This is an excellent question. Since I specialize in advanced cancers, and especially triple negative breast cancer (TNBC), let me unpack the issues and offer some evidence-based guidance. First we know that women with a mutation in BRCA1 or BRCA2 have a high risk of developing breast cancer, and also of the development of contralateral cancer after the initial diagnosis of breast cancer, and that the SERM tamoxifen can reduce the risk of contralateral breast cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene [Hereditary Breast Cancer Clinical Study Group. Narod et al., Lancet 2000].

The dilemma arises from the estrogen-receptor status (ER) of BRCA-positive breast tumors: precancerous changes in the breast that have lost the cytoplasmic receptor (ie, tissues that are ER-negative) are not affected by tamoxifen, so that as established in the NSABP-P1 Trial, tamoxifen reduces the incidence of ER-positive tumors, but has no effect on the incidence of ER-negative tumors [NSABP-P1) Breast Cancer Prevention Trial. King et al., JAMA 2001].

Indeed, all of the breast cancer risk reduction trials using SERMs and including tamoxifen [NSABP-P1, the IBIS-I, the Royal Marsden Tamoxifen Prevention Trial, and the Italian Randomized Tamoxifen Prevention Trial] demonstrate that these agents are effective in reducing the risk of only ER-positive breast cancer, and so they do not help prevent the development of ER-negative breast cancer (which sits at 30% of all breast cancers in white populations), and is an even higher proportion (40% or more) in African American (AA) populations. [ASCO Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction (Visvanathan et al., J Clin Oncol 2009)].

However, the real issue here is whether the occurrence of a cluster of TNBC tumor biologies in the family elevates in any significant way or to an clinically relavant degree the risk of development of TNBC-specific - rather than breast cancer (BC) in general - disease in another member of that family?

The first consideration that must come to bear on this question is that to date there is no evidence of a heritable elevated risk of one tumor biology (ER-positive, HER2-positive, or TNBC, etc.) or subtype (luminal, basal, etc.) over another in the general population, and even in AA (African-American) subpopulations, although risk of TNBC may be greater than undifferentiated or Caucasian subgroups, even at a high 40% observed incidence of TNBC tumor biology over other BC tumor types in African-Americans, that still leaves the majority (60%+) as non-TNBC, in keeping with known general distributions of BC tumor subtypes.

But we must now weigh in a second consideration: since the cluster is plausibly suggestive of a TNBC gene signature operating at a molecular level in the family, one would still at least have to entertain the possibility that the risk of TNBC development could rise to majority (50%) status, that is, more likely than not.

If this is considered a possible and non-trivial event, then attempted chemoprevention via tamoxifen, operating as it does on early precancerous lesions, would in this very special case be largely irrelevant since precancerous changes in the breast that have lost the cytoplasmic receptor (ER-negative tissue) cannot be affected by tamoxifen (as concluded explicitly also by the NSABP-P1 investigators).

Therefore a BRCA-positive woman in a family with a TNBC tumor biology cluster in (especially first-degree) family members, especially if she is in an elevated risk category for TNBC development, such as of African-American (AA) descent, or higher risk such as young age, should certainly be sent to receive both genetic and clinical oncologic counseling that would weigh as more favorable the choice of prophylaxis by BPM (bilateral prophylactic mastectomy) and/or prophylactic oophorectomy (OO), over SERM-based (tamoxifen or raloxifene) chemoprevention, should the woman elect chemoprevention at all (not all, or even the majority of BRCA-positive women do).

So, in the absence of more specific and dispositive data, this question has no single definitive response but it certainly suggests circumstances in which tamoxifen chemoprevention would be devaluated, and BPM and/or OO would have more favorable consideration, and recommendation, in conjunction with the counseling guidance received from both a genetic counselor and a breast oncologist, preferably with specific TNBC expertise. (Note this has nothing to do with the irrelevance and inefficacy of tamoxifen in ER-negative breast cancers, since that is in women with active breast cancer, not - as here - in a BRCA-positive healthy (non-BC) woman, as Rohan posed the question).

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

This is the most comprehensive and detailed answer that anyone can hope for. Thanks.

Thank you for a very comprehensive and clear answer.