Symposium discusses precision medicine approaches for familial cancers
Genes that predispose for seemingly rare cancers have helped explain some of the mechanisms involved in more common sporadic cancers. Identifying genes linked to familiar cancers has also opened opportunities for early detection, targeted therapy, and chemoprevention. But the path between identification of familial cancers and targeted therapy or chemoprevention is neither short nor direct.
Researchers spent 40 years moving from early descriptions of familial neuroblastoma to identifying point mutations to the ALK gene that predispose for neuroblastoma. Targeted therapy trials are ongoing.
“ALK is the major familial neuroblastoma gene,” said Yael P. Mossé, MD, Genes, Genomics, and Pediatric Research Disease Affinity Group, who identified the gene in 2008. “There are three main hot spots for point mutations and other, low frequency mutations. ALK is a tractable target for pharmacologic inhibition, but the sensitivity depends on the mutation type.”
Mossé moderated the symposium Familial Predisposition: Precision Medicine and Targeted Therapy and related panel discussion. Registrants can watch both through June 21, 2021.
Not all clinically observed ALK mutations are functionally relevant, Mossé added, and some mutations cause primary resistance to direct kinase inhibition. Crizotinib, the first targeted therapy trialed for neuroblastoma, produces clinical response in one mutation type and early resistance in other mutations. Adding chemotherapy improves response, but resistance eventually appears and progression follows.
When a phase 1 trial found that lorlatinib, a more specific third-generation ALK inhibitor, can overcome primary resistance to crizotinib, an ongoing crizotinib trial was amended to replace the less effective agent with lorlatinib. TITAN, Transatlantic Integration Targeting ALK in Neuroblastoma, is a collaboration between researchers in North America and Europe to conduct parallel trials and merge data to evaluate lorlatinib in the context of different regimens.
The association of BRCA1 and BRCA2 with breast, prostate, pancreas, and ovarian cancers has had broader clinical impact.
“Risk reduction surgery can prevent breast and ovarian cancer significantly in BRCA1/2 mutation carriers,” said Susan M. Domchek, MD, Basser Center for BRCA, University of Pennsylvania Abramson Cancer Center. “PARP inhibitors are effective in BRCA1 and BRCA2 mutation associated tumors.”
Both olaparib and talazoparib monotherapy improve progression-free survival, response rates, and health-related quality of life compared to non-platinum-based chemotherapy, Dr. Domcheck said. But there is no overall survival benefit.
BRCA1/2 pathogenic variants are reliable predictors of response to PARP inhibitors in canonical tumors, less so in non-canonical tumors. And genes in the same pathway, including ATM and CHEK2, appear not to have the same therapeutic susceptibility as BRCA1/2.
Prevention is the ultimate goal of cancer genetics, said Uri Tabori, MD, The Hospital for Sick Children. But early detection and surveillance are usually the first clinical benefits, followed by improved diagnosis and awareness, then biologically rational therapies.
Mismatches during DNA replication are common, Dr. Tabori noted. And while repairing mismatches is vital in maintaining genomic stability, the mismatch repair system in humans is not robust. There are more opportunities for DNA mismatching than there are proofreading systems to catch and correct errors.
Constitutional mismatch repair deficiency syndrome (CMMRD) cancers are more common than has been reported, Tabori continued, and carry a mutation burden 100- to 1,000-fold higher than other childhood or adult tumors. Microsatellite signatures is a robust and cheap functional assay to detect mismatch repair defects.
“Early detection correlates in improved survival, including brain tumors, over at least 12 years,” Tabori said. “Even partial surveillance offers benefits. The challenge is to implement surveillance in low- and middle-income countries.”
Immune checkpoint inhibitors for hypermutated tumors show early promise, he said. And mutations in the RAS/MAPK pathway that drive these hypermutated tumors also confer sensitivity to MEK inhibition. Novel therapeutic combinations are being integrated into adaptive clinical trials.
Multiple genotoxic agents are associated with accelerated tumor formation in individuals who carry the TP53 mutation in Li-Fraumeni syndrome (LFS). LFS is associated with multiple cancers that cluster in different age ranges and types. Most mutations affect cell repair and homeostasis.
TP53 itself may be a druggable target, said David Malkin, MD, University of Toronto and The Hospital for Sick Children. And many secondary LFS drivers offer opportunities for treatment, including statins and mTOR inhibitors, and prevention with metformin.
LFS increases oxidative metabolism compared to controls, which prompted preclinical and phase 1 work with metformin to inhibit mitochondrial respiration and delay tumorigenesis. The MILI (metformin in Li-Fraumeni) trial will explore the potential to delay cancer and improve outcomes in 500 patients in North America and Europe during three years of treatment and five years of follow up.
“There is a window of opportunity for intervention in LFS if we can figure out what these interventions might be,” Dr. Malkin said.