative. Her husband is not of Ashkenazi Jewish descent and there is no significant family history of cancer on his side. The daughters are advised to begin high-risk screening at the age of 32, 10 years earlier than their mother was diagnosed, but no genetic testing is indicated for them.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Breast cancer screening is an important aspect of women’s preventative health care, with proven mortality benefits.^1,2 Different recommendations have been made for the age at initiation and the frequency of breast cancer screening in an effort to maximize benefit while minimizing unnecessary health care costs and harms of screening.

The American College of Obstetricians and Gynecologists (ACOG) and the National Comprehensive Cancer Network (NCCN) recommend initiating mammography screening at age 40, with annual screening (although ACOG offers deferral of screening to age 50 and biennial screening through shared decision making).^3,4 The American Cancer Society (ACS) recommends offering annual mammography at ages 40 to 44 and recommends routinely starting annual mammography from 45 to 54, followed by either annual or biennial screening for women 55 and older.¹ Finally, the US Preventive Services Task Force (USPSTF) recommends biennial mammography screening starting at age 50.⁵ No organization alters screening recommendations based on a woman’s race/ethnicity.

Details of the study

Stapleton and colleagues recently performed a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) Program database to evaluate the age and stage at breast cancer diagnosis across different racial groups in the United States.⁶ The study (timeframe, January 1, 1973 to December 31, 2010) included 747,763 women, with a racial/ethnic distribution of 77.0% white, 9.3% black, 7.0% Hispanic, and 6.2% Asian.

The investigators found 2 distinct age distributions of breast cancer based on race. Among nonwhite women, the highest peak of breast cancer diagnoses occurred between 45 and 50 years (FIGURE). By contrast, breast cancer diagnoses peaked at 60 to 65 years in white women.

Similarly, a higher proportion of nonwhite women were diagnosed with their breast cancer prior to age 50 compared with white women. While one-quarter of white women with breast cancer develop disease prior to age 50, approximately one-third of black, Asian, and Hispanic women with breast cancer will be diagnosed before age 50 (TABLE).

These data suggest that the peak proportion of breast cancer diagnoses in nonwhite women occurs prior to the age of initiation of screening recommended by the USPSTF. Based on these results, Stapleton and colleagues recommend reconsideration of the current USPSTF guidelines to incorporate race/ethnicity–based differences. To diagnose the same proportion of breast cancer cases among nonwhite women as is currently possible among white women at age 50, initiation of breast cancer screening would need to be adjusted to age 47 for black women, age 46 for Hispanic women, and age 47 for Asian women.

Study strengths and weaknesses

This is a unique study that uses the SEER database to capture a large cross section of the American population. The SEER database is a valuable tool because it gathers data from numerous major US metropolitan areas, creating a diverse representative population that minimizes confounding from geographical trends. Nevertheless, any study utilizing a large database is limited by the accuracy and completeness of the data collected at the level of the individual cancer registry. Furthermore, information regarding medical comorbidities and access and adherence to breast cancer screening is lacking in the SEER database; this provides an opportunity for confounding.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Breast cancer screening is an important aspect of women’s preventative health care, with proven mortality benefits.^1,2 Different recommendations have been made for the age at initiation and the frequency of breast cancer screening in an effort to maximize benefit while minimizing unnecessary health care costs and harms of screening.

The American College of Obstetricians and Gynecologists (ACOG) and the National Comprehensive Cancer Network (NCCN) recommend initiating mammography screening at age 40, with annual screening (although ACOG offers deferral of screening to age 50 and biennial screening through shared decision making).^3,4 The American Cancer Society (ACS) recommends offering annual mammography at ages 40 to 44 and recommends routinely starting annual mammography from 45 to 54, followed by either annual or biennial screening for women 55 and older.¹ Finally, the US Preventive Services Task Force (USPSTF) recommends biennial mammography screening starting at age 50.⁵ No organization alters screening recommendations based on a woman’s race/ethnicity.

