Benefit from anti-EGFRs in RAS and BRAF wild-type metastatic transverse colon cancer: a clinical and molecular proof of concept study

Abstract

Objective: Primary tumour location is regarded as a reliable surrogate of colorectal cancer biology. Sensitivity to anti-EGFRs (Epidermal Growth Factor Receptor) of metastatic transverse colon cancers (mTCCs) has usually been assumed similar to right-sided tumours; however, evidence about the clinical behaviour of mTCC is limited. Thus, to verify sensitivity of mTCC to anti-EGFRs we conducted the present study.

Methods: Patients with RAS/BRAF wild-type microsatellite stable (MSS) mTCC receiving anti-EGFR monotherapy, or in combination with irinotecan if clearly irinotecan-refractory, were included. Hypothesising an overall response rate (ORR) of 35%, 11 patients, of whom at least 3 were responders, were necessary to be able to reject the null hypothesis of an ORR of 5%, with α and β errors of 0.05 and 0.20. PRESSING panel and consensus molecular subtypes (CMS) were assessed on tumour samples, whereas in-silico data were obtained from TCGA dataset.

Results: Among nine eligible patients, four and three achieved response and disease stabilisation (ORR 44%). At a median follow-up of 23.1 months, median progression-free survival and overall survival were 7.3 (95% CI 3.9 to NA) and 15.0 months (95% CI 10.0 to NA), respectively. A MET amplification and an ERBB4 S303F substitution were detected in patients with rapid disease progression, while others had PRESSING panel-negative tumours with CMS2 or CMS4 subtypes.

Conclusions: RAS/BRAF wild-type MSS mTCCs may be sensitive to anti-EGFRs, as confirmed by molecular analyses.

Keywords: CMS subtypes; PRESSING panel; anti-EGFR, RAS and BRAF mutations; transverse colon cancer.

Figure 1

Consort diagram of the study depicting the process of patients’ selection. A total of 401 patients with RAS and BRAF wild-type mCRC treated with an anti-EGFR containing regimen were reviewed. After screening for primary tumour location, 24 patients with mTCC were identified, of whom 9 received an anti-EGFR as single agent or in combination with irinotecan if clearly irinotecan-refractory and were included. mCRC, metastatic colorectal cancer; mTCC, metastatic transverse colon cancer.

Figure 2

Kaplan-Meier curves for PFS (panel A) and OS (panel B) of patients with mTCC receiving an anti-EGFR based therapy. mTCC, metastatic transverse colon cancer; OS, overall survival; PFS, progression-free survival.

Figure 3

(A) Bar plot showing the frequency of pressing panel negative and positive in the KRAS and BRAF wt cases of COAD and READ TCGA datasets. (B) Bar plot showing the frequency of CMS classes in the KRAS and BRAF wt and pressing panel positive cases of COAD and READ TCGA datasets. Numbers of cases are reported on the top of each bar. COAD, colon adenocarcinoma; READ, rectum adenocarcinoma.