Joshua T. Jones

PURPOSE: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. RESULTS: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. CONCLUSIONS: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.

Summary ues (Figure 1B), the siRNAs targeting the gene productsSTIM (stromal interaction molecule) 1 and STIM2 stood Ca 2+ signaling in nonexcitable cells is typically initiated out in their ability to suppress the sustained Ca 2+ sig- by receptor-triggered production of inositol-1,4,5-tris- nals while showing little effect on the peak amplitude. phosphate and the release of Ca 2+ from intracellular Although STIM1 and STIM2 were identified previously stores [1]. An elusive signaling process senses the as potential tumor growth suppressors [8, 12, 13], they Ca 2+ store depletion and triggers the opening of had not been suspected of having a role in Ca 2+ signal- plasma membrane Ca 2+ channels [2–5]. The resulting ing. Nevertheless, both proteins have been biochemi- sustained Ca 2+ signals are required for many physio- cally characterized and have been shown to form ho- logical responses, such as T cell activation and differ- mo- and hetero-oligomers as well as to have a entiation [6]. Here, we monitored receptor-triggered