HER2-Positive Gastric Cancer


Dr Catenacci highlights clinical trials in HER2-positive gastric cancer that may provide insight on differences in mechanism of resistance from one tumor type to another.

Daniel Catenacci, MD: What is the utility of anti-HER2 therapy beyond progression in the first line? This comes on the back of anti-HER2 therapies being evaluated in breast cancer through later lines, which of course a number of studies have shown a benefit with even trastuzumab beyond first progression, lapatinib, T-DM1 [trastuzumab emtansine], etc. Even pertuzumab in the first-line setting, in addition to trastuzumab, and perioperative approaches. Breast cancer has had a lot of success with continued and altering of manners of inhibiting HER2.

On the other hand, unfortunately in gastroesophageal cancer, the first study, ToGA, did show a benefit, but a number of second-line studies and first-line studies have been negative. In the first-line setting, lapatinib plus chemotherapy was not shown to be better than chemotherapy alone for HER2-positive tumors in the LOGiC study.

Pertuzumab, added to chemotherapy plus trastuzumab, was not better than chemotherapy plus trastuzumab, although it trended, it was not statistically significant, and it’s not an improved indication for pertuzumab in the JACOB study. In the second-line setting we’ve had a number of studies beyond progression anti-HER2 therapy. The first was the TyTAN study, which was paclitaxel with or without lapatinib, which was a negative study, as well as the GATSBY study, which was T-DM1 versus taxane in the second-line setting, which was also negative.

We’ve also had a smaller phase 2 study that was randomizing to chemotherapy with or without trastuzumab beyond progression, and that study did not show benefit.

What we’ve learned though since those studies were done, and even during those studies, is that the mechanism of resistance to trastuzumab in the first-line setting for gastroesophageal cancer tends to be different than in breast cancer. In breast cancer, there are mechanisms that lead to resistance while the patient retains HER2 amplification in their tumor cells, and signaling for HER2 is still dependent.

On the other hand, in gastroesophageal cancer, or at least a subgroup of them, there is evolution of the disease that is no longer HER2-dependent, it is no longer HER2 amplified. If you rebiopsy the disease that’s progressing, it is HER2-negative if you do immunohistochemistry and FISH [fluorescence in situ hybridization] testing. The reason for that is because the biology of the cancer is different, and it’s heterogenous even within the patient. They have the same founder mutations and tumor suppressors, TP53, etc, but then they have branched evolution, where only a subset of the disease is HER2 amplified, while other components of the patient’s cancer are not.

When you treat with HER2 therapy in the first-line setting you can control those HER2-amplified clones, but the HER2-negative clones blossom and become the new burden of disease.

In all of the second-line studies that were done, it was assumed that a patient’s tumor was still HER2 amplified because it was before first-line therapy, and that is at least partially responsible for why they have likely failed because up to half of the patients enrolled weren’t having HER2-positive disease.

The question of whether selecting patients for continued anti-HER2 therapy beyond first progression, if their cancer is still HER2 dependent, if is there a benefit from any of these anti-HER2 therapies, remains an open question.

Transcript edited for clarity.

Case: A 71-Year-Old Man With HER2+ Gastric Cancer

Initial Presentation

  • A 71-year-old man complained of a 3-month history of abdominal pain and bloating, a sensation of fullness
  • PMH: HTN, medically controlled; colonoscopy at age 53 was unremarkable; no family history of cancer
  • PE: patient appeared tired, abdominal distention; otherwise unremarkable

Clinical Workup

  • Labs: Hb 9.7 g/dL, plt 111 x 109/L; other lab values WNL
  • Upper endoscopy with biopsy: showed an ulcerative lesion 5.8 cm mass in the cardia of the stomach; biopsy confirmed gastric adenocarcinoma
  • CT of chest/abdomen/pelvis confirmed a 5.8 cm lesion with indistinct margins in the cardia of the stomach; 2 suspicious hepatic lesions
  • EUS: gastric cancer lesion confirmed invasion of the muscularis propria
  • Mutational testing: MSI high, PD-L1 0%, HER2 3+ by IHC
  • Stage IV gastric adenocarcinoma; ECOG 2


  • He was started on XELOX/CAPOX + trastuzumab
    • Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment
  • Treatment initiated with a pembrolizumab
    • After 24-months of treatment without progression of disease pembrolizumab was discontinued
  • The patient was started on trastuzumab deruxtecan; repeat HER2 expression testing was not indicated
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