Colorectal cancer

Overview

• Epidemiology (US 2025): ~154,000 new cases (colon + rectal); ~53,000 deaths. Second leading cause of cancer death in the US; affects men and women roughly equally. 5-yr relative survival ~90% for localized, ~15% for distant disease. Anatomic distribution has shifted proximally over recent decades, with a sharp rise in rectal cancer and CRC overall in adults <50.
• Risk factors: age, family hx, IBD (ulcerative colitis > Crohn: ~5 to 10% risk by 20 yr; high synchronous cancer rate), hereditary syndromes, obesity, red/processed meat, alcohol, smoking, low fiber, sedentary. HRT is protective in women. Prior adenomatous polyps confer ~3% subsequent cancer risk.
• Hereditary CRC (~5 to 10%):
  • Lynch syndrome (HNPCC): MLH1, MSH2, MSH6, PMS2, EPCAM (EPCAM deletion silences MSH2). Autosomal dominant, high penetrance; most common hereditary CRC syndrome (~3% of CRC; ~20% of dMMR/MSI-H CRC). Right-sided, mucinous, MSI-H, early onset (median age 45). Also endometrial, ovarian, gastric, pancreatic, biliary, urothelial, small bowel. Diagnosed by Amsterdam/Bethesda criteria historically, but a push exists for universal germline testing in all CRC. Screening colonoscopy q1 to 2 yr from age 20 to 25 (MLH1/MSH2/EPCAM); MSH6/PMS2 start age 30 to 35, q1 to 3 yr.
  • FAP: APC (key Wnt-pathway regulator; loss of APC frees β-catenin to drive oncogene transcription). Hundreds to thousands of polyps; ~100% lifetime CRC risk if untreated (mean age at CRC dx ~39). ~0.5 to 1% of all CRC, but somatic APC/β-catenin mutations are found in 80 to 85% of sporadic CRC. Prophylactic colectomy; screening colonoscopy from age ~10.
  • MUTYH-associated polyposis (MAP): autosomal recessive.
  • Peutz-Jeghers (STK11), juvenile polyposis (SMAD4, BMPR1A), serrated polyposis.
• Screening (USPSTF 2021 / ACS): start at age 45 (was 50). Colonoscopy q10 yr (gold standard); FIT annually; multitarget stool DNA (Cologuard) q3 yr, CT colonography also options. Multitarget stool DNA is more sensitive than FIT for CRC (92.3% vs 73.8%) and for advanced precancerous lesions (42.4% vs 23.8%). Shorter intervals for inherited syndromes, IBD, prior polyps/CRC, and strong family history (one first-degree relative <60 or two at any age: start by age 40 or 10 yr before youngest case, then q5 yr).

Carcinogenesis pathways and molecular subtypes

• Three key pathways: CIN (chromosomal instability: early APC, TP53, KRAS mutations; ~85% of CRC), MSI (loss of MMR gene function → microsatellite instability), and CIMP (CpG island methylation: hypermethylation of promoters such as MGMT; overlaps with MSI via MLH1 hypermethylation).
• Adenoma-to-carcinoma sequence: stepwise accumulation of mutations (APC → KRAS → TP53) drives progression from normal mucosa to invasive cancer.

Note: apart from CMS1, these subtypes are not yet used in routine clinical decision-making.

