In this post, James M. Cleary, MD, PhD, answers key questions from attendees of a webinar developed for advanced practice providers on the care of patients with advanced gastric cancer.
What molecular testing is recommended for patients with advanced gastric cancer?
Molecular testing and the use of these findings is an area where gastric cancer treatment has changed considerably in recent years. Microsatellite instability (MSI)/mismatch-repair deficiency (dMMR) tumor status should be assessed in all patients newly diagnosed with advanced gastric cancer. Immunohistochemistry (IHC) is generally the fastest way to assess this, and results can come back in a couple of days. Likewise, it is very important to test for PD-L1 expression via IHC, as these results can inform the decision about whether to combine first-line chemotherapy with PD-1-directed immunotherapy.
HER2 amplification status should also be assessed in all patients with suspected locally advanced/recurrent/metastatic gastric cancer using IHC, with or without in situ hybridization. If you have a patient with HER2-amplified disease, HER2-directed therapy should be strongly considered.
The other thing I do with all my patients with advanced gastric cancer is to order next generation sequencing (NGS). NGS testing results do take a little longer to come back than some other forms of testing, but with NGS testing, you will get MSI/dMMR tumor status and tumor mutational burden status, and you will also find out if there are any rare, but actionable, molecular alterations like NTRK or RET fusions. Finding an actionable mutation could provide a patient with additional molecularly guided treatment options.
How is HER2-negative advanced gastric cancer treated in the first-line setting?
If the PD-L1 combined positive score (CPS) is negative for this population, 5-FU or capecitabine plus oxaliplatin or cisplatin is recommended. If PD-L1 CPS is elevated, we can strongly consider adding nivolumab or pembrolizumab to the aforementioned chemotherapy regimen. The CheckMate-649 study assessed first-line chemotherapy (XELOX or FOLFOX) with or without nivolumab in patients with HER2-negative advanced gastric/GEJ/esophageal adenocarcinoma. There was a significant survival improvement with the addition of nivolumab, especially in patients with PD-L1 CPS ≥5. Likewise, the KEYNOTE-859 trial showed that in combining first-line pembrolizumab with chemotherapy (5-FU plus cisplatin or capecitabine plus oxaliplatin) for patients with HER2-negative advanced gastric/GEJ adenocarcinoma, patients had better survival with the addition of pembrolizumab to chemotherapy vs chemotherapy alone, especially those with a PD-L1–positive disease.
What about HER2-positive advanced gastric cancer?
For patients with HER2-positive advanced or metastatic gastric cancer, the preferred first-line regimen is 5-FU or capecitabine plus oxaliplatin or cisplatin plus trastuzumab. If the patient has a PD-L1 CPS ≥1, pembrolizumab should be added to this regimen. Note that this recommendation for pembrolizumab is a recent change; prior to recent findings, all patients with advanced HER2-positive disease were receiving this agent in addition to chemotherapy. The KEYNOTE-811 study showed that for patients with HER2-positive gastric cancer, those with PD-L1 CPS <1 did not derive as much survival benefit from the addition of pembrolizumab to chemotherapy plus trastuzumab vs those with PD-L1 CPS ≥1, resulting in a change in our use of this agent for HER2-positive disease.
What causes patients with gastric cancer to lose HER2 positivity?
HER2 is amplified and/or overexpressed in approximately 10%-15% of gastric cancers. One of the things we are learning is molecular heterogeneity in HER2-amplified gastric cancers. I am currently taking care of a patient where we biopsied both the primary gastric lesion and metastatic liver lesion and the gastric lesion was HER2-amplified and the liver lesion was not. Therefore, if the patient receives HER2-directed therapy, the HER2-amplified tumor cells may die off, but the HER2 non-amplified cells will not.
HER2 heterogeneity is a known resistance mechanism to anti-HER2 drugs. Since loss of HER2 amplification is an escape mechanism, please check your patients to make sure their disease remains HER2-amplified if you have completed first-line HER2-targeted therapy and plan treatment with another HER2-directed approach for second-line therapy (eg, trastuzumab deruxtecan).
Are there specific indicators in a family history that are worthy of an immediate referral for genetic counseling, besides having a first degree relative with a history of gastric cancer?
If your patient with gastric cancer has family members with lobular breast cancer, that is a red flag, because it is known that a germline CDH1 mutation increases the risk of lobular breast cancer. If your patient has a germline CDH1 mutation, they are at high risk for developing an aggressive form of stomach cancer called hereditary diffuse gastric cancer (HDGC). HDGC can cause linitis plastica, a diffuse thickening of the stomach wall without formation of a mass. Therefore, if you have a patient with diffuse gastric cancer who has a family history of lobular breast cancer, the presence of CDH1 mutations should be suspected and the patient should be sent for germline testing.
Along with the family history, I also consider the age when the patient developed gastric cancer. The more we learn about gastrointestinal malignancies and the many germline mutations that affect the risk of developing cancer, the more we find that it is never wrong to send someone to a high-risk genetics clinic to have their blood drawn for germline testing.
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