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Open surgery for 34% of inpatient breast biopsies
Open breast biopsy accounted for 34% of breast biopsies in 25,965 U.S. inpatients between 2008 and 2010, a retrospective study found.
The finding suggests that minimally invasive breast biopsy techniques are underutilized, with a national rate that’s far off the widely acknowledge goal of having at least 90% of biopsies for suspicious breast lesions be minimally invasive, Dr. Linda Adepoju reported.
Most breast biopsies are performed in outpatient settings. Although the study analyzed a national data sample for hospitalized patients, the rate of open breast biopsy is consistent with previous studies of outpatient databases for individual institutions or states that have reported rates of open breast biopsy from 24% to 36%, noted Dr. Adepoju of the University of Toledo (Ohio).
She and her associates analyzed data from 46 states in the Healthcare Cost and Utilization Project National Inpatient Sample for 2008-2010, excluding 222 cases in which an open breast biopsy and minimally invasive breast biopsy were performed during the same hospital stay.
Open breast biopsy rates were significantly higher in women aged 49 years or younger (47%), compared with older women (29%), and in Asian women (40%) or Hispanic women (41%), compared with white women (34%) or black women (31%). Open breast biopsy also was significantly more likely in women who had private insurance than in women covered by Medicaid or Medicare – 41% vs. 31% (Am. J. Surg. 2014;208:382-90).
The type and location of hospital also was associated with open biopsy rates, with higher rates in small, private, rural, and/or nonteaching hospitals.
"Interventions targeting small, rural, and nonteaching hospitals could significantly decrease hospital costs and improve the overall quality of breast care," Dr. Adepoju and her associates commented, but "we must be sensitive" to the needs and limitations of various health care delivery settings, they added.
"A critical access hospital in rural Ohio may not be able to afford a mammographer and stereotactic equipment" for minimally invasive breast biopsy. Previous data "are clear that patients preferably seek their care in and near their community. Given workforce shortages and the current economic climate, this may mean accepting higher open breast biopsy rates in rural America," the investigators concluded.
Patients who had open breast biopsies in the current study were more likely to need more than one biopsy for diagnosis (1.2%), compared with women who had minimally invasive breast biopsies (0.5%). Hematoma drainage was needed in 1.4% of patients after open breast biopsy and 0.6% after minimally invasive biopsy. Open breast biopsy also was more expensive, based on analysis of data from the University of Toledo, averaging $1,700 in Medicare reimbursement, compared with $300-$1,100 for minimally invasive breast biopsy, depending on the specific procedure, Dr. Adepoju reported.
Previous data have shown that minimally invasive breast biopsies are less expensive, less scarring, require less recovery time, cause fewer complications, reduce the time between diagnosis and definitive treatment, produce fewer positive margins, and facilitate preoperative multidisciplinary treatment planning, compared with open breast biopsies.
The report from the third international consensus conference on image-detected breast cancer in 2009 called minimally invasive breast biopsy a best practice that should be the gold standard for initial diagnosis and proposed a goal of limiting open breast biopsy to 5%-10% of cases (J. Am. Coll. Surg. 2009;209:504-20).
Dr. Adepoju reported having no financial disclosures.
On Twitter @sherryboschert
The methodology of the study makes it impossible to know the overall national rates of breast biopsy techniques because the National Inpatient Sample data that the investigators analyzed capture only inpatient procedures, while most breast biopsies are done in outpatient settings, Dr. Taylor S. Riall said in an interview.
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The study may underestimate the national rate of minimally invasive breast biopsy because of that. Regardless, the true rate is likely below national goals of 90% of breast biopsies being done using minimally invasive methods, she said.
Because the National Inpatient Sample data represent single hospital stays that cannot be linked to show multiple admissions for individuals, it’s possible that some of the 34% of patients who had open breast biopsies previously underwent failed minimally invasive breast biopsies. "If minimally invasive breast biopsy was done first, then open biopsy, this is appropriate" in cases with failed (nondiagnostic) minimally invasive biopsies, she said.
The study looked at patient and hospital factors associated with biopsy rates but not at physician factors. "While there is geographic variation in the use of minimally invasive breast biopsy, there also is significant variation across physicians and facilities. Based on data we recently reviewed, I feel that physician practice and referral patterns are a major contributor to underuse of minimally invasive breast biopsy," Dr. Riall said.
