Volumetric Tumor Response and Progression in EGFR-mutant NSCLC Patients Treated with Erlotinib or Gefitinib.

RATIONALE AND OBJECTIVES: The aims of this study were to investigate the association between 8-week tumor volume decrease and survival in an independent cohort of epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first-line erlotinib or gefitinib, and to assess the rate of their volumetric tumor growth after the volume nadir. MATERIALS AND METHODS: In patients with advanced NSCLC harboring sensitizing EGFR mutations treated with first-line erlotinib or gefitinib, computed tomography (CT) tumor volumes of dominant lung lesions were analyzed for (1) the association with survival, and (2) the volumetric tumor growth rate after the volume nadir. RESULTS: In 44 patients with the 8-week follow-up CT, the 8-week tumor volume decrease (%) was significantly associated with longer overall survival when fitted as a continuous variable in a Cox model (P = 0.01). The growth rate of the logarithm of tumor volume (logeV), obtained using a linear mixed-effects model adjusting for time since baseline, was 0.096/month (SE: 0.013/month; 95% confidence interval [CI]: 0.071-0.12/month), which was similar to the rate of 0.12/month (SE: 0.015/month; 95%CI: 0.090-0.15/month) observed in the previous report. CONCLUSIONS: The 8-week tumor volume decrease was validated as a marker for longer survival in the independent cohort of EGFR-mutant NSCLC patients treated with first-line erlotinib or gefitinib. The volumetric tumor growth rate after the nadir in this cohort was similar to that of the previous cohort, indicating the reproducibility of the observation among different patient cohorts.

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.