Teaching pack: Colorectal cancer

Colorectal cancer is the third most common cancer and second leading cause of cancer death worldwide (about 1.9 million cases and 900,000 deaths a year). It is the disease where screening works best: removing adenomas at colonoscopy prevents cancer, and stool and blood tests catch it early. Most cases arise through the adenoma-carcinoma sequence driven by APC loss, KRAS mutation, and TP53 loss (chromosomal instability); about 15% arise through mismatch-repair deficiency (dMMR/MSI-high), either sporadically via MLH1 methylation or through Lynch syndrome. Incidence is rising sharply in adults under 50 for reasons that remain unexplained.

Treatment splits along biology. Localised disease is cured by surgery, with adjuvant FOLFOX or CAPOX for stage III (3 months suffices for low-risk disease) and, since ATOMIC (2025), atezolizumab added for dMMR stage III. Rectal cancer uses total neoadjuvant therapy with chemoradiation and increasingly organ preservation; dMMR rectal cancer can be treated with six months of dostarlimab and no surgery at all (AZUR-1, FDA priority review). Metastatic disease is stratified by RAS, BRAF, HER2, MSI, and sidedness: left-sided RAS/BRAF wild-type tumours get chemotherapy with an EGFR antibody (PARADIGM); others get bevacizumab; BRAF V600E disease gets encorafenib + cetuximab + chemotherapy first line (BREAKWATER, OS doubled to 30 months); KRAS G12C disease gets sotorasib or adagrasib with an EGFR antibody; HER2-amplified disease gets tucatinib + trastuzumab or T-DXd; dMMR disease gets pembrolizumab or nivolumab + ipilimumab first line, with 5-year survival above 50%. Later lines: trifluridine/tipiracil + bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2), regorafenib. Liver-limited metastases are resected or ablated with curative intent in a meaningful minority.

• ctDNA-guided adjuvant therapy.
• Immunotherapy cures in dMMR without surgery.
• First-line targeted therapy for BRAF V600E.
• dMMR disease: immunotherapy first line gives median OS over 6 years (KEYNOTE-177); neoadjuvant IO achieves 68% pCR and 100% 3-year DFS in colon (NICHE-2) and complete organ preservation in rectal cancer (dostarlimab, AZUR-1).
• BRAF V600E first-line targeted triplet doubled survival to 30 months (BREAKWATER); full approval in 2026.
• Adjuvant atezolizumab for dMMR stage III colon cancer halves recurrence (ATOMIC, 2025): the first adjuvant IO success in CRC.

1. 19575-Fluorouracil synthesised
2. 1988Vogelstein's adenoma-carcinoma sequence
3. 1990MOSAIC and the adjuvant era; Lynch syndrome genes identified (1993)
4. 2000Irinotecan and oxaliplatin combinations
5. 2004Bevacizumab and cetuximab approved
6. 2004Bevacizumab and cetuximab approved
7. 2008KRAS mutation predicts anti-EGFR failure
8. 2014Extended RAS and sidedness
9. 2015Consensus molecular subtypes; trifluridine/tipiracil approved
10. 2017Pembrolizumab for MSI-high tumours

• Daraxonrasib (product)
• Autogene cevumeran (product)
• Signatera (product)
• AZUR-1 (trial)
• MOUNTAINEER & MOUNTAINEER-03 (trial)
• CIRCULATE-Japan (GALAXY / VEGA / ALTAIR) (trial)
• Zoldonrasib (product)
• CheckMate 8HW (trial)
• ctDNA-guided adjuvant therapy as the default in stage II-III colon cancer (idea)
• Making microsatellite-stable colorectal cancer immunotherapy-responsive (idea)
• Neoadjuvant checkpoint inhibitor → surgery (or no surgery) in dMMR colorectal cancer (pairing)
• Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood) (technology)

• PARADIGM (phase 3, n=823): Overall survival, left-sided: 37.9 months vs 34.3 months, HR 0.82
• FRESCO-2 (phase 3, n=691): Overall survival: 7.4 months vs 4.8 months, HR 0.66
• SUNLIGHT (phase 3, n=492): Overall survival: 10.8 months vs 7.5 months, HR 0.61
• CheckMate 8HW (phase 3, n=839): Progression-free survival, first line: 54.1 months vs 5.9 months, HR 0.21
• ATOMIC (Alliance A021502) (phase 3, n=712): Disease-free survival at 3 years: 86.4 percent vs 76.6 percent, HR 0.5
• KEYNOTE-177 (phase 3, n=307): Progression-free survival: 16.5 months vs 8.2 months, HR 0.6

• MSS metastatic disease is immunotherapy-resistant.
• Early-onset CRC causes unknown.
• KRAS G12D (most common) undrugged.
• Microsatellite-stable metastatic disease (95%) remains immunotherapy-resistant; liver metastases actively suppress systemic immunity.
• KRAS G12D and G12V, the most common drivers, have no approved inhibitor; RAS(ON) inhibitors are the first credible attempt.
• Early-onset colorectal cancer is rising ~2% per year with no established cause and no screening before 45.

1. What did the dostarlimab rectal cancer study show?
   Answer

   In mismatch-repair-deficient locally advanced rectal cancer, dostarlimab alone produced a complete clinical response in 100% of patients, sustained in more than 40 patients by 2025, allowing surgery and radiation to be avoided.
2. What is exercise oncology and is there real evidence?
   Answer

   Structured exercise during and after treatment; the CHALLENGE trial (2025) randomised colon cancer survivors and showed improved disease-free and overall survival, the first level-1 evidence, plus less fatigue and neuropathy.
3. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
4. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
5. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
6. Which biomarkers must be tested at diagnosis of advanced non-small-cell lung cancer?
   Answer

   EGFR, ALK, ROS1, BRAF V600E, MET exon 14/amplification, RET, NTRK, KRAS G12C, HER2 mutations, and PD-L1 TPS.

• NCCN Colon Cancer guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428
• NCCN Rectal Cancer guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461
• ESMO metastatic colorectal cancer guideline: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/metastatic-colorectal-cancer
• NCI PDQ colon cancer treatment: https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Colorectal_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1429
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461