"These practice patterns may be tied to reimbursement, lack of knowledge of the guidelines, access to minimally invasive breast biopsy facilities, or referral networks. Many surgeons may work in settings where mammography and biopsy are done before they even see a patient, whereas other surgeons may see patients before diagnosis and be responsible for this decision. Targeting interventions at the hospital and physician factors that are associated with low rates of minimally invasive breast biopsy can definitely improve outcomes," she added.
Organizational networks that are associated with low rates of minimally invasive breast biopsy should be assessed to find ways to increase those rates, Dr. Riall suggested. "Who do these patients see first? Do groups of physicians who refer to each other have practice patterns that violate the current recommendations?"
More in-depth analysis of racial disparities also is in order, she said. "Are these patients choosing open biopsy? If so, why? Or, alternatively, are they seeing physicians that exclusively or mostly do open biopsy? The answers to these questions will guide interventions to improve minimally invasive breast biopsy rates."
Dr. Taylor S. Riall is a professor of surgery and the John Sealy Distinguished Chair in Clinical Research at the University of Texas, Galveston. She reported having no financial disclosures.
The methodology of the study makes it impossible to know the overall national rates of breast biopsy techniques because the National Inpatient Sample data that the investigators analyzed capture only inpatient procedures, while most breast biopsies are done in outpatient settings, Dr. Taylor S. Riall said in an interview.
|
|
|
The study may underestimate the national rate of minimally invasive breast biopsy because of that. Regardless, the true rate is likely below national goals of 90% of breast biopsies being done using minimally invasive methods, she said.
Because the National Inpatient Sample data represent single hospital stays that cannot be linked to show multiple admissions for individuals, it’s possible that some of the 34% of patients who had open breast biopsies previously underwent failed minimally invasive breast biopsies. "If minimally invasive breast biopsy was done first, then open biopsy, this is appropriate" in cases with failed (nondiagnostic) minimally invasive biopsies, she said.
The study looked at patient and hospital factors associated with biopsy rates but not at physician factors. "While there is geographic variation in the use of minimally invasive breast biopsy, there also is significant variation across physicians and facilities. Based on data we recently reviewed, I feel that physician practice and referral patterns are a major contributor to underuse of minimally invasive breast biopsy," Dr. Riall said.
"These practice patterns may be tied to reimbursement, lack of knowledge of the guidelines, access to minimally invasive breast biopsy facilities, or referral networks. Many surgeons may work in settings where mammography and biopsy are done before they even see a patient, whereas other surgeons may see patients before diagnosis and be responsible for this decision. Targeting interventions at the hospital and physician factors that are associated with low rates of minimally invasive breast biopsy can definitely improve outcomes," she added.
Organizational networks that are associated with low rates of minimally invasive breast biopsy should be assessed to find ways to increase those rates, Dr. Riall suggested. "Who do these patients see first? Do groups of physicians who refer to each other have practice patterns that violate the current recommendations?"
More in-depth analysis of racial disparities also is in order, she said. "Are these patients choosing open biopsy? If so, why? Or, alternatively, are they seeing physicians that exclusively or mostly do open biopsy? The answers to these questions will guide interventions to improve minimally invasive breast biopsy rates."
Dr. Taylor S. Riall is a professor of surgery and the John Sealy Distinguished Chair in Clinical Research at the University of Texas, Galveston. She reported having no financial disclosures.
The methodology of the study makes it impossible to know the overall national rates of breast biopsy techniques because the National Inpatient Sample data that the investigators analyzed capture only inpatient procedures, while most breast biopsies are done in outpatient settings, Dr. Taylor S. Riall said in an interview.
|
|
|
The study may underestimate the national rate of minimally invasive breast biopsy because of that. Regardless, the true rate is likely below national goals of 90% of breast biopsies being done using minimally invasive methods, she said.
Because the National Inpatient Sample data represent single hospital stays that cannot be linked to show multiple admissions for individuals, it’s possible that some of the 34% of patients who had open breast biopsies previously underwent failed minimally invasive breast biopsies. "If minimally invasive breast biopsy was done first, then open biopsy, this is appropriate" in cases with failed (nondiagnostic) minimally invasive biopsies, she said.
The study looked at patient and hospital factors associated with biopsy rates but not at physician factors. "While there is geographic variation in the use of minimally invasive breast biopsy, there also is significant variation across physicians and facilities. Based on data we recently reviewed, I feel that physician practice and referral patterns are a major contributor to underuse of minimally invasive breast biopsy," Dr. Riall said.
