Introduction

Colorectal cancer (CRC) is a heterogeneous malignancy arising from the epithelial lining of the colon or rectum. Although many tumors develop through a stepwise progression from normal mucosa to adenoma and ultimately invasive adenocarcinoma, CRC encompasses multiple biologically distinct diseases characterized by differences in anatomic location, genomic alterations, microsatellite status, tumor microenvironment, and clinical behavior.

CRC remains a major cause of cancer morbidity and mortality. In the United States, approximately 158,850 new cases and 55,230 deaths are estimated in 2026, while 5-year relative survival across all stages is approximately 65%.

Importantly, the epidemiology of CRC is changing. Incidence and mortality are increasing among individuals younger than 50, emphasizing the importance of early screening, recognition of hereditary cancer syndromes, and evaluation of symptoms in younger adults.

At the same time, treatment has shifted from a predominantly chemotherapy-based approach toward increasingly precise molecular stratification. MMR/MSI status, RAS mutations, BRAF V600E, HER2 amplification/overexpression, tumor sidedness, and other genomic alterations can materially influence treatment selection.

Epidemiology

CRC is among the most common malignancies worldwide. Globally, approximately 1.9 million new cases occurred in 2024.

Key Considerations

• CRC can develop in the proximal colon, distal colon, or rectum, with clinically important differences in biology among these locations.
• Most colorectal malignancies are adenocarcinomas.
• Five-year relative survival across all stages is approximately 65.4%, although prognosis varies markedly by stage.
• Early-onset colorectal cancer has become an increasingly important clinical and public-health concern.

The favorable prognosis of localized CRC reinforces the importance of screening and early diagnosis, while metastatic disease remains associated with substantially greater morbidity and mortality.

Risk Factors

CRC results from interactions among age, environmental exposures, chronic inflammatory states, inherited cancer susceptibility, and acquired somatic genomic alterations.

Modifiable (~65%)

• Obesity
• Physical inactivity
• Cigarette smoking
• Heavy alcohol consumption
• Unhealthy diet

Non-Modifiable (~35%)

• Age
• Personal/family history
• Inflammatory bowel disease, particularly longstanding ulcerative colitis or Crohn colitis
• Hereditary cancer syndromes

Recognition of hereditary CRC (i.e., Lynch syndrome and/or Familial adenomatous polyposis) is important not only for the individual patient, but also for cancer surveillance and genetic counseling of family members.

Pathophysiology

CRC develops through the progressive accumulation of genetic and epigenetic abnormalities that disrupt cellular proliferation, differentiation, apoptosis, DNA repair, and immune surveillance.

Several molecular pathways are particularly important.

1) Chromosomal Instability Pathway

The classic adenoma-carcinoma sequence frequently begins with loss of normal APC tumor-suppressor activity, resulting in dysregulation of WNT signaling and accumulation of β-catenin.

Additional alterations may subsequently develop, including: APC → KRAS → TP53/SMAD pathway alterations → invasive carcinoma

This process generally occurs over many years, creating the biological rationale for colonoscopic identification and removal of precancerous adenomas.

2) Microsatellite Instability Pathway

The DNA mismatch-repair system corrects replication errors.

Loss of functional MMR proteins produces mismatch repair deficiency (dMMR) and accumulation of insertion/deletion errors within repetitive DNA sequences known as microsatellites, producing microsatellite instability-high (MSI-H) tumors.

Because dMMR/MSI-H cancers accumulate large numbers of mutations and potentially immunogenic neoantigens, they can be particularly responsive to immune-checkpoint inhibition.

3) Serrated/Hypermutated Pathway

A subset of CRC develops through serrated precursor lesions and is frequently associated with:

• BRAF V600E
• CpG island methylator phenotype
• MLH1 promoter methylation
• MSI-H in some tumors

Important Biomarkers

CRC is now best understood not as one disease, but as a collection of molecularly defined subgroups.

Comprehensive molecular characterization has therefore become increasingly important in metastatic disease. The 2026 ASCO and ESMO metastatic CRC guidelines places molecular characterization directly within the routine diagnostic and treatment pathway.

Clinical Presentation

Early CRC may be asymptomatic, particularly when identified through screening.

Common manifestations include:

• Change in bowel habits
• Hematochezia or rectal bleeding
• Iron-deficiency anemia
• Fatigue
• Abdominal pain
• Unintentional weight loss
• Change in stool caliber
• Bowel obstruction

Rectal cancers may present with:

• Rectal bleeding
• Tenesmus
• Urgency
• Pain
• Altered defecation

Metastatic disease commonly involves the liver, lungs, peritoneum, and distant lymph nodes.

Diagnosis

Diagnosis typically requires endoscopic visualization and histopathologic confirmation.

