Pathophysiology of Colorectal Cancer PDF

Pathophysiology of Colorectal Cancer Dr. Van Den Berg Associate Professor Objectives Define risk factors for the development of colorectal cancer Identify the pathogenesis and natural progression of colorectal carcinoma Describe the common signs and symptoms associated with CRC. Recall the various t...

Pathophysiology of Colorectal Cancer Dr. Van Den Berg Associate Professor Objectives Define risk factors for the development of colorectal cancer Identify the pathogenesis and natural progression of colorectal carcinoma Describe the common signs and symptoms associated with CRC. Recall the various treatment strategies for colon cancer 2 Colorectal Cancer Transverse Ascending www.aboutcancer.com Descending 3 Colorectal Cancer in the U.S. Incidence (estimated 2024) New cases: 106,590 colon + 46,220 rectal 1 in 21 individuals Distant Mortality (estimated 2024) Annual deaths: 53,010 years68 years Median age 68 years Increasing 2%/yr in patients < 50 yo https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html Unstaged Localized Regional 5-Year Survival 4 Developmental Risk Factors Inflammatory Bowel Disease Type 2 Diabetes Mellitus Lifestyle Factors/ Diet Prior colon cancer Age >50 NCCN: Colon.1.2016 CRC Genetics/ Family History 5 Effect of Age on CRC Surveillance, Epidemiology, and End Results Program 6 7 Lifestyle Factors-Modifiable Dietary High fat, processed red meats Very low intake of fruits and vegetables Low calcium, vitamin D Limited physical activity Exposure to carcinogens Alcohol- mod-heavy Tobacco-long term 8 Modifiable (Lifestyle) Risk Factors Red meat associated risk may be related to preparation method, nitrate/nitrite content or fat content, undigested remnants of protein, bacterial degradation/ fermentation that cause DNA adducts causing mutations ~20% of CRCs are associated with smoking and smoking is associated with poorer survival. Heavy drinkers of alcohol experience increased risk (RR 1.56) 9 Adenomatous Polyps Mucosal surface protrusion Adenomatous polyps are considered premalignant Cancer probability varies Histology Appearance Size 10 Pathogenesis/Natural Progression of CRC 11 Local Signs and Symptoms Right Colon Left Colon Pain Weakness Melena Nausea Mass Pain Melena Constipation Nausea/Vomiting Melena Constipation Tenesmus Diarrhea Pain Recto-Sigmoid 12 Diagnostic Work-up Initial Digital rectal exam (DRE) Fecal occult blood test Colonoscopy Work-up CT scan Chest/Abdomen/Pelvis PET If potentially re-sectable Chemistry/CBC Carcinoembryonic antigen (CEA) KRAS mutation Lymph node biopsy (minimum 12 nodes) CBC= complete blood count NCCN: Colon.1.2015 13 Distribution of Colorectal Cancer 1% 24% 13% 10% 12% 25% 9% Appendix Cecum Ascending Colon Transverse Colon Descending Colon Sigmoid Colon Rectosigmoid Colon Rectum 6% 14 Metastatic Disease Bone Liver Jaundice LFT changes Ascites NCCN: Colon.1.2016 Lung Dyspnea Cough Peritoneum Pain 15 Carcinoembryonic Antigen (CEA) Cell surface glycoprotein expressed on mucosal cells Tumor marker Non-specific Seen in breast, lung, stomach cancers Seen with tobacco use Often used as surveillance/prognostic tool Following surgical resection Follow-up while on chemotherapy Increasing levels may signify early recurrence/relapse NCCN: Colon.1.2016 LexiComp. Lab Tests and Diagnostic Procedures. 16 KRAS Gene encoding for RAS protein (GTPase) involved in signal transduction Downstream to epidermal growth factor receptor (EGFR) and needed for activity Approximately 50 +/-% of colorectal cancers have wild type (+) (normal) 35% - 45% will have Ras mutation, which confers resistance to targeted therapy EGFR inhibitors (i.e., cetuximab/panitumumab) Decrease effect on response/survival NCCN: Colon.2.2016 LexiComp. Lab Tests and Diagnostic Procedures. 17 Other important gene mutations APC (adenomatous polyposis coli gene)- tumor suppressor, most common gene mutation in sporadic and familial/ inherited CRC P53 B-Raf- mutually exclusive from KRas mutations MLH1, MSH2 or MSH6 - DNA Repair genes associated with Lynch Syndrome- more responsive to immune therapy 18 Colorectal Cancer Staging Stage Tumor Size Nodal Involvement Metastasis Duke Stage Stage I T1 T2 N0 M0 A Stage IIA T3 N0 M0 B Stage IIB T4a N0 M0 B Stage IIC T4b N0 M0 B Stage IIIA T1-2 T1 N1/N1c N2a M0 C Stage IIIB T3-T4a T2-3 T1-2 N1/N1c N2a N2b M0 C NCCN: Colon.1.2016 19 Colorectal Cancer Staging (cont.) Stage Tumor Size Nodal Involvement Metastasis Duke Stage Stage IIIC T4a T3-4a T4b N2a N2b N1-2 M0 C Stage IVA Any T Any N M1a D Stage IVB Any T Any N M1b D NCCN: Colon.1.2015 20 MANAGEMENT OF COLON CANCER 21 Prognosis 5-year Overall Survival by Stage Survival depends on stage 100% Only 40% diagnosed are localized 78% Prognostic factors 72% 75% Percent Bowel obstruction/ perforation High post-op CEA Distant metastasis Primary on right side 93% 50% 25% 8% 0% Stage I NCCN: Colon.1.2016 Stage II Stage III Stage IV 22 Goals of Therapy Localized Disease Metastatic Disease Curative Conversion to resectable disease Stage IVA Palliation Symptomatic relief Extension of survival Patients now live 23+ months with metastatic disease 23 Treatment According to Stage Localized Disease Stage I Resection of primary tumor 80%-90% cured with surgery Stage II Surgery +/- chemotherapy Stage III Surgery + Chemotherapy 6 Months 5-Fluorouracil/capecitabine based with oxaliplatin Radiation Limited to select patients Metastatic Disease Systemic chemotherapy +/- targeted therapy Surgery If single resectable metastasis Radiation Palliative NCCN: Colon.1.2015 24 Colorectal Molecular Subtypes CIMP, CpG island methylator phenotype; MSI, microsatellite instability; SCNA, somatic copy number alterations. Guinney et al. Nat Med 2015: 21:1350 25