"These practice patterns may be tied to reimbursement, lack of knowledge of the guidelines, access to minimally invasive breast biopsy facilities, or referral networks. Many surgeons may work in settings where mammography and biopsy are done before they even see a patient, whereas other surgeons may see patients before diagnosis and be responsible for this decision. Targeting interventions at the hospital and physician factors that are associated with low rates of minimally invasive breast biopsy can definitely improve outcomes," she added.
Organizational networks that are associated with low rates of minimally invasive breast biopsy should be assessed to find ways to increase those rates, Dr. Riall suggested. "Who do these patients see first? Do groups of physicians who refer to each other have practice patterns that violate the current recommendations?"
More in-depth analysis of racial disparities also is in order, she said. "Are these patients choosing open biopsy? If so, why? Or, alternatively, are they seeing physicians that exclusively or mostly do open biopsy? The answers to these questions will guide interventions to improve minimally invasive breast biopsy rates."
Dr. Taylor S. Riall is a professor of surgery and the John Sealy Distinguished Chair in Clinical Research at the University of Texas, Galveston. She reported having no financial disclosures.
Open breast biopsy accounted for 34% of breast biopsies in 25,965 U.S. inpatients between 2008 and 2010, a retrospective study found.
The finding suggests that minimally invasive breast biopsy techniques are underutilized, with a national rate that’s far off the widely acknowledge goal of having at least 90% of biopsies for suspicious breast lesions be minimally invasive, Dr. Linda Adepoju reported.
Most breast biopsies are performed in outpatient settings. Although the study analyzed a national data sample for hospitalized patients, the rate of open breast biopsy is consistent with previous studies of outpatient databases for individual institutions or states that have reported rates of open breast biopsy from 24% to 36%, noted Dr. Adepoju of the University of Toledo (Ohio).
She and her associates analyzed data from 46 states in the Healthcare Cost and Utilization Project National Inpatient Sample for 2008-2010, excluding 222 cases in which an open breast biopsy and minimally invasive breast biopsy were performed during the same hospital stay.
Open breast biopsy rates were significantly higher in women aged 49 years or younger (47%), compared with older women (29%), and in Asian women (40%) or Hispanic women (41%), compared with white women (34%) or black women (31%). Open breast biopsy also was significantly more likely in women who had private insurance than in women covered by Medicaid or Medicare – 41% vs. 31% (Am. J. Surg. 2014;208:382-90).
The type and location of hospital also was associated with open biopsy rates, with higher rates in small, private, rural, and/or nonteaching hospitals.
"Interventions targeting small, rural, and nonteaching hospitals could significantly decrease hospital costs and improve the overall quality of breast care," Dr. Adepoju and her associates commented, but "we must be sensitive" to the needs and limitations of various health care delivery settings, they added.
"A critical access hospital in rural Ohio may not be able to afford a mammographer and stereotactic equipment" for minimally invasive breast biopsy. Previous data "are clear that patients preferably seek their care in and near their community. Given workforce shortages and the current economic climate, this may mean accepting higher open breast biopsy rates in rural America," the investigators concluded.
Patients who had open breast biopsies in the current study were more likely to need more than one biopsy for diagnosis (1.2%), compared with women who had minimally invasive breast biopsies (0.5%). Hematoma drainage was needed in 1.4% of patients after open breast biopsy and 0.6% after minimally invasive biopsy. Open breast biopsy also was more expensive, based on analysis of data from the University of Toledo, averaging $1,700 in Medicare reimbursement, compared with $300-$1,100 for minimally invasive breast biopsy, depending on the specific procedure, Dr. Adepoju reported.
Previous data have shown that minimally invasive breast biopsies are less expensive, less scarring, require less recovery time, cause fewer complications, reduce the time between diagnosis and definitive treatment, produce fewer positive margins, and facilitate preoperative multidisciplinary treatment planning, compared with open breast biopsies.
The report from the third international consensus conference on image-detected breast cancer in 2009 called minimally invasive breast biopsy a best practice that should be the gold standard for initial diagnosis and proposed a goal of limiting open breast biopsy to 5%-10% of cases (J. Am. Coll. Surg. 2009;209:504-20).
Dr. Adepoju reported having no financial disclosures.
On Twitter @sherryboschert
Open breast biopsy accounted for 34% of breast biopsies in 25,965 U.S. inpatients between 2008 and 2010, a retrospective study found.
