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Rishabh Jain Explores RB1 Loss as a Driver of CDK4/6 Resistance in BRCA2 Breast Cancer
Rishabh Jain/X

Rishabh Jain Explores RB1 Loss as a Driver of CDK4/6 Resistance in BRCA2 Breast Cancer

Rishabh Jain, Medical Oncologist at AIIMS, shared a post on LinkedIn:

“Why do some HR+ BRCA2 breast cancers fail CDK4/6 inhibitors so quickly?

A new analysis of 5,800+ breast cancers reveals an evolutionary mechanism of resistance.

Key insight:

  • gBRCA2 tumors are primed to lose RB1.

That combination drives early CDK4/6 inhibitor resistance.

What the study found:

  • gBRCA2 tumors frequently have RB1 hemizygosity at baseline.
  • HRD-driven mutagenesis enables a second RB1 hit under CDK4/6 pressure.
  • Result → rapid emergence of RB1 loss-of-function resistance clones.

Clinical signal:

PFS on CDK4/6i + ET

  • gBRCA2: 9.0 months.
  • Wild-type: 15.6 months.
  • HR 2.17 (P <0.00001).

But here’s the twist:

  • PARP inhibitors outperform CDK4/6i in this subgroup.

In patients treated after CDK4/6 failure:

  • 84% response rate with PARPi.
  • 73% had longer PFS on PARPi than prior CDK4/6 therapy.

Conceptual takeaway:

  • Baseline allelic configuration predicts resistance trajectory.
  • gBRCA2 + RB1 hemizygosity.
  • HRD-driven RB1 loss.
  • CDK4/6 inhibitor escape.

Implication: For HR+/HER2− metastatic breast cancer with germline BRCA2, earlier PARP inhibition may be biologically rational.”

Rishabh Jain

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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Rishabh Jain

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Allen Zhu Anna D. Staniszewska Anton Safonov Antonio Marra Ben O'Leary Bob T. Li Bradley Wubbenhorst BRCA2 Breast Cancer Britta Weigelt cancer CDK4/6 Chaitanya Bandlamudi Colombe Chappey Daniel Muldoon Dara Ross David B. Solit David N. Brown Diana Mandelker Eleni Sofianopoulou Elisabetta Marangoni Emanuela Ferraro Emily Nizialek Enrico Moiso Fergus Couch Fresia Pareja Hong Shao HR+ Ivan Bieche Jorge S. Reis-Filho Julia Ah-Reum An Kara N. Maxwell. Katherine L. Nathanson Kenneth Offit Laia Vicente Larry Norton Laura Courtois Luca Boscolo Bielo Marc Ladanyi Marie Will Mark E. Robson Mark R. Albertella Mark T.A. Donoghue Maurizio Scaltriti Mehnaj Ahmed Michael F. Berger Miika Mehine Minna Lee Natalia Lukashchuk Nicholas C. Turner Nikolaus Schultz OncoDaily Oncology Pedram Razavi Pier Selenica Rania El Botty RB1 Rishabh Jain Ronglai Shen Sarat Chandarlapaty Sohrab Shah Susan M. Domchek Susana Ros Violeta Serra Xin Huang Yuan Liu