Details of the study

Stapleton and colleagues recently performed a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) Program database to evaluate the age and stage at breast cancer diagnosis across different racial groups in the United States.⁶ The study (timeframe, January 1, 1973 to December 31, 2010) included 747,763 women, with a racial/ethnic distribution of 77.0% white, 9.3% black, 7.0% Hispanic, and 6.2% Asian.

The investigators found 2 distinct age distributions of breast cancer based on race. Among nonwhite women, the highest peak of breast cancer diagnoses occurred between 45 and 50 years (FIGURE). By contrast, breast cancer diagnoses peaked at 60 to 65 years in white women.

Similarly, a higher proportion of nonwhite women were diagnosed with their breast cancer prior to age 50 compared with white women. While one-quarter of white women with breast cancer develop disease prior to age 50, approximately one-third of black, Asian, and Hispanic women with breast cancer will be diagnosed before age 50 (TABLE).

These data suggest that the peak proportion of breast cancer diagnoses in nonwhite women occurs prior to the age of initiation of screening recommended by the USPSTF. Based on these results, Stapleton and colleagues recommend reconsideration of the current USPSTF guidelines to incorporate race/ethnicity–based differences. To diagnose the same proportion of breast cancer cases among nonwhite women as is currently possible among white women at age 50, initiation of breast cancer screening would need to be adjusted to age 47 for black women, age 46 for Hispanic women, and age 47 for Asian women.

Study strengths and weaknesses

This is a unique study that uses the SEER database to capture a large cross section of the American population. The SEER database is a valuable tool because it gathers data from numerous major US metropolitan areas, creating a diverse representative population that minimizes confounding from geographical trends. Nevertheless, any study utilizing a large database is limited by the accuracy and completeness of the data collected at the level of the individual cancer registry. Furthermore, information regarding medical comorbidities and access and adherence to breast cancer screening is lacking in the SEER database; this provides an opportunity for confounding.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Breast cancer screening is an important aspect of women’s preventative health care, with proven mortality benefits.^1,2 Different recommendations have been made for the age at initiation and the frequency of breast cancer screening in an effort to maximize benefit while minimizing unnecessary health care costs and harms of screening.

The American College of Obstetricians and Gynecologists (ACOG) and the National Comprehensive Cancer Network (NCCN) recommend initiating mammography screening at age 40, with annual screening (although ACOG offers deferral of screening to age 50 and biennial screening through shared decision making).^3,4 The American Cancer Society (ACS) recommends offering annual mammography at ages 40 to 44 and recommends routinely starting annual mammography from 45 to 54, followed by either annual or biennial screening for women 55 and older.¹ Finally, the US Preventive Services Task Force (USPSTF) recommends biennial mammography screening starting at age 50.⁵ No organization alters screening recommendations based on a woman’s race/ethnicity.

Details of the study

Stapleton and colleagues recently performed a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) Program database to evaluate the age and stage at breast cancer diagnosis across different racial groups in the United States.⁶ The study (timeframe, January 1, 1973 to December 31, 2010) included 747,763 women, with a racial/ethnic distribution of 77.0% white, 9.3% black, 7.0% Hispanic, and 6.2% Asian.

The investigators found 2 distinct age distributions of breast cancer based on race. Among nonwhite women, the highest peak of breast cancer diagnoses occurred between 45 and 50 years (FIGURE). By contrast, breast cancer diagnoses peaked at 60 to 65 years in white women.

Similarly, a higher proportion of nonwhite women were diagnosed with their breast cancer prior to age 50 compared with white women. While one-quarter of white women with breast cancer develop disease prior to age 50, approximately one-third of black, Asian, and Hispanic women with breast cancer will be diagnosed before age 50 (TABLE).

These data suggest that the peak proportion of breast cancer diagnoses in nonwhite women occurs prior to the age of initiation of screening recommended by the USPSTF. Based on these results, Stapleton and colleagues recommend reconsideration of the current USPSTF guidelines to incorporate race/ethnicity–based differences. To diagnose the same proportion of breast cancer cases among nonwhite women as is currently possible among white women at age 50, initiation of breast cancer screening would need to be adjusted to age 47 for black women, age 46 for Hispanic women, and age 47 for Asian women.

