Anti-HER2 ribozyme(Merck & Co., Inc.)

HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors.

84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2⁺n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2⁺n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value <0.05, adjusted for multiple testing correction.

83 biopsies were eligible for analyses following quality control (TRAP cohort n = 40; control cohort n = 43); there were no significant differences in clinical characteristics between the TRAP vs. control the cohort or HER2 positive vs. HER2 negative biopsies. HER2 expression was found to associate with epithelial markers (EPCAM p < 0.001; E-cadherin p < 0.001). Moreover, HER2 expression was associated with a lower expression of immune cell infiltration, such as NK-cells (p < 0.001) and CD8 T-cells (p < 0.001), but also lower expression of immune exhaustion markers (PDCD1LG2, CTLA4; p < 0.001). In non-responders to anti-HER2 treatment, baseline biopsies showed increased expression of immune exhaustion markers, as well as hypoxia and VEGF signalling.

HER2 expression was associated with epithelial tumor characteristics. The HER2 positive TIME showed reduced immune cell infiltration but also lower expression of inhibitory signals associated with immune exhaustion, questioning the mechanism behind potential clinical benefit of co-administration of anti-HER2 agents and checkpoint inhibitors. As limited response was associated with increased VEGF signalling, studies could investigate potential synergism of targeting VEGF and HER2.

A 62-year-old woman showed an elevation of carcinoembryonic antigen (CEA) level 15 years after the left breast cancer, i.e., tubule forming type luminal micro invasive cancer, operation. Positron emission tomography/computed tomography (PET/CT) showed avid radio-tracer uptake in her right axillary and supraclavicular lymph nodes. Mammography, ultrasound (US), PET/CT, and magnetic resonance imaging showed no abnormalities in her right breast. US of the enlarged lymph nodes showed very low internal echoes. Pathological study using a core needle biopsy specimen of a right axillary node showed human epidermal growth factor receptor type 2 (HER2) positive atypical cells growing in solid and trabecular fashions. Under the presumed diagnosis of right occult breast cancer, the patient received anti-HER2 agents-containing chemotherapy, leading to marked shrinkage of the enlarged lymph nodes with normalization of the elevated CEA level. To confirm the pathological efficacy, sentinel plus sampling node biopsy was done to the patient. Postoperative pathological study of the resected nodes showed fibrosis and no viable cancer cells. The patient further received radiotherapy both to the right breast and suprarclavicular region followed by adjuvant anti-HER2 agents therapy, and has been well without any recurrences for 39 months. Diagnostic physicians should note that metastatic lymph nodes of occult breast cancer show very low internal echoes.