Clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens in patients with advanced HER2 positive gastric cancer

Shusuke Yagi, Takeru Wakatsuki, Noriko Yamamoto, Keisho Chin, Daisuke Takahari, Mariko Ogura, Takashi Ichimura, Izuma Nakayama, Hiroki Osumi, Eiji Shinozaki, Mitsukuni Suenaga, Junko Fujisaki, Yuichi Ishikawa, Kensei Yamaguchi, Ken Namikawa, Yusuke Horiuchi, Shusuke Yagi, Takeru Wakatsuki, Noriko Yamamoto, Keisho Chin, Daisuke Takahari, Mariko Ogura, Takashi Ichimura, Izuma Nakayama, Hiroki Osumi, Eiji Shinozaki, Mitsukuni Suenaga, Junko Fujisaki, Yuichi Ishikawa, Kensei Yamaguchi, Ken Namikawa, Yusuke Horiuchi

Abstract

Background: We recently reported the clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using surgical specimens; patients with homogeneously HER2 positive gastric cancer benefitted more from trastuzumab. However, the majority of patients are diagnosed by endoscopic biopsy, and surgical specimens are not available in these patients. The aim of this study is to verify clinical significance of HER2 heterogeneity on trastuzumab efficacy using biopsy specimens.

Methods: Eighty-seven patients, who received trastuzumab-based chemotherapy and whose endoscopic biopsy specimens were available for HER2 assessment, were consecutively enrolled. When all tumor cells in all biopsy specimens overexpressed HER2 protein, it was defined as homogeneously HER2 (homo-HER2) positive group, and the others were defined as heterogeneously HER2 (hetero-HER2) positive group. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were evaluated.

Results: Thirty-four patients (39%) were diagnosed as the homo-HER2 group and 53 patients (61%) were the hetero-HER2 group. After the median follow-up period of 17.8 months, the median PFS and OS were 7.6 and 17.8 months, respectively. Significant survival differences were shown between the two groups; the homo-HER2 group showed significantly longer PFS (10.8 vs. 6.1 months, HR 0.469 95% CI 0.29-0.77, p = 0.003) and OS (29.3 vs. 14.4 months, HR 0.352 95% CI 0.20-0.61, p < 0.001). ORR was 68.6% in this cohort. Higher response rate (85.2% vs 58.1%, p = 0.020) and deeper response (- 49.0% vs - 40.0%, p = 0.018) were also found in the homo-HER2 group.

Conclusions: Similar to surgical specimens, we verified clinical significance of HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens.

Keywords: Endoscopic biopsy specimens; Gastric cancer; HER2 heterogeneity; Predictive marker; Trastuzumab.

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures followed were in accordance with the Ethical Standards of the Responsible Committee on Human experimentation (Institutional and National) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.

Figures

Fig. 1
Fig. 1
Representative images of homogeneously HER2 positive gastric cancer. a Hematoxylin-eosin stains shows differentiated adenocarcinoma. HER2 IHC shows that almost all tumor cells overexpress HER2 protein in each specimen corresponding to HE stains. Representative images of heterogeneously HER2 positive gastric cancer. b HER2 IHC shows that HER2 protein overexpressed in some specimens
Fig. 2
Fig. 2
Progression-free survival and overall survival. Significantly longer progression-free survival is seen in the homo-HER2 positive group compared with the hetero-HER2 positive group (a). Significantly longer overall survival is also seen in the homo-HER2 positive group compared with the hetero-HER2 positive group (b)
Fig. 3
Fig. 3
Best change from baseline in size of target lesion. Water-fall plot reveals that patients in the homo-HER2 positive group obtain deeper tumor shrinkage compared with the hetero-HER2 positive group (a). Scatter plot shows statistically significant difference in tumor shrinkage between two groups (p = 0.018) (b)

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Source: PubMed

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