The traditional CRC treatment path (chemo-surgery-chemo) is being upended. New data shows giving immunotherapy before surgery can be so effective that the surgery itself becomes the "adjuvant" or follow-up treatment, representing a major paradigm shift.
Mismatch repair deficient (dMMR/MSI-H) tumors respond to immunotherapy because their DNA repair mechanism—an "autocorrect" for genetic code—is broken. This creates over 25 times more mutations, making the cancer highly visible and attackable by the immune system.
The NEST study demonstrated that a novel FC-enhanced CTLA-4 inhibitor can induce immune responses in microsatellite stable (MSS) colon cancer. This is the most common subtype, typically resistant to immunotherapy, opening a new treatment avenue for the majority of CRC patients.
Administering immunotherapy while the primary tumor and lymph nodes are intact allows them to act as an "in-situ vaccine." This generates a more diverse and powerful systemic immune response against cancer cells throughout the body compared to treating after surgical removal of these antigenic sources.
Unlike in rectal cancer where pre-surgical shrinkage is key, the primary objective of neoadjuvant immunotherapy in operable colon cancer is to activate a systemic immune response. This targets and eliminates unseen micro-metastases, the true cause of recurrence, thereby increasing the overall cure rate.
There is an alarming and unexplained rise in early-onset colorectal cancer, making it the top cause of cancer death for individuals under 50. These younger patients often present with more advanced, aggressive disease and have poorer outcomes despite receiving aggressive treatments.
Measuring circulating tumor DNA (ctDNA) to detect minimal residual disease (MRD) after treatment is a powerful predictor of recurrence. This biomarker could be used as a surrogate endpoint in clinical trials, allowing for accelerated drug approvals based on early data rather than waiting years for survival outcomes.