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Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579)

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Abstract

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m2 day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.

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Acknowledgments

We would like to thank Sarah Jackson for her assistance in reviewing the genomic data presented in the manuscript. We would also like to acknowledge the patients who were brave enough to participate in this clinical trial.

Conflict of interest

V Kaklamani and S. Jain are consultants for EISAI. E. Hughes, K. Timms, A. Gutin, V. Abkevich, Z. Sangale, C. Solimeno, K. Brown, J. Jones, and AR Hartman are employees of Myriad Genetics, Inc. and Myriad Genetic Laboratories, Inc. and receive salaries and stock. J. Jeruss, K. Siziopikou, C. Meservey, B. Jovanovic, I. Helenowski, S. Khan, K. Bethke, N. Hansen, R. Uthe, S. Giordano, S. Rosen, K. Hoskins, J. Von Roenn, S. Jain, and V. Parini have no conflicts to disclose.

Financial support

VGK was financially supported by Dolores Knes Fund, Lynn Sage Foundation, and Harris Family Fund, and JSJ was financially supported by Central Surgical Association, Society of Surgical Oncology, Saslow Family and A Sister’s Hope (JSJ) under the grant nos. NIH K22 CA138776 and R01GM097220. This work was specifically funded by the Society of Surgical Oncology/Susan G. Komen of the Cure Clinical Investigator Award (JSJ). This clinical trial was supported by EISAI. Genomic assays were performed at Myriad Genetics, Inc.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA

    Virginia G. Kaklamani, Caitlin Meservey, Regina Uthe, Sara Giordano, Steven Rosen, Jamie Von Roenn, Sarika Jain & William Gradishar

  2. Department of Surgery, Northwestern University, Chicago, IL, USA

    Jacqueline S. Jeruss, Seema A. Khan, Kevin Bethke & Nora Hansen

  3. Myriad Genetics, Inc., Salt Lake City, UT, USA

    Elisha Hughes, Kirsten M. Timms, Alexander Gutin, Victor Abkevich, Zaina Sangale, Cara Solimeno, Krystal L. Brown, Joshua Jones & Anne-Renee Hartman

  4. Department of Pathology, Northwestern University, Chicago, IL, USA

    Kalliopi Siziopikou

  5. Department of Preventive Medicine, Northwestern University, Chicago, IL, USA

    Borko Jovanovic & Irene Helenowski

  6. University of Illinois Chicago, Chicago, IL, USA

    Kent Hoskins

  7. Pathology Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

    Vamsi Parini

  8. Breast Oncology Program, CTRC, University of Texas Health Science Center San Antonio, 7979 Wurzbach Road, San Antonio, TX, 78229, USA

    Virginia G. Kaklamani

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  1. Virginia G. Kaklamani
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  3. Elisha Hughes
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Correspondence to Virginia G. Kaklamani.

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Kaklamani, V.G., Jeruss, J.S., Hughes, E. et al. Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat 151, 629–638 (2015). https://doi.org/10.1007/s10549-015-3435-y

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