How do you approach use of tamoxifen for chemo-prevention in post-menopausal women with non-BRCA germline mutations?

I am not aware of any prospective studies specifically looking at non-BRCA mutations and tamoxifen’s role in chemoprevention in this population, although some retrospective studies in BRCA mutated patients have demonstrated a significant beneficial effect.

The NSABP breast cancer prevention trial demonstrated a beneficial effect of tamoxifen in terms of chemo prevention in > 60 year old women with a Gail model score of at least 1.66, but this was not stratified for proven hereditary high risk genetic mutations. 

The three studies that have been conducted to study the effect of chemopreventive tamoxifen in women with a strong family history of breast cancer are The Royal Marsden Trial, The International Breast Cancer Intervention Study, and the Milan study.

The Royal Marsden Trial accrued nearly 2500 women between the ages of 30 and 70, randomly assigned to either tamoxifen 20 mg/day or a placebo for 8 years and were followed for an additional 8 years. After patients were followed for up to 16 years, the risk of ER-positive invasive breast cancer was significantly lower in the tamoxifen group than in the placebo group (HR 0.61, 95% CI 0.43–0.86, P=0.005); the risk of ER-negative breast cancer was not significantly lower in the tamoxifen group (HR 1.4, 95% CI 0.7–2.6, P=0.3).

In 2002, the International Breast Cancer Intervention Study randomly assigned about 7000 women aged 35–70 years who were at increased risk of breast cancer to receive tamoxifen 20 mg/day or placebo for 5 years. Of these women, about 3500 had a first-degree relative with early-onset breast cancer and about 4000 had two or more first-degree or second-degree relatives with breast cancer. After a median follow-up of 96 months, 142 women in the tamoxifen group were diagnosed with breast cancer compared with 195 women in the placebo group (HR 0.73, 95% CI 0.58–0.91, P=0.004). The reduction was limited to ER-positive cancers (HR 0.66, 95% CI 0.50–0.87).

The Milan study had much smaller numbers and did not show a beneficial effect of tamoxifen. 

Based on these, I would offer tamoxifen for chemo prevention in high risk patients meeting the criteria used in the NSABP breast cancer prevention Trial, as well as strong family history with/without BRCA or non-BRCA high risk hereditary mutations. The role of risk reducing prophylactic surgeries in BRCA and non-BRCA high risk hereditary mutations should also be discussed.