A quarter of patients with high-risk, recurrent and metastatic endometrial cancer have HER2 over-expression and may potentially benefit from therapy with the HER2-targeted antibody-drug-conjugate trastuzumab-deruxtecan (T-DXd).
The study, published in the Journal of Clinical Oncology [link here], investigated the prevalence of HER2 overexpression in 806 patients comprising high-risk, recurrent and advanced endometrial cancer (EC) including all histotypes and molecular classes.
It found HER2 expression was absent and considered HER2-negative in the majority of patients (74.8%) while any HER2 overexpression – faint IHC reactivity (IHC 1+), moderate reactivity (IHC 2+) or strong reactivity (IHC 3+) – was seen in 25.2%.
Of those, 7.9% were HER2-positive (4.5% IHC 3+ and 3.5% IHC 2+ with amplification of ERBB2), and 17.2% were HER2-low (10% IHC 1+ and 7.2% IHC 2+ without amplification).
“HER2 overexpression (low or positive) was observed more commonly in recurrent/metastatic and primary advanced disease, compared with the stage I-III high-risk population,” the study said.
HER2-positive tumours were almost all (98.4%) of the p53abn molecular class and were often (44%) of the serous EC subtype while HER2-low was not restricted to a specific histotype or molecular class.
“Given the strong association between HER2-positivity and p53abn EC, HER2 amplification may act as an oncogenic driver in these tumours. In contrast, HER2-low expression less likely plays a role in tumour progression,” the study said.
“Nevertheless, HER2-low expression has gained clinical relevance as it may represent a druggable target. Testing for HER2-low expression in future studies investigating the efficacy of T-DXd in EC should be performed on all EC, regardless of histotype or molecular class.”
The study found no independent prognostic value in high-risk EC.
“This was also supported by previous work demonstrating no significant independent prognostic value of HER2-positivity in EC,” the investigators said.
“Similarly, a lack of prognostic significance has been observed for HER2-low in other malignancies.”
The investigators, including Professor Linda Milshkin from the Peter MacCallum Cancer Centre in Melbourne, said there were some challenges identified in HER2 scoring in the EC population such as heterogeneity of staining.
“Future research should focus on the development of reproducible testing methods to reliably identify non-amplified HER2 protein–expressing tumours that may benefit from T-DXd.”