Prognostic relevance of KRAS genotype in metastatic colorectal cancer patients unfit for FIr-B/FOx intensive regimen

Abstract

First-line triplet chemotherapy plus bevacizumab (FIr-B/FOx) can improve efficacy of metastatic colorectal cancer (MCRC), KRAS wild-type and mutant. Prognostic relevance of KRAS genotype was evaluated in patients unfit for FIr-B/FOx, treated with conventional medical treatments. Consecutive MCRC patients not eligible for FIr-B/FOx regimen due to age (≥75 years) and/or comorbidities were treated with tailored conventional first-line treatments. KRAS codon 12/13 mutations were screened by direct sequencing. Activity and efficacy were evaluated and compared according to medical treatments, age (non-elderly and elderly ≥65 years), comorbidity stage (Cumulative Illness Rating Scale), metastatic extension (liver-limited and other/multiple metastatic), and KRAS genotype, using log-rank. Selected first line treatments were medical in 37 patients (92.5%), and surgical in 3 patients (7.5%). Medical treatment regimens: triplet, 18 (45%); doublet, 15 (37.5%); mono-therapy, 4 (10%). At median follow-up of 8 months, objective response rate (ORR) was 37%, median progression-free survival (PFS) 7 months, liver metastasectomies 8% (liver-limited disease 37.5%), median overall survival (OS) 13 months. Triplet regimens failed to significantly affect clinical outcome, compared to doublet. According to KRAS genotype, ORR, PFS and OS were, respectively: wild-type 50%, 8 months, 13 months; mutant 25%, 6 months, 9 months. KRAS genotype wild-type compared to mutant significantly affected PFS, while not OS. KRAS c.35 G>A mutation (G12D) significantly affected worse PFS and OS compared to wild-type and/or other mutations. KRAS genotype, specifically the c.35 G>A KRAS mutation, may indicate poor prognosis in MCRC patients unfit for intensive medical treatments.

Toxicity Syndromes, Patient-Related Clinical Indicator of Toxicity Burden Induced by Intensive Triplet Chemotherapy-Based Regimens in Gastrointestinal Cancers With Metastatic Disease

“…Analysis of TS could be integrated in the therapeutic pathway of cancer patients in clinical practice and in clinical studies to globally evaluate tolerability of cancer treatments. It could be, also, particularly useful for a more proper evaluation of tolerability in the therapeutic pathway of individual cancer patients unfit for standard treatments, due to elderly status and/or their clinical status, or unfit for intensive regimens (33,34), to optimize simultaneous care of cancer patients (35), and in patients treated with innovative non-infusional targeted-drugs, as well as in adjuvant treatments of early cancers, to even more properly weigh the balance between adjunctive efficacy of cancer treatment and its safety in potentially curable 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?

“…In KRAS exon 2 mutant patients harbouring the prevalent c.35 G > A transversion, median PFS and OS were significantly worse compared to wild-type and/or other than c.35 G > A KRAS mutant patients, maybe due to increased aggressiveness and resistance to medical treatment [17]. In patients unfit for FIr-B/FOx, treated with conventional medical regimens, KRAS exon 2 mutant compared to wildtype patients showed a significantly different PFS, and not OS [24]. Furthermore, KRAS c.35 G > A mutant genotype affected significantly worse PFS and OS, compared to wildtype and/or other mutant.…”

“…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.…”

Untitled

“…Overall, KRAS exons 2-4 (KRAS 2-4 ), NRAS exons 2-4 (NRAS 2-4 ), BRAF exon 15 (BRAF 15 ) mutant (mut) MCRC patients are prevalent [3][4][5][6]. KRAS 2 mut characterize 45-55% MCRC, mostly consisting of codon 12 (80%) c.35 G>A (G12D) and c.35 G>T (G12V) transversions [7,8], and codon 13, prevalently c.38 G>A (G13D) mut, and impair the intrinsic GTPase activity of RAS, leading to constitutive, growth-factor-receptor independent activation of downstream signaling [9][10][11].…”

“…Treatment strategy of MCRC patients differs according to patient's fitness (age, comorbidity), metastatic extension (liver-limited (L-L) or other/multiple metastatic sites (O/MM)), and KRAS 2-4 /NRAS 2-4 /BRAF 15 genotype [9,6,15]. KRAS 2-4 /NRAS 2-4 wt or mut genotype addresses the addiction of anti-Vascular Endothelial Growth Factor (VEGF) or anti-Epidermal Growth Factor Receptor (EGFR) to first line triplet or doublet chemotherapy of MCRC [3,[16][17][18]: anti-EGFR drugs in RAS wt [16][17][18]; anti-VEGF drugs in RAS wt and mut patients [3].…”