A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer

Abstract

Purpose: Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred infield (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFRmutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P ¼ 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.

Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer

“…The positive prognostic role of EGFR mutations is likely due to the higher intracranial response rates observed with EGFR TKIs, a better extra-cranial disease control and, finally, an increased sensitivity to loco-regional treatments, such as WBRT and SRS [33–36]. …”

Whole brain radiotherapy plus simultaneous in-field boost with image guided intensity-modulated radiotherapy for brain metastases of non-small cell lung cancer

“…Several studies showed that the radiosensitivity of brain metastases is associated with the mutation status of epidermal growth factor receptor (EGFR) [25-27]. Compared to patients with the wild-type, those with activating EGFR mutations had higher response rates and better survival following WBRT (54% VS. 24%, P  = 0.045; 17.3 months VS .…”

Radiotherapy in the Era of Precision Medicine

“…In HNSCC, for example, EGFR overexpression is a marker of poorer outcomes (57)(58)(59). However, in lung adenocarcinoma, EGFR mutant cells are 500-1000 fold more sensitive to radiation than wild-type cells in vitro (60) and retrospective clinical data show that patients with EGFR mutant tumors demonstrated significantly better response rates compared to patients whose tumors lacked mutations in EGFR (61,62). It remains unclear whether the demonstrated sensitivity to radiation in EGFR mutant patients is causative or correlative.…”