Patients who had non–small cell lung cancer (NSCLC) with homologous recombination gene mutations had better outcomes, although no single gene in the pathway appeared to have a causal role.
Homologous recombination (HR) gene mutations might be a meaningful biomarker to predict response to platinum-based chemotherapy in patients with advanced and metastatic non–small cell lung cancer (NSCLC), new report findings suggest.
This study, published in Frontiers in Oncology, shows people with HR gene mutations had more than double the overall response rate (ORR) to platinum-based chemotherapy compared with those without the mutations.
The study authors noted that while targeted therapies and immunotherapies have led to dramatic results for many patients with NSCLC, not all patients respond to those therapies.
“Platinum-based chemotherapies, which focus on DNA damage in tumor cells, are still a part of the backbone treatment regimen for NSCLC,” the investigators wrote.
However, they noted that there is not yet a solid biomarker to identify patients who are likely to respond best to chemotherapy.
“Therefore, screening for chemotherapy-benefit populations would certainly enhance clinical practice,” they said.
Previous research suggests that patients with high expression of DNA damage response (DDR) genes are poor candidates for platinum-based therapy, but the investigators said there are not yet any reliable DDR biomarkers.
“Homologous recombination, a sub-process of DDR, is the most important mechanism associated with DNA double-strand break repair,” they wrote. “Deficiencies in the HR pathway may theoretically lead to higher genomic instability and sensitivity to platinum.”
Homologous recombination deficiency (HRD) has been linked with the response of other types of tumors, including ovarian and breast cancer, to platinum-based chemotherapies, thanks in large part to the wider rollout of next-generation sequencing (NGS). The study investigators decided to find out whether there might be a similar link between HR gene mutations and platinum-based chemotherapy outcomes in patients with NSCLC.
The investigators retrospectively analyzed a cohort of 129 people with advanced NSCLC, of whom 54 had received platinum-based chemotherapy with or without angiogenic therapy. The authors used NGS to look for gene mutations and then used Cox regression analysis to identify links between the HR gene mutation and patient outcomes.
Their results showed that HR mutations were significantly associated with sensitivity to platinum-based chemotherapy. In the cohort, the objective response rate (ORR) to platinum-based chemotherapy among people with BRCA1/2 mutations was 75% compared with 30.4% among patients with BRCA1/2 wild type. The median progression-free survival (PFS) was 7.5 and 5.5 months, respectively. Patients with HR gene mutations had ORRs of 60% compared with 23.6% for people with wild-type HR genes. Those with mutations had a median PFS of 7.5 months compared with 5.2 months in patients without the mutations.
The investigators found that when they conducted a univariate analysis, they could not identify any single gene on the HR pathway that correlated strongly with PFS and overall survival (OS) after platinum-based chemotherapy, with the exception of one gene that was only mutated in a single patient.
“But when these HR genes were analyzed together, univariate and multivariate Cox regression analyses of PFS and OS suggested that they may play an important role in platinum response,” they wrote.
The authors did not find any links between HR gene mutations and an increased risk of adverse events.
“In brief, our results indicate that NGS profiling of HR gene mutations show potential as a tool for developing effective biomarkers that predict the efficacy of platinum-based chemotherapy in advanced and metastatic NSCLC,” they concluded.
Zhang L, Guan S, Meng F, Teng L, Zhong D. Next-generation sequencing of homologous recombination genes could predict efficacy of platinum-based chemotherapy in non-small cell lung cancer. Front Oncol. 2022;12:1035808. doi:10.3389/fonc.2022.1035808