OpenOnco Handbook

Metastatic colorectal cancer: first-line biomarker reasoning

draft hcp_learner en

Deterministic learning chapter over OpenOnco KB entities, synthetic cases, and source records.

Learning objectives

  1. Prioritize MSI/MMR, RAS, BRAF, HER2, sidedness, and oligometastatic status before first-line mCRC treatment selection.
  2. Explain why MSI-H/dMMR disease takes precedence over routine chemotherapy backbones.
  3. Recognize when RAS wild-type left-sided disease and BRAF V600E disease push the learner toward different systemic strategies.

At a glance

  • mCRC first-line reasoning starts with resectability/oligometastatic status and molecular classification.
  • MSI-H/dMMR is treatment-defining and can route to pembrolizumab monotherapy in the OpenOnco model.
  • Extended RAS status and primary tumor sidedness gate EGFR-antibody eligibility.
  • BRAF V600E is a poor-prognosis signal; fit patients may need intensified chemotherapy reasoning.
  • The chapter is OpenOnco-authored educational content, not official ESMO or CME material.

Biomarker hierarchy

The mCRC first-line chapter treats MSI/MMR, extended RAS, BRAF V600E, HER2, and sidedness as pre-treatment gates. MSI-H/dMMR disease is evaluated before routine cytotoxic doublet or triplet selection.

Linked entities

ALGO-CRC-METASTATIC-1LALGO-CRC-METASTATIC-1LalgorithmsBIO-MSI-STATUSMSI status (MSI-H / MSI-L / MSS)biomarkersRF-CRC-MSI-H-ACTIONABILITYMSI-high / dMMR mCRC — treatment-defining biomarker. KEYNOTE-177 established pembrolizumab 1L over FOLFOX+bev (PFS 16.5 vs 8.2 mo). This RF intensifies toward the immunotherapy track and overrides the default RAS/BRAF-driven chemo algorithm. redflags

Section sources

  • SRC-NCCN-COLON-2025 NCCN Colon / Rectal Cancer
  • SRC-ESMO-CRC-2024 ESMO colorectal cancer guideline (2024) (TODO: confirm citation)
  • SRC-KEYNOTE-177-ANDRE-2020 Pembrolizumab versus Chemotherapy for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer

RAS and sidedness

RAS wild-type status is necessary but not sufficient for EGFR-antibody reasoning. The OpenOnco algorithm also expects left-sided primary tumor context before routing to the RAS-WT left-sided track.

Linked entities

RF-CRC-RAS-WTMetastatic colorectal cancer with RAS wild-type status: KRAS exon 2 (codons 12, 13), exon 3 (codons 59, 61), exon 4 (codons 117, 146) AND NRAS exon 2/3/4 ALL wild-type by NGS or extended-RAS PCR. Defines the ~50% of mCRC eligible for anti-EGFR monoclonal antibody therapy (cetuximab, panitumumab) when combined with chemotherapy backbone. Left-sided RAS-WT mCRC particularly benefits from 1L anti-EGFR + FOLFOX/ FOLFIRI (CALGB/SWOG-80405, FIRE-3, PRIME, CRYSTAL — survival benefit driven by left-sided primaries; right-sided RAS-WT does NOT benefit and routes to bevacizumab + chemo). redflagsIND-CRC-METASTATIC-1L-RAS-WT-LEFTIND-CRC-METASTATIC-1L-RAS-WT-LEFTindicationsREG-FOLFOX-CETUXFOLFOX + Cetuximabregimens

Section sources

  • SRC-NCCN-COLON-2025 NCCN Colon / Rectal Cancer
  • SRC-ESMO-CRC-2024 ESMO colorectal cancer guideline (2024) (TODO: confirm citation)

Common traps

Do not start with chemotherapy backbone choice before confirming MSI/MMR and RAS/BRAF status. Do not ignore liver-limited oligometastatic disease, obstruction or perforation risk, and frailty because they change the intent or feasibility of the plan.

Linked entities

RF-CRC-OLIGOMET-LIVER-DEFINITIONLiver-limited oligometastatic colorectal cancer (CRLM, colorectal liver metastases) — a distinct subset of stage IV CRC where intensified treatment with hepatic resection (or ablation) added to systemic chemo is potentially curative. Definition (per NCCN Colon v3.2025 + ESMO CRC 2024 + EORTC 40983 / Nordlinger 2008 trial framework): ≤5 liver metastatic lesions, all R0-resectable on multidisciplinary review, no extrahepatic disease, ECOG 0-1 fitness, controllable primary tumour. Triggers MDT (medical onc + hepatobiliary surgery + radiation onc + radiology) consideration of perioperative FOLFOX (or FOLFOXIRI in selected patients) + hepatic metastasectomy. Distinct from gastroesophageal OMEC-1 oligomet (RF-OLIGOMET-DEFINITION) — CRC oligomet uses ≤5 liver lesions (not ≤3 distant), restricts to liver only (extrahepatic excluded), and HER2-positive does NOT disqualify (anti-HER2 second-line track separate from periop intensification decision). redflagsRF-CRC-BRAF-V600E-POOR-PROGNOSISBRAF V600E mutation in mCRC: ~8-10% prevalence, poor prognosis (median OS halved vs BRAF-WT on standard chemo). Cetuximab/panitumumab ineffective. Encorafenib + cetuximab (BEACON CRC) is preferred 2L+; some 1L data favor FOLFOXIRI + bev intensification in MSS BRAF-mutant. redflagsRF-CRC-FRAILTY-AGEFrailty/age profile precluding doublet-intensive or triplet chemo: ECOG ≥3, OR (age ≥80 + Charlson ≥3), OR composite (age ≥75 + albumin <3.0 + ≥2 comorbidities). Triggers de-escalation toward 5-FU/LV mono, capecitabine mono, or best supportive care. redflags

Section sources

  • SRC-NCCN-COLON-2025 NCCN Colon / Rectal Cancer
  • SRC-ESMO-CRC-2024 ESMO colorectal cancer guideline (2024) (TODO: confirm citation)

Worked synthetic cases

  • patient_crc_metastatic_msi_h_pembro_mono MSI-H metastatic CRC - MSI-H first-line immunotherapy, biomarker hierarchy examples/patient_crc_metastatic_msi_h_pembro_mono.json
  • patient_crc_metastatic_ras_wt_left_folfox_cetux RAS-WT left-sided mCRC - RAS and sidedness, EGFR-antibody eligibility examples/patient_crc_metastatic_ras_wt_left_folfox_cetux.json

Practice questions

0 of 3 answered · 0 correct

Answers, score, and reasoning tags are kept in your browser session only and clear when you close this tab. Multi-select questions require every correct option (and no extras) for a credit.

Question 1 type_a intro HQ-CRC-MET-1L-001

In the OpenOnco mCRC first-line learning model, which biomarker state is evaluated before routine cytotoxic doublet selection?

Question 2 type_a intermediate HQ-CRC-MET-1L-002

A metastatic CRC case is extended-RAS wild-type. What additional clinical feature is modeled as important before routing to the RAS-WT left-sided EGFR-antibody track?

Question 3 type_k intermediate HQ-CRC-MET-1L-003

Which statements are true for OpenOnco first-line metastatic CRC reasoning?