George Kumar, Senior Director at AstraZeneca, shared a post LinkedIn:
“How do germline mutations shape the evolutionary trajectory of therapy resistance in breast cancer?
A massive new integrated clinicogenomic analysis of over 5,800 patients has shed light on the interplay between germline and somatic alterations, specifically regarding CDK4/6 inhibitors.
Key Findings:
- The Vulnerability: Tumors associated with germline BRCA2 (gBRCA2) are uniquely predisposed to acquired RB1 loss-of-function. This leads to poor outcomes on standard frontline CDK4/6i therapies.
- The Mechanism: This resistance is driven by a dual threat: baseline RB1 hemizygosity (lowering the barrier to biallelic inactivation) and ongoing homologous recombination deficiency.
- A Better Path Forward: Preclinical models and clinical data both show that PARP inhibition consistently outperforms CDK4/6i in these specific carriers.
By prioritizing PARP inhibition in gBRCA2 carriers, we may be able to intercept these RB1-loss trajectories and significantly delay resistance. This brings us one step closer to a predictive framework for forecasting drug resistance based on pre-treatment mutational signatures!”
Title: Homologous recombination deficiency and hemizygosity drive resistance in breast cancer
Authors: Anton Safonov, Minna Lee, David N. Brown, Luca Boscolo Bielo, Miika Mehine, Chaitanya Bandlamudi, Ben O’Leary, Hong Shao, Laia Vicente, Daniel Muldoon, Allen Zhu, Susana Ros, Antonio Marra, Pier Selenica, Ivan Bieche, Bradley Wubbenhorst, Emanuela Ferraro, Laura Courtois, Rania El Botty, Mehnaj Ahmed,
Enrico Moiso, Julia Ah-Reum An, Mark T. A. Donoghue, Marie Will, Fresia Pareja,
Emily Nizialek, Natalia Lukashchuk, Eleni Sofianopoulou, Yuan Liu, Xin Huang,
Colombe Chappey, Anna D. Staniszewska, Dara Ross, Diana Mandelker, Marc Ladanyi, Nikolaus Schultz, Michael F. Berger, Maurizio Scaltriti, Jorge S. Reis-Filho,
Bob T. Li, Kenneth Offit, Larry Norton, Ronglai Shen, Kara N. Maxwell, Fergus Couch, Susan M. Domchek, Elisabetta Marangoni, Sohrab Shah, Mark R. Albertella,
Violeta Serra, Britta Weigelt, David B. Solit, Katherine L. Nathanson, Mark E. Robson, Nicholas C. Turner, Sarat Chandarlapaty, Pedram Razavi.
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