Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial

Abstract

Background: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. Patients and Methods: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. Results: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n ¼ 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right-versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P ¼ 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy. Conclusions: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making. The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.

Tumour immune microenvironment biomarkers predicting cytotoxic chemotherapy efficacy in colorectal cancer

“…The same group repeated the analysis using patients enrolled on the MOSAIQ trial (adjuvant CAPOX vs capecitabine) but did not find any association, 125 which may be due to different fluoropyrimidine use or oxaliplatin schedule, which have shown different interactions in other immune biomarker studies. 36 CMS1 patients have worse OS with FOLFIRI-based regimes compared with the other CMS subtypes in the FIRE-3 trial 126 ; however, they also show improved OS with the addition of bevacizumab in the metastatic setting. 127 Published studies suggest a trend to 5FU/oxaliplatin resistance in CMS4 (or similar classifier) patients, both in the adjuvant 127 128 and metastatic setting, 129 where first-line irinotecan regimes showed better response rates and survival.…”

AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

“…The CMS4 subtype presents with the poorest clinical outcome and is associated with features such as high stroma infiltration, activated transforming growth factor β (TGFβ) signalling and epithelial-mesenchymal transition (EMT) [ 11 ]. Compared to other CMS, CMS4 tumours are more resistant to chemo- and targeted therapies currently used in the clinic [ 5 , 6 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The aggressive nature of this subtype combined with its refractory response to therapy highlight the need to better understand the biological behaviour that distinguishes it from other subtypes.…”

HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome

“…5a, b ). Besides, exploratory analysis of previous trials such as FIRE-3 trial (first-line therapy with FOLFIRI 44 plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic CRC patients) and CALGB/SWOG 80405 45 (a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC), showed CMS classification is prognostic for mCRC; however, at present time has no direct impact on clinical decision-making and may need further refinement. Therefore, we propose the addition of median.hERV high subtype of CRC to CMS can facilitate clinical decision-making and improve CMS classification for patient selection.…”