Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, affecting both men and women. Early detection and personalized treatment are crucial in improving survival rates and reducing the burden of this disease. Advances in pharmacogenomics (PGx) have opened new avenues for personalized medicine, offering better treatment and screening options for CRC.
Understanding Colorectal Cancer
Colorectal cancer originates in the colon or rectum, part of the digestive tract. It typically begins as a benign polyp, which may develop into cancer over time. Risk factors for CRC include age, family history, genetic predispositions (e.g., Lynch syndrome, familial adenomatous polyposis), lifestyle factors (diet, smoking, alcohol consumption), and inflammatory bowel diseases.
Symptoms of CRC can vary but often include changes in bowel habits, rectal bleeding, abdominal pain, and unexplained weight loss. Due to the often asymptomatic nature of early-stage CRC, regular screening is essential for early detection.
Current Screening Methods
Screening for CRC aims to identify precancerous polyps or early-stage cancer in asymptomatic individuals. The most common screening methods include:
Fecal Occult Blood Test (FOBT) and Fecal Immunochemical Test (FIT): These non-invasive tests detect hidden blood in the stool, an early sign of CRC. They are cost-effective and easy to administer but require regular testing.
Colonoscopy: A colonoscopy is a comprehensive screening method where a flexible tube with a camera is inserted into the colon and rectum to detect and remove polyps. It is highly effective but more invasive and requires bowel preparation.
Sigmoidoscopy: Similar to a colonoscopy but limited to the rectum and lower colon, this procedure is less invasive but also less comprehensive.
CT Colonography (Virtual Colonoscopy): This imaging technique uses CT scans to visualize the colon and rectum. It is less invasive than a traditional colonoscopy but may miss smaller polyps.
DNA Stool Tests: These tests detect genetic mutations associated with CRC in stool samples. They are non-invasive and can provide information on genetic risk factors.
Treatment Options for Colorectal Cancer
Treatment for CRC depends on the stage and location of the cancer, as well as the patient's overall health. Common treatment modalities include: Surgery, Radiation Therapy, Chemotherapy, Targeted therapy and Immunotherapy.
Surgery: Surgery is the primary treatment for localized CRC. Depending on the cancer's location and extent, the surgeon may perform a partial colectomy (removal of part of the colon) or a total colectomy (removal of the entire colon).
Radiation Therapy: Radiation therapy uses high-energy rays to kill cancer cells. It is often used before surgery to shrink tumors or after surgery to eliminate any remaining cancer cells.
Chemotherapy: Chemotherapy involves the use of drugs to kill cancer cells or inhibit their growth. It is often used in combination with surgery and/or radiation therapy, especially in advanced stages of CRC.
Targeted Therapy: Targeted therapies use drugs or other substances to specifically target cancer cells without harming normal cells. Examples include monoclonal antibodies and small molecule inhibitors that block specific pathways involved in cancer growth.
Immunotherapy: Immunotherapy helps the body's immune system recognize and attack cancer cells. It is a promising approach for certain types of CRC, particularly those with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).
The Role of Pharmacogenomics in Colorectal Cancer
Personalized Treatment
Chemotherapy Response: Genetic variations can affect how patients metabolize and respond to chemotherapy drugs. For example, variations in the DPYD gene can influence the metabolism of fluoropyrimidines (e.g., 5-fluorouracil), a common chemotherapy drug for CRC. Identifying patients with DPYD variants can help adjust dosages to minimize toxicity and improve outcomes.
Targeted Therapy: Genetic testing can identify specific mutations (e.g., KRAS, NRAS, BRAF) that predict response to targeted therapies. For instance, patients with KRAS mutations are unlikely to benefit from EGFR inhibitors (e.g., cetuximab), guiding clinicians to alternative treatments.
Immunotherapy: Immunotherapy helps the body's immune system recognize and attack cancer cells. High Microsatellite Instability (MSI-H) or mismatch repair deficiency (dMMR) are biomarkers associated with better responses to immunotherapy in certain cases of CRC. Genetic testing for these markers can identify patients who are likely to benefit from immune checkpoint inhibitors (e.g., pembrolizumab).
Improved Screening and Risk Assessment
Genetic Predispositions: Individuals with a family history of CRC or known genetic syndromes (e.g., Lynch syndrome) can benefit from genetic testing to assess their risk. Identifying high-risk individuals allows for more intensive surveillance and early intervention.
Molecular Screening: PGx can enhance stool-based DNA tests by incorporating additional genetic markers associated with CRC. This can improve the sensitivity and specificity of these tests, leading to earlier detection.
Personalized Surveillance: PGx can help determine the optimal screening frequency and methods for individuals based on their genetic risk profile. High-risk individuals may require more frequent colonoscopies, while those at lower risk may benefit from less invasive methods.
CRC Consensus Molecular Subtypes:
In 2015, an International consortium developed the CMS (Consensus Molecular Subtypes), dividing CRC into 4 subtypes based on gene expression & other factors to guide treatment options:
CMS1 (Microsatellite Instability Immune, 14%): High tumor mutational load, microsatellite instability, hypermethylation (CIMP+), BRAF mutation, strong immune activation.
CMS2 (Canonical, 37%): Epithelial characteristics, WNT-β-catenin pathway activation, MYC signaling.
CMS3 (Metabolic, 13%): Features metabolic dysregulation.
CMS4 (Mesenchymal, 23%): TGF-β activation, stromal invasion, angiogenesis; associated with worse survival.
Mixed Features (13%): Indicates intra-tumoral heterogeneity or transition phenotype.
Prognostic Value: CMS subtypes provide independent prognostic information beyond tumor stage.
CMS4 has the worst prognosis.
Predictive Value in Treatments:
CMS1 may respond better to bevacizumab.
CMS4 shows no benefit from oxaliplatin or anti-EGFR therapies, regardless of RAS status.
References:
Battaglin F, Puccini A, Naseem M, Schirripa M, Berger MD, Tokunaga R, McSkane M, Khoukaz T, Soni S, Zhang W, Lenz HJ. Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives. J Cancer Metastasis Treat. 2018;4(3):12. doi: 10.20517/2394-4722.2018.04. Epub 2018 Mar 7. PMID: 34532592; PMCID: PMC8442855.
-Written by Sohni Tagore
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