Immunotherapy Before or After Surgery? ATOMIC & NICHE-2 in dMMR-Positive Colon Cancer

⏰ Does Timing Make a Difference?

In cancer treatment, particularly colorectal cancer, immunotherapy is becoming increasingly important. Yet the question of when and in which patients it should be used , including whether treatment belongs before surgery (neoadjuvant) or after surgery (adjuvant) , remains a major oncology debate.

This article focuses on locally advanced (stage III), dMMR-positive colon cancer. dMMR (DNA mismatch repair deficiency) indicates dysfunctional tumor DNA repair. This biological defect makes tumors more sensitive to immunotherapy.

Approximately 10-15% of stage III colon cancers are dMMR-positive . These patients respond less well to conventional chemotherapy but may benefit substantially from immunotherapy.

Consequently, when to administer immunotherapy—before or after surgery—is more than academic; it is a question directly affecting clinical decisions.

The issue matters because of its potential to change clinical practice . We examine recent major studies, including phase III ATOMIC and phase II NICHE-2 , to explore it in detail.

🎯 Our Aim: To provide healthcare professionals with a current perspective and make the topic understandable to patients and families.

Neoadjuvant or Adjuvant Immunotherapy in dMMR-Positive Stage III Colon Cancer?

Recently reported phase III ATOMIC study resultsprovided important data in locally advanced dMMR-positive colon cancer for the adjuvant (postsurgical) immunotherapy approach.

However, they reignited specialist debate about the best treatment plan .

🔎 No Direct Comparison Yet: No study directly comparing adjuvant immunotherapy + chemotherapy with neoadjuvant immunotherapy through a randomized trial is currently available.

However, ATOMIC and NICHE-2 study subgroup analyses, may clarify whether one approach suits everyone and which patients benefit most from each strategy .

The Strength of Adjuvant Immunotherapy: ATOMIC

American Society of Clinical Oncology (ASCO) 2025 Presented at the meeting, the ATOMIC studyprovided strong data for advocates of adjuvant treatment.

In the study, stage III, dMMR (mismatch repair deficiency) patients, 355 in number, received standard postsurgical FOLFOX chemotherapy plus atezolizumab immunotherapy.

• 📌 Result: Compared with chemotherapy alone, the combination reduced recurrence or death risk by 50%.

• 📊 DFS (Survival Without Disease Recurrence): In the combination arm, 86.4%, versus chemotherapy alone, 76.6% .

Study author Dr. Frank A. Sinicropesaid these data establish a new standard treatment combination for dMMR-positive stage III colon cancer and will change clinical practice .

📊 ATOMIC vs. NICHE-2: Comparative Summary

Success with Neoadjuvant Immunotherapy: NICHE-2

European Society for Medical Oncology (ESMO) 2023 Presented at the annual meeting, the NICHE-2 studydemonstrated neoadjuvant treatment's potential.

• 🧬 Study Design: Stage III dMMR colon cancer patients, 111 in number, received presurgical ipilimumab and nivolumab immunotherapy.

• 🎯 Result: Among patients receiving presurgical immunotherapy, 100% remained at 3 years recurrence-free , exceeding the specified success threshold of 93%.

These data highlight presurgical immunotherapy, for its potential to reduce the need for postsurgical chemotherapy or eliminate it completely .

Views Supporting the Adjuvant Approach

ATOMIC investigator Dr. Christopher Lieulists the strengths of adjuvant immunotherapy:

1. Avoiding Unnecessary Treatment:

   Patients appearing lower-stage on CT (stage I–II) may prove stage III after surgery. Adjuvant immunotherapy then becomes relevant.

2. Synergy with Chemotherapy:

   Combined treatment may target tumors through immune and cytotoxic mechanisms.

3. Avoiding Surgical Delays:

   Rare immune complications during neoadjuvant immunotherapy may delay surgery. The adjuvant approach avoids this risk.

Dr. Lieu emphasizes: “Giving everyone neoadjuvant treatment is not the answer. If you initially believe disease is stage I or II, postsurgical adjuvant treatment may make more sense.”

Views Supporting the Neoadjuvant Approach

NICHE-2 data are cited to suggest that neoadjuvant immunotherapy may be more effective than the adjuvant approach .

Furthermore, chemotherapy's limited efficacy in dMMR colorectal cancer has brought presurgical immune-based approaches to the forefront.

• 🔻 Tumor Shrinkage: Neoadjuvant immunotherapy shrinks tumors before surgery (down-staging), potentially improving clear-margin rates. If a pathological complete response occurs, patients may avoid postsurgical chemotherapy.

• ⚠️ Aggressive Disease: Particularly in biologically aggressive cases, neoadjuvant treatment may be more appropriate.

Whether neoadjuvant treatment should ultimately lead to surgery or nonoperative surveillance remains unclear. Both approaches should be individualized through patient-physician decisions.

🧩 Conclusion and Commentary

Neoadjuvant and adjuvant immunotherapyhave not yet been directly compared in a randomized trial. This gap, however, does not diminish the clinical strength of existing evidence.

The NICHE-2 study, particularly with 100% recurrence-free survival at 3 years , strikingly demonstrates neoadjuvant immunotherapy's potential. Conversely, ATOMIC's methodological limitations suggest that the adjuvant approach's clinical value may have been overstated.

Clinical decisions should depend on more than statistics: biologically informed patient selection and treatment timing's biological rationale also matter.

📌 What truly makes the difference is correct interpretation of MMR/MSI tests and management based not only on stage but also on the molecular profile .

Stage I–II patients face overtreatment risk, which must be considered. In stage III dMMR patients, however, early immunotherapy's effect on survival deserves serious consideration.

In conclusion: For all dMMR-positive or MSI-H locally advanced colon cancer patients, the fundamental approach should be neoadjuvant immunotherapy .

ATOMIC may provide an adjuvant option for patients who received no neoadjuvant treatment and whose presurgical care lacked this biological perspective.

NICHE-2 should be the foundation; all patients identified by imaging as stage III should receive dMMR and MSI testing , and if positive:

✅ Information about neoadjuvant treatment and potential benefits should be discussed openly with the patient and treatment planned accordingly.