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BRCA Carriers at Increased Risk of Contralateral Cancer

Laino, Charlene

doi: 10.1097/01.COT.0000411538.72725.14
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SAN ANTONIO—Breast cancer survivors who carry a BRCA mutation are at increased risk for developing a new primary tumor in the contralateral breast compared with women who are not carriers, Dutch researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium (Abstract S4-2).

ALEXANDRA J

ALEXANDRA J

BRCA mutation carriers who receive their first diagnosis before age 41 and who have triple-negative breast tumors appear to be at particularly heightened risk, said Alexandra J. van den Broek, MSc, a doctoral candidate in the Departments of Psychosocial Research and Epidemiology at the Netherlands Cancer Institute.

“If the findings are confirmed in other studies, age criteria and receptor status of the first breast tumor may be included in guidelines for prophylactic measures and screening in the follow-up of BRCA1 and BRCA2 mutation carriers,” she said.

Five to 10 percent of breast cancers occur in women with a genetic predisposition for the disease, usually due to mutations in either the BRCA1 or BRCA2 genes. It is established that the average lifetime risk of breast cancer increases from 13% for noncarriers to 50% to 80% for BRCA1 carriers and to 45% for BRCA2 carriers.

What is not well known, however, is whether being a mutation carrier increases the risk of contralateral breast cancer, Dr. van den Broek said.

“However, it is important to provide precise risk estimates of contralateral breast cancer and identify risk factors for contralateral breast cancer in these high-risk patients.”

To help fill in the knowledge gap, the researchers conducted the Breast Cancer Outcome Study of Mutation Carriers of 5,065 women with invasive breast cancer. Patients were diagnosed with their primary tumor before age 50, between 1970 and 2003, at 10 hospitals in the Netherlands.

A total of 154 patients (3.04%) were BRCA1 mutation carriers, and 57 (1.13%) were BRCA2 mutation carriers.

Over a nine-year period, 9% developed cancer in their other breast.

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10-Year Risks

The 10-year risk of developing contralateral breast cancer was 20.3% for BRCA1 mutation carriers and 11.1% for BRCA2 mutation carriers. In contrast, noncarriers had only a 6.0% likelihood of developing a tumor in their other breast over 10 years.

The 10-year risk shot up to 26% for carriers diagnosed with their first breast cancer when they were 40 or younger. This was significantly higher than the 11.6% risk among women diagnosed between ages 41 and 50.

The 10-year risk for BRCA mutation carriers whose primary tumors had triple-negative status was 18.9% vs 11.2% for noncarriers; the finding did not reach statistical significance, however, probably because of the small number of women in the carrier subgroup, van den Broek said, noting, though, that the difference in risk was significant, at five years.

Mutation carriers with a triple-negative first tumor diagnosed between the ages of 41 and 50 had a 15% risk of developing a contralateral breast tumor over 10 years. But carriers diagnosed with a first breast tumor that did not have triple-negative status between the ages of 41 and 50 had a 10-year cumulative risk of contralateral breast cancer of only 3.5%—almost the same as noncarriers.

Triple-negative tumors, which account for about 15% of all invasive breast cancers, are notoriously difficult to treat because they lack receptors for estrogen and progesterone as well as HER2, which are targeted by current therapies.

Looked at another way, mutation carriers with a triple-negative first tumor diagnosed between the ages of 41 and 50 had a 15% risk of developing a contralateral breast tumor over 10 years, she said. But carriers diagnosed with a first breast tumor that did not have triple-negative status between the ages of 41 and 50 had a 10-year cumulative risk of contralateral breast cancer of only 3.5%—-“almost the same as noncarriers.”

In response to a question from the audience, she said the researchers also looked at whether the treatment choice for the primary breast cancer had an impact on the rates of contralateral breast cancer, but it did not make any difference.

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Commentary

Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital, said the findings “could be important for identifying those women for whom prophylactic double mastectomy makes more sense.”

She said that although she wouldn't change clinical practice based on this study alone and that the findings require prospective validation, “this is a conversation we are already having with our patients. So if a carrier is young or has triple-negative disease, I will note these preliminary findings in our discussion weighing the pros and cons of a bilateral mastectomy approach versus more intensive screening.”

Claudine Isaacs, MD, Director of the Clinical Breast Cancer Program at Georgetown's Lombardi Comprehensive Cancer Center, said the findings are in line with other recent research suggesting that BRCA1 mutation carriers diagnosed at a younger age face a higher risk of recurrence.

Studies like this help clinicians individualize therapy even further among subsets of women for whom treatment is already tailored—in this case, BRCA mutation carriers, she said.

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Risk by Atypia Type

At the same session, other researchers reported that the development of invasive versus noninvasive breast cancer was not significantly affected by the atypia type of breast lesions (Abstract S4-4).

Women diagnosed with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and borderline ADH/DCIS are at all increased risk for breast cancer, but the precise degree of risk varies widely in the literature, said Suzanne B. Coopey, MD, a fellow in the Division of Surgical Oncology at Massachusetts General Hospital, who presented the results.

Information from prior studies is limited by grouping ADH and ALH together and by small cohort sizes, she explained. She and her colleagues reviewed some 76,000 electronic pathology reports from about 43,000 women treated at three large Boston area hospitals from 1987 to 2010. About 3,000 of the women were diagnosed with atypical breast lesions over the 14-year period, with a mean follow-up period of 66 months.

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Chemoprevention

The breast cancer risk at 10 years was significantly higher in those with ALH (20.2%) or LCIS (16.3%), compared with those with ADH (14.8%) or borderline ADH/DCIS (14.5%), the study showed.

However, there was little difference in risk between ADH and borderline ADH/DCIS or between LCIS and ALH, Dr. Coopey said.

“Importantly, the study also showed that chemoprevention with tamoxifen, raloxifene, and/or exemestane significantly reduces breast cancer risk for all atypia types.”

Specifically, the 10-year risk of breast cancer was 19.9% for patients with ADH not given the drugs versus 8.5% for those given chemoprevention. Among patients with ALH, the risk dropped from 18.7% to 8.5%, and for LCIS, the risk fell from 32.4% to 10.3%.

Among patients with borderline ADH/DCIS, the 10-year risk of breast cancer was 14.7% among patients who did not receive chemoprevention versus 2.3% for those who did.

© 2012 Lippincott Williams & Wilkins, Inc.
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