Abstract OT3-01-05: Functional MRI signatures of immune response to targeted breast cancer therapy
Authors: Gadi VK , Stanton S , Dintzis SM , Calhoun KE , Hippe DS , Partridge SC 
Published: March 2017

Background: Emerging data has shown that the immune system participates in both tumor development and tumor elimination and control. In breast cancer, activation of the immune system may mediate the effects of several anticancer drugs. In HER2+ and triple negative breast cancers, even 10% increases in tumor infiltrating lymphocytes (TILs) predict improved prognosis to adjuvant chemotherapy. Furthermore, the monoclonal antibody trastuzumab is known to increase peripheral Th1 immunity in women with HER2+ breast cancer, which may be reflected by increased TILs. An imaging approach to measure and monitor immune response would provide an essential non-invasive tool to select appropriate therapies based on an individual's response. Dynamic contrast-enhanced (DCE) MRI, reflecting blood flow and capillary permeability, and diffusion weighted (DW) MRI, reflecting cellularity, hold unique potential to provide quantitative imaging markers of therapy-induced immune response in breast tumors.

Trial Design: We propose to use trastuzumab to invoke immune response in patients with HER2+ tumors. Each subject will undergo a multiparametric MRI exam (with DCE and DW-MRI) and tissue sampling before and after a single dose of targeted anti-HER2 therapy with trastuzumab, prior to surgery. Pretreatment tissue will be obtained form the diagnostic core biopsy, and post-trastuzumab tissue will be collected from a research biopsy or the surgical excision, requiring at most a single additional biopsy. A variety of quantitative parameters will be extracted from the MRI scans. Whole tumor characterization will be performed, to calculate histogram-based metrics and second order textural features. Functional MRI features will be compared with histologic assessment of TILs, VEGF expression, and other immune response markers in tumors treated with HER2-targeted therapy. After the study window, patients will undergo standard of care treatment at the discretion of their physician.

Specific Aims: The primary objective will be to identify quantitative MRI markers of immune response to HER2-targeted treatment. We will implement a high-resolution multiparametric MRI approach and determine whether early changes on MRI after a preoperative run-in dose of trastuzumab correlate with tumor immune response markers as measured by histologic assessment.

Statistical Methods: The magnitude of response will be determined for individual MRI and histologic markers following one cycle of trastuzumab, and Pearson and Spearman correlation coefficients will be used to assess associations between changes in MRI and histologic markers. With 50 patients, we will have 80% power to detect a significant correlation between MRI and histologic markers as small as r = 0.39 (R2 = 15%), based on a 2-sided test of the null hypothesis r = 0 at the 0.05 significance level.

Accrual: Three patients have been accrued to date, with a target of 50 HER2+ patients. Patients may consent to either 1) preoperative run-in of a single cycle of anti-HER2 treatment or 2) neoadjuvant targeted anti-HER2 only treatment regimen (e.g., co-enrollment in TBCRC 026 or comparable trial), either of which allows for monitoring at pre and post 1 cycle of anti-HER2 treatment.

Contact information: VK Gadi (vkgadi@uw.edu) or Savannah Partridge (scp3@uw.edu).

Citation Format: Gadi VK, Stanton S, Dintzis SM, Calhoun KE, Hippe DS, Partridge SC. Functional MRI signatures of immune response to targeted breast cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-05.