Manish Shah, MD: The treatment of gastric cancer after relapse, unfortunately, happens too often because most patients with gastric cancer will, in fact, have recurrence. I think one question is the timing. Let’s say a patient received perioperative FOLFOX therapy and surgery and then, 2 years later, they developed recurrence. In my view, all treatment drugs are available, and I might consider a platinum/5-FU combination in the first-line setting. If, however, patients received FLOT therapy perioperatively and unfortunately had a recurrence within 6 months, our options are limited because they probably have a primary refractory disease. I might go with FOLFIRI or something like that, something that’s not cross-resistant. I think the details of the timing matter in terms of time to recurrence. But for most patients, the recurrence tends to be a year or later, so I would consider all drug options.

A key question with regard to this is molecular testing. We commonly do molecular testing on the primary tumor, and if they’re HER2-positive, we use that; if they’re PD-L1—positive, we use that. These markers in gastric cancer tend to be dynamic, so if you’re HER2-positive and receive trastuzumab in the first-line setting, about 30% of the time you will lose your HER2 positivity at the time of progression. So, the fact is that trastuzumab may have killed the clone that was HER2-positive but the remaining clone that developed resistance is HER2-negative. That may be why second-line trastuzumab, T-DM1, and lapatinib are actually ineffective. If I were to try to consider second-line therapy, I would re-biopsy and check to make sure they’re HER2-positive in the second-line setting.

With regard to mismatch repair deficiency, there’s no evidence that it changes. We tend to test for that in the primary tumor, and if they’re mismatch-repair proficient or microsatellite stable, I don’t reexamine that in the metastatic setting or at the time of recurrence. In terms of PD-L1, there are a lot of data that PD-L1 is a dynamic marker and chemotherapy and radiation can, in fact, induce PD-L1 staining. But we don’t really have much data on repeat biopsy and changes in PD-L1. So right now, that’s not an indication to repeat a biopsy, but I wouldn’t be surprised if that changes in the future.

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