The finding suggests that minimally invasive breast biopsy techniques are underutilized, with a national rate that’s far off the widely acknowledge goal of having at least 90% of biopsies for suspicious breast lesions be minimally invasive, Dr. Linda Adepoju reported.
Most breast biopsies are performed in outpatient settings. Although the study analyzed a national data sample for hospitalized patients, the rate of open breast biopsy is consistent with previous studies of outpatient databases for individual institutions or states that have reported rates of open breast biopsy from 24% to 36%, noted Dr. Adepoju of the University of Toledo (Ohio).
She and her associates analyzed data from 46 states in the Healthcare Cost and Utilization Project National Inpatient Sample for 2008-2010, excluding 222 cases in which an open breast biopsy and minimally invasive breast biopsy were performed during the same hospital stay.
Open breast biopsy rates were significantly higher in women aged 49 years or younger (47%), compared with older women (29%), and in Asian women (40%) or Hispanic women (41%), compared with white women (34%) or black women (31%). Open breast biopsy also was significantly more likely in women who had private insurance than in women covered by Medicaid or Medicare – 41% vs. 31% (Am. J. Surg. 2014;208:382-90).
The type and location of hospital also was associated with open biopsy rates, with higher rates in small, private, rural, and/or nonteaching hospitals.
"Interventions targeting small, rural, and nonteaching hospitals could significantly decrease hospital costs and improve the overall quality of breast care," Dr. Adepoju and her associates commented, but "we must be sensitive" to the needs and limitations of various health care delivery settings, they added.
"A critical access hospital in rural Ohio may not be able to afford a mammographer and stereotactic equipment" for minimally invasive breast biopsy. Previous data "are clear that patients preferably seek their care in and near their community. Given workforce shortages and the current economic climate, this may mean accepting higher open breast biopsy rates in rural America," the investigators concluded.
Patients who had open breast biopsies in the current study were more likely to need more than one biopsy for diagnosis (1.2%), compared with women who had minimally invasive breast biopsies (0.5%). Hematoma drainage was needed in 1.4% of patients after open breast biopsy and 0.6% after minimally invasive biopsy. Open breast biopsy also was more expensive, based on analysis of data from the University of Toledo, averaging $1,700 in Medicare reimbursement, compared with $300-$1,100 for minimally invasive breast biopsy, depending on the specific procedure, Dr. Adepoju reported.
Previous data have shown that minimally invasive breast biopsies are less expensive, less scarring, require less recovery time, cause fewer complications, reduce the time between diagnosis and definitive treatment, produce fewer positive margins, and facilitate preoperative multidisciplinary treatment planning, compared with open breast biopsies.
The report from the third international consensus conference on image-detected breast cancer in 2009 called minimally invasive breast biopsy a best practice that should be the gold standard for initial diagnosis and proposed a goal of limiting open breast biopsy to 5%-10% of cases (J. Am. Coll. Surg. 2009;209:504-20).
Dr. Adepoju reported having no financial disclosures.
On Twitter @sherryboschert
FROM THE AMERICAN JOURNAL OF SURGERY
Key clinical point: Inpatient breast biopsies may underemploy minimally invasive techniques.
Major finding: Open breast biopsies comprised 34% of breast biopsies.
Data source: Retrospective analysis of National Inpatient Sample data on 25,965 women who underwent breast biopsy in 2008-2010.
Disclosures: Dr. Adepoju reported having no financial disclosures.
No rise in breast cancer recurrence found with TNF inhibitor use
Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.
The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.
Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.
The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).
During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.
The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.
Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."
This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.
Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.
The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.
Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.
The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).
During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.
The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.
Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."
This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.
Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.
The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.
Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.
The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).
During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.
The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.
Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."
This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: There appears to be little risk of breast cancer recurrence for RA patients who take TNF inhibitors nearly 10 years after their original diagnosis.
Major finding: During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years.
Data source: A population-based, case-control study of 120 RA patients with a history of breast cancer who took a TNF inhibitor and 120 matched control patients with RA and a history of breast cancer who had never taken a biologic.
Disclosures: This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.
Bisphosphonates don’t cut risk of breast cancer
Three to four years of therapy with the bisphosphonates alendronate and zoledronic acid, taken at doses used to treat osteoporosis, did not decrease the risk of incident breast cancer in postmenopausal women, according to a report published online Aug. 11 in JAMA Internal Medicine.
