Rectal Cancer: Testing and Immunotherapy Breakthroughs

Rectal Cancer: How New Testing and Immunotherapy Are Changing the Future

Not long ago, the treatment journey for rectal cancer almost always included surgery, radiation, and sometimes chemotherapy. These treatments are effective but can be life-changing, often leading to permanent changes in bowel, bladder, or sexual function. Today, however, new research is rewriting that story.

Why Testing Matters More Than Ever

Every rectal cancer patient should now be tested for mismatch repair deficiency (MMRd) or microsatellite instability (MSI-H). These genetic features, found in about 10–15% of colorectal cancers, tell us how the tumor repairs its DNA. When these pathways are faulty, the cancer cells accumulate mutations—and, paradoxically, that makes them more visible to the immune system.

For patients, this is crucial. If your rectal cancer is MMRd or MSI-H, you may be eligible for immunotherapy instead of the traditional combination of surgery, chemotherapy, and radiation.

Tumors That Vanish with Immunotherapy

A groundbreaking NEJM study in 2022 from Memorial Sloan Kettering showed that patients with MMRd/MSI-H rectal cancer treated with an anti-PD-1 immunotherapy for six months had 100% complete clinical responses. In plain terms: every patient’s tumor disappeared, and none needed surgery, radiation, or chemotherapy.

This was the first time doctors could say to a group of rectal cancer patients: “Your body’s immune system, with the help of immunotherapy, may do all the work.”

By 2024, this study established a new standard of care: all rectal cancer patients should be tested for MMRd/MSI-H before beginning treatment.

How Long Should Immunotherapy Last?

One of the big open questions is how long patients need to stay on immunotherapy. A recent 2025 NEJM editorial reviewed data across colorectal cancers and suggested that longer immunotherapy courses may give more durable responses. In practice, this may mean continuing treatment beyond six months, as long as the patient is responding well. Future clinical trials are already being designed with this in mind.

Beyond Immunotherapy: Aspirin and PI3K Testing

Another exciting development comes from the ALASSCA Trial (2025, JCO Late-Breaking Abstract). This study looked at patients with stage I–III colorectal cancer who had PI3K pathway driver alterations. These patients took daily low-dose aspirin (160 mg) for three years, which reduced recurrence rates by more than 50%.

This is the first biomarker-driven randomized trial in non-metastatic colorectal cancer. If confirmed in full publication, it will make PI3K testing an important part of care, much like MMRd/MSI testing is today.

What This Means for Patients

• Testing is the new foundation. Every rectal cancer patient should be tested for MMRd/MSI and, soon, PI3K pathway alterations.

• Some tumors may not need surgery or radiation. For patients with MMRd/MSI-H tumors, immunotherapy may allow the tumor to dissolve completely.

• The field is moving fast. New questions, like how long to continue immunotherapy, are shaping the next generation of clinical trials.

• Personalized care is here. Instead of one pathway for all patients, your treatment can now be tailored to the biology of your tumor.

Final Thoughts

The treatment of rectal cancer is entering a new era. For the first time, some patients may avoid surgery and radiation entirely. Others may benefit from something as simple as aspirin, guided by their tumor’s genetic makeup.

If you or a loved one is facing a diagnosis of rectal cancer, ask your doctor about MMR/MSI testing and PI3K testing. These results could open the door to treatments that are less invasive, more targeted, and—most importantly—more effective.

References

1. Cercek A, et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New England Journal of Medicine. 2022;386(25):2363–2376. Link

2. NEJM Editorial. Duration of Immunotherapy in Colorectal Cancer. New England Journal of Medicine. 2025.

3. ALASSCA Trial. Daily Aspirin in Stage I–III Colorectal Cancer with PI3K Alterations (Late-Breaking Abstract). Journal of Clinical Oncology. 2025;43(4_suppl):LBA125.

4. NEJM Correspondence. Advanced Rectal Cancer Treatment Advances. New England Journal of Medicine. 2024. Link