BRCA2 (Breast cancer 2, early onset)

Three pathogenic variants, BRCA2 [c.6509A>G; c.7879A>T; c.5574_5577delAATT] and PALB2 [c.1592delT], were identified in high-risk genes important for breast cancer prediction. Identification of population-based variants may improve breast cancer screening and management in Sri Lanka.

P2/3, N=582, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2026 --> Dec 2026

P2, N=120, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Nov 2026

We specifically find that gBRCA2-associated tumours are uniquely predisposed to develop acquired RB1 loss-of-function alterations, resulting in poor outcomes on standard-of-care frontline CDK4/6 inhibitor (CDK4/6i) combinations...Our findings suggest that prioritizing PARP inhibition in gBRCA2 carriers may intercept RB1-loss trajectories and delay resistance. More broadly, we establish a predictive framework for forecasting drug-resistant trajectories based on pre-treatment allelic configuration and mutational signatures.

The BRAIx risk score is a strong intermediate-term predictor of breast cancer (current to 4-year risk). Calibrating the score on a training dataset produces population-specific probabilities for calculating individual-specific risk scores for screening clients based on their mammogram images. These risk scores enable future development of personalised screening pathways to transform population breast cancer screening and save lives. Identification of women given an all clear but at very high risk, similar to those carrying BRCA1 and BRCA2 mutations, could reveal insights into both familial and non-familial causes of breast cancer.

At 20 months the patient is disease-free with regular menses and intact fertility. We review diagnostic clues, differential diagnoses, molecular taxonomy and fertility-sparing strategies, underscoring the value of comprehensive genomic profiling for accurate classification and prognostication of this uncommon uterine tumor.

P2, N=70, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2026 --> Nov 2026

P3, N=579, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2026 --> Nov 2026

Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.

Genomic instability, either due to mismatch repair protein deficiency or due to HRD, may play a role in MGA, MGA-associated carcinogenesis and distinct morphological patterns.

In conclusion, while substantial progress has been made in characterizing genetic risk in Asian prostate cancer, European-derived models show reduced accuracy. Future priorities include large-scale multiethnic collaborations, prospective validation studies, and development of predictors for aggressive disease.

HRD status is a prognostic biomarker in HGSC. Its correlation with SET patterns supports histology as an initial screening tool. Importantly, NACT is correlated with reduced detectable HRD positivity and lower GSS, underscoring the need for HRD testing before chemotherapy to ensure accurate assessment and guide treatment.