ESMO 2016: Comprehensive Genomic Profiling Identifies Potentially Actionable Mutations in Small Bowel Adenocarcinoma

Results from the largest and most comprehensive genomic characterisation of small bowel adenocarcinoma (SBA) to date were reported at the ESMO 2016 Congress in Copenhagen, Denmark on 9 October. This study also characterised and compared the frequency of alterations identified in SBA with alterations detected in colorectal carcinoma (CRC) and gastric carcinoma (GC) and identified potentially targetable genomic alterations in all three series.

SBAs are rarely occurring cancers that have a lower incidence than other intestinal derived cancers, with diagnosis often being made at a later stage, thus resulting in worse overall survival than CRC or GC, according to lead author Alexa Schrock, Clinical Development, Foundation Medicine in Cambridge, USA.

The investigators used hybrid-capture based comprehensive genomic profiling (CGP) to prospectively analyse clinical samples from 358 patients with SBA, 6,353 patients with CRC, and 889 patients with GC.

Complete molecular profiles were prepared for patients with SBA, CRC and GC and compared with available clinical features. The majority (52-55%) of patients in the 3 series were male; SBA patients tended to be marginally older than the patients with the other two cancer types with a median age of 60 years.

The alterations identified included APC alterations, which occurred at a frequency of 76% in CRC and 27% in SBA (p < 0.001). BRAF alterations were found in 8% each of CRC and SBC samples. BRAF V600E mutations occurred less commonly in SBA, and represented just 10% of BRAF-mutated samples in this series. ERBB2 and EGFR amplifications were detected more often in GC, but ERBB2 (7%) and EGFR (1.4%) point mutations were most common in SBA compared to the other tumour types tested.

High microsatellite instability (MSI-H) more frequently occurred in SBA (6.9% of cases) than in CRC (3.9%), or GC (4%). Targetable alterations including EGFR and ERBB2 alterations, BRAF mutations, PI3K pathway and MEK1 mutations, and RTK fusions were detected in all three series, according to Dr. Schrock who noted that one SBA patient whose tumour harboured a GOPC-ROS1 fusion had demonstrated a clinical response to the ALK/ROS1 inhibitor crizotinib.

Overall, the molecular profile of SBA was distinct from CRC or GC, and the genomic alterations identified in unspecified SBA were similar to those identified in duodenal adenocarcinoma.

Conclusions

The authors concluded that this study offers the first large scale genomic comparison of SBA with CRC and GC, as well as a comparison of unspecified SBAs with tumours of the duodenum. Using CGP over the course of clinical care can identify targetable genomic alterations across diverse intestinal tumour types and allows patients to be matched with appropriate targeted therapies.

The authors also noted that the higher incidence of microsatellite instability identified in SBA suggests that a subset of patients with SBA may benefit from treatment with anti-PD-1/PD-L1 therapies.

Reference

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Genomic profiling of small bowel adenocarcinoma: Insights from a comparative analysis with gastric and colorectal cancer and opportunities for targeted therapy

A.B. Schrock, C.E. Devoe, R. McWilliams, J. Sun, J.T. Ruggiero, P. Stephens⁶, J.S. Ross, R. Wilson, V.A. Miller, S.M. Ali, M.J. Overman