Study strengths and weaknesses

This is a unique study that uses the SEER database to capture a large cross section of the American population. The SEER database is a valuable tool because it gathers data from numerous major US metropolitan areas, creating a diverse representative population that minimizes confounding from geographical trends. Nevertheless, any study utilizing a large database is limited by the accuracy and completeness of the data collected at the level of the individual cancer registry. Furthermore, information regarding medical comorbidities and access and adherence to breast cancer screening is lacking in the SEER database; this provides an opportunity for confounding.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Jame Abraham, MD, FACP, an Editor on The Journal of Community and Supportive Oncology, shares his top selections in breast cancer from this year's annual meeting of the American Society of Clinical Oncology in Chicago.

1001 Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC) (Aditya Bardia et al). The study drug was well tolerated and produced objective responses in this heavily pretreated population, with an overall response rate of 31% at 6 months and a clinical benefit rate of 48%.

LBA1 TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score (Joseph A Sparano et al)

506 PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results (Helena Margaret Earl et al). Six months of trastuzumab was found to be noninferior to 12 months, although cardiac events were reduced in the 6-month group compared with the 12-month group (4% vs 8% of patients, respectively, ended treatment because of cardiotoxicity).

In addition, Dr David Henry, the Editor-in-Chief of JCSO, also selected:
500 Adjuvant denosumab in early breast cancer: disease-free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

Jame Abraham, MD, FACP, an Editor on The Journal of Community and Supportive Oncology, shares his top selections in breast cancer from this year's annual meeting of the American Society of Clinical Oncology in Chicago.

1001 Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC) (Aditya Bardia et al). The study drug was well tolerated and produced objective responses in this heavily pretreated population, with an overall response rate of 31% at 6 months and a clinical benefit rate of 48%.

LBA1 TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score (Joseph A Sparano et al)

506 PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results (Helena Margaret Earl et al). Six months of trastuzumab was found to be noninferior to 12 months, although cardiac events were reduced in the 6-month group compared with the 12-month group (4% vs 8% of patients, respectively, ended treatment because of cardiotoxicity).

In addition, Dr David Henry, the Editor-in-Chief of JCSO, also selected:
500 Adjuvant denosumab in early breast cancer: disease-free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

Jame Abraham, MD, FACP, an Editor on The Journal of Community and Supportive Oncology, shares his top selections in breast cancer from this year's annual meeting of the American Society of Clinical Oncology in Chicago.

1001 Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC) (Aditya Bardia et al). The study drug was well tolerated and produced objective responses in this heavily pretreated population, with an overall response rate of 31% at 6 months and a clinical benefit rate of 48%.

LBA1 TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score (Joseph A Sparano et al)

506 PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results (Helena Margaret Earl et al). Six months of trastuzumab was found to be noninferior to 12 months, although cardiac events were reduced in the 6-month group compared with the 12-month group (4% vs 8% of patients, respectively, ended treatment because of cardiotoxicity).

In addition, Dr David Henry, the Editor-in-Chief of JCSO, also selected:
500 Adjuvant denosumab in early breast cancer: disease-free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

Cancer survivors who have trouble sleeping saw improvements with both cognitive-behavioral therapy designed specifically for insomnia (CBT-I) and acupuncture, according to results from the randomized, controlled CHOICE trial. But the former is more efficacious.

“Insomnia can have deleterious effects on quality of life and function, and occurs in up to 60% of cancer survivors,” lead study author Jun J. Mao, MD, chief of integrative medicine service at Memorial Sloan Kettering Cancer Center, New York, said in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology.

“CBT-I is a highly effective therapy and can be considered the gold standard of treatment,” he noted. However, this modality may be limited by poor adherence and nonresponse. Moreover, it is highly specialized and not currently available in many cancer centers or communities.

Functional imaging studies have shown that acupuncture can regulate brain regions involving cognition and emotion that are essential to sleep regulation, and clinical research has shown that it can improve pain- and hot flash–related sleep disturbances, according to Dr. Mao. About 73% of U.S. comprehensive cancer centers offer acupuncture for symptom management.

