Clinical Correlation of Extensive-Stage Small Cell Lung Cancer Genomics
A partir d'échantillons tumoraux prélevés sur 50 patients atteints d'un cancer du poumon à petites cellules de stade étendu, cette étude identifie une association entre l'absence de mutations du gène RB1 et la réponse à une chimiothérapie
Background Genomic studies in small cell lung cancer (SCLC) lag far behind those performed in non-small cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of ‘every-day’ SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.
Patients and Methods A total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or IHC of tumor specimens.
Results In all, 39 patients had ES-SCLC; 15 patients had either primary refractory/ resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (p=0.038) in predicting response to first line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 to wild-type. Patients with mutant RB1 had both better OS (11.7 vs. 9.1 months p=0.04) and PFS (11.2 vs. 8.6 months, p =0.06) compared to patients with wild-type RB1. Interestingly, about 25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.
Conclusion We found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.
Annals of Oncology , résumé, 2016