In a post hoc analysis of data from two large multicenter, randomized, double-blind, controlled clinical trials assessing the effectiveness of alendronate or zoledronic acid for osteoporosis, the development of incident breast cancer was not significantly different between women taking the drugs and women taking placebo, said Trisha F. Hue, Ph.D., of the department of epidemiology and biostatistics at the University of California, San Francisco, and her associates.
Numerous previous observational studies, as well as a metaanalysis pooling the data from several observational studies, had shown that bisphosphonates taken for osteoporosis significantly lowered the risk of breast cancer by 32%-39%. Their findings, however, may have been confounded by indication, because other conditions in postmenopausal women – notably, low levels of estradiol and high levels of sex hormone–binding globulin (SHBG) – are strongly associated both with low bone density, fractures, and bone loss with a low risk of ER-positive breast cancer, Dr. Hue and her associates said. Thus, they suggested, the postmenopausal women who are most likely to be given bisphosphonates for bone health already have a lower risk of breast cancer.
Such confounding can be averted by using a randomized trial design, so Dr. Hue and her colleagues assessed whether bisphosphonates reduced incident breast cancer by analyzing data from the Fracture Intervention Trial (FIT) and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT).
Among the 6,194 FIT participants in this study, there were 103 cases of invasive breast cancer during a mean of 3.8 years of follow-up. The incidence of breast cancer was 1.8% (57 women) among women taking alendronate and 1.5% (46 women) in those taking placebo, a nonsignificant difference in favor of placebo.
Among the 7,580 HORIZON-PFT participants in this study, there were 62 cases of invasive breast cancer during 3 years of follow-up. The incidence of breast cancer was 0.9% (33 women) among women taking zoledronic acid and 0.8% (29 women) among those taking placebo, which was, again, a nonsignificant difference in favor of placebo, the investigators said (JAMA Intern. Med. 2014 Aug. 11 [doi:10.1001/jamainternmed.2014.3634]).
The total of breast cancer cases was relatively small, so Dr. Hue and her associates pooled the data from both studies to increase the sample size. The combined incidence of breast cancer was 1.3% (90 women) taking bisphosphonates and 1.1% (75 women) taking placebo – again, a nonsignificant difference favoring placebo.
The discrepancy between these findings from randomized controlled trials and the results of previous observational studies illustrates "the hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done)" and highlights the value of confirming such findings in randomized controlled trials, Dr. Hue and her associates said.
This study received no industry support. FIT was supported by Merck, and HORIZON-PFT was supported by Novartis; both companies were involved in data collection and management. Dr. Hue reported no potential financial conflicts of interest. One of her associates reported serving as a consultant for Merck Sharpe & Dohme.
Three to four years of therapy with the bisphosphonates alendronate and zoledronic acid, taken at doses used to treat osteoporosis, did not decrease the risk of incident breast cancer in postmenopausal women, according to a report published online Aug. 11 in JAMA Internal Medicine.
In a post hoc analysis of data from two large multicenter, randomized, double-blind, controlled clinical trials assessing the effectiveness of alendronate or zoledronic acid for osteoporosis, the development of incident breast cancer was not significantly different between women taking the drugs and women taking placebo, said Trisha F. Hue, Ph.D., of the department of epidemiology and biostatistics at the University of California, San Francisco, and her associates.
Numerous previous observational studies, as well as a metaanalysis pooling the data from several observational studies, had shown that bisphosphonates taken for osteoporosis significantly lowered the risk of breast cancer by 32%-39%. Their findings, however, may have been confounded by indication, because other conditions in postmenopausal women – notably, low levels of estradiol and high levels of sex hormone–binding globulin (SHBG) – are strongly associated both with low bone density, fractures, and bone loss with a low risk of ER-positive breast cancer, Dr. Hue and her associates said. Thus, they suggested, the postmenopausal women who are most likely to be given bisphosphonates for bone health already have a lower risk of breast cancer.
Such confounding can be averted by using a randomized trial design, so Dr. Hue and her colleagues assessed whether bisphosphonates reduced incident breast cancer by analyzing data from the Fracture Intervention Trial (FIT) and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT).
Among the 6,194 FIT participants in this study, there were 103 cases of invasive breast cancer during a mean of 3.8 years of follow-up. The incidence of breast cancer was 1.8% (57 women) among women taking alendronate and 1.5% (46 women) in those taking placebo, a nonsignificant difference in favor of placebo.
