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KRAS variant may have prognostic role in locally advanced rectal cancer
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A single nucleotide polymorphism of KRAS mRNA, rs61764370, may serve as a biomarker of response to neoadjuvant treatment and a predictor of favorable outcomes for patients with locally advanced rectal cancer, according to the results of a randomized phase 2 study.
However, the polymorphism did not appear to predict cetuximab (Erbitux; Bristol-Myers Squibb, Lilly) benefit in the study population, the researchers noted.
The miRNA tumor suppressor Let-7 acts by down-regulating several oncogenes, including KRAS. The single nucleotide polymorphism rs61764370 (T>G base substitution) in the Let-7 complementary site 6 (LCS-6) of KRAS mRNA has predicted prognosis in early stage colorectal cancer as well as benefit from anti-EGFR monoclonal antibodies in metastatic colorectal cancer.
Nicola Valeri, MD, PhD, leader of the gastrointestinal cancer biology and genomics team at Centre for Molecular Pathology at The Institute for Cancer Research in London, and colleagues evaluated DNA from patients with locally advanced rectal cancer enrolled on the EXPERT-C trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX, with or without cetuximab.
The trial included 164 patients, 94.5% (n = 155) of whom had tumor tissue available for analysis.
Complete response in patients with KRAS or BRAF wild-type tumors served as the primary endpoint.
Median follow-up was 64.9 months (range, 62.8-67.2).
Seventy-nine percent of patients (n = 123) had the LCS-6 TT genotype (CAPOX = 65; CAPOX plus cetuximab = 58) and 20.6% (n = 32) had the LCS-6 TG genotype (CAPOX = 13; CAPOX plus cetuximab = 19).
More patients with LCS-6 variants had tumors harboring KRAS (54.8% vs. 41.5%), KRAS/NRAS (58.1% vs. 45.8%) and BRAF (6.5% vs. 1.7%) mutations.
TG allele carriers achieved a significantly higher complete response rate after neoadjuvant chemotherapy (28.1% vs. 10.6%; P = .02). More TG carriers also achieved 5-year PFS (77.4% vs. 64.5%) and OS (80.3% vs. 71.9%); however; the trends did not reach statistical significance in this cohort.
Cetuximab did not influence complete response or survival outcomes.
Thirty-one patients with the LCS-6 TT genotype and five patients with the LCS-6 TG genotype experienced tumor recurrence. The most frequent sites of tumor recurrence included the lung (44.4%), liver (41.7%), peritoneum (19.4%) and lymph nodes (16.7%).
All liver metastases occurred among patients with the TT genotype (P = .038).
The researchers observed that patients with the LCS-6 TT genotype experienced a stronger negative prognostic effect associated with KRAS mutations for PFS (HR = 1.7) and OS (HR = 1.79) compared with patients harboring the TG genotype (PFS, HR = 1.33; OS, HR = 1.01). However, the association did not reach statistical significance.
The researchers acknowledged the small patient population and the use of investigational therapeutic regimens that do not represent the current standard of care are limitations to these findings.
“Our analysis suggests that, in a Caucasian population, the rs61764370 single nucleotide polymorphism may influence the prognostic relevance of KRAS mutation which has been increasingly reported as a marker of resistance to chemoradiotherapy in locally advanced rectal cancer and poor prognosis in distal colon cancer and rectal cancer,” Valeri and colleagues concluded. “If our findings are confirmed, testing for KRAS and rs61764370 could potentially provide useful data for patient stratification in clinical trials of neoadjuvant treatment for locally advanced rectal cancer. Further studies to elucidate the mechanisms whereby single nucleotide polymorphism may increase tumor chemoradio-sensitivity and mitigate the unfavorable prognosis of KRAS-mutant tumors are warranted.” – by Cameron Kelsall
Disclosure: Valeri reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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