Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features.

INTRODUCTION: Most breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors. METHODS: Clinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers. RESULTS: BRCA1 carriers aged > or = 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04). CONCLUSIONS: BRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.

Multimodal assessment of protein functional deficiency supports pathogenicity of BRCA1 p.V1688del.

Unequivocal discrimination between neutral variants and deleterious mutations is crucial for appropriate counseling of individuals with a BRCA1 or BRCA2 sequence change. An increasing number of variants of uncertain significance (VUS) are being identified, the unclassified biological effect of which poses clinical concerns. A multifactorial likelihood-based approach recently suggested disease causality for BRCA1 p.V1688del, a VUS recurrent in Italian breast/ovarian cancer families. Whether and how this single amino acid deletion in the BRCA1 COOH terminus (BRCT) domain affects the function of the mutant protein (DeltaValBRCA1) has not been elucidated. We undertook comprehensive functional characterization of DeltaValBRCA1, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function. Our model predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant DeltaValBRCA1 was less stable than wild-type BRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80 and to relocalize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and KPNA2, which is likely responsible for improper subcellular localization of DeltaValBRCA1. In addition, we found four new breast/ovarian cancer families of Italian ancestry who carried this sequence alteration. These results provide the first evidence of the effect of BRCA1 p.V1688del on protein stability and function, supporting the view that it is a deleterious mutation. Multimodal analyses like ours could advance understanding of tumor suppression by BRCA1 and ultimately contribute to developing efficient strategies for screening and characterization of VUS.

Physicians' experiences with BRCA1/2 testing in community settings.

PURPOSE: We surveyed a national sample of nonacademic physicians who ordered BRCA1/2 testing to understand their implementation of genetic testing and to assess recommendations for surveillance and cancer risk management of women with positive test results. PATIENTS AND METHODS: We surveyed physicians (N = 611 of 1,050; response rate, 58.2%) practicing in nonacademic settings who ordered BRCA1/2 testing during 2004 to 2005. We described physicians' experiences with testing and used multivariable regression models to identify factors associated with more complete counseling and with recommendations for cancer risk management for a BRCA1 mutation carrier. RESULTS: Most physicians (68.2%) usually or always discussed six counseling items before testing. In adjusted analyses, physicians who were assisted by genetic counselors, nurse geneticists, or others (v counseling by themselves), those who spent more than 60 minutes in counseling, and medical oncologists (v surgeons or geneticists) were more likely to discuss all six items (all P < .05). A total of 61.4% of physicians would recommend bilateral prophylactic mastectomy to a 38-year-old BRCA1 mutation carrier who had completed childbearing. After adjustment, geneticists and gynecologists were less likely than medical oncologists and surgeons to recommend prophylactic mastectomy (P < .001), as were physicians in the Northeast versus those in other regions of the United States (P = .01). CONCLUSION: Community-based physicians seem to be successfully incorporating BRCA1/2 testing into their practices. Physicians' recommendations for surveillance of mutation carriers are generally consistent with practice guidelines, yet recommendations for preference-based procedures such as prophylactic mastectomy vary by physician characteristics such as specialty and geographic region. The providers whom patients see for testing may contribute to variations in prophylactic treatments.