Workup & staging

• Colonoscopy with full bowel evaluation (synchronous lesion in ~5%).
• Imaging: CT chest/abdomen/pelvis. Pelvic MRI for rectal ca.
• Biomarkers (mandatory):
  • MMR/MSI on all CRC tissue (implications for early-stage adjuvant decisions and for checkpoint-inhibitor eligibility in advanced disease).
  • Extended RAS (KRAS + NRAS exons 2, 3, 4) + BRAF V600E on all metastatic CRC before anti-EGFR therapy is considered.
  • HER2 IHC/ISH (esp. if RAS/BRAF WT).
  • NTRK fusions (rare).
  • CEA baseline + monitor.
• MMR/MSI testing methods and terminology:
  • dMMR = loss of nuclear expression of ≥1 MMR protein on IHC: paired MLH1/PMS2 or MSH2/MSH6 loss, or isolated PMS2 or isolated MSH6 loss. MSI-H = instability in ≥2 of 5 core (Bethesda) microsatellite markers by PCR, or by NGS. dMMR and MSI-H are used interchangeably but are technically not identical.
  • MSI-H = dMMR; MSI-L = pMMR = MSS.
  • Somatic vs germline: germline mutation in MLH1/MSH2/MSH6/PMS2 defines Lynch but does NOT by itself determine immunotherapy eligibility (not all Lynch tumors are MSI-H); tumor dMMR/MSI status is what is needed. ~20% of dMMR/MSI-H CRC is germline (Lynch); the rest are sporadic.
  • MLH1 promoter hypermethylation silences MLH1 in sporadic tumors. If MLH1 is lost on IHC, reflex to BRAF V600E and/or MLH1 promoter methylation testing: if positive, favors sporadic rather than Lynch. Sporadic dMMR tumors often also lack PMS2 and carry BRAF mutation.
• Prevalence of dMMR/MSI-H by stage: ~15% stage II, ~8% stage III, ~4 to 5% stage IV.
• Staging (AJCC 8th, 2017):
  • Stage I (T1-2N0): surgery alone.
  • Stage II: T3-4N0; subdivide IIA/B/C. T4b = invasion/adherence to other organs.
  • Stage III: N+ disease. N1c = tumor deposits without positive nodes (risk-equivalent to N1); nodal micrometastases (>0.2 mm) count as node-positive.
  • Stage IV: metastatic. M1c = peritoneal metastases (stage IVC).
• Circulating tumor DNA (ctDNA): 130 to 150 bp fragments, short half-life (up to ~2.5 h), a real-time marker of tumor burden. Postoperative detection of minimal residual disease (MRD) is highly specific with high PPV (~90 to 100%) for occult micrometastasis and gives a median lead-time of ~8 to 9 months. Sensitivity depends on tumor volume; clinical utility for escalation/de-escalation of adjuvant therapy is under study.

Localized CRC, colon (stages I to III)

• Hemicolectomy with regional LN (≥12 LN required for adequate staging).
• Right colon ca: hemicolectomy with ileocolic anastomosis.
• Stage 0 (carcinoma in situ / intramucosal): endoscopic resection usually curative, but nodes are not assessed.

• Standard adjuvant cytotoxic classes: fluoropyrimidine (5-FU or capecitabine) and oxaliplatin; checkpoint inhibition (atezolizumab + FOLFOX, ATOMIC) is emerging for stage III dMMR. NO irinotecan, bevacizumab, or anti-EGFR (cetuximab), regardless of RAS status, in the adjuvant setting. Individualize oxaliplatin in older adults: fit patients >70 can receive FOLFOX/CAPOX (similar time-to-recurrence benefit); weigh neuropathy risk, comorbidity, and recurrence risk rather than applying an age cutoff.
• Stage II:
  • Low-risk (no high-risk features): observation OR consider 6-mo capecitabine/5-FU (counsel on low absolute benefit).
  • High-risk features: T4, <12 LN sampled, perforation, obstruction, LVI, perineural invasion, poorly differentiated/undifferentiated histology (interpreted in MSI context), close/R1 margins, high-tier tumor budding → consider adjuvant chemo (FOLFOX/CAPOX or fluoropyrimidine alone); offer for T4, oxaliplatin benefit in stage II unproven, individualize.
  • dMMR/MSI-H stage IIA: excellent prognosis (>95% long-term DFS); do NOT benefit from and may be HARMED by 5-FU monotherapy → observation. dMMR/MSI-H stage IIB/IIC should still receive a fluoropyrimidine + oxaliplatin.
  • Gene-expression signatures (Oncotype DX Colon, ColoPrint) are prognostic but not predictive of chemo benefit; not routinely recommended.
• Stage III:
  • MOSAIC trial: FOLFOX vs 5-FU/LV. Stage III ↑ OS with FOLFOX (~67% vs ~59%, delta ~8%); benefit greater in N2 (delta ~12%) than N1 (delta ~6%). No oxaliplatin benefit in stage II. NSABP C-07 and XELOXA confirmed the oxaliplatin role.
  • Adjuvant FOLFOX or CAPOX is standard. 5-FU/LV or capecitabine alone if oxaliplatin contraindicated (neuropathy).
  • IDEA collaboration (12,834 pts): 3 vs 6 months of oxaliplatin-based adjuvant. Noninferiority not formally met overall (absolute 3-yr DFS difference only 0.9%; 5-yr OS ~82% both), but grade ≥2 neurotoxicity much lower with 3 months. For low-risk (T1-3, N1): 3 months = 6 months, so 3 months (CAPOX often favored) is reasonable. For high-risk (T4 or N2): 6 months preferred. Beyond 75% of planned cycles, oxaliplatin may be stopped for neuropathy without loss of benefit (fluoropyrimidine is the mainstay). PPI effect on capecitabine is uncertain; a randomized crossover PK trial found esomeprazole did not reduce capecitabine exposure.
  • Adjuvant atezolizumab + FOLFOX (ATOMIC = Alliance A021502, Sinicrope ASCO 2025 Plenary): stage III dMMR colon ca; 3-yr DFS 86.4% vs 76.6% (HR 0.50). Emerging SOC for adjuvant dMMR stage III; FDA priority review (decision expected Oct 2026). Paradigm shift toward IO-based adjuvant in dMMR.
  • NICHE-2 (Chalabi NEJM 2024): neoadjuvant ipilimumab 1 mg/kg x1 + nivolumab 3 mg/kg x2 (2 wk apart), then surgery in non-metastatic dMMR colon ca → near-100% pathologic response (95% MPR, 68% pCR), 3-yr DFS 100%. Proof-of-concept for neoadjuvant IO in dMMR (all patients had surgery, pathologic response assessed at resection), not an organ-sparing nonoperative strategy; not yet SOC but increasingly considered.
  • ctDNA-guided therapy (DYNAMIC, stage II): postop ctDNA-positive → adjuvant chemo; ctDNA-negative → can omit chemo. Investigational; not yet routine.
• DPD deficiency: a patient with severe grade 3 to 4 diarrhea, mucositis preventing eating, fever, and grade 4 neutropenia after 5-FU/FOLFOX → test for dihydropyrimidine dehydrogenase (DPD) deficiency. DPD is the rate-limiting enzyme converting 5-FU to dihydrofluorouracil; deficiency causes 5-FU accumulation and severe toxicity. FDA boxed warning (label change Oct 2025; FDA safety communication Feb 2026): test for DPYD variants BEFORE starting capecitabine or 5-FU unless immediate treatment is necessary; avoid in complete DPD deficiency.
• Lifestyle: exercise ↑ OS and PFS; vitamin D: phase II SUNSHINE PFS signal, but phase III SOLARIS (A021703) negative, so no established PFS benefit.
• Appendiceal adenocarcinoma: ≥T2 or high-grade features → right hemicolectomy for staging. Adjuvant FOLFOX is for node-positive (stage III) or selected high-risk stage II disease, not completely resected T2N0 (stage I). Use CT TAP, not PET.

