Small Bowel Adenocarcinoma Shows ‘Unique’, Targetable Genomic Profile

Over 90% of small bowel adenocarcinoma patients may have genetic alterations that are targetable by current therapies

medwireNews: A large-scale genomic analysis has highlighted key differences in genetic changes found in patients with small bowel adenocarcinoma (SBA) compared with colorectal cancer (CRC) and gastric carcinoma (GC) patients, including the presence of targetable alterations.

“The characterization of SBA as a unique genomic entity, distinct from CRC and GC, should prompt further investigation into the optimal clinical management of this rare cancer”, recommend Michael Overman, from The University of Texas MD Anderson Cancer Center in Houston, USA, and co-workers.

“Identification of multiple clinically relevant genomic alterations and mutational profiles is encouraging in a population with limited treatment options and poor prognosis”, they write in JAMA Oncology.

Clinical samples were taken from primary or metastatic sites in 317 patients with SBA, 6353 patients with CRC and 889 individuals with GC between 2012 and 2016. Approximately half (54.7%) of the patients were male and the median age was 56 years.

Hybrid-capture-based genomic profiling revealed that the three tumour types had distinct profiles for the seven most common gene alterations, the researchers say.

For example, a significant difference in the genetic alteration rate was identified between SBA and CRC for APC (26.8 vs 75.9%), TP53 (58.4 vs 75.0%) and CDKN2A (14.5 vs 2.6%), while SBA and GC patients differed significantly with regard to the rate of alterations in KRAS (53.6 vs 14.2%), APC (26.8 vs 7.8%) and SMAD4 (17.4 vs 5.2%).

Alterations in other WNT pathway genes were generally mutually exclusive from APC alterations and these occurred in 11.9% of wild-type ABC patients with SBA, including CTNNB1 in 6.3%, RNF43 in 5.0% and AXIN1 in 0.6%.

Michael Overman et al identified several potentially targetable alterations in SBA patients, including PIK3CA in 16.1%, with activation mutations in exon 9 and exon 20 in the majority of cases.

HER2 amplification was identified in 2.2% of SBA patients and HER2 point mutations, including activating mutations, in 8.2%, while three patients had both forms of HER2 alteration. In addition, EGFR mutations were found in 2.5% of SBA patients and activating receptor tyrosine kinase rearrangements in 0.9%.

Although BRAF mutations occurred in 7.6% of SBA patients and 9.1% of their CRC counterparts, V600E mutations were found in just 10.3% of the former versus 73.2% of the latter; BRAF alterations were detected in 1.8% of GC patients, just 17.6% of whom had V600E aberrations.

“Overall, clinically relevant [genomic alterations], defined as those associated with an approved therapy or active clinical trial, were identified in 91.5% of SBA, 88.7% of CRC, and 71.1% of GC cases”, the researchers emphasize.

In addition, FBXW7 mutations, previously linked to mTOR targeted therapy, were detected in 6.9% of SBA patients and ERBB3 in 6.3%, which may be potentially targetable using a small inhibitor RNA approach. And varying targeted approaches have been suggested for other gene alterations found in SBA, including NF1 (6.0%), CTNNB1 (5.7%), MDM2 (5.7%) and PTEN (5.7%).

The researchers also found that 7.6% of 170 assessed SBA samples were classified as having high microsatellite instability (MSI-H) compared with 4.0% and 3.9% of CRC and GC specimens, respectively.

Noting the absence of approved drugs and guidelines for the treatment of SBA in the USA, the researchers say that “the finding of potentially targetable [genomic alterations] in most (91%) SBAs is of great relevance, as it suggests further therapeutic options for patients for whom no well-established standards exist.”

They note a small number of case reports suggesting benefit for anti-EGFR treatment for SBA patients but also alterations that are linked to resistance to such therapy were also present, which could guide treatment decisions.

Reference

Schrock AB, Devoe CE, McWilliams R, et al. Genomic profiling of small-bowel adenocarcinoma. JAMA Oncol; Advance online publication 15 June 2017. doi:10.1001/jamaoncol.2017.1051

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