Homologous recombination deficiency (HRD) in breast cancer

Three DNA-based measures of genomic instability (loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions) are summed into an HRD score, with deficiency defined as a score of 42 or more or a BRCA1/2 mutation. In three neoadjuvant platinum trials in triple-negative disease, HR deficiency predicted residual cancer burden 0 or I and pathological complete response (odds ratios 4.96 and 6.52 in the platinum, gemcitabine and iniparib trial; 10.18 and 17.00 in two cisplatin trials), remained significant after adjustment for clinical variables, and identified responders among BRCA1/2 non-mutated tumours (Telli 2016). In GeparSixto, HRD was measured in 193 of 315 triple-negative participants: 136 (70.5 percent) were HR deficient, 82 of them (60.3 percent) with a high score but no tumour BRCA mutation; HR deficiency independently predicted pathological complete response (odds ratio 2.60), and adding carboplatin raised the rate from 33.9 to 63.5 percent in HR-deficient tumours but only from 20.0 to 29.6 percent in non-deficient tumours, with the interaction test not significant, so HRD predicted response but not carboplatin benefit; carboplatin improved disease-free survival in triple-negative disease overall (hazard ratio 0.56) (Loibl 2018). Beyond germline BRCA, olaparib produced confirmed responses in metastatic breast cancer with germline PALB2 mutations (objective response 82 percent, median progression-free survival 13.3 months) and somatic BRCA1/2 mutations (50 percent, 6.3 months) but none with ATM or CHEK2 mutations alone (TBCRC 048, Tung 2020). Regulatory use differs from ovarian cancer: NICE's adjuvant olaparib recommendation rests on a germline BRCA mutation (TA886), not an HRD score, and the platinum recommendation in NG101 1.8 applies to all triple-negative disease needing neoadjuvant chemotherapy, HRD-tested or not. The site's general HRD term and the hrd-positive readout carry the ovarian thresholds and assays.