Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: Results of GASTric cancer HER2 reassessment study 3 (GASTHER3).

Abstract

27 Background: Although discordance of HER2 positivity between primary and metastatic lesions was well known, changes of HER2 positivity after chemotherapy have not been studied in gastric cancer (GC). Methods: A total of 48 HER2-positive advanced GC (AGC) patients who were treated with trastuzumab-containing 1stline chemotherapy and had paired biopsies at baseline and after progression were enrolled. Scores of HER2 immunohistochemistry (IHC) were reviewed and in situ hybridization (ISH) was conducted when tissues were available. Results: Thirty-nine patients were treated with capecitabine, cisplatin/oxaliplatin, and trastuzumab (XPT) while the other 9 received XPT plus pertuzumab/placebo. Objective response rate (ORR) was 76% (26 out of 34) and median progression free survival (PFS) and overall survival were 8.3 and 16.3 months, respectively. At baseline, HER2 was positive with IHC 2+ and ISH+ in 5 and with IHC 3+ in 43. Loss of HER2 positivity after progression was observed in 14 (28.6%); 10 with IHC 0 or 1+ and 4 with IHC 2+ but ISH- at 2nd biopsy. HER2 remained positive in the other 34; 4 with IHC2+ and ISH+, and 30 with IHC 3+ at 2nd biopsy. Applying H-score formula, mean scores decreased from 201 to 170 (Wilcoxon test; p=0.047). HER2 genetic heterogeneity (5% to <50% of tumor nuclei showing a HER2:CEP17 ratio ≥2) was noted only 1 out of 34 ISH-assessable patients (2.9%) at baseline while 7 out of 32 ISH-assessable patients (21.9%) had heterogeneity at 2nd biopsy. The mean ratio was changed from 6.5 (1.2-15.8) to 5.0 (0.4-15.2) (paired t-test, p=0.019) and all patients with genetic heterogeneity at 2ndbiopsy showed HER2 negative conversion. Among 13 who received 2ndline T-DM1, 3 showed HER2 negative conversion. Those 3 had no objective response at all and very short PFS (1.2, 1.3 and 3.4 months), whereas the others with stable HER2 status showed 44% of ORR and median PFS of 2.7 (0.4-36.8) months. Conclusions: A substantial portion of initially HER2-positive AGC patients showed HER2 negative conversion with increased HER2 heterogeneity after trastuzumab-containing chemotherapy. Loss of HER2 positivity could be a predicting factor for 2nd line anti-HER2 treatment.