New Horizons in Colon Cancer Treatment: Neoadjuvant Immunotherapy for Mismatch Repair–Deficient High Risk Stage II/III Colon Cancer

Colon cancer treatments have long relied on surgery, chemotherapy, and radiation. However, recent breakthroughs in immunotherapy, particularly for mismatch repair–deficient (dMMR) tumors, are reshaping how certain high-risk cancers are treated. A recent study published in The New England Journal of Medicine provides encouraging data on the effectiveness of neoadjuvant immunotherapy for patients with locally advanced dMMR colon cancer, suggesting a path to improved outcomes with fewer side effects.

Understanding Mismatch Repair Deficiency in Colon Cancer

Mismatch repair deficiency (dMMR) is a genetic anomaly found in approximately 10-15% of nonmetastatic colon cancers. dMMR tumors have an impaired ability to repair DNA replication errors, leading to high rates of mutations. This characteristic, while dangerous in cancer development, also makes these tumors more responsive to immunotherapy.

In the past, dMMR tumors were treated similarly to mismatch repair–proficient (pMMR) tumors. However, because dMMR tumors are often resistant to conventional chemotherapy, researchers have been investigating alternative treatments, with immunotherapy emerging as a promising option.

Neoadjuvant Immunotherapy: A Promising Approach

Neoadjuvant immunotherapy refers to administering immune-based treatments before surgical intervention. In the study, patients with nonmetastatic, locally advanced dMMR colon cancer received a combination of nivolumab (a PD-1 inhibitor) and ipilimumab (a CTLA-4 inhibitor) before surgery. This approach aimed to reduce the tumor size and eliminate cancer cells more effectively, potentially allowing for less invasive surgeries.

The primary goals of the study were:

1. Safety: To evaluate whether neoadjuvant immunotherapy could be administered without delaying surgery.
2. Efficacy: To assess the effectiveness of this treatment in achieving high rates of disease-free survival and significant tumor reduction.

Key Findings from the Study

The study’s results were groundbreaking for dMMR colon cancer treatment, showing that:

• Safety and Surgical Timing: Nearly all patients (98%) underwent surgery on time, with only a small percentage experiencing delays due to treatment-related side effects. This indicates that the treatment is feasible without causing significant surgical delays.
• Pathological Response: Among patients who underwent surgery, 95% showed a major pathological response (defined as having less than 10% residual tumor) after just two cycles of immunotherapy. Even more impressive, 68% achieved a pathological complete response, with no detectable cancer cells in the resected tumor.
• Recurrence-Free Survival: At a median follow-up of 26 months, no patients had experienced disease recurrence, suggesting long-term benefits.

These outcomes suggest that neoadjuvant immunotherapy not only shrinks tumors effectively but may also reduce the need for more aggressive treatments post-surgery, offering a less toxic approach to cancer management.

How Neoadjuvant Immunotherapy Works for dMMR Tumors

The immunotherapy agents used in this study, nivolumab and ipilimumab, work by harnessing the body’s immune system to recognize and attack cancer cells. dMMR tumors, which accumulate mutations, present many abnormal proteins that make them visible to the immune system. By inhibiting certain immune checkpoints (PD-1 and CTLA-4), nivolumab and ipilimumab prevent cancer cells from evading immune detection, allowing the body to target and destroy them more effectively.

Implications for Future Colon Cancer Treatment

These findings could mark a shift in treatment standards for locally advanced dMMR colon cancer. Traditionally, patients with stage III dMMR colon cancer undergo surgery followed by adjuvant chemotherapy. However, with neoadjuvant immunotherapy showing such high rates of tumor response, it’s possible that future treatment protocols could incorporate immunotherapy first, with surgery as a follow-up.

This approach holds several potential benefits:

• Reduction in Adjuvant Chemotherapy: Because dMMR tumors respond poorly to chemotherapy, many patients derive minimal benefit from it. Neoadjuvant immunotherapy may provide a more effective option, reducing the need for postoperative chemotherapy and its associated side effects.
• Lower Risk of Recurrence: The study’s results, showing no recurrences at 26 months, suggest that early immunotherapy could enhance long-term disease control.
• Potential for Organ Preservation: In some cancers, neoadjuvant therapy can reduce tumor size sufficiently to allow for less extensive surgery, preserving more of the organ and maintaining a higher quality of life for the patient.

Considerations and Future Directions

While the results of this study are highly promising, it is important to consider several factors:

1. Patient Selection: Neoadjuvant immunotherapy may be most beneficial for patients with nonmetastatic dMMR tumors. Patients with pMMR colon cancer, who do not exhibit the same responsiveness to immunotherapy, may not experience the same benefits.
2. Long-Term Data: Although no recurrences were observed at a median follow-up of 26 months, longer-term studies are necessary to confirm sustained disease-free survival and overall survival.
3. Further Research in Multicenter Trials: While this phase 2 study provides robust data, larger, randomized trials could further validate these findings and help refine patient selection criteria.

A New Standard of Care?

The potential of neoadjuvant immunotherapy to transform treatment for locally advanced dMMR colon cancer is compelling. With high rates of tumor response and promising disease-free survival, this approach could eventually become a standard of care, reducing the reliance on chemotherapy and offering a more targeted, less toxic treatment.

As immunotherapy continues to advance, studies like this one pave the way for personalized and effective cancer treatments that improve patient outcomes and quality of life. For now, these findings offer hope to patients with dMMR colon cancer, suggesting a future in which their treatment journey may be less grueling and more successful than ever before.

About the author

Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. Currently practicing at the renowned Orlando Health Cancer Institute, he brings a wealth of expertise to the complex and challenging world of oncology.