Dr Catenacci evaluates the case of a 71-year-old man with gastric cancer, and provides insight on molecular testing in gastric cancer and initial treatment options.
Daniel Catenacci, MD: We’ll be presenting this case, a 71-year-old man complained of a 3-month history of abdominal pain and bloating, and a sensation of fullness. Past medical history included hypertension, which was controlled. He had a colonoscopy at age 53 that was unremarkable, and no family history of cancer. On physical examination he appeared tired, he had abdominal distension, but otherwise was unremarkable.
The laboratory work-up showed a hemoglobin of 9.7 [g/dL], platelets 111 [x 109], and other laboratory values were within normal limits. He had an upper endoscopy for work-up, which showed an ulcerative lesion, a 5.8-cm mass in the cardia of the stomach, that was biopsied and confirmed to be invasive adenocarcinoma.
Staging CT scans of the chest, abdomen, and pelvis confirmed this lesion with indistinct margins in the cardia of the stomach, as well as 2 hepatic lesions. An endoscopic ultrasound had been done and confirmed invasion into the muscularis propria.
Mutational and molecular profiling revealed that the patient had a tumor that was HER2-positive with an immunohistochemistry [IHC] score of 3+. It was also tested for microsatellite instability, and in this case was high. And PD-L1 testing was CPS, or combined positivity score, of 0.
The patient was therefore at a stage IV disease. His performance status was a 2, mostly due to symptoms directly related to the cancer. The patient was started on first-line chemotherapy with capecitabine and oxaliplatin, or CAPOX, with trastuzumab. He did get dose reduced for grade 2 diarrhea that was attributed to the capecitabine. However, despite the dose reductions, he was unable to improve this symptom, and after 4 cycles discontinued treatment.
The patient then was changed to second-line therapy and started on pembrolizumab. After 24 months of treatment without progression of disease, the pembrolizumab was discontinued. The patient then did have progression of disease, and therefore, the patient was started on trastuzumab deruxtecan. Repeat HER2 testing was not done.
My impressions of this case, and whether this is a typical case, is that when we have a patient who presents, these are typical symptoms, and typical presentation in terms of staging and often presents outright with stage IV disease, as this patient, to the liver.
With respect to molecular profiling, which we should be doing on all our patients, the standard had been for a number of years now to test for HER2, and the standard way to do so would be with immunohistochemistry first. And if the patient is 0 or 1+ by immunohistochemistry, that would be considered negative. If it’s 3+ by IHC, then it would be positive. If it’s 2+, then it would be called equivocal and reflexed to FISH [fluorescence in situ hybridization] testing. The FISH testing would be considered positive if the ratio of the HER2 probe to the control probe was 2 or higher. And the staining by IHC has to be in 10% of cells or higher. So 2+ is 10% or higher, and 3+ is 10% or higher of the cells.
In addition to that, we’ve now come to learn that microsatellite instability is an important subgroup of this disease. About 3% or so of all patients with gastroesophageal cancer will have microsatellite instability in the stage IV setting.
The incidence is a bit higher in the perioperative setting, almost even up to 10%, but in this setting we would expect a low rate, but a real rate. And the reason why that’s important is because if you do have a patient with microsatellite instability, generally, as opposed to this case, they are mutually exclusive, and HER2 amplification does not usually co-occur with microsatellite instability. This was done for purposes of being able to talk about what to do in these scenarios.
In the setting of just taking microsatellite instability first, the standard of care at the moment is to use pembrolizumab. It’s approved for all solid tumors, including gastroesophageal cancer, and is approved in the second-line setting or higher. The response rate in solid tumors, including this gastroesophageal subgroup, is around 50% of patients, which is higher than first-line chemotherapy with FOLFOX [folinic acid, fluorouracil and oxaliplatin] in all-comers who are HER2-negative.
In addition to that, we’ve had data from a number of studies emphasizing the importance of doing this for microsatellite unstable tumors. Patients who are diagnosed, and should be checked for this, if they have that, the consensus has been to move immunotherapy to the first-line setting. This has been demonstrated with the KEYNOTE-062 study subgroup analysis. This has been demonstrated in colorectal cancer in the KEYNOTE-177 study.
Transcript edited for clarity.
Case: A 71-Year-Old Man With HER2+ Gastric Cancer