Breast Cancer Risk-reducing Strategies in BRCA1/2 Mutation Carriers

__Abstract__ Breast cancer (BC) is the most common type of cancer in women in developed countries. Currently, approximately 14,000 women are diagnosed with BC every year in the Netherlands. One out of eight Dutch women (12%-13%) will develop BC during their life, and 3% to 4% of all Dutch women will die from BC. A genetic predisposition may be responsible for about 5% to 10% of all BC cases. Approximately 25% of these cases can be attributed to a mutation in one of the BReast CAancer (BRCA) genes, BRCA1 and BRCA2. Both genes act as tumour suppressor genes and are involved in important cell functions, including cell cycle control, gene expression regulation, and DNA repair mechanisms. Cells with deficiencies in genes involved in DNA repair are unable to repair DNA double-strand breaks, resulting in genomic instability and a predisposition to

Toxicity of (neo)adjuvant chemotherapy for BRCA1- and BRCA2-associated breast cancer

Treatment with (neo)adjuvant chemotherapy for breast cancer, as currently given, causes cell damage by induction of double-strand DNA breaks. Because BRCA1 and BRCA2 proteins play a role in the repair of DNA damage, the efficacy of (neo)adjuvant chemotherapy may be increased in BRCA1/2-associated breast cancer patients. As a downside, acute chemotherapy-related toxicity may also be increased. We selected all female patients who were treated at the Erasmus MC Cancer Institute, with (neo)adjuvant chemotherapy for primary or locoregional recurrence of breast cancer (PBC/LR) between January 1, 2004 and December 31, 2014. The primary outcome was the relative total dose intensity (RTDI), calculated for anthracyclines and taxanes separately. Secondary outcomes were the occurrence of febrile neutropenia, delay in chemotherapy administration, and switch to another chemotherapy regimen due to toxicity. In total, 701 patients treated for PBC/LR were eligible for data analyses, among which 85 BRCA1/2 mutation carriers (n = 67 BRCA1 and n = 18 BRCA2). The mean RTDI for anthracyclines was not significantly different between both groups (98.7 % in the BRCA1/2, 96.6 % in the sporadic group, p = 0.27). Also the mean RTDI for taxanes was not significantly different between the groups (93.6 % in the BRCA1/2-associated, 90.0 % in the sporadic group, p = 0.12). Linear regression analysis revealed no significant effect of BRCA1/2 mutation carriership on the RTDIs. No significant differences were found in the percentages of patients presenting with febrile neutropenia, having a delay in chemotherapy administration or switching to an altered chemotherapy regimen. Additionally, the odds ratios showed no significant effect of BRCA1/2 mutation carriership on the secondary outcome variables. (Neo)adjuvant chemotherapy-related toxicity was not different between BRCA1/2-associated and sporadic breast cancer patients suggesting that the DNA damage repair mechanism of non-cancer cells with only one normal copy of either the BRCA1 or BRCA2 gene is sufficiently functional to handle acute chemotherapy-associated toxicity

The impact of menstruation persistence or recovery after chemotherapy on survival in young patients with hormone receptor negative breast 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 frequ

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers

Background In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival beneft of BRRM over BC surveillance has been reported yet. Methods In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specifc mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20–0.90) for overall mortality and 0.06 (95% CI 0.01–0.46) for BC-specifc mortality. BC-specifc survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15–1.36). BC-specifc survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specifc survival as surveillance. Our fndings support a more individualized counseling based on BRCA mutation type

Long-term morbidity and health after early menopause due to oophorectomy in women at increased risk of ovarian cancer: Protocol for a nationwide cross-sectional study with prospective follow-up (HARMOny Study)

Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO

Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy

Risk-reducing salpingo-oophorectomy (RRSO) is associated with 50% reduction of BRCA1/2-associated breast cancer (BC) risk, possibly through decreased growth activity. In this pilot study, tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO were compared with those of PBCs originating without RRSO. From a cohort of 271 women with BRCA1/2-associated screen detected BC, we selected 20 patients with PBC detected ≥12 months after RRSO (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at diagnosis (± 2.5 y) and for BRCA1 or BRCA2 mutation. Pathology samples were revised for histological subtype, tumor differentiation grade, mitotic activity index (MAI), estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated from revised magnetic resonance and mammographic images. Median age at PBC diagnosis was 52 y (range 35-67). PBCs after RRSO had lower MAIs (12 vs. 22 mitotic counts/2 mm, P = 0.02), were smaller (11 vs. 17 mm, P = 0.01), and tend to be PR-positive more often than PBCs without RRSO (38% vs. 13%, P = 0.07). Differentiation grade, ER, and HER2 status were not different. Median DT was 124 d (range 89-193) in the RRSO group and 93 days (range 54-253) in the non-RRSO group (P = 0.47). BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological phenotype. When confirmed in larger series, this may have consequences for BC screening protocols after RRSO