Abstract PD9-08: ImPrint immune signature in 10,000 early-stage breast cancer patients from the real-world FLEX database
Authors: Brufsky Adam M. , Kuilman Midas , Mukhtar Rita , Wolf Denise M. , Yau Christina , O’Shaughnessy Joyce , Graham Cathy , Gadi Vijayakrishna K. , Whitworth Pat , Hindenburg Alexander , Grady Ian , Srkalovic Gordon , Hoskins Kent , Dhakal Ajay , Ma Cynthia , Hunter Natasha , Crozier Jennifer , Mavromatis Blanche , Mittempergher Lorenza , Finn Christine , Modh Shraddha , Yoder Erin B. , Dauer Patricia , Menicucci Andrea , van der Baan Bas , Audeh William , Esserman Laura J. 
Published: March 2023

Abstract
BACKGROUND: Immune checkpoint inhibitors in combination with chemotherapy have demonstrated an improvement of pathologic complete response (pCR) in patients with HR-HER2- and MammaPrint (MP) High Risk, HR+HER2- tumors in the I-SPY2 TRIAL. However, not all patients benefit from immune checkpoint blockade and these new agents come with additional financial burden and significant long-lasting side effects such as adrenal insufficiency. Thus, it is imperative to better understand who benefits. Response Predictive Subtypes (RPS) were developed in the I-SPY2 TRIAL using pre-treatment expression data from 987 MP High Risk patients; 39% of HR+HER2- tumors and 63% of HR-HER2- tumors were identified as immune sensitive. In I-SPY2.2, RPS tumor classification uses ImPrint, a 53-gene signature that has been independently validated to predict the likelihood of a pCR with PD1-PDL1 immune checkpoint inhibitors with high sensitivity and specificity. Using a real-world dataset of 10,000 patients enrolled in the FLEX trial, we identified immune sensitive (ImPrint+) patients within immunohistochemistry (IHC) subtypes and within MP and BluePrint (BP) subgroups.
METHODS: FLEX (NCT03053193) is an ongoing registry trial with 97 sites open in the United States and 2 international sites. Patients enrolled in FLEX have early-stage breast cancer and receive standard of care MP testing with or without BP molecular subtyping and consent to clinically annotated full genome data collection. MP is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. MP High Risk can be further stratified into High 1 and High 2, which have demonstrated differences in chemosensitivity and pCR rates in the I-SPY2 TRIAL (NCT01042379). BP, an 80-gene molecular subtyping signature, categorizes patients’ tumors as Luminal-, HER2- or Basal-Type.
RESULTS: Of the 10,021 patients, 9.1% of the FLEX patient population are ImPrint+ and are predicted to have a meaningful pCR rate with immune checkpoint inhibitors. Younger (≤ 50 years) or pre/peri-menopausal patients, patients with larger or node-positive tumors, and patients of Black or Latin race/ethnicity independently had a higher likelihood of having ImPrint+ tumors (Table 1). ImPrint+ tumors were identified in all clinical subtypes by IHC. There is a higher likelihood of ImPrint+ tumors being MP High 2 or BP Basal-Type tumors. Within BP Basal tumors, 74.7% of HR+ and 66.0% of HR- tumors were ImPrint+.
CONCLUSIONS: The focus of immune therapy trials has been on patients with HR-HER2-, MP High Risk patients. Indeed, most patients who are predicted to benefit have MP High 2 or BP Basal-Type tumors, including some HR+ patients, which is consistent with I-SPY2 results. Importantly, this large real-world dataset enables the identification of populations who may benefit from immune therapy outside of traditional clinical trial populations and supports the testing of checkpoint inhibitors in the immune-positive subtype. Younger women and patients of Black or Latin race/ethnicity who typically have more aggressive tumors also have higher proportions of ImPrint+ tumors. Thus, it is critical that these populations be included in clinical trials. This first look at immune sensitivity in over 10,000 FLEX patients with ImPrint generates preliminary data and hypotheses that will be explored in future FLEX substudies, including an analysis of lobular cancers and long-term outcomes in ImPrint+ patients across all races and ages.
Table 1. Clinical characteristics of ImPrint+ and ImPrint- tumors.
Citation Format: Adam M. Brufsky, Midas Kuilman, Rita Mukhtar, Denise M. Wolf, Christina Yau, Joyce O’Shaughnessy, Cathy Graham, Vijayakrishna K. Gadi, Pat Whitworth, Alexander Hindenburg, Ian Grady, Gordon Srkalovic, Kent Hoskins, Ajay Dhakal, Cynthia Ma, Natasha Hunter, Jennifer Crozier, Blanche Mavromatis, Lorenza Mittempergher, Christine Finn, Shraddha Modh, Erin B. Yoder, Patricia Dauer, Andrea Menicucci, Bas van der Baan, William Audeh, Laura J. Esserman. ImPrint immune signature in 10,000 early-stage breast cancer patients from the real-world FLEX database [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-08.