Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers.

BRCA1 and BRCA2 alterations are associated with an increased risk of developing breast carcinoma. The authors hypothesized that the progression of breast neoplasia may differ between patients with hereditary disease and patients with nonhereditary disease and that this difference in progression may be visualized by studying the prevalence of precursor lesions and neoplastic lesions. The authors developed two case cohorts of high-risk patients with a strong family history of breast carcinoma who underwent prophylactic mastectomy. The first cohort was comprised of women who underwent therapeutic mastectomy and contralateral prophylactic mastectomy, and the second cohort was comprised of women who underwent bilateral prophylactic mastectomy. Patients without a family history of breast carcinoma who underwent unilateral or bilateral prophylactic mastectomy were selected as a control group. DNA from peripheral blood leukocytes was screened for BRCA1 and BRCA2 mutations. The available pathologic materials were reviewed independently by two pathologists, and all neoplastic and precursor lesions were identified and classified. Proliferation activity was assessed using MIB-1 immunohistochemistry on all available lesions from the unilateral mastectomy cohort. The 28 women from the unilateral cohort with deleterious BRCA1/2 mutations had a lower prevalence of proliferative fibrocystic changes (PFC) (7%) compared with their matched control group (25%) (P = 0.075) and with patients who had a family history but no BRCA1/2 mutation (22-33%). None of the 11 deleterious mutation carriers from the bilateral cohort (0%) had PFC compared with 36% of women in the matched control group (P = 0.03). There was no major difference in the prevalence of other precursor lesions (including in situ carcinoma) in either cohort. Invasive carcinomas from the deleterious mutation carriers in the unilateral cohort were of higher grade compared with the control group (P = 0.003) and patients without a mutation (P < 0.0001) but were of similar grade compared with carriers of unclassified variant BRCA1/2 alterations (P = 0.20). Neoplastic lesions from the deleterious mutation carriers in the unilateral cohort had higher MIB-1 proliferation indices compared with other patients with and without a family history of breast carcinoma. The current data suggest that the progression rate of breast neoplasia is accelerated in women who carry BRCA1/2 deleterious mutations compared with other patients who have breast carcinoma with or without a family history. This increased progression rate should be taken into account when considering the surveillance of asymptomatic women.

Adem C ，Reynolds C ，Soderberg CL ，Slezak JM ，McDonnell SK ，Sebo TJ ，Schaid DJ ，Myers JL ，Sellers TA ，Hartmann LC ，Jenkins RB ... -  《CANCER》

Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved?

Reynolds C ，Davidson JA ，Lindor NM ，Glazebrook KN ，Jakub JW ，Degnim AC ，Sandhu NP ，Walsh MF ，Hartmann LC ，Boughey JC ... -  《-》

Association between clinical characteristics and risk-reduction interventions in women who underwent BRCA1 and BRCA2 testing: a single-institution study.

Women who are at increased risk for breast and ovarian cancers, especially BRCA1 and BRCA2 mutation carriers, face a myriad of risk-reduction options, including increased surveillance, chemoprevention, prophylactic oophorectomy, and prophylactic mastectomy. However, little is known about which clinical, demographic, or cancer-related factors are associated with risk-reduction interventions. The authors conducted a retrospective review of records for 554 women who had undergone testing at The University of Texas M. D. Anderson Cancer Center between 2000 and 2006 for deleterious BRCA1 and BRCA2 gene mutations. Data were collected on the risk-reduction interventions these women adopted after they underwent genetic testing. These data were tested for associations with demographic and clinical characteristics. Among the 554 women who underwent genetic testing for BRCA mutation, 78 were found to have a deleterious mutation in the BRCA1 gene, and 54 had a mutation in the BRCA 2 gene. Of the 554 women, 85 underwent prophylactic mastectomy, 30 prophylactic oophorectomy, and 52 both surgeries; 387 women opted for surveillance. Women who had BRCA mutations, a history of breast cancer or ductal carcinoma in situ (DCIS), or previous breast biopsies were more likely to have prophylactic surgery. Women with a family history of ovarian cancer were more likely to undergo prophylactic oophorectomy. Women with a personal history of ovarian cancer or advanced breast cancer were more likely to undergo surveillance only. Women with breast cancer who had had a total mastectomy as part of their prior breast cancer treatment underwent prophylactic mastectomy more frequently than women who either had breast-conserving surgery or no history of breast cancer. In multivariate analysis, only positive BRCA mutation carrier status was associated with having had prophylactic surgery. In addition, breast cancer history was significantly associated with prophylactic mastectomy. Women who were BRCA carriers, women who had a history of breast cancer, DCIS, or breast biopsy, or had a family history of ovarian cancer were more likely to have undergone surgery for cancer risk reduction. Women with ovarian cancer or advanced breast cancer were more likely to have undergone surveillance.

Uyei A ，Peterson SK ，Erlichman J ，Broglio K ，Yekell S ，Schmeler K ，Lu K ，Meric-Bernstam F ，Amos C ，Strong L ，Arun B ... -  《CANCER》

ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers.

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2-related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations.

Adem C ，Soderberg CL ，Hafner K ，Reynolds C ，Slezak JM ，Sinclair CS ，Sellers TA ，Schaid DJ ，Couch F ，Hartmann LC ，Jenkins RB ... -  《GENES CHROMOSOMES & CANCER》

Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.

《LANCET》