Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

Abstract

The retinoblastoma gene (RB1) encodes the retinoblastoma (RB) pocket protein that plays an important role in cell cycle progression. Here we determine the frequency and prognostic significance of RB1 mutation in non small cell lung cancer (NSCLC), restricting inclusion to Stage III and IV patients with linked genomic and clinical data. The primary outcome was median overall survival (OS). We identified RB1 mutation in 8.2% of NSCLC patients. The median OS for wild-type (wt) RB1 was 28.3 months vs 8.3 months for mutant RB1 (Hazard Ratio = 2.59, P = 0.002). Of special interest, RB1 mutation also correlated with lack of response to immunotherapy. Our study focused on RB1 mutation in locally advanced and advanced non small cell lung cancer to better facilitate comparisons with small cell lung cancer (SCLC). In our SCLC cohort, RB1 mutation was identified in 75% of patients and wt RB1 was associated with significantly shorter OS (P = 0.002). The different outcomes of RB1 mutation observed among lung cancer subtypes suggest a more complicated mechanism than simple regulation of cell cycle or response to chemotherapy.

Keywords: genomics; immunotherapy; non small cell lung cancer; response; retinoblastoma; small cell lung cancer.

Figure 1

Kaplan‐Meier Curve for OS in NSCLC. RB1 mutation was identified in 8.2% of NSCLC patients (16 of 195 patients). With a median follow‐up of 15.1 months, the median OS for wt RB1 was 28.3 months and for mutant RB1 was 8.3 months

Figure 2

Mutation Distribution along RB Protein in NSCLC. Missense mutations labeled in green. Truncating mutations (nonsense, frameshift deletion, frameshift insertion, splice site) labeled in black. Single nucleotide polymorphisms (SNPs) and exon loss labeled in purple. DUF = Domain of unknown function (green). RB_A (red) and RB_B (blue) domains contain cyclin folds. RB_B also contains LXCXE binding site. RB_C (yellow) is the C terminal domain which binds E2F complexes

Figure 3

Immuno‐histochemical detection of RB1 and p16INK4A in two RB1 mutant NSCLC tumors (400X). Description of exact RB1 mutation given on left