Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). HRDetect predicted status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; = 0.006) with the same optimal threshold, even after adjusting for mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT ( = 0.0003) and 1.3-year extended median OS ( = 0.04). Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of mutation status and hope this work will guide the development of clinical trials..

These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

CONTEXT The optimal learner to simulator ratio for procedural skills training is not known. Research in motor learning suggests observational training in pairs, termed 'dyad training', may be as effective as directed selfregulated learning (DSRL).OBJECTIVES This study was conducted to compare the relative effectiveness and efficiency of dyad versus DSRL training of simulation-based lumbar puncture (LP). METHODSWe conducted a two-group randomised equivalence trial. First-year internal medicine residents (n = 50) were randomly assigned to learn LP either in dyads or as individual learners on a simulator, using a directed self-regulated approach (i.e. the learning sequence was defined for them, but they defined the pace of learning). Participants were videotaped performing a simulated LP on a pre-test, an immediate post-test, and a 6-week delayed retention test. In duplicate, blinded raters independently evaluated all trainee performances using a previously validated 5-point global rating scale (GRS) and 35-item checklist.RESULTS Our analyses showed no significant differences (p = 0.69) on pre-test, post-test or retention test GRS scores between the dyad (mean AE standard deviation [SD] scores by test: 2.39 AE 0.57, 3.48 AE 0.62, 3.12 AE 0.85, respectively) and DSRL (mean AE SD scores by test: 2.67 AE 0.50, 3.34 AE 0.77, 3.21 AE 0.79, respectively) groups. Both groups improved significantly from pre-test to post-test (p < 0.001) and retained that performance following the 6-week delay. Dyad participants experienced significantly greater pre-test to post-test gains than DSRL participants (p = 0.02). There was no significant difference in total practice time between the groups (20.94 minutes for individuals and 24.20 minutes for dyads; p = 0.175).CONCLUSIONS Our results indicate that learning in pairs is as effective as independent DSRL. Dyad training permits the more efficient use of simulators as two learners use the same resources as an individual.

BRCA1 and BRCA2 germline mutation–associated breast cancers are known to be deficient in the process of homologous recombination and often respond favorably to drugs targeting this important DNA repair pathway. There is emerging evidence that a significant proportion of patients with BRCA1/ BRCA2 wild-type breast cancer are also deficient in homologous recombination, and it is hypothesized that these patients may derive similar benefit from drugs targeting this pathway. Current research has focused on the development of a companion diagnostic to identify these sporadic BRCA-like tumors. This review outlines the various approaches that researchers have taken to predict homologous recombination deficiency as part of correlative biomarker work in various studies and clinical trials in breast cancer. As some of these tests of homologous recombination deficiency move closer to clinical use, understanding the approach and limitations of each is of relevance to clinicians who treat patients with breast cancer.