Colonoscopy

• Visualization of the primary lesion
• Tissue biopsy
• Identification and removal of synchronous polyps
• Assessment for additional colorectal lesions

Imaging

Staging generally incorporates cross-sectional imaging such as:

• CT chest
• CT abdomen/pelvis
• MRI in selected circumstances

Staging

CRC is staged using the TNM system.

Stage I

Tumor invades into but has not substantially extended beyond the bowel wall and lacks nodal involvement.

Stage II

Tumor extends through the bowel wall, but regional lymph nodes remain negative.

Stage III

Regional lymph-node involvement is present.

Stage IV

Distant metastatic disease is present.

Common metastatic sites include:

• Liver
• Lung
• Peritoneum
• Distant lymph nodes

Accurate staging is essential because treatment differs substantially between localized, locally advanced, oligometastatic, and widely metastatic disease.

Current Treatment Landscape

Localized Colon Cancer:

• Surgery
  • Surgical resection is the foundation of potentially curative treatment for localized colon cancer.
  • The procedure generally involves:
    • Resection of the involved bowel segment
    • Regional lymphadenectomy
    • Adequate pathologic nodal evaluation

Stage I: Surgery alone is usually sufficient.

Stage II: The role of adjuvant chemotherapy depends on recurrence risk and tumor biology. Patients with stage II dMMR/MSI-H tumors generally have a relatively favorable prognosis and may derive limited benefit from fluoropyrimidine monotherapy. High-risk clinicopathologic features may include:

• T4 disease
• Bowel obstruction
• Perforation
• Inadequate lymph-node sampling
• Poor differentiation in appropriate circumstances
• Lymphovascular or perineural invasion

Stage III: Adjuvant chemotherapy is routinely considered. Common regimens include:

• FOLFOX (5-fluorouracil, Leucovorin, & Oxaliplatin)
• CAPOX (Capecitabine & Oxaliplatin)

Treatment duration may be individualized according to recurrence risk, regimen, expected benefit, and cumulative toxicity, particularly oxaliplatin-associated peripheral neuropathy.

Metastatic CRC:

Metastatic CRC represents one of the clearest examples of precision oncology. Treatment selection incorporates: MMR/MSI → RAS → BRAF → HER2 → tumor sidedness → prior therapies → extent/resectability of metastases → patient fitness and treatment goals

The latest ASCO & ESMO Clinical Practice Guideline for Metastatic Colorectal Cancer specifically integrates diagnosis, molecular characterization, staging, systemic therapy, and local treatment into the management pathway.

• Chemotherapy: Backbone regimens commonly include:
  • FOLFOX
  • CAPOX
  • FOLFIRI (5-FU, Leucovorin, & Irinotecan)
  • FOLFOXIRI (5-FU, Leucovorin, Oxaliplatin, & Irinotecan)
  • Selection depends on factors including:
    • Performance status
    • Comorbidities
    • Disease burden
    • Prior therapy
    • Molecular subtype
    • Treatment goals
    • Expected toxicities
• Anti-VEGF Therapy: Angiogenesis is central to colorectal tumor growth and metastatic progression. Bevacizumab is commonly combined with fluoropyrimidine-based chemotherapy.
  • Important class-related adverse effects include:
  • Hypertension
  • Proteinuria
  • Bleeding
  • Thromboembolic events
  • Impaired wound healing
  • Gastrointestinal perforation
  • The timing of anti-VEGF therapy around surgery therefore requires careful consideration.
• Anti-EGFR Therapy: Cetuximab and panitumumab inhibit epidermal growth factor receptor signaling. Their efficacy is strongly dependent on molecular context. Expanded RAS testing, including KRAS and NRAS, is essential because activating RAS mutations can drive signaling downstream of EGFR and confer resistance to EGFR-directed antibodies. Clinical benefit is particularly relevant in appropriately selected patients with:
  • RAS wild-type disease
  • BRAF wild-type disease
  • Left-sided primary tumors
  • Common toxicities include:
    • Acneiform rash
    • Paronychia
    • Infusion reactions, particularly with cetuximab
• Immunotherapy and MSI-H/dMMR CRC (Nivolumab + Ipilumab): One of the major advances in CRC has occurred in MSI-H/dMMR metastatic disease. Checkpoint blockade can produce deep and durable responses in this molecular subgroup.
• BRAF V600E-Mutated CRC (encorafenib): BRAF V600E defines a distinct molecular subgroup historically associated with poor prognosis. Targeting BRAF alone is inadequate because blockade can lead to compensatory EGFR-mediated pathway reactivation. Consequently, effective therapy incorporates simultaneous targeting of BRAF and EGFR.
• HER2-Positive Colorectal Cancer (Trastuzumab + Tucatinib): HER2 amplification/overexpression occurs in a subset of CRC and may function both as a therapeutic target and a mechanism of resistance to anti-EGFR treatment. For appropriately selected patients with RAS wild-type, HER2-positive unresectable or metastatic CRC, HER2-targeted approaches are now available.
• Later-Line Therapies: Patients with refractory disease may receive treatment including:
  • Trifluridine/tipiracil, frequently combined with bevacizumab
  • Fruquintinib
  • Regorafenib
  • Biomarker-selected targeted therapy
  • Clinical trials
  • Important toxicities include hypertension, hand-foot syndrome, proteinuria, diarrhea, and asthenia.