• Surveillance colonoscopy for all stages: at 1 yr after surgery; if no adenoma, next at 3 yr (4 yr postop), then 5 yr (9 yr postop). If advanced adenoma found, repeat in 1 yr; for nonadvanced adenoma base interval on polyp findings.
• Stage II and III: add H&P q3 to 6 mo, CEA q3 to 6 mo, and CT TAP q6 to 12 mo.

Metastatic CRC, first-line

• MSI-H/dMMR CRC carries 10 to 100× the somatic mutation load of MSS tumors, with dense lymphocytic infiltrate: excellent responsiveness to checkpoint inhibitors and good overall prognosis, but ↓ response to 5-FU chemo. More common on the right, poorly differentiated/mucinous.
• 1L nivolumab + ipilimumab (CheckMate 8HW): 79% reduction in progression vs chemo (HR 0.21). FDA Apr 2025.
• Pembrolizumab (KEYNOTE-177): 1L pembro 200 mg q3wk vs investigator-choice mFOLFOX6/FOLFIRI ± bev or cetuximab. mPFS 16.5 vs 8.2 mo (HR 0.60); 24-mo PFS 48% vs 19%; ORR 43.8% vs 33.1% (11% CR with pembro). OS not statistically significant at final analysis (HR 0.74, prespecified threshold not met), largely due to ~60% crossover.
• KEYNOTE-177 5-yr update (André, Ann Oncol 2025): sustained PFS benefit for pembro vs chemo ± bev in 1L dMMR mCRC; 5-yr PFS 34% vs 11%. mOS 77.5 vs 36.7 mo (HR 0.73) trended in favor of pembro but not adjusted for crossover. NCCN Category 1 preferred alongside CheckMate 8HW.
• CheckMate-142 (pretreated dMMR mCRC): single-agent nivolumab ORR 34% (CR 9%); nivo + ipi ORR 55%, disease control 80% (non-randomized comparison).
• Avoid chemo as 1L in dMMR/MSI-H (significantly inferior). Do NOT routinely use checkpoint inhibitors in unselected pMMR/MSS CRC; exception: pathogenic POLE/POLD1 proofreading-deficient (ultramutated) tumors can respond. TMB-high alone does not reliably predict benefit in MSS CRC.

