Pathological complete response (pCR) association with a novel homologous recombination deficiency HRD signature (HRDsig) in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant therapy (Tx).

Abstract

591 Background: The current standard of care for stage II-III TNBC is neoadjuvant Tx combining carboplatin, paclitaxel, and immune checkpoint inhibitor (ICI) followed by doxorubicin and cyclophosphamide (AC) + ICI. This regimen is often associated with significant toxicity. This study aimed to investigate if HRDsig could identify patients with TNBC who have a greater benefit from the addition of platinum in the neoadjuvant Tx regimen. Methods: This study included patients with TNBC who underwent genomic testing using Foundation Medicine tissue comprehensive genomic profiling (CGP) assays and had records of neoadjuvant Tx. Patient clinical data was obtained by the US-wide de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic breast cancer database (CGDB), originated from ~280 US cancer clinics between January 2011 and June 2023. pCR rates were compared between patients HRDsig(+) vs. HRDsig(-) who were stratified by having received platinum vs. non-platinum Tx and between patients receiving non-platinum vs. platinum neoadjuvant Tx stratified by HRDsig status. The interaction effect of HRDsig and platinum Tx in relation to pCR was evaluated by logistic regression. Results: 497 patients met the inclusion criteria, 159 (32%) with HRDsig(+) and 338 (68%) with HRDsig(-). Among HRDsig(+) patients, 54 (34%) received platinum and 105 (66%) non-platinum Tx. HRDsig(+) vs. HRDsig(-) patients were more likely to have pCR receiving both platinum Tx (37.0% vs. 4.4%, p<0.001) and non-platinum Tx (23.8% vs. 5.2%, p<0.001). Platinum vs. non-platinum Tx showed a trend towards moderately enriched pCR rates in the HRDsig(+) group (37.0% vs. 23.8%, odds ratio [OR]=1.87, 95% confidence interval [CI] 0.97-3.84, p=0.08), but not in the HRDsig(-) group (4.5% vs. 5.2%, OR=0.86, 95% CI 0.23-2.55, p=0.767). HRDsig(+) was independently associated with pCR (OR=5.65, 95% CI 2.80-11.89, p<0.001), while platinum Tx and pCR were not associated (OR=0.84, 95% CI 0.23-2.45, p=0.767). A strong treatment interaction between HRDsig status and platinum Tx was not observed (p=0.242, OR=2.24, 95% CI 0.61-9.58). Conclusions: In the neoadjuvant Tx setting, patients with TNBC that were HRDsig(+) were substantially more likely to achieve a pCR. There was a trend towards higher pCR rates among HRDsig(+) patients receiving platinum vs. non-platinum Tx, while this effect was not observed among HRDsig(-) patients. TNBC patients (especially stage II) often experience significant toxicity from chemotherapy regimens. These hypothesis-generating results suggest that HRDsig may help identify patients who achieve additional benefit from platinum agents. These results warrant further evaluation in randomized cohorts to potentially validate this utility.