Emerging Therapeutic Strategies

CRC research is increasingly focused on addressing molecularly defined mechanisms of resistance.

1) Earlier Biomarker-Directed Therapy

The success of frontline BRAF-directed therapy and immunotherapy illustrates an important movement away from treating CRC solely according to line of therapy. Instead, treatment is moving toward: Disease stage + molecular subtype + tumor location + prior treatment + resistance biology

2) KRAS-Directed Therapy

Historically, RAS mutations were primarily viewed as negative predictive biomarkers for anti-EGFR therapy. However, direct KRAS-directed therapies, particularly targeting KRAS G12C, have established proof of principle that mutant RAS can be therapeutically targeted. Combination strategies targeting KRAS together with EGFR or downstream signaling are under extensive investigation. Development of agents targeting additional RAS variants could further expand the treatable CRC population.

3) ctDNA-Guided Therapy

Prospective trials continue to investigate whether ctDNA can safely guide:

• Chemotherapy omission
• Chemotherapy escalation
• Duration of therapy
• Surveillance intensity
• Intervention at molecular rather than radiographic recurrence

4) Immunotherapy in Earlier-Stage dMMR Disease

The striking activity of checkpoint inhibition in dMMR tumors has generated intense interest in moving immunotherapy into earlier disease settings, including locally advanced colon and rectal cancers. Particularly provocative results with neoadjuvant immune-checkpoint blockade have challenged traditional assumptions about the need for chemotherapy, radiation, and surgery in selected dMMR tumors. Longer follow-up is necessary to understand durability and optimal patient selection.

Pharmacist Considerations

• Verification and optimization of chemotherapy dosing
• Molecular test interpretation
• Oral anticancer-agent counseling
• Drug-interaction assessment
• Toxicity prevention and management
• Adherence monitoring
• Supportive-care optimization
• Financial/access assistance

Regimen-specific issues include:

• Oxaliplatin
  • Acute cold-induced dysesthesia
  • Cumulative peripheral neuropathy
• Irinotecan
  • Early and delayed diarrhea
  • Myelosuppression
• Fluoropyrimidines
  • Mucositis
  • Hand-foot syndrome
• Myelosuppression

Importantly, severe or unexpectedly early fluoropyrimidine toxicity should raise consideration of DPD deficiency and impaired fluoropyrimidine metabolism.

• Anti-EGFR therapy
  • Acneiform rash
• Infusion reactions
• Anti-VEGF therapy
  • Hypertension
  • Proteinuria
  • Bleeding
  • Thrombosis
  • Wound-healing complications
  • GI perforation
• Checkpoint inhibitors
  • Colitis
  • Hepatitis
  • Pneumonitis
  • Endocrinopathies
  • Dermatologic toxicity
  • Other immune-mediated adverse events

Because modern CRC therapy increasingly depends on sequential targeted treatments, pharmacists can also help ensure that MMR/MSI, KRAS/NRAS, BRAF, HER2, and other clinically relevant molecular results are available before major therapeutic decisions are made.

Key Takeaways

• Colorectal cancer is a biologically heterogeneous and increasingly molecularly defined malignancy.
• Approximately 158,850 new cases and 55,230 deaths are expected in the United States in 2026.
• Surgery remains the cornerstone of curative treatment for localized colon cancer.
• Biomarker testing is critical because it provides prognostic, hereditary, and therapeutic information while helping guide treatment selections.
• ctDNA/MRD is emerging as one of the most promising tools for postoperative risk stratification, although exactly how it should dictate treatment remains under active investigation.
• The future of CRC treatment is increasingly defined by stage, molecular biology, anatomy, and residual disease vs. stage and chemotherapy history alone.

References

• NCCN Guidelines for Patients: Colon Cancer, Version 2.2026, based on the April 2026 professional guideline.
• ASCO & ESMO Clinical Practice Guideline for Metastatic Colorectal Cancer, 2026.
• American Cancer Society Colorectal Cancer Statistics 2026.
• SEER Colorectal Cancer Cancer Stat Facts.

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.