Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia

Cancer. 2016 Jan 15;122(2):304-11. doi: 10.1002/cncr.29615. Epub 2015 Dec 7.

Abstract

Background: Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority.

Methods: Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations were described.

Results: Nineteen of 88 survivors of BC with TRL (22%) had an additional primary cancer and 40 of the 70 survivors with an available family history (57%) had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in BRCA1 (3 subjects; 6%), BRCA2 (2 subjects; 4%), TP53 (tumor protein p53) (3 subjects; 6%), CHEK2 (checkpoint kinase 2) (1 subject; 2%), and PALB2 (partner and localizer of BRCA2) (1 subject; 2%).

Conclusions: Survivors of BC with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. The data from the current study support the role of these genes in TRL risk and suggest that long-term follow-up studies of women with germline mutations who are treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function after cytotoxic exposures are warranted. Cancer 2016;122:304-311. © 2015 American Cancer Society.

Keywords: breast cancer; inherited; leukemia; therapy-related.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / genetics
  • Breast Neoplasms / therapy
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease / epidemiology*
  • Germ-Line Mutation
  • Humans
  • Leukemia, Radiation-Induced / chemically induced
  • Leukemia, Radiation-Induced / genetics*
  • Middle Aged
  • Prognosis
  • Registries
  • Retrospective Studies
  • Risk Assessment
  • Survivors

Substances

  • Antineoplastic Agents

Supplementary concepts

  • Breast Cancer, Familial