A New Possibility for Rectal Cancer Treatment Without Surgery: HER2-Targeted Therapy

The Heavy Burden of Rectal Cancer Surgery

More than a third of patients diagnosed with rectal cancer need total mesorectal excision to remove the tumor completely. This procedure is effective from an oncological perspective, but its physical and psychosocial costs are very high.

HER2 Amplification: A Small but Important Subgroup in Rectal Cancer

HER2 amplification is relatively rare in colorectal cancers — occurring in %1-5 of the general population and around %5 of RAS wild-type patients with metastatic disease. However, this small subgroup has clinically important features. As Dr. Foote from MSK noted, HER2-driven rectal tumors may display a particularly aggressive pattern of behavior and spread to sites such as the brain and bones, where rectal cancer does not typically spread. HER2 therefore represents a strong candidate as both a prognostic and a predictive biomarker.

Study Design: Two-Stage Induction

Foote and his team's prospective, single-arm phase 2 study is built on a two-stage induction in which HER2-targeted therapy is given first alone and then combined with chemotherapy:

Patients who did not achieve cCR were referred for standard-of-care chemoradiotherapy or surgery. The clever aspect of this design is that it offers an opportunity to proactively select patients who can avoid surgery entirely — while also retaining standard treatments for patients who do not respond.

Impressive Results: %50 Clinical Complete Response

The study population had high-risk features: %70 node-positive disease, large tumors close to the sphincter — meaning the vast majority of patients would have required major rectal surgery under the conventional approach. The response rates achieved in this context are particularly noteworthy. The %78 early response rate, which Foote described as "much higher than expected," proves that HER2-targeted therapy shows substantial activity against rectal tumors even on its own.

Who Responded? HER2 IHC 3+ and Gene Copy Number

One of the study's most intriguing findings was that clinical complete responses were observed only in patients with HER2 IHC 3+ tumors . This dramatic response was not achieved in IHC 2+ tumors, even with FISH amplification. HER2 gene copy number was also markedly higher in responding patients. These findings suggest that the intensity of HER2 gene amplification — not merely its presence — could be a predictor of treatment response.

Foote emphasized this observation: "HER2 gene copy number may be a more robust biomarker for predicting response." This supports the idea that the patient population generally grouped into a single "HER2-positive" category in oncology should actually be divided into two subcategories: tumors with a strong HER2 drive (IHC 3+, high gene copy number) and tumors with weak HER2 dependence (IHC 2+). This distinction could shape inclusion criteria for future studies.

Follow-Up Findings: Recurrence, but No Need for Surgery

Results at the study's median follow-up of 26 months are very promising. All patients who achieved a clinical complete response remain alive without metastatic disease. However, three patients experienced local recurrence — within an average of 4 months. The important finding here is: All three patients with recurrence were successfully salvaged without surgery. This involved minor procedures similar to colonoscopy or radiation. In other words, even recurrence emerged as a condition that could be detected early and managed, rather than a failure of the "watch-and-wait" approach.

Safety Profile: Manageable Side Effects

Grade 1 or 2 adverse events were observed in %90 of the study population — meaning almost all patients experienced some form of side effect, but the vast majority remained mild to moderate and manageable. Grade 3 events were relatively rare and transient; the most notable was elevated liver enzymes in %30 of patients receiving the HER2 combination. No grade 4 or 5 events were reported — meaning there were no life-threatening or fatal adverse events. This safety profile suggests that the combined regimen has a profile that could be translated into routine clinical practice.

Background: Why Were Trastuzumab + Tucatinib Chosen?

The evidence base on which the MSK team relied when designing this early-stage rectal cancer study was the MOUNTAINEER trial in metastatic disease. This phase 2 study evaluated tucatinib + trastuzumab in patients with chemotherapy-refractory HER2+ RAS wild-type metastatic colorectal cancer. Results were impressive: a confirmed objective response rate of %39,3, a median duration of response of 15,2 months, and a median overall survival of 23,9 months. These results led to the FDA's accelerated approval of the combination in 2023.

Dr. Foote's point is this: the hypothesis that MOUNTAINEER's impressive data in advanced disease could translate into even stronger effects in early disease — particularly before the tumor has metastasized — provides a strong rationale. Indeed, the general rule in oncology is that if a treatment works in metastatic disease, it has considerable potential to work even better in an earlier stage.

Organ-Preserving Oncology: A Growing Field

In MSK's landmark 2022 study, all 12 patients with dMMR (mismatch repair-deficient) locally advanced rectal cancer achieved a %100 clinical complete response with dostarlimab immunotherapy alone — no patient needed surgery. This striking result opened the door to the paradigm that "selective treatment matched to the molecular profile of some rectal tumors may allow both surgery and radiotherapy to be avoided entirely."

Tanabe emphasizes that the neoadjuvant treatment window is evolving from merely an opportunity to "shrink the tumor before surgery" into "a window in which surgery can be avoided entirely." Identifying the specific HER2 population and matching it with appropriate targeted therapy offers an opportunity for organ preservation with less surgery and even a watch-and-wait pathway that could avoid surgery altogether.

The Future: BRAF, EGFR, and Other Targets Under Consideration

Foote's answer to a question after his presentation sheds light on future research directions. When asked how this organ-preserving approach could be applied to other molecular targets, he said it certainly could — emphasizing that HER2-targeted therapies have been very successful in advanced metastatic colorectal cancer and that a case could be made for evaluating BRAF and EGFR inhibitors as well.

Implications for Practice in Turkey

Because this study is still at the pilot stage, it cannot be applied directly to practice in Turkey. However, several important strategic messages emerge. The first is the need for routine HER2 assessment in patients with rectal cancer. Currently in Turkey, HER2 testing is requested mainly in metastatic colorectal cancer, especially in RAS wild-type and retrospective patients. Baseline HER2 IHC and, when necessary, FISH assessment in locally advanced rectal cancer — especially in large, node-positive tumors near the sphincter — could be considered a forward-looking approach.

The second is to review reimbursement and access conditions for the tucatinib and trastuzumab combination in metastatic colorectal cancer in Turkey. These drugs are currently used widely in breast cancer, but access in colorectal cancer can be limited. The third is the opportunity for Turkey's major oncology centers to lead domestic studies on the organ-preserving rectal cancer paradigm — particularly centers implementing the multidisciplinary approach of the MSK model. Finally, both patient and physician education is needed for acceptance of the "watch-and-wait" approach; this approach is still new in Turkey, and infrastructure requirements remain, including regular MRI follow-up and an experienced multidisciplinary team.

This article was created using various editorial tools, including artificial intelligence, as part of the process. It was reviewed by human editors before publication.