Main results of the CHOICE (Choosing Options for Insomnia in Cancer Effectively) trial showed that patients in both the CBT-I and acupuncture groups reduced their Insomnia Severity Index scores by more than one-half at the end of the 8-weeks treatment period, but the reduction was a statistically significant 2.6 points greater with CBT-I. Benefit of each treatment was still evident after 12 weeks.

Response rate was higher with CBT-I than with acupuncture only among patients having mild insomnia at baseline, and the two treatments yielded similar improvements in mental and physical quality of life.

“Among cancer patients with insomnia, we found that both acupuncture and CBT-I produced clinically meaningful and durable benefit, but overall, CBT-I is more effective in reducing insomnia severity,” Dr. Mao concluded. “Our hope is that by doing this type of research, we can help patients and clinicians pick the right kind of treatment and help them to manage their sleep. Our next step is to really examine for what type of patient treatment would be beneficial, and how to deliver this type of effective treatment to the broader community of cancer patients.”

Insomnia among cancer survivors is both prevalent and problematic, agreed ASCO President Bruce E. Johnson, MD, FASCO.

“The most common way we treat this is pharmacologically, with sleeping pills,” he noted. “This trial shows that two different methods using something other than medications can help people with sleep, and not only do they help people with sleep, but they improve their quality of life.

“We think this information will be helpful for clinicians who end up having to decide, and also, we would use this information to help decide about how the severity of the insomnia is going to influence the treatment,” maintained Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute in Boston, and a leader of the center’s lung cancer program.

Study details

The CHOICE trial did not have any restrictions on cancer type or stage; more than a half-dozen types were represented among the 160 patients enrolled, with breast cancer (31%) and prostate cancer (23%) accounting for the largest shares. The majority of patients were white (70%) and had moderate to severe insomnia (79%).

Patients were randomized to receive either acupuncture sessions (10 sessions, with points selected to treat insomnia plus comorbid symptoms such as fatigue and anxiety) or CBT-I (7 sessions), each over the course of 8 weeks.

Main results showed that at the end of treatment, the reduction in Insomnia Severity Index was 8.3 points with acupuncture and 10.9 points with CBT-I (P = .0007), Dr. Mao reported. Benefit of each treatment was sustained after 12 weeks.

In stratified analysis, the rate of response (defined as a greater than 8-point reduction) was higher with CBT-I than with acupuncture among patients with mild insomnia (Insomnia Severity Index of 8-14) (85% vs. 18%; P less than .0001), but not among patients with moderate or severe insomnia (Insomnia Severity Index of 15 or higher) (75% vs. 66%; P = .26).

The two treatments were similarly efficacious with respect to quality of life, assessed with the Patient-Reported Outcomes Measurement Information System over the entire course of the trial, for both the physical health component (P = .4) and the mental health component (P = .36).

Dr. Mao disclosed no relevant conflicts of interest. The study received funding from the Patient-Centered Outcomes Research Institute.

SOURCE: Mao JJ et al. ASCO 2018. Abstract 10001.

Cancer survivors who have trouble sleeping saw improvements with both cognitive-behavioral therapy designed specifically for insomnia (CBT-I) and acupuncture, according to results from the randomized, controlled CHOICE trial. But the former is more efficacious.

“Insomnia can have deleterious effects on quality of life and function, and occurs in up to 60% of cancer survivors,” lead study author Jun J. Mao, MD, chief of integrative medicine service at Memorial Sloan Kettering Cancer Center, New York, said in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology.

“CBT-I is a highly effective therapy and can be considered the gold standard of treatment,” he noted. However, this modality may be limited by poor adherence and nonresponse. Moreover, it is highly specialized and not currently available in many cancer centers or communities.

Functional imaging studies have shown that acupuncture can regulate brain regions involving cognition and emotion that are essential to sleep regulation, and clinical research has shown that it can improve pain- and hot flash–related sleep disturbances, according to Dr. Mao. About 73% of U.S. comprehensive cancer centers offer acupuncture for symptom management.