Among the 7,580 HORIZON-PFT participants in this study, there were 62 cases of invasive breast cancer during 3 years of follow-up. The incidence of breast cancer was 0.9% (33 women) among women taking zoledronic acid and 0.8% (29 women) among those taking placebo, which was, again, a nonsignificant difference in favor of placebo, the investigators said (JAMA Intern. Med. 2014 Aug. 11 [doi:10.1001/jamainternmed.2014.3634]).
The total of breast cancer cases was relatively small, so Dr. Hue and her associates pooled the data from both studies to increase the sample size. The combined incidence of breast cancer was 1.3% (90 women) taking bisphosphonates and 1.1% (75 women) taking placebo – again, a nonsignificant difference favoring placebo.
The discrepancy between these findings from randomized controlled trials and the results of previous observational studies illustrates "the hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done)" and highlights the value of confirming such findings in randomized controlled trials, Dr. Hue and her associates said.
This study received no industry support. FIT was supported by Merck, and HORIZON-PFT was supported by Novartis; both companies were involved in data collection and management. Dr. Hue reported no potential financial conflicts of interest. One of her associates reported serving as a consultant for Merck Sharpe & Dohme.
Three to four years of therapy with the bisphosphonates alendronate and zoledronic acid, taken at doses used to treat osteoporosis, did not decrease the risk of incident breast cancer in postmenopausal women, according to a report published online Aug. 11 in JAMA Internal Medicine.
In a post hoc analysis of data from two large multicenter, randomized, double-blind, controlled clinical trials assessing the effectiveness of alendronate or zoledronic acid for osteoporosis, the development of incident breast cancer was not significantly different between women taking the drugs and women taking placebo, said Trisha F. Hue, Ph.D., of the department of epidemiology and biostatistics at the University of California, San Francisco, and her associates.
Numerous previous observational studies, as well as a metaanalysis pooling the data from several observational studies, had shown that bisphosphonates taken for osteoporosis significantly lowered the risk of breast cancer by 32%-39%. Their findings, however, may have been confounded by indication, because other conditions in postmenopausal women – notably, low levels of estradiol and high levels of sex hormone–binding globulin (SHBG) – are strongly associated both with low bone density, fractures, and bone loss with a low risk of ER-positive breast cancer, Dr. Hue and her associates said. Thus, they suggested, the postmenopausal women who are most likely to be given bisphosphonates for bone health already have a lower risk of breast cancer.
Such confounding can be averted by using a randomized trial design, so Dr. Hue and her colleagues assessed whether bisphosphonates reduced incident breast cancer by analyzing data from the Fracture Intervention Trial (FIT) and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT).
Among the 6,194 FIT participants in this study, there were 103 cases of invasive breast cancer during a mean of 3.8 years of follow-up. The incidence of breast cancer was 1.8% (57 women) among women taking alendronate and 1.5% (46 women) in those taking placebo, a nonsignificant difference in favor of placebo.
Among the 7,580 HORIZON-PFT participants in this study, there were 62 cases of invasive breast cancer during 3 years of follow-up. The incidence of breast cancer was 0.9% (33 women) among women taking zoledronic acid and 0.8% (29 women) among those taking placebo, which was, again, a nonsignificant difference in favor of placebo, the investigators said (JAMA Intern. Med. 2014 Aug. 11 [doi:10.1001/jamainternmed.2014.3634]).
The total of breast cancer cases was relatively small, so Dr. Hue and her associates pooled the data from both studies to increase the sample size. The combined incidence of breast cancer was 1.3% (90 women) taking bisphosphonates and 1.1% (75 women) taking placebo – again, a nonsignificant difference favoring placebo.
The discrepancy between these findings from randomized controlled trials and the results of previous observational studies illustrates "the hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done)" and highlights the value of confirming such findings in randomized controlled trials, Dr. Hue and her associates said.
This study received no industry support. FIT was supported by Merck, and HORIZON-PFT was supported by Novartis; both companies were involved in data collection and management. Dr. Hue reported no potential financial conflicts of interest. One of her associates reported serving as a consultant for Merck Sharpe & Dohme.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Alendronate and zoledronic acid do not appear to reduce the risk of breast cancer.
Major finding: The incidence of breast cancer was 1.8% in women taking alendronate and 1.5% in those taking placebo, a nonsignificant difference; the incidence of breast cancer was 0.9% in women taking zoledronic acid and 0.8% in those taking placebo, again, a nonsignificant difference.
