1551P - Clinicopathologic characteristics and genomic profiling of HER2-low advanced gastric cancer

Background

Recent advances in HER2-targeting agents, including HER2 antibody-drug conjugates have shown promising results in targeting HER2-low expressing cancers. We performed retrospective study to characterize clinicopathologic features and genomic profiling of HER2-low advanced gastric cancer (AGC) compared to HER2-high or HER2-none expressing tumors.

Methods

We retrospectively analyzed patients with stage IV AGC with known HER2 status who were systemically treated in Yonsei Cancer Center, Korea. HER2-low tumors were defined as HER2 IHC 2+/ISH- or HER2 IHC 1+. Patients whose pre-treatment tumors were molecularly profiled with in-house next-generation sequencing (NGS) were further evaluated. Clinicopathologic characteristics including biomarker distribution and survivals, and genomic profiling including oncogenic signalling pathways were analyzed according to HER2 status.

Results

Among total 953 patients diagnosed as recurrent/metastatic AGC from August 2008 to February 2022, HER2-high, HER2-low, and HER2-none (HER2 IHC 0) patients were 122 (12.8%), 244 (25.6%), and 587 (61.6%), respectively. For HER2-low tumors compared to HER2-high and HER2-none, there was no statistical difference in distribution of pathology, EBV, MSI, or PD-L1 expression status. HER2-low patients showed similar survival as HER2-none, but shorter survival compared to HER2-high, in terms of progression-free survival of palliative first-line chemotherapy (6.3 vs 6.0 vs 8.5 months, P=0.0002) and overall survival (14.8 vs 14.4 vs 20.7 months, P=0.0001). There was no difference in survival between HER2 IHC 2+/ISH- and IHC 1+. HER2-low tumors had enhanced survival with the first-line chemotherapy when combined with immunotherapy. Among patients who have undergone in-house NGS excluding EBV-positive or MSI-H tumors (n=183), HER2-low tumors showed similar TMB compared to HER2-high and HER2-none tumors, but highest genetic alteration rates in PI3K pathway (62 vs 54 vs 54%), TGF-ß pathway (32 vs 22 vs 29%), and JAK/STAT pathway (15 vs 9 vs 8%).

Conclusions

We observed that HER2-low AGC patients showed similar but distinct clinicopathologic and genomic profile compared to HER2-none patients. Further strategies to target HER2-low AGC patients are warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.