• Historical benchmarks: 5-FU/LV alone ORR ~20%, mOS ~10 to 12 mo. Adding oxaliplatin/irinotecan raised mOS toward ~24 mo when patients receive sequential active lines. Infusional (not bolus) fluoropyrimidine is superior, especially with irinotecan; oxaliplatin is ineffective as a single agent.
• FOLFOX ORR ~50%, mOS ~16 mo (neuropathy). FOLFIRI ORR ~40 to 50%, mOS ~17 mo (diarrhea). FOLFOX and FOLFIRI are equivalent; choose by expected toxicity, and expose the patient to all active agents over the course of therapy.
• FOLFOXIRI triplet (fit patients / high burden / conversion-to-resection): TRIBE FOLFOXIRI + bev vs FOLFIRI + bev → mOS 29.8 vs 25.8 mo (HR 0.80), 5-yr survival doubled (25% vs 12.5%), with a nonsignificant signal of benefit in BRAF-mutant. OLIVIA and STEAM confirmed higher response and liver-resection rates. TRIBE2: upfront FOLFOXIRI + bev with reinduction vs sequential FOLFOX/bev → FOLFIRI/bev → ORR 62% vs 50%, mPFS2 19.2 vs 16.4 mo (HR 0.74). Reserve for those needing rapid/deep response, given added toxicity.

• Bevacizumab (anti-VEGF): chemo + bev ↑ OS (HR ~0.77) and PFS (HR ~0.66); at progression, continue bev and switch the chemo backbone (ML18147: bev beyond progression ↑ OS, HR 0.81). Ziv-aflibercept and ramucirumab give similar beyond-progression benefit. Fluoropyrimidine + bev is preferred for maintenance; bev alone was non-inferior for the primary endpoint in AIO 0207 and can be considered if fluoropyrimidine is not tolerated; bev monotherapy is not standard later-line salvage.
  • Bevacizumab AEs: grade 3 to 4 HTN, proteinuria/nephrotic syndrome (check UA), impaired wound healing (stop ≥6 wk before surgery; half-life ~3 wk), bleeding, arterial and venous thromboembolism, and (key in CRC) bowel perforation. Relieve a clinically significant obstruction first (surgery, diversion, or selected stenting); start systemic therapy after stabilization and avoid bevacizumab during active obstruction / until surgical healing.
• Anti-EGFR (cetuximab, panitumumab): RAS WT required for conventional anti-EGFR (chemo combinations without a matched inhibitor); exceptions: cetuximab + encorafenib (BRAF V600E) and anti-EGFR + KRAS G12C inhibitors, and some class III BRAF mutants. RAS mutations (~40 to 55%) cause constitutive downstream signaling and negate EGFR blockade. CRYSTAL (FOLFIRI ± cetuximab): in KRAS exon 2 WT, response 57% vs 40%, mPFS 9.9 vs 8.4 mo, mOS 23.5 vs 20 mo. PRIME (FOLFOX ± panitumumab): similar. Do NOT combine anti-EGFR with bevacizumab (antagonistic).
  • Anti-EGFR AEs: acneiform rash (~20% grade 3-4 vs 0.2%), grade 3-4 diarrhea, hypomagnesemia, hypersensitivity (esp. chimeric cetuximab). STEPP trial: preemptive oral doxycycline + topical corticosteroid reduced skin toxicity to 29% (vs 62% reactive); use preemptively in all patients.
• Sidedness (CALGB/SWOG 80405, FIRE-3, CRYSTAL): mnemonic "Right is Bright: more BRAF, more MSI-H, give Bev"; Right has more KRAS (plus BRAF, MSI-H); left is more often RAS/BRAF WT, so if RAS/BRAF WT and MSS, give anti-EGFR + FOLFOX (more HER2+).
  • Left-sided RAS/BRAF WT (splenic flexure to rectum): anti-EGFR preferred (OS advantage; left has WT BRAF, more copy-number change/CIN).
  • Right-sided RAS/BRAF WT (cecum to hepatic flexure): bevacizumab preferred; do NOT use anti-EGFR 1L even if RAS WT. Right tumors are enriched for BRAF V600E, MSI, hypermutation, CIMP.
  • RAS-mutant: bevacizumab + chemo; anti-EGFR contraindicated.

