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Mechanistic basis for PI3K inhibitor antitumor activity and adverse reactions in advanced breast cancer

Breast Cancer Research and Treatment volume 181, pages 233–248 (2020)Cite this article

Abstract

Purpose

The phosphatidylinositol 3-kinase (PI3K) pathway is involved in several physiological processes, including glucose metabolism, cell proliferation, and cell growth. Hyperactivation of this signaling pathway has been associated with tumorigenesis and resistance to treatment in various cancer types. Mutations that activate PIK3CA, encoding the PI3K isoform p110α, are common in breast cancer, particularly in the hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) subtype. A number of PI3K inhibitors have been developed and evaluated for potential clinical use in combinations targeting multiple signaling pathways in cancer. The purpose of this review is to provide an overview of PI3K inhibitor mechanisms of action for antitumor activity and adverse events in advanced breast cancer (ABC).

Methods

Published results from phase 3 trials evaluating the efficacy and safety of PI3K inhibitors in patients with ABC and relevant literature were reviewed.

Results

Although PI3K inhibitors have been shown to prolong progression-free survival (PFS), the therapeutic index is often unfavorable. Adverse events, such as hyperglycemia, rash, and diarrhea are frequently observed in these patients. In particular, hyperglycemia is intrinsically linked to the inhibition of PI3Kα, a key mediator of insulin signaling. Off-target effects, including mood disorders and liver toxicity, have also been associated with some PI3K inhibitors.

Conclusion

Recent clinical trial results show that specifically targeting PI3Kα can improve PFS and clinical benefit. Broad inhibition of class I PI3Ks appears to result in an unfavorable safety profile due to off-target effects, limiting the clinical utility of the early PI3K inhibitors.

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Fig. 1
Fig. 2

Adapted from Gymnopoulos et al. [103]

Fig. 3

Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Acknowledgements

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Casandra M. Monzon, PhD, Healthcare Consultancy Group, LLC, for medical editorial assistance with this manuscript.

Funding

Dr. Pamela R. Drullinsky’s institution has received funding from Novartis and Hoffman-Roche (NIH/NCI Cancer Center Support Grant P30 CA008748).

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  1. Department of Medicine, Breast Cancer Medicine Service, Memorial Sloan-Kettering Nassau, 1101 Hempstead Tpke, Uniondale, NY, USA

    Pamela R. Drullinsky

  2. David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

    Sara A. Hurvitz

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PRD and SAH contributed to the conception of the manuscript, interpretation of available data, drafting, revision, and final approval of the manuscript.

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Correspondence to Pamela R. Drullinsky.

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Dr. Sara A. Hurvitz receives research funding paid to her institution from: Ambrx, Amgen, Bayer, Daiichi-Sankyo, Genentech/Roche, GSK, Immunomedics, Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, and Dignitana.

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Drullinsky, P.R., Hurvitz, S.A. Mechanistic basis for PI3K inhibitor antitumor activity and adverse reactions in advanced breast cancer. Breast Cancer Res Treat 181, 233–248 (2020). https://doi.org/10.1007/s10549-020-05618-1

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Keywords

  • PI3K
  • PIK3CA
  • Advanced breast cancer
  • Hyperglycemia