Main results of the CHOICE (Choosing Options for Insomnia in Cancer Effectively) trial showed that patients in both the CBT-I and acupuncture groups reduced their Insomnia Severity Index scores by more than one-half at the end of the 8-weeks treatment period, but the reduction was a statistically significant 2.6 points greater with CBT-I. Benefit of each treatment was still evident after 12 weeks.

Response rate was higher with CBT-I than with acupuncture only among patients having mild insomnia at baseline, and the two treatments yielded similar improvements in mental and physical quality of life.

“Among cancer patients with insomnia, we found that both acupuncture and CBT-I produced clinically meaningful and durable benefit, but overall, CBT-I is more effective in reducing insomnia severity,” Dr. Mao concluded. “Our hope is that by doing this type of research, we can help patients and clinicians pick the right kind of treatment and help them to manage their sleep. Our next step is to really examine for what type of patient treatment would be beneficial, and how to deliver this type of effective treatment to the broader community of cancer patients.”

Insomnia among cancer survivors is both prevalent and problematic, agreed ASCO President Bruce E. Johnson, MD, FASCO.

“The most common way we treat this is pharmacologically, with sleeping pills,” he noted. “This trial shows that two different methods using something other than medications can help people with sleep, and not only do they help people with sleep, but they improve their quality of life.

“We think this information will be helpful for clinicians who end up having to decide, and also, we would use this information to help decide about how the severity of the insomnia is going to influence the treatment,” maintained Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute in Boston, and a leader of the center’s lung cancer program.

Study details

The CHOICE trial did not have any restrictions on cancer type or stage; more than a half-dozen types were represented among the 160 patients enrolled, with breast cancer (31%) and prostate cancer (23%) accounting for the largest shares. The majority of patients were white (70%) and had moderate to severe insomnia (79%).

Patients were randomized to receive either acupuncture sessions (10 sessions, with points selected to treat insomnia plus comorbid symptoms such as fatigue and anxiety) or CBT-I (7 sessions), each over the course of 8 weeks.

Main results showed that at the end of treatment, the reduction in Insomnia Severity Index was 8.3 points with acupuncture and 10.9 points with CBT-I (P = .0007), Dr. Mao reported. Benefit of each treatment was sustained after 12 weeks.

In stratified analysis, the rate of response (defined as a greater than 8-point reduction) was higher with CBT-I than with acupuncture among patients with mild insomnia (Insomnia Severity Index of 8-14) (85% vs. 18%; P less than .0001), but not among patients with moderate or severe insomnia (Insomnia Severity Index of 15 or higher) (75% vs. 66%; P = .26).

The two treatments were similarly efficacious with respect to quality of life, assessed with the Patient-Reported Outcomes Measurement Information System over the entire course of the trial, for both the physical health component (P = .4) and the mental health component (P = .36).

Dr. Mao disclosed no relevant conflicts of interest. The study received funding from the Patient-Centered Outcomes Research Institute.

SOURCE: Mao JJ et al. ASCO 2018. Abstract 10001.

Cancer survivors who have trouble sleeping saw improvements with both cognitive-behavioral therapy designed specifically for insomnia (CBT-I) and acupuncture, according to results from the randomized, controlled CHOICE trial. But the former is more efficacious.

“Insomnia can have deleterious effects on quality of life and function, and occurs in up to 60% of cancer survivors,” lead study author Jun J. Mao, MD, chief of integrative medicine service at Memorial Sloan Kettering Cancer Center, New York, said in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology.

“CBT-I is a highly effective therapy and can be considered the gold standard of treatment,” he noted. However, this modality may be limited by poor adherence and nonresponse. Moreover, it is highly specialized and not currently available in many cancer centers or communities.

Functional imaging studies have shown that acupuncture can regulate brain regions involving cognition and emotion that are essential to sleep regulation, and clinical research has shown that it can improve pain- and hot flash–related sleep disturbances, according to Dr. Mao. About 73% of U.S. comprehensive cancer centers offer acupuncture for symptom management.

