Importance of Biomarker Testing, Patient Goals and Education When Treating Gastric Cancer

Gastric cancer is the fifth most common cancer and the fourth leading cause of death from cancer worldwide.¹ Occurrence of gastric cancer is linked to Helicobacter Pylori infection, as well as genetic risk factors, and lifestyle factors such as alcohol consumption and smoking. Due to ambiguous symptoms in early-stage gastric cancer and the lack of preventive screenings, gastric cancer is most often diagnosed at advanced stages of the disease.

Given that prognosis is more favorable the sooner gastric cancer is diagnosed, early detection is extremely important. Standard diagnosis techniques for gastric cancer include endoscopic and imaging tests.² However, the addition of biomarker testing can improve prognosis and patient quality-of-life by personalizing the treatment regimen.

Recently, ACCCBuzz had an opportunity to speak with Nataliya Uboha, MD, PhD, associate professor at the University of Wisconsin’s Carbone Cancer Center (UWCCC) in Madison, Wisconsin. Dr. Uboha is a faculty leader for Early Phase Oncology Therapeutics Program at UWCCC and is a nationally recognized expert in gastroesophageal malignancies and neuroendocrine tumors. She is a co-chair for ECOG-ACRIN Upper GI Working Group, a co-chair for NCI Esophagogastric Taskforce and is a member of the National Cancer Institute Upper GI Taskforce.

ACCCBuzz: How do you incorporate a patient’s goals into creating a treatment plan? Are there questions that you commonly ask? 

Dr. Uboha: Incorporating a patient's goals into creating an oncology treatment plan is a crucial aspect of patient-centered care. The aim is not only to address the medical aspects of cancer but also to consider the patient's values, preferences, and lifestyle.

Shared decision making is critical for optimal outcomes. I spend a significant portion of our visits explaining various treatment options, their associated benefits, and risks. I ensure that patients have appropriate knowledge about the treatments available to them. We also talk about patient's personal priorities and goals.  These discussions typically involve gathering information about patient’s daily activities, work, and social support. Appreciation of cultural values can further help tailor treatments and set up realistic expectations.

Here are some of the questions I frequently ask: “What is your understanding of your diagnosis and what treatments can achieve?”, “Is there anything you worry about the most as you start on treatment?”, “Who is in your life?”, “What things are important to you in your life?”, “If there is one thing or symptom we could improve upon now, what would that be?”

ACCCBuzz: A number of biomarker driven treatment options have emerged in the gastric cancer treatment landscape. What tests should be considered prior to initiating therapy for a patient? 

Dr. Uboha: There are several established biomarkers that should be evaluated prior to treatment selection.³ In metastatic setting, the following tumor evaluations should be performed:

• Mismatch repair protein (MMR) protein expression or microsatellite instability (MSI) status. Deficient MMR protein expression or microsatellite instability is predictive for immunotherapy responses.

• Evaluation of human epidermal growth factor receptor-2 (HER-2) status. Tumors are considered HER-2 positive if immunohistochemistry (IHC) score is 3+ or IHC score is 2+ and fluorescence in situ hybridization (FISH) test is positive. About 20% of advanced gastroesophageal adenocarcinomas are HER-2 positive.

• Programmed death ligand-1 (PD-L1) Combined Positive Score (CPS) evaluation. There are different antibodies for assessment and there are different thresholds for positivity, depending on the study and treatment regimen. However, in clinical practice, 22C3 pharmDx assay is often used for assessment of tumor PD-L1 status in patients with upper GI cancers. For HER-2 negative tumors, nivolumab is usually added to chemotherapy for PD-L1 CPS≥5 tumors.⁴ For HER-2 positive tumors, pembrolizumab is utilized for PD-L1 CPS≥1 tumors.⁵  

• All my patients have their tumor tissue analyzed by Next Generation Sequencing for the presence of other potentially actionable alterations, given recent increase in biomarker-based therapies. However, these results do not affect my treatment selection in the first-line setting. 

• In early-stage disease, only MMR IHC or MSI testing can have an impact on treatment selection. Currently, the presence or absence of other biomarkers does not influence therapy choice for early-stage tumors. 

• There are several emerging biomarkers. I anticipate that testing for Claudin 18.2 expression will soon become part of our standard practice in advanced disease setting. Claudin 18.2 is a major component of tight junctions, and its expression is observed in approximately 30% of gastroesophageal adenocarcinomas. 

ACCCBuzz: How do biomarkers help inform treatment options?  

Dr. Uboha: There are now several clinically relevant biomarkers that have associated therapies. The presence or absence of these biomarkers can influence what therapies we give to patients. For example, patients with PD-L1 CPS≥5 tumors should be treated with immunotherapy in addition to chemotherapy. Tumors with HER-2 overexpression should be treated with anti-HER-2 agents. Biomarker based treatments have been shown to improve patient outcomes.^4,5

ACCCBuzz: Upon progression on front-line therapy, what are key considerations in selecting subsequent therapy?  

