Colorectal Cancer: It Starts and It Runs

The Silent Epidemic Striking Younger Lives

The Alarming Surge: More Than Just an "Old Person's Disease"

Rising Cases in Young Adults

Colorectal cancer (CRC) ranks as the third most common cancer globally, causing over 900,000 deaths yearly 5 . While overall rates are declining due to better screening, cases among adults under 50 are rising sharply.

Specialized Centers

Memorial Sloan Kettering Cancer Center (MSK) has established the world's first Center for Young Onset Colorectal Cancer to tackle this specific challenge 1 .

Key Fact

Research suggests young adults could face CRC as the leading cause of cancer death by 2030 9 .

Decoding the Start: Where Colorectal Cancer Begins

The Journey from Polyp to Cancer

Most colorectal cancers follow the adenoma-carcinoma sequence. This decade-long process starts when normal cells in the colon lining develop mutations, often forming precancerous polyps (adenomas). Over time, additional genetic hits transform some polyps into invasive cancer 3 7 .

Normal Colon Lining

Healthy epithelial cells

Mutation in APC Gene

Forms small benign polyp

KRAS Mutation

Polyp grows larger

TP53 Mutation

Malignant transformation

Invasive Cancer

Potential metastasis

Adenoma to carcinoma sequence

Illustration of the adenoma-carcinoma sequence in colorectal cancer development.

The Genetic Drivers: More Than Just Bad Luck

Three major molecular pathways drive CRC development, each with implications for treatment and prevention:

Subtype/Pathway Frequency Key Genetic Features Treatment Implications
CIN (CMS2 & CMS4) ~85% APC, KRAS, TP53 mutations; Chromosome gains/losses Often resistant to immunotherapy; Targeted therapies against KRAS/BRAF emerging
MSI-H/dMMR (CMS1) ~15% (Stage II/III), ~5% (Stage IV) Defective MMR genes (MLH1, MSH2, MSH6, PMS2); High mutation load Highly responsive to immune checkpoint inhibitors (e.g., Pembrolizumab, Nivolumab)
CIMP-High (Often CMS1 or CMS3) ~20% BRAF V600E mutation; MLH1 gene silencing BRAF inhibitors (e.g., Encorafenib) + anti-EGFR effective
KRAS Mutant (Various CMS) ~40% Mutations in KRAS (esp. G12C) Resistant to anti-EGFR antibodies; KRAS G12C inhibitors (e.g., Adagrasib) now available
The Young Onset Enigma

The rise in young-onset CRC (before age 50) is not fully understood, but likely involves:

  • Modern diets high in processed foods
  • Sedentary lifestyles
  • Obesity epidemic
  • Gut microbiome shifts 4 9
  • Environmental exposures 5 7
Research Focus

Intensive research efforts like IARC's DISCERN and ColoMARK projects aim to unravel the causes of early-onset CRC and identify novel biomarkers for early detection 5 .

Halting the Run: Revolutionizing Treatment

Precision Medicine: Targeting the Weak Spots

Treatment is no longer one-size-fits-all. Molecular profiling of tumors guides targeted attacks:

The drug adagrasib (Krazati®), combined with cetuximab, recently gained approval for advanced CRC with the KRAS-G12C mutation (found in ~4% of cases) 1 .

The BREAKWATER trial established encorafenib + cetuximab + mFOLFOX6 chemotherapy as the new standard first-line treatment for metastatic CRC with BRAF V600E mutations 2 9 .

For patients with MSI-H/dMMR tumors, immune checkpoint inhibitors like pembrolizumab (Keytruda) can be transformative. An MSK trial saw 100% of participants achieve complete tumor disappearance 1 4 .
Surgical Advances
  • Watch-and-Wait: ~50% of MSK rectal cancer patients avoid surgery after tumor shrinkage 1
  • Radiation-Sparing: Selected patients can skip radiation with equivalent outcomes 1
  • Robotic Surgery: Less pain, fewer infections, faster recovery 1

"The revolution in precision medicine - from immunotherapy curing previously untreatable dMMR cancers, to targeted combinations doubling survival in aggressive BRAF-mutant disease - offers unprecedented hope."

