Table 2.
Selected trial data for emerging biomarkers of response/resistance to standard treatments in mCRC
| Biomarker | References | No. of patients | Prior therapy | Treatment | Key findings |
|---|---|---|---|---|---|
| HER2 | [83] | 135 | Anti-EGFR therapy | Anti-EGFR therapy | Median PFS in patients receiving anti-EGFR therapy was significantly shorter in those with amplified compared with non-amplified HER2 tumours (2.9 vs 8.1 months, HR 5.0; p < 0.0001). These findings were confirmed in a second cohort: median PFS 2.8 vs 9.3 months (HR 6.6; p < 0.0001) |
| CA-2008-0012; NCT00853931 [185] | 34 | CT, Bev | Pmab | The level of HER2 protein expression was significantly associated with resistance to Pmab; HER2 was overexpressed in 4/11 non-responding and 0/21 responding cases (p = 0.035) | |
| HER3 | PICCOLO; ISRCTN93248876 [91] | 308 | Fluoropyrimidine ± oxaliplatin ± Bev | Pmab + Ir or Ir alone | High HER3 was predictive of Pmab benefit. In patients with high HER3 expression, median PFS was 8.2 months (Pmab + Ir) vs 4.4 months (Ir) (HR 0.33; 95% CI 0.19–0.58; p < 0.001). Patients with low HER3 expression gained no benefit in PFS: 3.3 months (Pmab + Ir) vs 4.3 months (Ir) (HR 0.96; 95% CI 0.67–1.38; p = 0.84), with significant interaction (p = 0.002). The binary model was also predictive for OS, with significant interaction (p = 0.01) |
| miR-31-3p | [97, 99] | 132 | FOLFOX/FOLFIRI/anti-EGFR | NA |
miR-31-3p expression level was significantly associated with PFS and OS In one study, statistical models based on miRNA expression discriminated between high and low risk of progression. PFS of high- and low-risk patients was 9 and 35.3 weeks, respectively (HR 4.10, 95% CI 1.3–13.2; p = 0.018) |
| New EPOC trial; NCT00482222 [98] | 149 | Adjuvant CT | Cmab + CT or CT alone | Median PFS for mid or high miR-31-3p expression was shorter in the Cmab vs the CT arm (26.7 vs 12.3 months, HR 2.28, 95% CI 1.27–4.09; p = 0.006). Low miR-31-3p expressors had similar outcomes irrespective of treatment (HR 1.06, 95% CI 0.43–2.61; p = 0.9) | |
| FIRE-3; NCT00433927 [99] | 340 | No prior systemic therapy | Cmab + FOLFIRI or Bev + FOLFIRI | Low miR-31-3p expressors had a significantly better OS (HR 0.61, 95% CI 0.41–0.88; p < 0.01; median OS: 39.4 vs 27.4 months, respectively), PFS (HR 0.74, 95% CI 0.55–1.00, p = 0.05; median PFS: 11.8 vs 10.5 months) and ORR (OR 4.0, 95% CI 1.9–8.2; p < 0.01) when treated with FOLFIRI plus Cmab as compared to FOLFIRI + Bev. miR-31-3p is predictive of Cmab effect on OS (p = 0.07), PFS (p = 0.08) and ORR (p = 0.06) | |
| HPP1-methylated free-circulating DNA | AIO‐KRK‐0207; NCT00973609 [161] | 467 | NR | Bev + CT or Bev alone or no maintenance | Patients with reduced HPP1-methylated free-circulating DNA after administration of combination CT had better OS compared with those with continued detectable levels of HPP1-methylated free-circulating DNA (p < 0.0001). |
Bev bevacizumab, CI confidence interval, Cmab cetuximab, CT chemotherapy, EGFR epidermal growth factor receptor, FOLFIRI leucovorin, fluorouracil, and irinotecan, FOLFOX leucovorin, fluorouracil, and oxaliplatin, HER human epidermal growth factor, HR hazard ratio, Ir irinotecan, mCRC metastatic colorectal cancer, miRNA microRNA, NA not applicable, NR not reported, OR odds ratio, ORR objective response rate, OS overall survival, PFS progression-free survival, Pmab panitumumab