• BRAF V600E mutant (~5 to 10%): right-sided, poor prognosis (mOS historically only ~12 to 14 mo), mutually exclusive with RAS, enriched in MSI-H. Does NOT respond to cetuximab alone (BRAF is downstream of EGFR). BEACON: encorafenib + cetuximab (doublet) vs triplet (+ binimetinib) vs FOLFIRI + cetuximab → mOS 9.3 mo for both doublet and triplet vs 5.9 mo control; adding a MEK inhibitor does not help, so the doublet (encorafenib + cetuximab) is preferred and better tolerated. Historically used 2L; do not switch to FOLFIRI/bev in this setting.
  • BREAKWATER (Kopetz Nat Med 2025 for ORR; Elez NEJM 2025 for PFS/OS): encorafenib + cetuximab + mFOLFOX6 1L vs chemo ± bev → mPFS 12.8 vs 7.1 mo (HR 0.53), mOS 30.3 vs 15.1 mo (HR 0.49). FDA Dec 20, 2024 (accelerated) → Feb 24, 2026 (traditional). New SOC 1L for BRAF V600E mCRC.
  • Non-V600E ("atypical") BRAF mutations (2 to 3%) are class II (RAS-independent) or III (RAS-dependent); class II respond poorly to anti-EGFR, but RAS-WT class III are EGFR-dependent and can respond (~50% vs ~8% class II); OS may be better than V600E.
• HER2-amplified (~2 to 5% mCRC, RAS-WT enriched): HERACLES (trastuzumab + lapatinib, KRAS-WT/HER2-amplified): ORR 30%, DCR 74% even in heavily pretreated. MyPathway (trastuzumab + pertuzumab): ORR ~30 to 38%. Tucatinib + trastuzumab (MOUNTAINEER, Strickler Lancet Oncol 2023): ORR 38%, mPFS ~8 mo; FDA Jan 19, 2023 for HER2+ RAS-WT mCRC after fluoropyrimidine + oxaliplatin + irinotecan. Trastuzumab deruxtecan (T-DXd) (DESTINY-CRC01 ORR 45%; DESTINY-CRC02 ORR 38% at 5.4 mg/kg): part of pan-tumor accelerated approval FDA Apr 5, 2024 for HER2 IHC 3+ solid tumors after prior therapy.
• KRAS G12C (~3 to 4% mCRC): Sotorasib + panitumumab (CodeBreaK 300, Fakih NEJM 2023): mPFS 5.6 mo at 960 mg; FDA Jan 16, 2025 after fluoropyrimidine + oxaliplatin + irinotecan. Adagrasib + cetuximab (KRYSTAL-1): ORR 34%; FDA accelerated approval (Jun 2024) after fluoropyrimidine + oxaliplatin + irinotecan.
• NTRK fusion (rare): larotrectinib, entrectinib.

Metastatic CRC, later lines / salvage

• Trifluridine/tipiracil (TAS-102): FTD (cytotoxic, incorporated into DNA) + tipiracil (thymidine-phosphorylase inhibitor preventing FTD degradation). RECOURSE: mOS 7.1 vs 5.3 mo vs placebo; main toxicity neutropenia (~40%). + bevacizumab (SUNLIGHT): mOS 10.8 vs 7.5 mo, new SOC for refractory mCRC (FDA Aug 2023).
• Regorafenib: multikinase TKI (VEGFR1-3, KIT, RET, FGFR1-2, PDGFR-β, BRAF). CORRECT: mOS 6.4 vs 5.0 mo (HR 0.77); CONCUR (Asian pts): 8.8 vs 6.3 mo (HR 0.55) vs placebo. Main AEs: hand-foot skin reaction, fatigue, diarrhea, HTN. ReDOS: dose ramp-up (80 mg → 160 mg) has similar activity with fewer AEs.
• Fruquintinib (FRESCO-2): mOS 7.4 vs 4.8 mo. FDA Nov 2023.
• Sequence: FOLFOX/FOLFIRI ± bev or anti-EGFR → switch chemo backbone (continue anti-VEGF beyond progression) → trifluridine/tipiracil + bev → regorafenib OR fruquintinib. Regorafenib and TAS-102 have similar efficacy but different toxicity (choose by AE profile).
• Anti-EGFR rechallenge (CHRONOS; REVERCE is a sequencing trial, regorafenib then cetuximab vs reverse without prior anti-EGFR, not a rechallenge trial): if RAS WT and ctDNA RAS WT, modest activity in selected cases.

