Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Abstract

Background Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers. Results There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%). Conclusions/Impact Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis.

Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicenter study in Italy

“…Although based on a few cases, our results may suggest that BRCA1-related BCs in men represent a rare event characterized by a phenotype similar to that observed in women. On the other hand, BRCA2-associated MBCs display a characteristic BRCA2-associated BC phenotype not identified in women [11]. In particular, BRCA2-associated MBCs present with high tumor grade, the absence of PR expression, and HER2 positive status.…”

“…In particular, BRCA1-related BCs have distinct morphology and show a triple negative (ER-, PR-, HER2-) phenotype [8]. By contrast, BRCA2-related BCs are a heterogeneous group not fully characterized [9][10][11]. The current knowledge on phenotypic characteristics of BRCA-associated MBCs is thus far quite limited [5].…”

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…More specifically, susceptibility loci for overall and oestrogen receptor (ER)-positive breast cancer for women in the general population tend to be associated with overall breast cancer risk for BRCA2 mutation carriers (who mostly (70-80%) develop ER-positive disease (Mavaddat et al 2012)), whereas those for ER-negative breast cancer tend to be associated with overall risk for BRCA1 mutation carriers (who mostly (70-80%) develop ER-negative disease (Mavaddat et al 2012)) (Milne & Antoniou 2011, Kuchenbaecker et al 2014. A systematic evaluation of the associations of 74 known breast cancer susceptibility alleles found that their associations with ER-positive breast cancer for BRCA1 and BRCA2 mutation carriers were more consistent with the associations of these SNPs with ER-positive breast cancer in the general population.…”

Twenty‐one–gene recurrence score assay in BRCA‐associated versus sporadic breast cancers: Differences based on germline mutation status

“…11 Interestingly, BRCA1-and BRCA2-associated tumors have been noted to have different gene expression profiles 13 and disparate chemosensitivity. 15 This study did not find statistically significant differences in terms of RSs in BRCA1-associated tumors versus BRCA2-associated tumors.…”