Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Abstract

Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G4A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P = 0.034) and more frequent pancreatic invasion (P = 0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G4A transitions and G12D mutations) were significantly correlated with higher pT classification (P = 0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P = 0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P = 0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wildtype KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

Patient with Lynch syndrome with subsequent development of small bowel adenocarcinoma

“…Despite these similarities between SBA and CRC, a genomic comparison of SBA with CRC and gastric carcinomas found that SBA is a molecularly unique intestinal cancer 11 17. Nonetheless, prognostic value of KRAS/BRAF mutations in SBA remains unclear9; while Jun et al found that patients with KRAS mutations had shorter survival times than those with wild-type genes, the results were not statistically significant. Moreover, it was found that mutation of KRAS was a worse prognostic predictor in SBA of lower pT classification 9.…”

“…SBA generally has a poor prognosis at all its stages, with a 5-year mean survival rate ranging from 50% to 60% for stage I, 39%–55% for stage II, 10%–40% for stage III and 3%–5% for stage IV,10 making SBA’s prognosis intermediate between that of colon and gastric cancers 9 10. Lymph node metastasis and distal small intestine location (jejunum and ileum) have been found to be the most important independent factors determining prognosis,9 with nodal metastasis being the main prognostic factor 10. While current SBA surgery guidelines require the removal of 8–10 regional lymph nodes to investigate for metastasis, as it correlates with improved prognosis,11 only a single lymph node was harvested from our patient’s excised tumour; considering that the exploratory laparotomy was performed urgently for small bowel obstruction (SBO)—with significant time spent on lysis of adhesions—rather than with the intention of a tumour resection or a suspicion for SBA, the recommended number of nodes was not removed.…”

“…Moreover, chemotherapy agents used in patients with advanced stage SBAs (fluoropyrimidines, platinum and irinotecan) are generally the same as those used to treat patients with advanced CRC9; yet, similarly, limited data exist on the role of biological factors in targeted therapy for patients with SBA, although adjuvant chemotherapy may improve prognosis and outcome in cases of invaded lymph nodes (stage III disease) 10 11. Despite the latter, our patient did not undergo adjuvant chemotherapy with 5-FU because of the favourable characteristics of her disease (high MSI and well differentiated) along with the full resection of her tumour (negative margins), which made it possible to undergo watchful waiting and close follow-up.…”

“…KRAS and BRAF mutations have been little studied in SBA, but similar to CRC, they are mutually exclusive 99. As mentioned previously, anti-EGFR therapy has not been evaluated in SBA, but given the findings of similar prevalence of KRAS mutations in SBA and CRC, there may be a potential role as therapy.…”

“…As mentioned previously, anti-EGFR therapy has not been evaluated in SBA, but given the findings of similar prevalence of KRAS mutations in SBA and CRC, there may be a potential role as therapy. Jun et al suggest that targeted therapies, such as anti-EGFR, could be beneficial in as much as two-thirds of patients with SBA with wild-type KRAS and BRAF genes and metastatic disease 9. Despite these similarities between SBA and CRC, a genomic comparison of SBA with CRC and gastric carcinomas found that SBA is a molecularly unique intestinal cancer 11 17.…”