Although there is a high ORR to platin/etoposide, small cell lung carcinoma (SCLC) patients inevitably recur, and second line topotecan has only a 20% ORR. Identification of genomic alterations beyond the canonically mutated TP53/RB1 may provide avenues to benefit from targeted therapy.
689 SCLC cases were assayed with hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify all four classes of genomic alterations (GA), base substitutions, short insertions/deletions, copy number alterations, and fusions to suggest possible benefit from targeted therapy.
The median patient age was 62 years, and the male:female ratio is 1:1. The commonly altered genes are TP53 (91%), RB (68%), MLL2 (13%), LRP1B (11%), RICTOR (11%) and FGF10 (9%). MYCL1 amplification was identified in 53 cases, as were 6 MYCL1 fusions (MYCL1-COL9A2, MYCL1-MSRB2, MYCL1-PABPC4, MYCL1-MACF1, MYCL1-JAZF1, and one with indeterminate partner) all of which arise from inter-chromosomal rearrangements. Other rearrangements of cancer relevant genes include three cases of c-MYC rearrangements co-occurring with MYC amplification, three cases of RICTOR rearrangements, and one case each of BRD4-NOTCH3 and EML4-ALK were all identified. A never smoker 46 yo male was diagnosed with SCLC, which was identified as harboring MYCL1-JAZF1 on CGP and had a 18 month near complete response to alisertib, after failing three previous lines of chemotherapy.
Beyond the intra-chromosomal RLF1-MYCL1 fusion first identified in 1991, we identify 6 novel MYCL1 fusions. Such fusions may be still more prevalent as the CGP assay identified these without focused coverage of the recurrent breakpoint in MYCL1 intron 1. Given the response of the index patient to an investigational aurora kinase inhibitor, alisertib, which is hypothesized to target MYCL downstream pathways, further focused investigation of MYCL1 fusions and other fusions in SCLC to assess possible functions as oncogenic drivers is warranted.
Clinical trial identification
Legal entity responsible for the study
S. Ali, M. Bailey, A.B. Schrock, G.M. Frampton, D.A. Fabrizio, J. He, J. Suh, J.S. Ross, P. Stephens, V. Miller: Employee of and equity interest in foundation medicine inc. S.J. Klempner: Speaker for foundation medicine inc. All other authors have declared no conflicts of interest.