Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects

Abstract

Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.

Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis

“…There is an expanding armamentarium of US Food and Drug Administration (FDA)-approved precision medicines as therapeutic options, both as histology-specific and tissueagnostic indications for many germline-aberrant cancers 13 : PARP inhibitors (olaparib, rucaparib, and niraparib) for treatment of germline or sporadic BRCA-mutated or homologous recombination-deficient breast, ovarian, prostate, and pancreas cancer 13 ; immune checkpoint inhibitors (pembrolizumab and dostarlimab) for patients with germline or sporadic high microsatellite instability/mismatch repairdeficient solid tumors; nivolumab 6 ipilimumab for the treatment of high microsatellite instability/mismatch repair-deficient colorectal cancers; hypoxia inducible factor 2a inhibitor belzutifan for patients with germline Von Hippel-Lindau-associated cancers; RET inhibitors for RET germline-positive medullary thyroid cancers; selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas; and everolimus for TSC1/2-associated cancers (Subependymal Giant-Cell Astrocytomas, renal angiomyolipoma and seizures). 14 What About the Cost?…”

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review

“…Sometimes a genotype–phenotype correlation is less evident, and only systematic tumour and germline testing may identify a hereditary condition. Hereditary cancers caused by germline defects often result in particular molecular alterations that open opportunities for precision medicine by targeted therapies 1 . Effective cascade testing of relatives should be used as an adjunct to systematic tumour and genetic testing and may improve outcome through surveillance and preventive measures 2 .…”

Advances in PARP Inhibitors for Prostate Cancer

“…PARPi are also naturally a therapy of choice against cancers exhibiting DNA repair deficiencies such as homologous recombination deficiency. Similarly, PARPi can be beneficial for patients with hereditary syndromes impairing DNA repair such as BRCA1 or BRCA2 [ 77 ]. Furthermore, whereas HRR gene mutations can induce prostate cancer by increased genomic instability, prostate cancers with these mutations have also been determined to be more aggressive, rapidly progressive and have a greater metastatic potential [ 78 ].…”