The results of this study suggest that BRCA1
carriers who are older at the time of diagnosis of their first invasive breast cancer are more likely to have an ER+ breast cancer than are BRCA1
carriers who are younger at diagnosis. Menopausal status was also a predictor of ER positivity, with ER+ breast cancers being more common in post-menopausal carriers. However, this difference was not significant in multiple covariate analysis, perhaps because of the confounding between menopausal status and age. In particular, only 14% of BRCA1
carriers younger than age 50 years in our study were post-menopausal. As mutation carriers increasingly become surgically menopausal at younger ages it will be important to determine the relative contributions of age and menopausal status for predicting ER status of the breast cancers that develop in this population. Our data are consistent with those of Foulkes and colleagues [16
] who also found an increase in ER+ breast cancers with increasing age among BRCA1
mutation carriers. These investigators noted that this increase in ER positivity paralleled that seen in breast cancers that develop in non-mutation carriers. They did not study the effect of menopausal status on ER status of these cancers. The observation that BRCA1
mutation carriers who are older or post-menopausal at the time of diagnosis of breast cancer are more likely to have an ER+ breast cancer may help to define a population of BRCA1
mutation carriers for whom estrogen-modifying agents will be particularly effective.
Of the BRCA1
cancers in this series, 34% were ER+. This is consistent with the 31% frequency of ER+ BRCA1
breast cancers recently reported in the retrospective series by Atchley and colleagues [8
Our comparison of the pathologic features of ER+ and ER- BRCA1 cancers revealed that the ER+ cancers less often had features typically associated with BRCA1 cancers, such as high mitotic rate, pushing margins, marked lymphocytic infiltrate, and geographic necrosis/fibrotic focus. These differences were not due to differences in histologic grade, because most remained significant when only high-grade ER+ and ER- cancers were compared. Although previous studies have noted that ER- BRCA1 cancers are more likely to be high-grade invasive ductal carcinomas compared with ER+ BRCA1 cancers, this is the first report to our knowledge analyzing the relation of ER status to other pathologic features that have come to be considered to be BRCA-related.
The differences in pathologic features between ER+ and ER- BRCA1 cancers raise the possibility that at least some BRCA1 ER+ cancers may be 'incidental', and not caused by a complete loss of BRCA1 function in the cancer cells. In order to address the issue of whether ER+ BRCA1 cancers are more akin to sporadic ER+ breast cancers than to ER- BRCA1 cancers, we performed a case-control analysis in which the pathologic features of these tumors were compared with those of a control group of ER+ sporadic breast cancers. We found that BRCA1-associated ER+ cancers had a much more limited distribution of histologic types and were significantly more often pure invasive ductal carcinomas with a high mitotic rate than ER+ sporadic cancers.
There are several possible explanations for our observation that the histopathology of ER+ BRCA1
breast cancers differs significantly from both ER- BRCA1
cancers as well as ER+ sporadic breast cancers. First, it may be that although some ER+ BRCA1
breast cancers develop from complete loss of BRCA1
function, others still have intact BRCA1
function resulting in tumors that as a group have phenotypic features that are intermediate between ER- BRCA1
and ER+ sporadic breast cancers. The issue of whether ER+ BRCA1
-associated breast cancers demonstrate LOH for the wild-type (wt) BRCA1
allele has been investigated. In this regard, Manié and colleagues recently found 4 of 19 ER+ BRCA1
-associated breast cancers did not show loss of the wt BRCA1
]. King and colleagues [20
] demonstrated that 11 of 22 BRCA1
-associated invasive breast cancers did not show LOH for wt BRCA1
; no mention of ER status was included in their study. The results of these studies are difficult to compare because of differences in patient populations and molecular methodology. Nonetheless, taken together the results of these two studies raise the possibility that not all BRCA1
-associated breast cancers exhibit complete loss of BRCA1
function. However, the frequency of this phenomenon, particularly for ER+ BRCA1
cancers, remains to be more clearly defined.
It is also possible that no breast cancer that develops in a BRCA1
mutation carrier is really 'incidental' or sporadic, even if LOH of wt BRCA1
does not exist. Haploinsufficiency of BRCA1
, which exists in the BRCA1
heterozygous state, has been shown to have demonstrable effects on the breast tissue of BRCA1
carriers. Normal breast tissue from BRCA1
carriers has been shown to grow abnormally in three-dimensional mammosphere cultures (even though 75% of cells show retention of BRCA1
], and express increased aromatase [22
] compared with reduction mammoplasty specimens from non-mutation carriers. Likewise, MCF-7 cells with BRCA1
haploinsuffiency demonstrate decreased efficiency in homologous recombination [23
]. Haploinsufficiency of BRCA1
may predispose both to the development of breast cancer as well as to a more limited histopathologic profile. Finally, if loss of BRCA1
function does exist in the majority of ER+ BRCA1
breast cancers, it is possible that ER+ and ER- BRCA1
cancers originate from different cells of origin (e.g. early progenitor cell vs stem cell) leading to different phenotypic expressions. The cell of origin for BRCA1
-associated breast cancers is still being determined [24
One of the strengths of this study is that the pathologic features of all cancers in this study, both BRCA1 and control, were reviewed by two dedicated breast pathologists (SJS and LCC). It should be noted that more of the BRCA1 ER- breast cancers identified were unavailable for pathologic review. Although 34% of the cases in the clinical analysis were ER+, 42% of the cancers reviewed pathologically were ER+. Given the uniformity of many of the pathologic features of the BRCA1 ER- breast cancers in this study, we think it is unlikely that this substantially affected the major findings of our study.
One potential limitation of the case-control study is that BRCA1 and 2 genetic testing information was not available for all of the women with sporadic cancers. However, as BRCA1 and BRCA2 cancers comprise only 5 to 10% of all cancers and potential controls were excluded if a family history of breast or ovarian cancer was noted in the medical record, it seems very unlikely that more than a few of the 'control' cases had germline BRCA1 mutations. We intentionally chose controls from the general hospital population rather than from those who tested negative for BRCA mutations through the genetic testing clinic. Thus, our group of controls is more likely to represent sporadic breast cancers than those identified through a genetic testing program, many of whom may have inherited breast cancers, although not through a germline BRCA1 or 2 mutation.