HER-2 S310F

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

We present the largest study of BC variant frequencies in a cohort of Irish breast cancer patients to date and confirm NGS is feasible and identifies clinically relevant and actionable variants. We confirm that the frequency of PIK3CA alterations, in addition to codon specificity, are comparable to those observed in European and US cohorts and demonstrate that the detection of clinically relevant biomarkers is not confined to ER positive HER2 negative BC. The tissue failure rate (19%) underscores the need for cfDNA testing to identify the expanding range of actionable targets in BC to improve access to emerging targeted therapies and biomarker-driven clinical trials.

P2; Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P2, N=102, Active, not recruiting, AstraZeneca | Trial completion date: Jan 2028 --> Jul 2026

Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.

Lastly, MTAP loss, an emerging biomarker for new synthetic lethality based anti-cancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than non-MPUC (26.9%) (p = 0.018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC, but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted.

HER2 status did not influence ADFS for NMIBC; PFS and OS for MIBC regardless of neoadjuvant cisplatin chemotherapy (chemo); OS for 1st line (1L) MetBC treated with gemcitabine plus platinum (GC) chemo or 2nd line (2L) immune checkpoint inhibitor (ICI) therapy post 1L-chemo (table). We present one of the largest and comprehensive study of HER2 mutation in BC. Overall, HER2 amplification was significantly less frequent for NMIBC. HER2 alterations were not a prognostic marker for NMIBC or MIBC independent of neoadjuvant cisplatin-based chemo, MetBC- 1L GC-chemo and 2L ICI post GC-chemo.

Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.

Novel therapeutic strategies for NMIBC are urgently needed. ERBB2 alterations are frequently observed in high grade NMIBC and are associated with enrichment of oncogenic co-alterations, especially in homologous recombination repair genes. Preclinical studies and early phase clinical trials are warranted to study anti-HER2 small molecule inhibitors and antibody-drug conjugates in NMIBC.

Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n >6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting.