Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer

Abstract

Background Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. Methods We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. Results 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049). Conclusions This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information.

Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

“…The reported efficacy of radiotherapy in the presence of DDR pathogenic variants 19,21–23 (Table 3) was supported by our data showing prolonged local PFS in radiation‐treated patients in the pDDR group. However, although Luo et al 19 showed that variants in DDR genes in patients with stage III NSCLC were associated with a good response to radiotherapy, their study was limited by the inclusion of patients who were given concurrent chemotherapy. The added value of our research is the increased sensitivity observed to radiotherapy in patients with advanced NSCLC with systemic therapy or no systemic treatment.…”

Palliative radiotherapy indications during the COVID-19 pandemic and in future complex logistic settings: the NORMALITY model

“…From the search results of 161 documents, 13 papers were selected for data extraction [ 4 – 9 , 13 – 19 ]. Globally, 19 clinical presentation items (CPIs) were identified.…”

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

“…As the DDR pathway plays a role in radiation repair, pathogenic alterations would be hypothesized to lead to radiation sensitivity. Prior studies that have found patients with DDR pathway gene alterations to have improved local-regional outcomes after radiotherapy were mostly limited to patients without subsequent ICI exposure . This suggests that the local-regional control benefit imparted by consolidative ICI treatment could minimize the difference in outcomes between patients with and without alterations in DDR genes.…”