Practical Perspectives on Treatment of Advanced Gastric/GEJ Cancers - Episode 13
Minaxi Jhawer, MD: Having gained an in-depth understanding of the molecular profile and the biology of tumors over the years, we’re able to target the disease in a more personalized, sophisticated manner. It still means personalizing the care for that particular patient using the right chemotherapy combination, but it also means personalizing it for the tumor type, whether it’s HER2 expressing, PD-L1 overexpressing, or if a VEGF-targeted drug would work well in that disease. Put all this together to get the best care for these patients in a multidisciplinary fashion with the whole team involved along the way. I personally feel that having a pain and palliative team working alongside you and having something like MCCM [Medicare Care Choices Model] services, which go into the house of the patient and help support the patient and their family, brings better outcomes. You will have fewer hospital admissions because these patients are really well taken care of in the outpatient setting.
David Ilson, MD, PhD: Where do we see the treatment of gastroesophageal cancer proceeding with the advent of new research and other strategies? We had a lot of hope about the genomic profiling data, and I think they have been fruitful to a certain extent in validating HER2 testing and MSI [microsatellite instability] testing as biomarkers for specific therapies. Although these data are emerging, we’ve also found targets that have not been so useful. Drugs that target the EGFR pathway have universally been unsuccessful. Drugs that target the MET-amplified pathway have also been universally unsuccessful. There are ongoing trials of agents targeting the FGF pathway. With genomic sequencing, we can identify some small subsets of patients who may have targetable mutations for clinical trials. We’re also elucidating resistant mechanisms, where if a patient has a HER2 amplification, perhaps they have an amplification or activation of a parallel pathway that may convey resistance. I think these data are generating hypotheses where we can potentially look at combination strategies trying to target a pathway and potential resistance mechanisms.
The other area that’s going to move us forward, now that we have some signal of benefit for immunotherapy drugs, is looking at combination immunotherapy strategies. How can we make a nonimmunogenic tumor hot in order to stimulate an immune response? Immunomodulatory approaches, adding costimulatory drugs, and trying to identify better biomarkers in tumors are all part of ongoing active research. We do know that the patient’s cancer is often fluid and that when patients are exposed to treatments we may engender resistance. We have data from our center that in patients who progress on HER2-targeted therapy, about 15% to 20% actually become HER2 negative on repeat biopsy. So, there’s a lot of interest in resampling the patient’s tumor during the course of therapy.
One noninvasive way to do that is with what we call liquid biopsy, looking at circulating tumor DNA. If you just biopsy 1 tumor, you get 1 sample. Sometimes, different metastases are heterogeneous and have different mutations. Some tumors may respond, others may be resistant. The advantage of sampling the blood is that you’re looking at tumor DNA that’s released from all the different cancers in the body.
Noninvasive testing with circulating tumor DNA assessment is a very promising research strategy. Certainly, it’s bearing fruit in lung cancer, where we sample patients and identify that they have EGFR mutations and developed new mutations. We have drugs for those patients. I think the dynamic sampling of patients’ tumors with circulating tumor DNA is a very promising strategy, and hopefully it will lead to focusing and directing treatment and potentially enlisting patients on clinical trials. Another area is minimal residual disease. If a patient has been rendered free of their cancer and had adjuvant treatment, do we have measures that indicate they may be at higher risk of recurrence if they still have residual circulating tumor DNA? That’s an approach that’s being exploited in colorectal cancer to design adjuvant strategies.
Minaxi Jhawer, MD: The biggest ongoing challenge in gastric cancer is that there are no good screening methods to diagnose it early. Most of our patients are diagnosed in the advanced stage, either locally advanced and unresectable or metastatic, at which point the treatment is generally palliation to control symptoms and improve their quality of life. The greatest challenge is maintaining their quality of life, keeping them pain free, giving them ways and means to make it to the appointment, and really maintaining their life goals. That really requires a good supportive team to help do that.
Transcript Edited for Clarity