Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

BACKGROUND: Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. PATIENTS AND METHODS: Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. RESULTS: A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). CONCLUSIONS: Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Utility of Axillary Staging in Older Patients with HER2-Positive Breast Cancer.

BACKGROUND: The utility of sentinel lymph node biopsy (SLNB) in older patients remains controversial. Advancements in human epidermal growth factor receptor 2 (HER2)-directed therapy have revolutionized disease response rates and prognosis, supporting efforts to re-evaluate the utility of SLNB. We aimed to assess the differences in treatment and overall survival (OS) in older patients with HER2-positive breast cancer based on SLNB. METHODS: Using the National Cancer Database (2010-2020), patients ≥ 70 years of age diagnosed with cT1-2/cN0/M0, HER2-positive breast cancer were identified. Logistic regression assessed associations with SLNB, systemic therapy, and radiation. Cox proportional hazard models were used to identify factors associated with OS. Analyses were stratified by treatment sequence, i.e. upfront surgery or neoadjuvant therapy (NAT) followed by surgery. RESULTS: Of the 17,609 patients included, 94% underwent upfront surgery (n = 16,492) and the remaining underwent NAT (n = 1117). Those who underwent SLNB were more likely to receive adjuvant therapy, irrespective of nodal status {upfront surgery/systemic therapy (odds ratio [OR] 2.82, 95% confidence interval [CI] 2.17-3.67); upfront surgery/radiation (OR 3.97, 95% CI 3.03-5.21); NAT/radiation (OR 5.69, 95% CI 1.83-17.69)}. The breast pathologic complete response (pCR) rate was highest among the hormone receptor (HR)-negative/HER2-positive subtype (50.0%), of which none were found to be ypN+. Comorbidity burden was associated with significantly lower rates of adjuvant systemic therapy and worse OS. CONCLUSIONS: Patients who underwent SLNB, regardless of pN status, were more likely to receive adjuvant therapy. Nodal positivity is exceedingly rare for patients with a breast pCR following NAT, especially among the HR-negative/HER2-positive subtype. It is reasonable to consider omission of SLNB in select subgroups of older patients with HER2-positive breast cancer.

Clinical genetics in breast cancer.

As genetic testing becomes increasingly more accessible and more applicable with a broader range of clinical implications, it may also become more challenging for breast cancer providers to remain up-to-date. This review outlines some of the current clinical guidelines and recent literature surrounding germline genetic testing, as well as genomic testing, in the screening, prevention, diagnosis, and treatment of breast cancer, while identifying potential areas of further research.

BRCA1/2 mutation carriers & risk reducing mastectomy: Who undergoes surgery and potential benefits.

BACKGROUND: Risk-reducing mastectomy (RRM) is the most effective breast cancer risk-reduction strategy in BRCA1/2 mutation carriers. We examined factors associated with RRM and its relationship with overall survival (OS). METHODS: Patients aged 18-80y at diagnosis of their BRCA1/2 mutation were selected from our institutional database and stratified by RRM receipt. Differences were tested; unadjusted OS was estimated. RESULTS: Of the 306 patients, median age was 43y; median follow-up was 41.6mo. Patients undergoing RRM were more often married with a history of pregnancy (both p â€‹≤ â€‹0.05). Of female patients, 23.1% underwent RRM. Two patients had malignancy detected at RRM, and one developed breast cancer after RRM. Higher unadjusted OS was observed with RRM (p â€‹= â€‹0.02). CONCLUSIONS: Our analyses suggest that family-structure may play a role in a patient's decision to undergo RRM. We also demonstrated RRM is likely associated with improved survival, potentially underscoring the importance of this option for BRCA1/2 mutation carriers.