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Background: Combination of immune checkpoint inhibitor pembrolizumab and chemotherapy are standard of care therapy for patients with programmed death-ligand 1 positive (PD-L1+) metastatic triple negative breast cancer (mTNBC). However, a greater understanding of how immune checkpoint inhibitors and chemotherapies synergize to yield anti-tumor T cell responses is needed. The current phase I study evaluated the immunogenicity of doxorubicin plus pembrolizumab in patients with mTNBC. Patients and Methods: Patients with mTNBC, no prior anthracycline use, and 0-2 lines of prior systemic chemotherapies received pembrolizumab 200 mg IV and doxorubicin 50-60 mg/m2 IV every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. Patients were not selected based on PD-L1 expression. The primary objectives were safety and objective response rate per RECIST 1.1. Peripheral blood samples were collected at baseline, Cycle 2 Day 1 (C2D1), and post Cycle 3 for analysis by high parameter flow cytometry. Results: Ten patients were enrolled between March 2016 and November 2019. Best responses included one patient with complete response (CR), five with partial responses (PR), two with stable disease (SD), and one with progression of disease (PD). Flow cytometry showed increased CD3+ T cells (p=0.03) from pre-treatment to C2D1 with substantial inter-patient variation in CD3+ T cells. The expansion of proliferative exhausted-like PD-1+ CD8+ T cell population was identified in 8/9 patients, and exhausted CD8+ T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p=0.01). Notably, frequencies of PD-1 high proliferative CD8+ T cells contracted significantly from C2D1 to post Cycle 3 (p=0.005), with a return to near baseline frequencies in the majority of the patients. In the context of all identified T cell subsets, PD-1hi proliferative CD8+ T cells demonstrated the greatest increase in fold change from pre-treatment to C2D1. In contrast, PD-1lo proliferative CD8+ T cells demonstrated the greatest decrease in fold change from pre-treatment to C3D1. Conclusion: Anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin yielded robust peripheral blood T cell responses. Further studies dissecting the dynamics and durability of anti-tumor T cell responses and concurrent tumor immune microenvironment changes are needed to optimize combined immune checkpoint inhibitor and chemotherapy treatment for patients with mTNBC. Citation Format: Colt A. Egelston, Weihua Guo, Susan E. Yost, Xuan Ge, Jin Sun Lee, Paul H. Frankel, Yujie Cui, Christopher Ruel, Daniel Schmolze, Mireya Murga, Aileen Tang, Norma Martinez, Misagh Karimi, George Somlo, Peter Lee, James Waisman, Yuan Yuan. Immunogenicity of pembrolizumab and doxorubicin in a phase I trial for patients with metastatic triple negative breast cancer [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 OT2-08-03.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are the standard of care for hormone receptor positive (HR+) metastatic breast cancer (MBC). Mechanisms of intrinsic and acquired resistances have been proposed but are poorly understood in the real-world setting. The current study aims to study the association of genomic biomarkers and CDK 4/6i resistance mechanisms utilizing genomic data acquired through routine clinical practice. Methods: Tumor genomic data from patients with HR+ MBC who received FDA-approved CDK4/6i (palbociclib, ribociclib, and abemaciclib) were obtained by chart review. Progression free survival (PFS) was determined from the first day of treatment until date of disease progression. Patients were divided by number of lines of treatment (first line vs. ≥ 2 lines of therapy) and subcategorized into early progressors (< 6 months PFS), intermediate progressors (6-24 months PFS for first line and 6-9 months PFS for ≥ 2 lines of therapy), and late progressors (>24 months PFS for first line and > 9 months PFS for ≥ 2 lines of therapy). Genomic alterations from next-generation sequencing (NGS) were analyzed with PFS. PFS stratified by first vs. >2 lines of treatment were performed using a Cox proportional hazards model with hazard ratios and 95% confidence intervals reported. Results: Among 795 patients with HR+ MBC treated with CDK 4/6i between 2015 and 2020 including 673 patients from a main campus and 122 patients from community sites, a total of 131 patients had genomic data available for the analysis. The obtaining rate of genomic data was 18% (122 out of 673 patients) from the main campus and 7% (9 out of 122 patients) from community sites. Seventy-one patients were treated with CDK4/6i as the first line of MBC, and 60 were treated as second or sequential lines. 