Couch, Ronan

Abstract Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Experimental Design: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort. Results: Germline PV were observed in 6.5% and 4.6% of women with DCIS in the clinical testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PV frequencies were significantly lower among women with DCIS than those with IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PV were significantly associated with an increased risk of DCIS (OR > 2.0), but only BRCA2 PV were associated with high risk (OR > 4) in both cohorts. The cumulative incidence of CBC among carriers of PV in high-penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PV in ATM, BRCA1, BRCA2, CHEK2, and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of CBC in carriers of PV in high-penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

Few proton magnetic resonance spectroscopy studies have explored chemotherapy-related biochemical changes in brain regions. This observational study aimed to longitudinally assess short-term cognitive changes and brain metabolite concentrations in women undergoing chemotherapy for breast cancer. We analyzed 11 women with newly diagnosed stage 1 to 3 breast cancer. Patients were evaluated via objective cognitive testing, and patient self-report tests. Patients were examined using single voxel proton magnetic resonance spectroscopy in the medial frontal cortex, posterior cingulate gyrus, and left thalamus at baseline and after the completion of chemotherapy on a 1.5 Tesla scanner. At the posttreatment evaluation as compared to baseline, 7 of the 10 (70%) patients reported worsening memory on the MD Anderson symptom inventory (annualized change = 1.82 ± 2.88, P = .08), while the delayed recall raw score of the Rey Osterrieth complex figure test did not change from pre- to post-chemotherapy (mean annualized change = 5.00 ± 14.38, P = .30). The annualized change in the creatine concentration in the posterior cingulate gyrus was statistically significant. The annualized change in the MD Anderson symptom inventory was negatively correlated with the annualized change in the medial frontal N-acetylaspartate (Spearman correlation coefficient [rho] = −0.78, P = .01) and positively correlated with the annualized change in the posterior cingulate gyrus creatine (rho = 0.66, P = .04). Annualized changes in the Rey Osterrieth complex figure test were positively correlated with annualized changes in choline (rho = 0.83, P = .01) in the medial frontal cortex, choline (rho = 0.76, P = .04) in the left thalamus, and creatine (rho = 0.73, P = .02) in the medial frontal cortex. Our data suggest that chemotherapy may lead to the worsening of self-reported memory function, which is associated with alterations in brain metabolites.