Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

Aim BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methods BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. Results We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1 , risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). Conclusion Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.

The effect of hormone therapy on breast density following risk-reducing salpingooophorectomy in women with an increased risk for breast and ovarian cancer

Introduction: Hormone replacement therapy can diminish hormone depletion-related complaints in postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Recovery of menstruation after chemotherapy-induced amenorrhea in young hormone receptor-negative BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of recovery of menstruation on disease-free survival (DFS) and overall survival (OS) in young hormone receptor-negative BC patients treated with (neo)adjuvant chemotherapy. Methods: We selected 636 patients from a single-center cohort with early stage hormone receptornegative BC and under the age of 50 years when treated with chemotherapy. Sufficient data on course of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients (75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS. Results: Patients with recovery of menstruation after chemotherapy less frequently had lymph node involvement at diagnosis (45% vs 66%, p ¼ 0.001). After a median follow-up of 6.7 years, the adjusted hazard ratios were 1.45 (95% CI: 0.83e2.54) for DFS and 1.19 (95% CI: 0.71e1.98) for OS. Conclusion: No significantly increased recurrence risk was found for hormone receptor-negative BC patients with recovery of menstruation after chemotherapy. However, the outcome of the multivariable model is not reassuring and a potentially increased recurrence risk cannot be excluded. The results need to be validated in a larger prospective study for a more definitive answer.

Background: Long-term side-effects of cancer treatment are becoming more important as survival improves. Secondary cancer is a concern after radiotherapy, especially for patients treated at a young age. Since the BRCA1/2 genes play an essential role in DNA-repair, carriers of BRCA1/2 mutations are possibly more susceptible to the harmful side-effects of radiotherapy. Aim: To investigate whether breast cancer (BC) patients with a BRCA1/2 mutation are at increased risk of developing contralateral breast cancer (CBC) after treatment with adjuvant radiotherapy at a young age. Methods: BRCA1/2 mutation carriers previously diagnosed with BC were selected from the Dutch national HEBON study. We used a left-truncated Cox proportional hazards model to estimate the association between radiotherapy (yes/no) and CBC risk, stratifying for age (<40 vs ≥40) and censoring for contralateral prophylactic mastectomy. Results: Median follow-up was 10.1 years for the radiotherapy group (n=901), and 9.3 years for the non-radiotherapy group (n=609) (p=0.072). Median age at BC diagnosis and the distribution of BRCA1 and BRCA2 carriers was similar for both groups. Radiotherapy overall was not significantly associated with a higher risk of CBC (adjusted hazard ratio (HR) 1.31; 95%CI 0.91-1.89, n=1510). Six-hundred and forty patients were less than 40 years of age at BC diagnosis. Those treated with radiotherapy (n=366) had a higher stage and less often underwent mastectomy and prophylactic contralateral mastectomy. Stratifying by age at diagnosis yielded a HR of 1.66 (95%CI 0.93-2.95) for age<40 and a HR of 1.01 (95%CI 0.64-1.61) for age≥ 40. Conclusion: BRCA1/2 mutation carriers irradiated for primary BC under the age of 40 may have an increased risk of developing CBC. Citation Format: Mark van Barele, Delal Akdeniz, Bernadette AM Heemskerk-Gerritsen, Margreet HA Baaijens, Margriet GA Sattler, Marjanka K Schmidt, Agnes Jager, Maartje J Hooning, HEBON collaborators. The association between radiotherapy and contralateral breast cancer risk in young BRCA1/2-associated breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-5.