35 patients had early progression, 40 patients had intermediate progression, 44 patients had late progression, and 12 patients were indeterminate. The distribution of genomic alterations was not significantly different between each group. The genomic alterations that were associated with impaired PFS were ZNF703(hazard ratio, HR 2.1, N=13), ERBB2 (HR 1.9, N=12), MDM2 (HR 3.3, N=6), PALB2 (HR 3.8, N=5), ARFRP1 (HR 3.1, N=4), FRS1 (HR 2.9, N=4), IRS2 (HR 6.9, N=2), and JAK2 (HR 6, N=2). RNA seq analysis is currently underway. Conclusion: Tumor genomic tests are not routinely performed for patients with HR+ MBC, particularly less performed from community practices. In this single institution retrospective analysis, we identified genomic alterations, such as ZNF703, ERBB2, PALB2, and MDM2, as potential resistance mechanisms of CDK4/6i. Tumor genomics through standard clinical practice are essential to understand resistance mechanisms to CDK4/6i. Citation Format: Jin Sun Lee, Susan Yost, Yujie Cui, Paul Frankel, Sierra Min Li, Yate-Ching Yuan, Denise Morse, Judy Wong-Toh, Linda Bosserman, Joanne Mortimer, Yuan Yuan. Mechanisms of CDK4/6 inhibitor resistance in hormone receptor positive metastatic breast cancer: Single institution retrospective analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-35.

Introduction: Analysis of Dynamic Contrast Enhanced (DCE) MRI is widely used for measuring perfusion kinetics of cancerous tissue, though its implementation and results may vary between sites. Here we study the repeatability of quantitative DCE-MRI parameterization in a publicly available Glioblastoma (GBM) double-baseline dataset and set forth percent repeatability coefficients (%RC) which constitute a level of change at which a detectable biological change in biology may be differentiated from experimental noise. Methods: Double-baseline imaging data was previously acquired for The Cancer Imaging Archive, in the Quantitative Imaging Network (QIN) GBM Treatment Response (TR) dataset. This data includes dual baseline acquisitions of DCE-MRI MRI data performed within 5 days, for 29 patients. Each acquisition is analyzed using two vascular input function (VIF) methods: a manually segmented VIF from the superior sagittal sinus, and an automatically derived VIF determined from the top 10% of rapidly enhancing voxels. Each dynamic scan is analyzed the the Extended Tofts-Kety model (eTM; Ktrans, ve, vp) pharmacokinetic (PK) model. Bland-Altman analysis is then performed on the log-transformed PK parameters to determine the percent repeatability coefficients (%RC) of the data (95% confidence), as well as bias between first and second DCE scans. This analysis was repeated for two separate observers, writing their own analysis code, both of which are validated on a digital reference object to ensure consistency between analysis methods with zero noise. Results: For bothVIF determination methods, the 25-75th percentiles of the change in PK parameters was less than +/- 25%, the standard set forth by QIBA as a detectable biological change. For most parameters, VIF methods, and model combinations, the automatic VIF method has smallest %RC, indicating that automatic VIF determination may enhance the repeatability of the measurements between timepoints. The %RC was lowest for vp when using an automatically determined VIF. Using the automatically determined VIF and eTM, the %RCs of Ktrans, ve, and vp were measured as 72%, 82%, and 53%, respectively. Using the eTM and manually segmented VIF, the %RCs of Ktrans, ve, and vp were measured as 83%, 88%, and 66%. Conclusions: Using the QIN-GBM-TR dataset, the authors have determined that the %RC of Ktrans, ve, and vp to be 72%, 82%, and 53%, respectively (eTM, auto-VIF). Because these relative changes are large, we recommend that all sites abide by QIBA guidelines to enhance DCE parameterization reproducibility. We also recommend usage of an automated AIF determination method, as opposed to manual segmentation of large blood vessels. Citation Format: Ryan T. Woodall, Prativa Sahoo, Yujie Cui, Bihong Chen, Mark Shiroishi, Cristina Lavini, Paul Frankel, Margarita Gutova, Christine Brown, Jennifer Munson, Russell Rockne. Automated VIF methods improve DCE-MRI parameterization repeatability in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2459.