Main results of the CHOICE (Choosing Options for Insomnia in Cancer Effectively) trial showed that patients in both the CBT-I and acupuncture groups reduced their Insomnia Severity Index scores by more than one-half at the end of the 8-weeks treatment period, but the reduction was a statistically significant 2.6 points greater with CBT-I. Benefit of each treatment was still evident after 12 weeks.

Response rate was higher with CBT-I than with acupuncture only among patients having mild insomnia at baseline, and the two treatments yielded similar improvements in mental and physical quality of life.

“Among cancer patients with insomnia, we found that both acupuncture and CBT-I produced clinically meaningful and durable benefit, but overall, CBT-I is more effective in reducing insomnia severity,” Dr. Mao concluded. “Our hope is that by doing this type of research, we can help patients and clinicians pick the right kind of treatment and help them to manage their sleep. Our next step is to really examine for what type of patient treatment would be beneficial, and how to deliver this type of effective treatment to the broader community of cancer patients.”

Insomnia among cancer survivors is both prevalent and problematic, agreed ASCO President Bruce E. Johnson, MD, FASCO.

“The most common way we treat this is pharmacologically, with sleeping pills,” he noted. “This trial shows that two different methods using something other than medications can help people with sleep, and not only do they help people with sleep, but they improve their quality of life.

“We think this information will be helpful for clinicians who end up having to decide, and also, we would use this information to help decide about how the severity of the insomnia is going to influence the treatment,” maintained Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute in Boston, and a leader of the center’s lung cancer program.

Study details

The CHOICE trial did not have any restrictions on cancer type or stage; more than a half-dozen types were represented among the 160 patients enrolled, with breast cancer (31%) and prostate cancer (23%) accounting for the largest shares. The majority of patients were white (70%) and had moderate to severe insomnia (79%).

Patients were randomized to receive either acupuncture sessions (10 sessions, with points selected to treat insomnia plus comorbid symptoms such as fatigue and anxiety) or CBT-I (7 sessions), each over the course of 8 weeks.

Main results showed that at the end of treatment, the reduction in Insomnia Severity Index was 8.3 points with acupuncture and 10.9 points with CBT-I (P = .0007), Dr. Mao reported. Benefit of each treatment was sustained after 12 weeks.

In stratified analysis, the rate of response (defined as a greater than 8-point reduction) was higher with CBT-I than with acupuncture among patients with mild insomnia (Insomnia Severity Index of 8-14) (85% vs. 18%; P less than .0001), but not among patients with moderate or severe insomnia (Insomnia Severity Index of 15 or higher) (75% vs. 66%; P = .26).

The two treatments were similarly efficacious with respect to quality of life, assessed with the Patient-Reported Outcomes Measurement Information System over the entire course of the trial, for both the physical health component (P = .4) and the mental health component (P = .36).

Dr. Mao disclosed no relevant conflicts of interest. The study received funding from the Patient-Centered Outcomes Research Institute.

SOURCE: Mao JJ et al. ASCO 2018. Abstract 10001.

One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.¹

Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.

BRCA populations

For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.⁵

Technique

When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.

The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.

The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.⁶ Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.

Consequences of ovarian ablation

It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.^7,8

It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.

Hormone replacement therapy postoperatively

Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.

Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.

2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.

3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.

4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.

5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.

6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.

7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.

8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.

One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.¹

Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.

BRCA populations

For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.⁵

Technique

When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.

The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.

The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.⁶ Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.

Consequences of ovarian ablation

It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.^7,8

It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.

Hormone replacement therapy postoperatively

Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.

Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.

2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.

3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.

4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.

5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.

6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.

7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.

8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.

One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.¹

Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.

BRCA populations

For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.⁵

Technique

When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.

The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.

The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.⁶ Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.

Consequences of ovarian ablation

It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.^7,8

It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.

Hormone replacement therapy postoperatively

Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.

Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.

2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.

3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.

4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.

5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.

6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.

7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.

8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.