The management of HER2 positive gastroesophageal adenocarcinoma (GEA) needs a more coordinated approach by all HCPs involved in the management and/or care of the patient with cancer including pathologists, gastroenterologists, radiologists, other specialists, all nurses, and pharmacists. Treatment planning should integrate information about the tumor’s biological characteristics, the patient’s clinical presentation, and the available clinical evidence for making treatment decisions.
Patients with unresectable locally advanced or metastatic HER2-positive cancer of the stomach or esophagus can be treated with trastuzumab as part of a combination of therapies. Recently, additional HER2-targeted therapies as well as immunotherapies have become available as first-line therapies for patients with HER2-positive GEA. In August 2026, zanidatamab-hrii (in combination with chemotherapy and tislelizumab-jsgr) was approved for HER2-positive gastric, or esophageal cancer patients. As such, therapies must be selected in a multi-disciplinary manner and evidence supporting use of individual agents incorporated into decisions regarding patient care.
Establishing the Diagnosis and HER2 Status
Begin by confirming a diagnosis and accurately establishing the HER2 status for patients with newly diagnosed cancer. Work closely with pathologists to confirm quality and adequate tumor tissue for correlation with clinical findings and to support treatment decisions with HER2 testing influencing possible targeted therapy for patients.
Before finalizing a strategy for systemic cancer treatment where clinically possible, the diagnostic work-up should provide the complete view of all the tumor’s biomarkers. In concert with the treating oncologist, the pathologists must evaluate the quality and adequacy of the tissue from which the cancer was diagnosed and then test for HER2 using the appropriate assay(s).
HER2 status should be considered in the context of the other biomarkers, and a complete diagnostic work-up should be available to the treatment clinical team before a decision on systemic treatment is made whenever possible.
Integrating Biomarkers Into Treatment Planning
In gastric and GEJ adenocarcinoma PD-L1 expression can be measured by using the combined positive score (CPS), the IHCseq platform or similar technologies that support the quantification of proteins within tumor samples. The tumor sample will provide sufficient information for a multidisciplinary discussion on the appropriate immunotherapy in the individual patient.
For example, the FDA approved administration of pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma whose tumors have PD-L1 expression with a CPS of at least 1.
In addition to the presence of HER2 in tumor cells, other molecular characteristics of the tumor may influence treatment or be of importance for future treatment options. Pathology and molecular tests therefore should be part of the initial multidisciplinary approach and not only a separate laboratory test.
Assessing Disease Extent and Clinical Status
Radiology assesses the extent of the primary tumor and site(s) of metastatic disease. Imaging findings are reviewed in conjunction with clinical symptoms and signs, lab values, performance status, nutrition and organ function. Patients with large tumor burden, symptomatic cancer and rapidly progressive disease may have different goals of care than those with minimal tumor burden and relatively intact functional status.
For the large tumor burden, symptom(s), or aggressive disease, the priority for treatment of the patients with low tumor burden and relatively good performance status would be different. When choosing a first-line treatment for HER2+ GEA, a multidisciplinary team should look at both the cancer characteristics and the patient’s general condition, to select the appropriate treatment option for that patient.
Selecting the Initial Treatment Strategy
Choosing a First-Line HER2+ GEA treatment should be based on several factors including the patient’s eligibility to receive certain treatments, their biomarker status, the characteristics of their disease, their treatment goals, the supporting evidence and the approved indication for use of the various treatment options.
The use of trastuzumab with a fluoropyrimidine- and platinum-based chemotherapy regimen remains a common form of treatment of advanced HER2-positive gastric and GEJ adenocarcinomas. Additionally, for PD-L1-positive patients, the combination with pembrolizumab and a chemotherapy regimen is an approved treatment option for first-line therapy.
Newer HER2-directed treatments have been evaluated in certain settings. Importantly, however, there is considerable difference between the setting in which a treatment has been established as part of the standard therapy and the setting in which it is considered for another disease state or in an adjuvant setting.
Considering Patient-Specific Treatment Factors
We need to consider a number of different patient factors when choosing a treatment and in practical terms how it can be delivered in the clinical setting. These include performance status, age, co-morbidities, renal function, hepatic function, nutritional status, prior treatment, patient preference etc.
It is also important to assess the cardiac function of patients to be on the lookout for possible cardiac toxicity with the use of trastuzumab and to be able to monitor patients who may need close monitoring during treatment. Additional input to treat cancer can come from the roles of the pharmacy and the nursing teams. Potential drug interactions, the method of administration and the supportive care the patient needs to complete his/her treatment must be carefully assessed by both teams for possible barriers to treatment that can affect the adherence to treatment by both the patient and the health care team.
Coordinating Toxicity Monitoring
The plan for monitoring the patient on treatment and for identifying any treatment related adverse effects needs to be clearly outlined by the oncology team.
As well as causing treatment specific toxicities such as cardiac effects seen with HER2-directed therapies, immune checkpoint inhibitors can cause a spectrum of immune-mediated toxicity involving the lungs, liver, adrenal glands, gastrointestinal tract, skin and other organs. Communication with primary care physicians, emergency room physicians and specialists can be crucial in managing and resolving treatment related toxicities in a timely manner.
Reassessing Treatment During Therapy
First-line treatment is not a single event and needs to be assessed during treatment as well. Disease control, treatment side effects, patient’s general condition and preferences need to be assessed during treatment as well as after the end of treatment.
It is also important to continuously assess and weigh the degree of treatment success against side effects. In case of adequate therapy with acceptable side effects, it must be decided whether continued use of the same treatment or switches to alternative treatment options are indicated. In case of progression of disease or occurrence of severe and therapy resistant side effects, switching to alternative treatment options should be considered without delay.
Ongoing assessment of the effectiveness of treatment as well as the associated toxicity also will aid in the acknowledgment of subsequent therapeutic options.
The Role of the Multidisciplinary Team
An effective approach for managing patients with HER2-positive GEA cancer includes clear definitions of roles and responsibilities of the multidisciplinary team, that includes pathologists and interventional radiologists, medical oncologists, pharmacists and nurses. As a team, they evaluate the biomarker status of a tumor, define the extent of cancer in a patient and assess its response to treatment.
Importantly, communication within the multidisciplinary team is key to reaching a treatment decision for a patient with HER2 positive GEA in a timely fashion and includes assessment of biomarkers and confirmation of treatment.
Looking Ahead
As new therapies become available for patients with HER2-positive GEA, treatment approaches may continue to evolve. Zanidatamab-hrii, a HER2-targeted therapy approved for use in combination with chemotherapy and tislelizumab-jsgr in eligible patients, represents an additional treatment option.
Decision making by healthcare professionals regarding treatment of individual patients must be individualized and, therefore, must be based on accurate information regarding HER2 status as well as other biomarkers, an understanding of the individual patient’s cancer and its characteristics, a determination of the treatment’s tolerability by the individual patient, and continued assessment of both clinical benefit and potential for future treatment(s). As more evidence becomes available for the treatment of patients with HER2-positive GEA, the multidisciplinary team will translate that information into patient-centered, appropriate treatment options and consider issues related to safety, clinical benefit, and future treatment options.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.