Background: HER2-low tumors, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization (ISH), are not well characterized among gastric or gastroesophageal junction adenocarcinomas. More importantly, this patient population is currently treated as HER2-negative (HER2-low and HER2-zero [IHC score of 0]) without anti-HER-2 directed therapy. Herein, we describe a real-world outcome analysis of this distinct genomically defined underrepresented population.

Methods: De-identified, multimodal real-world data (RWD) of 429 advanced gastric, esophageal, and GEJ adenocarcinomas from the Tempus Lens database was analyzed. Inclusion criteria was a diagnosis of gastric, esophageal, or GEJ adenocarcinoma between January 2017 to May 2021 and treatment with first-line therapy. Median overall survival (mOS) was estimated using Kaplan-Meier methods.

Results: HER2-low was identified in 24.9% (107/429) of the total cohort. Histologies within HER2 low group were 83.2% (89/107) adenocarcinoma (NOS), 7.5% (8/107) signet ring cell carcinoma, 5.6% (6/107) diffuse-type, and 3.7% (4/107) mucinous-type. PDL-1 TPS status was available in only 50.5% (54/107) of the HER2-low group. TPS distribution was: 74.1% (40/54) for TPS <1, 22.2% (12/54) for TPS >=1-<10, and TPS >= 10: 3.7% (2/54). ERBB2 amplification or focal gain was detected in 1.1% (1/88) of patients in the HER-2 low group that had undergone tumor genomic sequencing, and 0% (0/28) of patients that had circulating tumor DNA (ctDNA) sequenced. The median follow-up time was 20.7 (8.5, 35.6) months. Median OS (mOS, months) was 9.8 (9.0, 12.7) for HER2-low, 13.2 (8.9, 27.0) for HER2(-), and 14.1 (11.0, 19.2) for HER2(+). Survival differences were also compared with variations across ERBB2 RNA expression and copy number variation (CNV). HER2 groups were defined on RNA expression and copy number estimates based on thresholds determined from the proportion of samples in each of the HER2 groups from IHC/ISH data. For RNA expression analysis, the mOS was 10.8 (8.8, 13.5) months for HER2-low, 10.9 (7.2, 17.4) months for HER2(-), and 13.0 (11.4, 20.5) months for HER2(+). For CNV data, the mOS(months) was: HER2-low: 10.9 (8.5, 14.1), HER2(-): 10.2 (7.0, 15.7), HER2(+): 14.2 (11.5, 21.4).

Conclusions: Our real-world, biomarker outcome analysis suggests that advanced gastric and GEJ patients with HER2-low expression identified by IHC and RNA expression have a poor prognosis with the shortest survival. Furthermore, our data suggest that there is a heterogeneity of PDL-1 enrichment within this group. Hence, targeting the expression of low levels of HER2 similar to the HER2+ group alone or in combination with immunotherapy should be evaluated in future clinical trials to improve efficacy outcomes.

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