In addition to research into the molecular mechanisms underlying these malignancies, studies are under way to better understand the optimal management of germline cancer syndromes, which can differ from treatments for sporadic, somatic mutation-driven tumors.2,11-13 There have been recent calls for prioritizing randomized controlled clinical trials for hereditary cancer syndromes’ management, including chemoprevention strategies and oncofertility management (fertility preservation) for women with germline BRCA-associated breast cancers.14,15
Knowing that a patient has a particular syndrome-associated mutation or resulting tumor phenotype can inform the surgical management of high-risk colon polyps or stem-cell donor selection for stem cell transplantation in patients with familial hematologic malignancies, for example.2,3,9-11,16 Aspirin chemoprevention is under investigation, and aspirin-use among patients with Lynch syndrome appears to reduce the risk of colorectal tumors and endometrial cancer.3 While chemoprevention is not yet a viable alternative to surgical prevention for colorectal cancer-associated familial adenomatous polyposis, cyclooxygenase-2 inhibition appears to inhibit colorectal tumor recruitment of new vasculature, Dr Wise noted.2
Chemoprevention research with high-risk hereditary colorectal cancer syndrome patients may lead to breakthroughs that will help prevent or decrease cancer risks for all patients, Dr Wise said.
With colorectal cancer, diet is a “big factor,” and likely plays a role in Lynch syndrome-associated cancers, he added.
Because MMR mutation-driven tumor cells cannot repair acquired mutations as cellular genomes become more disorganized, these tumors are usually hypermutated, resulting in tumor-specific antigens on their cell surfaces. That makes immunotherapies such as immune checkpoint inhibitors attractive.15
TP53 Targeting: The Path Forward for New Precision-oncology Treatments?
TP53 is believed to arrest cellular proliferation in response to DNA damage, preventing tumorigenesis by attenuating the accumulation of oncogene gain-of-function mutations.6
Germline TP53 mutations therefore represent a promising platform for developing new targeted therapies.6,16,17 Nutlins are under investigation as chemotherapy-adjuvant therapy agents for provoking cell cycle arrest in healthy non-target tissues, for example — and for stabilizing the antiproliferative function in TP53 wild-type cancers.6
p53 coded by mutated TP53 might differ enough from normal p53 to “serve as a tumor-specific neoantigen,” noted Edward Kastenhuber, MD, and Scott Lowe, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.6