Spatial heterogeneity of HER2 expression in luminal breast cancer

The National Cancer Institute awarded Thomas Jefferson University $646,208 on May 1, 2026, under the Cancer Detection and Diagnosis Research program (CFDA 93.394) to identify molecular targets for first-line combination therapies in patients with luminal estrogen receptor-positive breast cancer at elevated risk of latent metastases, with focus on HER2 endocrine escape pathways and combined endocrine therapy and HER2-targeted approaches to eliminate disseminated disease at diagnosis.

The project will use novel spatial multiplex immunofluorescence and related techniques to characterize HER2 expression heterogeneity in ER+ tumors and provide preclinical support for the efficacy of combined endocrine therapy and HER2-targeted therapies, including evaluation of antibody-drug conjugates such as trastuzumab-deruxtecan in lower-HER2-expressing tumors. The work aims to establish molecular criteria for rational recruitment of likely responders into clinical trials of new targeted first-line combination therapies and to identify tumors employing the HER2 endocrine escape pathway as a resistance mechanism.

Performance takes place in Philadelphia, Pennsylvania. The award runs from May 1, 2026, through April 30, 2031. This is a Project Grant, classified as assistance funding.

Abstract

Most patients who DIE from estrogen receptor-positive (ER+) breast cancer succumb to recurrent metastases that have developed resistance to endocrine therapy (ET) but were undetectable at diagnosis. By the time these latent metastases become clinically evident, the cancer cell burden has developed extensive heterogeneity, rendering second-line therapies ineffective for a cure. To reduce mortality from ER+ breast cancer, more accurate predictive tools are needed to guide tailored first-line combination therapies for patients at elevated risk of progression. Therefore, ongoing efforts are directed towards identifying first-line CO-treatments for high-risk patients that can synergize with ET to effectively eliminate latent disseminated disease. Our long-term objectives are to 1) identify molecular targets for first-line combination therapies in patients with luminal breast cancer who are at elevated risk for latent metastases; 2) provide preclinical support for the therapeutic efficacy of these combinations; and 3) establish molecular criteria for the rational recruitment of likely responders into clinical trials of new targeted first-line combination therapies. Although ER+ tumors employ alternative adaptive survival mechanisms in response to ET, this project will focus on identifying tumors that use the HER2 endocrine escape pathway and test the preclinical efficacy of combined ET and HER2-targeted first-line therapies to eliminate latent metastases at the time of diagnosis. HER2 represents a common endocrine resistance mechanism, and first-line HER2-targeted monoclonal antibodies combined with ET are effective against ER+HER2+ tumors. New and more potent HER2-targeted antibody-drug conjugates, in particular trastuzumab-deruxtecan (T-DXD), have demonstrated efficacy in the metastatic setting for ER+ tumors expressing lower levels of HER2. We will use novel spatial multiplex immunofluorescence techniques to analyze ER+/HER2- breast cancers, including both therapy-naïve and post-neoadjuvant endocrine- treated tumors, to identify ER+ tumors that exhibit HER2-associated proliferation and resistance to ET. Aim 1 will leverage objective and sensitive spatial-molecular analyses of tumors before and after neoadjuvant endocrine therapy. Aim 2 seeks to provide proof-of-principle efficacy for the first-line adjuvant combination of ET and HER2-targeted agents in preclinical trials. These trials aim to eliminate latent metastases using a panel of unique ER+ patient-derived xenograft models that spontaneously metastasize in prolactin-humanized mice. Aim 3 will investigate the molecular profiles of primary, therapy-naïve ER+ tumors to assess the elevated risk of latent metastases and identify predictors of HER2-associated recurrence in patients treated with adjuvant ET.