Prevention is Paramount

Screening Saves Lives

Starting at age 45 for average-risk individuals, screening options include:

Screening Test Frequency Pros
Colonoscopy Every 10 years Gold standard; Prevents & detects
FIT (Stool Test) Every year Non-invasive; Inexpensive
Stool DNA Test Every 3 years No prep; Detects some polyps
Blood Test (Shield™) Every 3 years Simple blood draw
Lifestyle as Medicine
  • The CHALLENGE Trial: Exercise reduced recurrence risk by 28% 9
  • Anti-Inflammatory Diets: 63% lower risk of death in stage III patients 9
  • Key Components:
    • Coffee, tea, leafy greens
    • Whole grains
    • Avoid red/processed meats
    • Regular physical activity

Spotlight on Discovery: The BREAKWATER Trial

A New Hope for BRAF-Mutant CRC

The phase 3 BREAKWATER trial (NCT04607421) tested new approaches for metastatic CRC with BRAF V600E mutation 2 9 .

Methodology
  • 637 patients with previously untreated, metastatic CRC
  • Three groups:
    • Encorafenib + Cetuximab only
    • Encorafenib + Cetuximab + mFOLFOX6 chemo
    • Standard chemo (control)
  • Primary goals: Progression-Free Survival (PFS) and Overall Survival (OS)
Key Results
Treatment Arm Median PFS Median OS
Triple Combo 12.8 months 30.3 months
Standard Chemo 7.1 months 15.1 months

Hazard Ratio: 0.49 for OS (P<.0001) - patients lived twice as long on average.

Scientific Importance

  • New Standard of Care: Encorafenib + Cetuximab + mFOLFOX6 is now first-line for metastatic BRAF V600E mutant CRC 2 9
  • Validates Targeted Combinations: Shows BRAF/EGFR inhibition with chemo is vastly superior
  • Highlights Molecular Testing: Critical to test for BRAF status at diagnosis

The Scientist's Toolkit

Cutting-edge research relies on sophisticated tools to model the disease and test new therapies:

MSI/dMMR Biomarkers

Detects mismatch repair protein deficiency or microsatellite instability in tumor tissue 1 4 7

Circulating Tumor DNA (ctDNA)

Detects tumor-derived DNA fragments in blood plasma ("Liquid Biopsy") 2 4

Patient-Derived Organoids

3D mini-tumors grown in the lab from a patient's own cancer cells 7

KRAS/BRAF/PIK3CA Mutation Panels

Next-generation sequencing to detect specific oncogenic mutations 1 2 7

The Future is Bright

Blood Tests

New blood-based tests like Shield™ (~83% accuracy) offer simpler screening 4 .

Vaccines

Early-phase trials exploring therapeutic cancer vaccines targeting mutations like KRAS 1 4 .

AI-Powered Precision

Artificial Intelligence improving diagnosis, predicting treatment response, and identifying targets 7 .

The Bottom Line

Colorectal cancer starts with genetic missteps in the gut lining, often fueled by our environment and lifestyle. The surge in young cases is a stark warning, but the revolution in precision medicine offers unprecedented hope. Screening remains our most powerful weapon. Starting at 45 (or earlier if high-risk), getting screened, knowing your family history, embracing a healthy lifestyle, and advocating for molecular testing if diagnosed, are crucial steps everyone can take to stop CRC in its tracks.

Key Facts
  • 3rd most common cancer globally
  • 900,000+ deaths yearly 5
  • Cases in under 50 rising sharply
  • Could be #1 cancer killer by 2030 9
  • Screening starts at age 45
Prevention Tips
  • Get screened at 45
  • Eat more fiber
  • Limit processed meats
  • Exercise regularly
  • Know family history
Warning Signs
  • Rectal bleeding
  • Persistent abdominal pain
  • Unexplained weight loss
  • Changes in bowel habits
  • Iron deficiency anemia

References