Drug therapy for hereditary cancers.

Evgeny N Imyanitov,Vladimir M Moiseyenko

doi:10.1186/1897-4287-9-5

Abstract

Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies.

Highlights

Search for hereditary cancer genes was always regarded as a high priority translational research with immediate health impact
While the initial practical focus of cancer genetic research was limited to various aspects of cancer detection and prevention, it is getting increasingly recognized that hereditary tumors may have distinct bioclinical characteristics and require tailored treatment strategies
This provides a critical biological difference between cancerous and normal cells: while BRCA-driven tumors are characterized by homologous recombination (HR) deficiency, normal tissues from the same individuals retain non-affected BRCA allele and the ability to cope with DNA damage [4,5]

Summary

Introduction

Search for hereditary cancer genes was always regarded as a high priority translational research with immediate health impact. This may constitute a critical gap between preclinical and clinical research, as single-agent therapy is almost never used as initial treatment of breast or ovarian cancers It is highly likely, that the standard combinations of cytotoxic compounds produce distinct spectrum of DNA lesions and mediate distinct responses of BRCA-deficient cells when compared to the same drugs acting alone. Topoisomerase I inhibitors are rarely used for the treatment of breast cancer, but included in some therapeutic schemes for ovarian cancer High sensitivity to these drugs was suggested for both BRCA1- [24,54] and BRCA2-defective cells [38,46,55], controversial results have been reported as well [27]. In the normal cells these lesions are converted to double-strand breaks during DNA replication and eliminated by homologous

Study design and main findings

Findings

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