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Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study

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Abstract

Purpose

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i.

Methods

We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020.

Results

Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6–34.9) vs 19.8 months (95% CI 15.7–29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months—NE), single-agent ET was 6.0 months (95% CI 3.3–14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months—NE).

Conclusions

Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

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Fig. 1
Fig. 2

Data availability

All data generated or analyzed during this study are included in this published article. Additional details on data requisition and analysis will be made available at request from the corresponding author.

Abbreviations

1L or 2L or 3L:

First line or second line or third line

CDK4/6(i):

Cyclin-dependent 4/6 kinases (inhibitor)

ET:

Endocrine therapy

HER2:

Human epithelial growth factor receptor 2

HR:

Hormone receptor

MBC:

Metastatic breast cancer

mTOR:

Mammalian target of rapamycin

NE:

Not evaluable

NR:

Not reached

OS:

Overall survival

PI3K:

Phosphatidylinositol 3-kinase

PI3K/mTORi:

Inhibitors of PI3K or mTOR in combination with endocrine therapy

PFS:

Progression-free survival

Q1:

25Th percentile

Q3:

75Th percentile

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Funding

This work was funded by Mayo Clinic Clinical and Translational Science (CTSA) grant UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) to KVG. This publication was supported in part by CTSA Grant Number KL2 TR002379 from the NCATS, and the Mayo Clinic Breast Cancer SPORE grant P50 CA116201, Career Enhancement Program, from the NIH to RLF.

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Authors and Affiliations

  1. Department of Oncology, Mayo Clinic, Rochester, MN, USA

    Grace M. Choong, Roberto A. Leon Ferre, Ciara C. O’Sullivan, Kathryn J. Ruddy, Tufia C. Haddad, Timothy J. Hobday, Prema P. Peethambaram, Minetta C. Liu, Matthew P. Goetz & Karthik V. Giridhar

  2. Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Savannah Liddell

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  1. Grace M. Choong
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Contributions

GMC, SL, KVG, and MPG contributed to the study conception and design. Material preparation, data collection, and analysis were performed by GMC, SL, and KVG. The first draft of the manuscript was written by GMC and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Karthik V. Giridhar.

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Conflict of interest

All authors declare no direct conflicts of interests related to material provided in this manuscript. GMC, SL, KJR, TJH, and PPP have no competing interests. RLF–consulting services for Gilead Sciences, AstraZeneca. Honoraria have been paid to the institution for research activities. COS—Research funding from Eli Lilly, Seattle Genetics, Bavarian Nordic, Minneamrita Therapeutics, Biovica, Nfrence Inc, AACRU, and Sermonix Pharmaceuticals. TCH—Research funding from Takeda Oncology for a phase II clinical trial for metastatic breast cancer. MCL—Research support from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro. MCL also sits on the advisory boards for Astra Zeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. MPG—Personal fees for CME activities from Research to Practice, Clinical Education Alliance, Medscape, personal fees serving as a panelist for a panel discussion from Total Health Conferencing, and personal fees for serving as a moderator for Curio Science. Consulting fees to institution from AstraZeneca, Biovica, Biotheranostics, Blueprint Medicines, Eagle Pharmaceuticals, Lilly, Novartis, Pfizer, Sanofi Genzyme, and Sermonix. Grant funding to institution from Lilly, Pfizer, and Sermonix. MPG is the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D. and receives financial support from the National Cancer Institute under the Mayo Clinic Breast Cancer SPORE (PC50CA116201). KVG—Honoraria to the institution from Novartis. Research funding from Pfizer.

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Choong, G.M., Liddell, S., Ferre, R.A.L. et al. Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study. Breast Cancer Res Treat 196, 229–237 (2022). https://doi.org/10.1007/s10549-022-06713-1

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