Efficacy of a CDK4/6 Inhibitor in a Patient with Breast Cancer and Liposarcoma: A Case Report and Review of the Literature

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Abstract

Background

The cyclin D/cyclin-dependent kinase (CDK)4/6 inhibitor of the CDK4 (INK4)/retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression. Selective CDK4/6 inhibitors specifically target a variety of tumors, with the main focus on hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative breast cancer (BC).

Case Report

We report on the efficacy of neoadjuvant palbociclib and letrozole application in a patient suffering from invasive estrogen receptor (ER)+/HER2- BC and concurrent well-differentiated and dedifferentiated liposarcoma (WD-DDLPS) of the thigh. Clinical and histological workup upon surgery revealed significant regressive changes in both the liposarcoma and the BC. The 24-month follow-up shows no signs of disease.

Conclusion

CDK4/6 inhibitors exhibit a high therapeutic potential, although reliable prognostic markers need to be identified.

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Most cited references 22

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Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.

Mercedes M Condy, Xuan Qin, Gary K. Schwartz … (2013)

CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS. Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active. We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response. Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.

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CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment.

Angela DeMichele, Amy Clark, Kay See Tan … (2015)

The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer.

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CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers

Smruthi Vijayaraghavan, Cansu Karakas, Iman Doostan … (2017)

Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours.

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Author and article information

Journal

Journal ID (nlm-ta): Breast Care (Basel)

Journal ID (iso-abbrev): Breast Care (Basel)

Journal ID (publisher-id): BRC

Title: Breast Care

Publisher: S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )

ISSN (Print): 1661-3791

ISSN (Electronic): 1661-3805

Publication date (Print): October 2019

Publication date (Electronic): 14 November 2018

Publication date PMC-release: 1 October 2020

Volume: 14

Issue: 5

Pages: 325-328

Affiliations

[1] ^aBrust-Zentrum Zürich, Zürich, Switzerland

[2] ^bInstitut für klinische Pathologie, Universitätsspital Zürich, Zürich, Switzerland

[3] ^cGemeinschaftspraxis Pathologie Zürich, Zürich, Switzerland

[4] ^dOrthopädie Zentrum Zürich, Zürich, Switzerland

[5] ^eOnkoZentrum Zürich, Zürich, Switzerland

Author notes

*Laura Loretan, Brust-Zentrum Zürich, Seefeldstrasse 214, 8008 Zürich, Switzerland, laura.loretan@ 123456bluewin.ch

Article

Accession ID: PMC6883449 Pmcid ID: PMC6883449 Pmc-uid ID: 6883449 Publisher ID: brc-0014-0325

DOI: 10.1159/000493370

PMC ID: 6883449

PubMed ID: 31798393

SO-VID: 71400897-a78d-40a2-809a-6413f2c3c18f

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Figures: 1, References: 39, Pages: 4

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Efficacy of a CDK4/6 Inhibitor in a Patient with Breast Cancer and Liposarcoma: A Case Report and Review of the Literature

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Abstract

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Case Report

Conclusion

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Karger: Oncology

Most cited references 22

Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.

CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment.

CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers

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