Cytotoxic and targeted therapy for hereditary cancers.

Aglaya G. Iyevleva,Evgeny N. Imyanitov

doi:10.1186/s13053-016-0057-2

Abstract

There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.

Highlights

First tumor-predisposing germ-line mutations were discovered a quarter of century ago and were immediately translated into appropriate diagnostic tests [1,2,3,4,5]
Tumors arising in patients with tuberous sclerosis mTOR inhibitors: everolimus
Veliparib was evaluated in heavily pretreated ovarian cancer patients with BRCA1/2 mutation, and induced tumor responses in 13/50 (26%) women; to experience with olaparib, there was a clear difference in response rates between platinum-resistant and platinumsensitive disease (20% vs. 35%) [51]

Summary

Background

First tumor-predisposing germ-line mutations were discovered a quarter of century ago and were immediately translated into appropriate diagnostic tests [1,2,3,4,5]. Identification of mutation carriers among cancer patients, their yet healthy relatives and, to a lesser extent, some other individuals rapidly entered clinical routine and saved thousands of lives by delivering specific diagnostic and preventive efforts to the subjects at-risk. Treatment schemes for hereditary and sporadic cancers remained virtually identical until this decade, the genetic testing was usually considered rather as a part of the follow-up than the component of the initial decision-making process. BRCA1/2-driven tumors usually arise via 2-hit mechanism: while the involved gene is present in heterozygous but still proficient state in the normal cells of the carrier, cancer cells are characterized by somatic loss of the remaining BRCA allele and demonstrate

Familial adenomatous polyposis

Hereditary medullary thyroid cancer

Conclusions and perspectives

Findings

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