Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease

Abstract

BackgroundBevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated.MethodsTumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test.ResultsIn all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively.ConclusionsThe KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

The prevalent KRAS exon 2 c.35 G>A mutation in metastatic colorectal cancer patients: A biomarker of worse prognosis and potential benefit of bevacizumab-containing intensive regimens?

“…We verified previously reported findings of significantly different outcome (PFS and OS) according to extension of metastatic disease (L-L compared to other/multiple metastatic (O/MM) patients) [26,31], in exon 2 KRAS wild-type and mutant patients (Fig. 1B).…”

“…Clinical factors, related to the patient's fitness for more effective treatment strategies (according to age and comorbidity status) [23,24], to the extension of metastatic disease (liver-limited or other/multiple metastatic) [25,26], to the proper treatment strategy (integrated medical and surgical, different medical regimens, lines of effective treatments) [25,27], and biological factors, in particular BRAF and KRAS genotype status [28][29][30][31], contribute to determine the clinical outcome in the individual MCRC patient. The proper definition of a bioclinical algorithm could help address tailored clinical management of individual patients.…”

“…The comparison of clinical outcome (PFS, OS) in equivalently treated MCRC patients, according to wild-type and mutant genotype, and also according to different KRAS mutations, evaluates prognostic relevance of KRAS genotype, depending from the balance between tumor aggressiveness, conferred by specific mutations, and treatment effectiveness, related to medical regimens and secondary liver surgery, further lines of treatment [31].…”

“…We recently evaluated the prognostic relevance of KRAS exon 2 genotype and of the prevalent codon 12 c.35 G > A (G12D) KRAS mutation in 59 MCRC patients enrolled in a previously published phase II study and in an expanded clinical program proposing BEV added to triplet chemotherapy, FIr-B/FOx intensive regimen, as first line treatment [25,26,53]: 31 (53%) KRAS wild-type and 28 (47%) KRAS mutant [31]. KRAS exon 2 mutations prevalently affected codon 12 (24 patients, 40.6%), specifically c.35 G > A (G12D) 15 (25.4%), c.35 G > T (G12 V) 7 (11.8%); codon 13, 4 (6.7%), c.38 G > A (G13D), 3 (5%) ( Table 1).…”

“…After a median follow-up of 21.5 months (Table 2) [25,31], among KRAS exon 2 wild-type patients, ORR was 90%, liver metastasectomies 35% (83% in liver-limited (L-L)), median PFS 14 months, median OS 38 months; among KRAS exon 2 mutant patients, ORR was 67%, liver metastasectomies 25% (54% in L-L), median PFS 11 months, median OS 20 months. KRAS exon 2 mutant compared with wild-type patients did not show significantly different PFS nor OS, even if OS was trendly worse in KRAS mutant patients (Fig.…”