Data source: A post hoc analysis of data from two large randomized clinical trials involving 6,194 postmenopausal women with osteoporosis who received either alendronate or placebo and 7,580 who received either zoledronic acid or placebo.
Disclosures: This study received no industry support. FIT was supported by Merck, and HORIZON-PFT was supported by Novartis; both companies were involved in data collection and management. Dr. Hue reported no potential financial conflicts of interest. One of her associates reported serving as a consultant for Merck Sharpe & Dohme.
Gene Expression Signatures in Breast Cancer: A Surgical Oncologist’s Perspective
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
PALB2 mutation increased lifetime risk of breast cancer
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Inherited loss-of-function mutations in PALB2 significantly increase women’s lifetime risk of breast cancer.
Major finding: Women with inherited loss-of-function mutations in the PALB2 gene were 9.47 times more likely to develop breast cancer than the general population.
Data source: Modified segregation analysis of breast cancer risk among 154 families in the United Kingdom whose 362 members had truncating, splice, or deletion mutations in the PALB2 gene.
Disclosures: The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported having been listed on patents related to breast cancer susceptibility genes. The authors reported no other conflicts of interest.
Recent use of oral contraceptives linked to breast cancer
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
FROM CANCER RESEARCH
Key clinical point: Recent use of oral contraceptives may increase breast cancer risk.
Major finding: Oral contraceptive use within the prior year was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3–1.9) relative to never or former use of oral contraceptives.
Data source: Nested case-control study of 1,102 women aged 20-49 years diagnosed with invasive breast cancer, compared with 21,755 controls.
Disclosures: The study was funded by The National Cancer Institute. The authors reported no financial conflicts of interest.
Encouraging data at ASCO 2014 for survival and fertility in some cancers
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
Early results show promise of topical tamoxifen for women with DCIS
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
FROM CLINICAL CANCER RESEARCH
Key clinical point: The use of a topical formulation of tamoxifen applied directly to the breast could achieve the same benefits as oral tamoxifen, but with fewer systemic effects, in the treatment of ductal carcinoma in situ (DCIS) or prevention of breast cancer.
Major finding: Concentrations of the tamoxifen metabolite 4-OHT and evidence of anticancer effects in breast tissue were comparable after 6-10 weeks of treatment in women treated with a gel formulation of 4-OHT and those treated with oral tamoxifen, but coagulation markers and 4-OHT levels in the plasma were higher among those on oral medication.
Data source: A phase II, double-blind, placebo-controlled study compared antiproliferative effects, breast tissue and plasma levels of 4-OHT, and coagulation parameters in 26 women with DCIS, randomized to daily treatment with 4-OHT gel applied to both breasts or oral tamoxifen, after 6-10 weeks of treatment, ending the day before surgical excision.
Disclosures: The authors had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
Early results show promise of topical tamoxifen for women with DCIS
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
FROM CLINICAL CANCER RESEARCH
Key clinical point: The use of a topical formulation of tamoxifen applied directly to the breast could achieve the same benefits as oral tamoxifen, but with fewer systemic effects, in the treatment of ductal carcinoma in situ (DCIS) or prevention of breast cancer.
Major finding: Concentrations of the tamoxifen metabolite 4-OHT and evidence of anticancer effects in breast tissue were comparable after 6-10 weeks of treatment in women treated with a gel formulation of 4-OHT and those treated with oral tamoxifen, but coagulation markers and 4-OHT levels in the plasma were higher among those on oral medication.
Data source: A phase II, double-blind, placebo-controlled study compared antiproliferative effects, breast tissue and plasma levels of 4-OHT, and coagulation parameters in 26 women with DCIS, randomized to daily treatment with 4-OHT gel applied to both breasts or oral tamoxifen, after 6-10 weeks of treatment, ending the day before surgical excision.
Disclosures: The authors had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
Survival benefit from contralateral prophylactic mastectomy small
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
FROM THE JOURNAL OF THE NATIONAL CANCER INSTITUTE
Key clinical point: The long-term survival benefit of contralateral prophylactic mastectomy is small.
Major Finding: The absolute 20-year survival benefit from contralateral prophylactic mastectomy was less than 1% among all age groups, regardless of estrogen receptor status and cancer stage.
Data Source: Results from a Markov model designed to simulate 20-year survival outcomes among those who did and did not have CPM, with considerations for variation in age, estrogen receptor status, and cancer stage.
Disclosures: The researchers disclosed no relevant financial conflicts.