Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGFβ pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83–5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47–7.54; p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.

Purpose: Combination of biological therapy and chemotherapy improves the survival of patients with metastatic colorectal cancer (mCRC). However, the optimal biological therapy sequence remains unclear. In this retrospective study, we evaluated the clinical outcomes of patients with mCRC treated with different sequences of biological therapies as first‐ and third‐line therapy.Methods: We only included patients with wild‐type KRAS exon 2 mCRC who had received cetuximab, bevacizumab, and standard chemotherapy. The patients were treated with cetuximab or bevacizumab as first‐ or third‐line therapy combined with a similar chemotherapy backbone.Results: In total, 102 patients were included. Forty‐six patients received first‐line cetuximab therapy followed by third‐line bevacizumab therapy (cetuximab → bevacizumab group) and 56 patients received first‐line bevacizumab therapy followed by third‐line cetuximab therapy (bevacizumab → cetuximab group). The cetuximab → bevacizumab group was associated with increased survival (OS) compared with the bevacizumab → cetuximab group (median OS: 30.4 months vs 25.7 months, hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.36‐0.86). When calculated from the start of second‐ and third‐line therapies, OS was also higher in the cetuximab → bevacizumab group (second‐line: 20.6 months vs 14.8 months, HR: 0.54, 95% CI: 0.34‐0.81; third‐line: 12.5 months vs 9.9 months, HR: 0.53, 95% CI: 0.35‐0.83). The cetuximab → bevacizumab group was also associated with better progression‐free survival than the bevacizumab → cetuximab group (8.8 vs 4.5 months, HR: 0.43, 95% CI: 0.25‐0.58) in the third‐line setting, but not in the first‐ or second‐line settings.Conclusions: Our study demonstrated that first‐line cetuximab therapy followed by third‐line bevacizumab therapy was associated with favorable clinical outcomes as compared to the reverse sequence.

(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13–0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.

Purpose: Fewer treatment options are available for refractory metastatic colorectal cancer (mCRC). In early trials, S-1 monotherapy was effective for mCRC patients after chemotherapy failure and its combination with oral leucovorin therapy offers promising results in untreated mCRC. Hence, we conduct a Phase II trial to assess the efficacy of S-1 plus oral leucovorin (SL) in refractory mCRC that progressed after multiple prior standard therapies. Methods: In this open-label, single-arm study, we enrolled the refractory mCRC patients who received fluoropyrimidine, oxaliplatin, and irinotecan treatment and at least one targeted therapy previously. The doses of SL were 40–60 and 30 mg twice daily separately. They were administered for 7 days in a 2-week cycle. Treatment was continued until disease progression. Results: Of the 41 enrolled patients, 36 patients were evaluable with 61.1% disease control rate. The median progression-free survival and overall survival were 2.55 and 7.63 months, respectively. Regression change in tumor size stayed 10%–20% in five patients (13.9%) through 18 weeks after treatment, and two patients continued free from tumor progression at 30 and 42 weeks. Compared with moderate heavily pretreated mCRC patient subgroup (≤4 prior regimens), the severe heavily pretreated subgroup (≥5 prior regimens) showed similar disease control rate and survival benefit. Grade 3 or higher toxicities were documented only in 11 patients (26.8%). Conclusion: SL shows potential as a salvage regimen in refractory mCRC patients especially in the severe heavily pretreated setting and is well tolerated in these patients.