Dr. Uboha: There are several factors that we consider when selecting second-line treatment options for patients with advanced gastric and gastroesophageal junction (GEJ) cancers. First, it is important to determine whether patients are fit to receive more systemic treatments. This should be assessed during each visit in the oncology clinic. Patients with Eastern Cooperative Oncology Group (ECOG) performance status >2 are likely to experience more harm than benefit from additional treatments. It is also important to consider what prior treatments patients have received and whether they have residual treatment related toxicities. For example, the presence of peripheral neuropathy or prior treatment with taxane therapy would make second-line paclitaxel less desirable and irinotecan may be a preferred choice.⁶

The presence of biomarkers may play a role as well. Patients with HER-2 positive tumors may be considered for treatment with trastuzumab deruxtecan in later lines if their tumors retain HER-2 expression.⁷ We must also consider other comorbidities and risk factors for treatment selection, such as recent stroke or active coronary artery disease, which would preclude the use of ramucirumab.^8,9 Last but not least, patient’s personal goals and preferences are key factors as well. Some patients may prefer to avoid weekly visits or IV treatments or may decide to shift to therapies focused on comfort only.

ACCCBuzz: How do you support patients to manage the adverse events they may experience?

Dr. Uboha: Patient education is very important prior any new treatment initiation. Before the start of the new therapies, our patients meet with chemotherapy nurses and an oncology pharmacist for “chemotherapy teaching.” During these meetings, patients are educated about anticipated side effects and supportive care medications.  Once the treatment is started, patients usually receive a call from a nurse or a pharmacist a week after treatment initiation to make sure they are tolerating treatment well. We also have a symptom management clinic, which is dedicated to addressing urgent issues in patients with active cancer. In addition, I work very closely with the palliative care team, which I tend to involve very early on in the care of patients with advanced cancers. This team helps manage treatment and cancer related symptoms.

ACCCBuzz: What role does nutritional support play in the treatment plan?  

Dr. Uboha: In our cancer center we have dedicated oncology registered dietitians (RD) who help support our patients. All patients with gastroesophageal cancers meet with a RD during their initial visit in our cancer center. Subsequently, RDs are involved on an as needed basis during the care continuum of each patient. The RD appointments occur during treatment visits or virtually as a telemedicine encounter to minimize the additional burden of clinic visits on patients. As patient’s nutritional needs can change through the course of their illness, both my team and the palliative care team can reengage RDs at any point during treatment if additional nutritional support is needed. 

Optimal nutritional support is essential for the best outcomes of patients with gastroesophageal cancers. Patients with good nutritional status have less treatment related toxicities and better quality of life.

References:

1. Thrift, A.P., Wenker, T.N. & El-Serag, H.B. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 20, 338–349 (2023). https://doi.org/10.1038/s41571-023-00747-0.
2. Alfonso GP, Solero PTS, Alsar SJ, Martin MA, Parrondo J (2021) Biomarkers in early colorectal, esophageal, and gastric cancer. Clin Case Rep Rev, 7: DOI: 10.15761/CCRR.1000508.
3. Dhakras P, Uboha N, Horner V et al. Gastrointestinal cancers: current biomarkers in esophageal and gastric adenocarcinoma. Translational Gastroenterology and Hepatology; Vol 5 (October 2020): Translational Gastroenterology and Hepatology 2020.
4. Shitara K, Ajani JA, Moehler M et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature 2022; 603 (7903): 942-948.
5. Janjigian YY, Kawazoe A, Bai Y et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023 Oct 19:S0140-6736(23)02033-0. doi: 10.1016/S0140-6736(23)02033-0. Online ahead of print. 
6. Lorenzen S, Thuss-Patience P, Pauligk C et al. FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel - results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO. Eur J Cancer 2022; 165: 48-57.
7. Shitara K, Bang YJ, Iwasa S et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020; 382 (25): 2419-2430.
8. Wilke H, Van Cutsem E, Cheul Oh S et al. RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors. Journal of Clinical Oncology 32, (15) suppl (May 20, 2014) 4076-4076.
9. Cyramza (ramucirumab) USPI Sections 5.4 and 6.3. Eli Lilly and Company, March 2022.

Nataliya Uboha, MD, PhD, is an Associate Professor at the University of Wisconsin’s Carbone Cancer Center and an independent advisor engaged by Lilly to provide her expert opinion.

Dr. Uboha’s Conflicts of Interest:  

• Research support: Ipsen, EMD Serono 
• Consulting: Pfizer, AstraZeneca, Astellas, Ipsen, BMS, Boston Gene, Grail, Elevation Oncology, Eisai 
• Long position holdings: Exact Sciences, Natera 

Developed under the direction and sponsorship of Lilly Medical Affairs and is intended for US healthcare professionals only. 

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