• Oxaliplatin's limiting toxicity is cumulative neuropathy. OPTIMOX1: oxaliplatin can be dropped after ~6 cycles with continued 5-FU maintenance and reintroduced at progression. OPTIMOX2/MRC COIN: complete treatment breaks without selection may be detrimental → maintenance is preferred over full stop.
• CAIRO3: after induction CAPOX + bev, maintenance capecitabine + bev outperformed a chemo-free interval. VALENTINO/PANAMA: after FOLFOX + panitumumab induction, maintenance with 5-FU + panitumumab beats panitumumab alone or 5-FU alone. Induction-maintenance (limited oxaliplatin upfront, then fluoropyrimidine + targeted agent) is a standard approach.
• Elderly not fit for oxaliplatin/irinotecan (AVEX): capecitabine + bevacizumab vs capecitabine alone → mPFS 9.1 vs 5.1 mo (HR 0.53), mOS 20.7 vs 16.8 mo. Acceptable SOC for older patients without contraindications to bev.

Oligometastatic and special situations

• Resectable / potentially resectable mets: always evaluate for potentially curative metastasectomy at a high-volume center. 5-yr survival after hepatic resection ~30 to 40% in pooled series, up to ~50 to 60% in selected modern series (worse with multiple lesions, short disease-free interval, prior stage III). R0 resection after conversion chemo approaches survival of initially resectable disease.
• Perioperative chemo for resectable liver mets: EORTC 40983 (perioperative FOLFOX): ITT 3-yr PFS 35.4% vs 28.1%, HR 0.79, p=0.058 (NS); eligible-patient analysis 36.2% vs 28.1%, HR 0.77, p=0.041 but no OS benefit at long follow-up; JCOG 0603 (adjuvant FOLFOX after liver-met resection) improved DFS (HR 0.67) but not OS. Benefit of chemo for clearly resectable disease is low. Cetuximab was detrimental in the perioperative setting (UK New EPOC); bevacizumab must be stopped ~6 wk before surgery.
• Liver-directed therapy: hepatic arterial infusion (HAI, e.g. FUDR) and Y-90 radioembolization improve liver-specific response/PFS but have NOT improved OS in meta-analyses/randomized trials; reserve for selected patients at experienced centers. Conversion chemo (FOLFOXIRI + bev for high-risk) can downstage to resection.
• Peritoneal carcinomatosis: PRODIGE 7 (ACCORD-15) showed HIPEC (oxaliplatin) added no OS benefit to cytoreductive surgery (mOS >41 mo both arms; 5-yr ~40%). Cytoreductive surgery is an option at specialized centers; HIPEC is not routinely recommended.
• Hereditary CRC management: early aggressive screening; risk-reducing colectomy for FAP; consider hysterectomy + BSO in Lynch (esp. postmenopausal). UC-associated cancer or confirmed dysplasia: total proctocolectomy (subtotal leaves an at-risk rectum). Individualize visible, completely resected dysplasia (surveillance possible); Crohn extent is individualized.

High-yield CRC pearls

• Test all CRC for MMR/MSI; metastatic: add extended RAS + BRAF + HER2 (if RAS WT).
• USPSTF 2021: screen at 45.
• IDEA: low-risk stage III (T1-3, N1) → CAPOX × 3 mo OK; T4/N2 → 6 mo.
• MOSAIC: FOLFOX benefits stage III (not stage II) for OS.
• Sidedness: left RAS/BRAF WT → anti-EGFR; right → bev. Right is Bright (BRAF, MSI-H, Bev).
• Adjuvant setting: NO irinotecan, bev, or cetuximab. Oxaliplatin benefit smaller >70; individualize by fitness, not a strict age cutoff.
• CheckMate 8HW / KEYNOTE-177: IO 1L for dMMR mCRC; avoid chemo 1L in dMMR.
• BREAKWATER: enco + cetux + FOLFOX 1L for BRAF V600E; BEACON doublet (enco + cetux) in later lines; no MEKi benefit.
• Sotorasib + panitumumab (CodeBreaK 300): KRAS G12C. Tucatinib + trastuzumab (MOUNTAINEER): HER2+ RAS-WT.
• Trifluridine/tipiracil + bev (SUNLIGHT); regorafenib (ReDOS ramp-up); fruquintinib (FRESCO-2) in refractory disease.
• DPD deficiency: severe 5-FU toxicity (mucositis, diarrhea, grade 4 neutropenia).
• Bevacizumab: bowel perforation risk (treat obstruction first), stop 6 wk before surgery.
• Lynch: dMMR, right-sided, mucinous; Bethesda/Amsterdam criteria. FAP: APC; prophylactic colectomy.
• Liver mets resection can be curative (5-yr OS ~25 to 60% post-metastasectomy).