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Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008)

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Abstract

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (n = 24) were collected and analyzed from patients (n = 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients (n = 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFβ.

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Abbreviations

AE/SAE:

Adverse events/serious adverse events

Akt:

Protein kinase B

ALK:

Anaplastic lymphoma receptor tyrosine kinase

ERK:

Extracellular signal-regulated kinase

HPV:

Human papillomavirus

IHC:

Immunohistochemical

IgG:

Immunoglobulin

JNK:

Jun N-terminal kinase

KA:

Keratoacanthoma

Kg:

Kilograms

Ki:

Kinesis

KO:

Knockout

Mg:

Milligrams

MM:

Malignant melanoma

NCI:

National Cancer Institute

RAF:

Rapidly accelerated fibrosarcoma

RAS:

Rat sarcoma

RCC:

Renal cell carcinoma

SCC:

Squamous cell carcinoma

SMAD:

Small body size mothers against decapentaplegic

TGFβ:

Transforming growth factor β

TGFBR:

Transforming growth factor β receptor

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Acknowledgments

This work was supported by Genzyme Corporation and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI).

Conflict of interest

Frank J. Hsu was an employee of Genzyme. Mario E. Lacouture and Joan Guitart were consultants for Genzyme. Jay A. Berzofsky received research support from Genzyme. All other authors do not have any conflict of interest.

Author information

Authors and Affiliations

  1. Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, MSK 60th Street Outpatient Center, Suite 302, New York, NY, 10065, USA

    Mario E. Lacouture

  2. Metabolism Branch and Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    John C. Morris & Jay A. Berzofsky

  3. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Donald P. Lawrence

  4. Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan

  5. Department of Medicine, The Ohio State University, Columbus, OH, USA

    Thomas E. Olencki

  6. Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA

    Geoffrey I. Shapiro

  7. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Bruce J. Dezube

  8. Genzyme Corporation, Cambridge, MA, USA

    Frank J. Hsu

  9. Departments of Dermatology and Pathology, Northwestern University, Chicago, IL, USA

    Joan Guitart

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  1. Mario E. Lacouture
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  2. John C. Morris
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  9. Frank J. Hsu
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Correspondence to Mario E. Lacouture.

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Lacouture, M.E., Morris, J.C., Lawrence, D.P. et al. Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008). Cancer Immunol Immunother 64, 437–446 (2015). https://doi.org/10.1007/s00262-015-1653-0

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  • DOI: https://doi.org/10.1007/s00262-015-1653-0

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