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Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial

Author

Listed:
  • Jorge Gómez Tejeda Zañudo

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Romualdo Barroso-Sousa

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Hospital Sírio-Libanês)

  • Esha Jain

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Repare Therapeutics)

  • Qingchun Jin

    (Dana-Farber Cancer Institute, Boston)

  • Tianyu Li

    (Dana-Farber Cancer Institute, Boston)

  • Jorge E. Buendia-Buendia

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Cellarity)

  • Alyssa Pereslete

    (Dana-Farber Cancer Institute)

  • Daniel L. Abravanel

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Arlindo R. Ferreira

    (Dana-Farber Cancer Institute
    Champalimaud Clinical Centre, Champalimaud Foundation)

  • Eileen Wrabel

    (Dana-Farber Cancer Institute)

  • Karla Helvie

    (Dana-Farber Cancer Institute)

  • Melissa E. Hughes

    (Dana-Farber Cancer Institute)

  • Ann H. Partridge

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Beth Overmoyer

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Nancy U. Lin

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Nabihah Tayob

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Dana-Farber Cancer Institute, Boston)

  • Sara M. Tolaney

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Nikhil Wagle

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School
    Genentech)

Abstract

The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100 mg palbociclib, 5 mg everolimus, 25 mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n = 6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial’s therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.

Suggested Citation

  • Jorge Gómez Tejeda Zañudo & Romualdo Barroso-Sousa & Esha Jain & Qingchun Jin & Tianyu Li & Jorge E. Buendia-Buendia & Alyssa Pereslete & Daniel L. Abravanel & Arlindo R. Ferreira & Eileen Wrabel & Ka, 2024. "Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45835-6
    DOI: 10.1038/s41467-024-45835-6
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    1. Dejan Juric & Pau Castel & Malachi Griffith & Obi L. Griffith & Helen H. Won & Haley Ellis & Saya H. Ebbesen & Benjamin J. Ainscough & Avinash Ramu & Gopa Iyer & Ronak H. Shah & Tiffany Huynh & Mari M, 2015. "Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor," Nature, Nature, vol. 518(7538), pages 240-244, February.
    2. Viktor A. Adalsteinsson & Gavin Ha & Samuel S. Freeman & Atish D. Choudhury & Daniel G. Stover & Heather A. Parsons & Gregory Gydush & Sarah C. Reed & Denisse Rotem & Justin Rhoades & Denis Loginov & , 2017. "Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. François Bertucci & Charlotte K. Y. Ng & Anne Patsouris & Nathalie Droin & Salvatore Piscuoglio & Nadine Carbuccia & Jean Charles Soria & Alicia Tran Dien & Yahia Adnani & Maud Kamal & Séverine Garnie, 2019. "Genomic characterization of metastatic breast cancers," Nature, Nature, vol. 569(7757), pages 560-564, May.
    4. François Bertucci & Charlotte K. Y. Ng & Anne Patsouris & Nathalie Droin & Salvatore Piscuoglio & Nadine Carbuccia & Jean Charles Soria & Alicia Tran Dien & Yahia Adnani & Maud Kamal & Séverine Garnie, 2019. "Author Correction: Genomic characterization of metastatic breast cancers," Nature, Nature, vol. 572(7767), pages 7-7, August.
    5. David M. Hyman & Sarina A. Piha-Paul & Helen Won & Jordi Rodon & Cristina Saura & Geoffrey I. Shapiro & Dejan Juric & David I. Quinn & Victor Moreno & Bernard Doger & Ingrid A. Mayer & Valentina Boni , 2018. "HER kinase inhibition in patients with HER2- and HER3-mutant cancers," Nature, Nature, vol. 554(7691), pages 189-194, February.
    6. Luigi Formisano & Yao Lu & Alberto Servetto & Ariella B. Hanker & Valerie M. Jansen & Joshua A. Bauer & Dhivya R. Sudhan & Angel L. Guerrero-Zotano & Sarah Croessmann & Yan Guo & Paula Gonzalez Ericss, 2019. "Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. Neil Vasan & José Baselga & David M. Hyman, 2019. "A view on drug resistance in cancer," Nature, Nature, vol. 575(7782), pages 299-309, November.
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