Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

Marilyne Labrie,Christopher L Corless,Christopher Boniface,Lina Gao,Allen Li ,Jeong Youn Lim ,Young Hwan Chang ,Kiara Siex,Annette Kolodzie,Koei Chin,Raymond C Bergan ,Shamilene Sivagnanam,Molly Downey,Paul T Spellman,Courtney B Betts ,Brett Johnson ,Jamie M Keck ,Alexander R Guimarães ,Hongli Ma,Aurora Blucher,Lisa M Coussens,Allison Creason ,Jeremy Goecks,Joe W Gray,Gordon B Mills,Swapnil Parmar,Jacqueline Vuky,Zahi Mitri

doi:10.1038/s41698-021-00232-w

Abstract

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

Highlights

Triple negative breast cancer (TNBC) is characterized by lack of expression of estrogen (ER) and progesterone (PR) receptors and human epidermal growth factor receptor 2 (HER2)
We demonstrated that: (1) serial tumor and blood samples can be collected with minimal risk and analyzed within a 28-day window with Clinical Laboratory Improvement Amendments (CLIA) assays, (2) multi-omics analysis of these samples provides complementary information that can help characterize basal states and adaptive responses of the tumor ecosystem to olaparib, (3) changes in tumor state and immune composition following olaparib treatment can be detected within one olaparib cycle and may predict benefit from therapy, and (4) changes in the tumor and ecosystem may aid in the identification of PARPi combinations that could result in therapeutic benefit
There was a strong consensus across the data obtained from different assay types and complementary supporting information that helped illustrate the complexity of each metastatic TNBC (mTNBC) tumor and response to treatment

Summary

Introduction

Triple negative breast cancer (TNBC) is characterized by lack of expression of estrogen (ER) and progesterone (PR) receptors and human epidermal growth factor receptor 2 (HER2). A key to developing therapies that induce durable responses is the recognition that TNBC represents a molecularly heterogenous disease with several clinically relevant subtypes. Immune checkpoint blockade (ICB) therapy in combination with chemotherapy was approved for frontline treatment of mTNBC expressing PD-L1 based on improved progression-free and overall survival[4,5]. Despite these promising advances, virtually all patients develop progressive disease on PARPi- or ICB-based therapies, indicating a critical need to implement patient specific combinations that can interdict or overcome resistance as it emerges in mTNBC

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Conclusion