Chemo Is Key Benefit in BRCA1, BRCA2 Carriers


STOCKHOLM — Adjuvant chemotherapy appears critical to overcoming adverse prognostic factors for recurrence and survival in women with BRCA1 or BRCA2 breast cancer, according to a large prospective study presented at the annual meeting of the European Society for Medical Oncology.

Although BRCA1 and BRCA2 carriers presented at a younger age and with more advanced disease than patients with sporadic breast cancers, those who had adjuvant chemotherapy fared as well overall as comparable patients in the control group.

Hazard ratios for distant disease recurrence and for death were far worse in the absence of adjuvant chemotherapy, however: 1.69 and 1.97, respectively, in BRCA1 carriers; 2.13 and 3.62 (P = .005), respectively, in BRCA2 carriers. That just one of these ratios is statistically significant owes to only a small number of carriers not receiving adjuvant chemotherapy, said study investigator Dr. Pamela J. Goodwin, Marvelle Koffler Chair in Breast Research and professor of medicine at the University of Toronto. In all, 87% of BRCA1 carriers and 79% of BRCA2 carriers had adjuvant chemotherapy. Those who did not have adjuvant therapy were likely treated 10 to 15 years ago, Dr. Goodwin suggested.

“The vast majority [of BRCA1 carriers] receives chemotherapy, and what seems to be happening is that the chemotherapy is overcoming the effect of the adverse prognostic factors,” she said in an interview.

Although adjuvant chemotherapy was slightly less frequent in BRCA2 carriers, the investigators saw a similar pattern. She added: “It seems to overcome the adverse prognosis. … Not getting chemotherapy is a major, major negative.”

Dr. Goodwin and her coinvestigators selected participants for the prospective study from population-based cancer registries in Ontario, Canada (1996-98), Northern California (1995-2000), and Australia (1992-1999). DNA samples were required. The population compared in the analyses comprised 92 BRCA1 carriers, 72 BRCA2 carriers, and 1,549 women with sporadic breast cancer.

Another 1,510 women were identified with other familial breast cancers. Although she did not discuss this population, Dr. Goodwin told her audience that “their results were virtually identical to the sporadic group.”

Analysis of the impact of adjuvant hormonal therapy is in progress, she added, and will be presented in December at the San Antonio Breast Cancer Symposium.

Compared with women with sporadic disease, the BRCA1 carriers tended to be younger and have higher-grade disease with negative receptors, Dr. Goodwin said. BRCA2 carriers presented with high-grade disease but had more nodal involvement. Tumor characteristics such as T stage, nodal status, and grade appeared to have similar prognostic effects in carriers and patients with sporadic disease, she said, but “effects of grade were less apparent in carriers.” Carrier status did not appear to have a significant effect on distant disease-free survival or overall status in BRCA1 carriers.

The effect was significant with respect to both in univariate analysis for BRCA2 carriers, but disappeared after adjustment for age and tumor characteristics. The unadjusted prognosis is important when counseling individual patients, Dr. Goodwin advised. “They are more concerned about how they will fare as individuals than whether their outcomes are swayed by age or tumor characteristics,” she said.

“Adjuvant chemotherapy appears to play a particularly important role in mutation carriers,” Dr. Goodwin said, concluding, “understanding the relative efficacy of different chemotherapeutic agents in the adjuvant setting in mutation carriers should be an important priority.”

In a discussion of the study, Dr. Judith Balmaña of the Hospital Universitari Vall d'Hebron in Barcelona cited numerous limitations, including selection bias, short follow-up, and small populations in earlier analyses that compared BRCA1 and BRCA2 carriers with women who had sporadic disease. The current study had a well-documented cohort, she said, and shows that the prognostic effects of BRCA status depend on chemotherapy use.

BRCA deficiency is a predictive biomarker of response to chemotherapy, said Dr. Balmaña, but “there is still no definitive word on the best treatment regimen for BRCA breast cancer.”

'It seems to overcome the adverse prognosis…. Not getting chemotherapy is a major negative.' DR. GOODWIN

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