HER-2 D769Y

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

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

P1, N=30, Recruiting, National Cancer Institute (NCI) | N=18 --> 30

P2, N=25, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Sep 2022

HER2 mutations are most common in EC among gynecologic cancers, with R678Q most frequent in our cohort, and T862A in cBioportal. While no HER2 -mutated tumors had a 3+ IHC score, increased HER2 expression (2+) was seen in tumors with L313V, R678Q, and T862A mutations, and HER2 rearrangement. Targeted therapy has already been applied in other tumor types with these HER2 mutations; however, further studies are necessary to explore the prognostic and therapeutic implications of these findings in gynecologic cancers.

Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab...ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.

P1, N=18, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024

P1, N=18, Not yet recruiting, National Cancer Institute (NCI)

P2, N=25, Active, not recruiting, City of Hope Medical Center | N=40 --> 25 | Trial completion date: Oct 2021 --> Dec 2022

Ronellenfitsch et al recently reported one case with ERBB2 D769Y mutation with good clinical response to lapatinib in 2020...Hybrid nerve sheath tumors are newly recognized disease and more than half of the cases have multiple peripheral nerve sheath tumors, suggestive of tumor syndrome. Patients with multiple peripheral nerve sheath tumors without systemic features of neurofibromatosis type1 or vestibular schwannomas should be screened for genetic/molecular tests including ERBB2 mutation that might provide treatment options for these patients.

P2, N=40, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2020 --> Oct 2021 | Trial primary completion date: Oct 2020 --> Oct 2021

Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.