Colorectal cancer Study Guide

📖 Core Concepts Colorectal cancer (CRC) – malignant growth originating in the colon or rectum; most are adenocarcinomas. Adenoma‑carcinoma sequence – stepwise progression from benign adenomatous polyps to invasive cancer driven by genetic hits (APC → KRAS → TP53, etc.). Wnt/β‑catenin pathway – APC loss → β‑catenin accumulation → transcription of proliferative genes. Microsatellite instability (MSI) – hypermutable phenotype caused by mismatch‑repair (MMR) deficiency (≈15‑18 % of CRCs). TNM staging – T (tumor depth), N (nodal spread), M (distant metastasis); determines prognosis & treatment. Screening modalities – colonoscopy (gold standard), fecal immunochemical test (FIT), flexible sigmoidoscopy; start at age 45 for average risk. Key molecular targets – KRAS/NRAS/BRAF (predict anti‑EGFR therapy response), VEGF (anti‑angiogenic therapy), PD‑1 (immune checkpoint blockade for MSI‑high tumors). --- 📌 Must Remember Epidemiology: 3rd most common cancer worldwide; ≈10 % of all cancers; >65 % of cases in developed nations. Risk factors: Obesity, smoking, heavy alcohol, red/processed meat, low fiber, sedentary lifestyle, IBD, family history (≥2 first‑degree relatives → 3× risk), Lynch syndrome, FAP. Screening ages: 45–75 (average risk); start at 40 if strong family/genetic risk. Survival trends: 5‑yr survival 65 % in US (2014); drops sharply with advanced stage (≈40 % with nodal disease, <5‑31 % with metastases). Chemotherapy regimens: CAPOX = capecitabine + oxaliplatin FOLFOX = folinic acid + 5‑FU + oxaliplatin FOLFIRI = folinic acid + 5‑FU + irinotecan Targeted therapy rule: Anti‑EGFR antibodies only if KRAS/NRAS wild‑type; anti‑VEGF (bevacizumab) usable regardless of KRAS status. Immunotherapy eligibility: MSI‑high or dMMR tumors → pembrolizumab (PD‑1 inhibitor). --- 🔄 Key Processes Adenoma‑carcinoma sequence APC loss → β‑catenin ↑ → adenoma formation KRAS activation → proliferation TP53 loss → genomic instability → carcinoma. Screening workflow Age ≥ 45 → choose test (colonoscopy every 10 yr, FIT every 2 yr, sigmoidoscopy every 10 yr). Positive FIT → diagnostic colonoscopy with polypectomy. Colonoscopy → remove all detected adenomas → reduce progression risk. Staging (TNM) T: depth of invasion (Tis → mucosa, T1‑T4). N: 0‑3 nodes involved. M: 0 (none) or 1 (distant). Combine to assign stage I‑IV. Treatment algorithm (non‑metastatic) Stage I: surgery alone. Stage II: surgery ± high‑risk features → consider adjuvant chemo. Stage III: surgery + adjuvant FOLFOX/FOLFOXIRI. Rectal T3/T4: neoadjuvant chemoradiation → surgery → adjuvant chemo. Metastatic management Resection of limited liver/lung mets if feasible. Systemic chemo (FOLFOX/FOLFIRI) ± targeted agents (anti‑EGFR if KRAS/NRAS WT, anti‑VEGF). MSI‑high → add pembrolizumab. --- 🔍 Key Comparisons Adenomatous vs. Serrated polyps Adenomatous: classic APC → KRAS pathway; higher malignant potential. Serrated: BRAF mutation, CpG island methylator phenotype (CIMP); distinct pathway to CRC. Colon vs. Rectal cancer treatment Colon: surgery ± chemo; radiation rarely used. Rectal: neoadjuvant chemoradiation common; sphincter‑preserving surgery goal. KRAS wild‑type vs. mutant Wild‑type: eligible for anti‑EGFR therapy (cetuximab, panitumumab). Mutant: anti‑EGFR ineffective; use chemotherapy ± anti‑VEGF. MSI‑high vs. MSS (microsatellite stable) MSI‑high: better prognosis, no benefit from standard 5‑FU chemo, responsive to PD‑1 blockade. MSS: standard chemo/targeted regimens; immunotherapy generally ineffective. --- ⚠️ Common Misunderstandings “All polyps become cancer.” → Only adenomatous (especially villous or >1 cm) have high malignant potential; hyperplastic polyps are low risk. “Chemotherapy cures stage II.” → Routine chemo is NOT recommended for stage II unless high‑risk features are present. “FIT detects all cancers.” → FIT is less sensitive for right‑sided lesions that bleed intermittently; a negative FIT does not rule out cancer. “MSI‑high tumors don’t need chemo.” → They may not benefit from 5‑FU alone, but can receive immunotherapy or combination regimens. --- 🧠 Mental Models / Intuition “Genetic hit ladder” – Visualize CRC development as climbing stairs: APC loss (first step), KRAS (second), TP53 (top). Missing a step → no cancer. “Screen‑and‑remove = prevent” – Think of colonoscopy like lawn mowing: cutting down all visible “weeds” (polyps) prevents them from growing into “trees” (cancer). “Molecular match‑making” – Match tumor genotype to therapy: KRAS/NRAS WT → EGFR inhibitor; MSI‑high → PD‑1 inhibitor; BRAF V600E → consider BRAF‑targeted combos. --- 🚩 Exceptions & Edge Cases Lynch syndrome patients – Start colonoscopy at 20–25 yr, repeat every 1–2 yr; consider prophylactic colectomy. FAP – Near‑certain CRC without prophylactic colectomy; surveillance begins in early teens. Obstructing tumor – Initial colonoscopy may be impossible; perform flexible sigmoidoscopy or CT colonography, then schedule full colonoscopy after decompression. Stage IV with resectable liver mets – Curative intent surgery plus peri‑operative chemotherapy can improve survival. --- 📍 When to Use Which Screening test selection – Colonoscopy for highest risk or when polyp removal needed; FIT for average‑risk adults preferring non‑invasive test. Adjuvant chemo decision (stage II) – Use if any high‑risk feature: T4, poor differentiation, lymphovascular invasion, <12 nodes examined, or perforation. Targeted therapy choice – KRAS/NRAS wild‑type → anti‑EGFR; any KRAS/NRAS mutation → anti‑VEGF (bevacizumab). Immunotherapy – Reserve for dMMR/MSI‑high metastatic disease or as frontline in selected cases. --- 👀 Patterns to Recognize Right‑sided vs. left‑sided tumors – Right‑sided often present with anemia/occult bleeding; left‑sided more likely cause change in bowel habits or obstruction. High‑risk histology – Villous architecture, >1 cm size, high‑grade dysplasia → higher progression risk. Molecular clustering – MSI‑high tumors often have better prognosis and distinct immunogenic profile. --- 🗂️ Exam Traps “All stage II patients receive chemo.” – Only high‑risk stage II get adjuvant chemo. “Radiation is standard for colon cancer.” – Radiation is rarely used for colon; reserved for rectal disease. “KRAS mutation predicts response to EGFR inhibitors.” – Opposite: KRAS mutation predicts non‑response. “FIT is more sensitive than colonoscopy.” – Colonoscopy is more sensitive; FIT is a screening tool, not diagnostic. “MSI‑high tumors respond to 5‑FU chemo.” – They show little benefit from 5‑FU alone; immunotherapy is preferred. ---