2018 National Academy of Medicine Annual Meeting October 15, 2018 Targeting Cancer with “Precision Prevention” Ernest Hawk, M.D., M.P.H.
Targeting Cancer with Precision Prevention MD Anderson What is “Precision Prevention?” “Precision medicine, sometimes referred to as personalized “The concept of precision medicine — prevention and treatment medicine, is broadly defined as treating patients based on strategies that take individual variability into account — is not characteristics that distinguish them from other patients with new…” --from Collins & Varmus, N Engl J Med 2015; 372;9: 793-795 the same disease.” --from AACR Cancer Progress Report 2018 “Precision medicine is health care that is based on you as an individual. It takes into account factors like where you live, what Kensler TW, et al. Cancer Prev Res. 9(1): 2–10, 2016 you do, and your family health history. Precision medicine’s goal Rebbeck TR, et al. Cancer Discov. 8(7): 1–9, 2018 is to be able to tell people the best ways to stay healthy.” --from All of Us Research Program website “Precision Prevention” Applied to Cancer Cancer Risk Groups Risk Agents Current Methods of Potential Future Methods of Identification Identification Dramatic exposures Tobacco, obesity, diet, prior Social history Wearable health tech devices Dose, frequency, duration chemoRx, immunosuppressives Past medical history Integrative exposure biomarkers Current meds Germline predisposition Genetic mutation Family history Large-scale population-based registries Polygenic risk score Genetic testing Subclinical neoplasia Past/present precancer or cancer Past medical history Liquid biopsies from tissues (or blood?) Martignetti JA, et al. Cold Spring Harb Mol Case Stud, online Oct 9, 2018 Screening test (imaging, Heitzer E, et al. npjPrec Onc 1:36; 1-9, 2017 molecular) Cohen JD, et al. Science 359:926-930, 2018
Targeting Cancer with Precision Prevention MD Anderson 3 Who Develops Colorectal Cancer (CRC) in 2018? General Population: Diet, Tobacco, Inactivity General Population 40% incidence of adenomas by 60 yo ~150,000 CRC cases/yr Lifetime risk 4.2-4.5% (2018) Moderate Risk Moderate-Risk: Precancerous Lesions or Prior Cancer High Risk Current/prior adenoma(s), cancer survivor MUTYH APC Lifetime risk ~ 10-20% Polyposis Polyposis MLH1 / MSH2 Lynch High-Risk: Germline Mutations Familial Adenomatous Polyposis (FAP), Lynch Syndrome (LS) Lifetime risk ~ 40-100%
Targeting Cancer with Precision Prevention MD Anderson 4 “Precision” Prevention of CRC & Related Mortality in Lynch Syndrome Screening Significantly Improve Outcomes Cumulative Proportion CRC-Free Cumulative Proportion Surviving P=0.087 P=0.03 Screening: 6 deaths total, 0 due to CRC Screening: 6 cases of CRC (4.5%) Control: 12 deaths total, 5 due to CRC Control: 14 cases of CRC (11.9%) 3-year interval screening with colonoscopy or barium enema with sigmoidoscopy 62% reduction in CRC incidence CRC-related mortality = 0% in screened vs. 36% in control Jarvinen, et al., Gastroenterol 1995; 108: 1405-1411
Targeting Cancer with Precision Prevention MD Anderson 5 “Precision” Prevention of CRC in Lynch Syndrome Clinical Guidelines for Mutation Carrier Identification & Surgical Intervention No pathologic findings Continued Surveillance Colonoscopy at age 20-25 or Positive for 2-5 yrs before earliest colon Colorectal Deleterious LS familial LS cancer if diagnosed <25 Adenocarcinoma Mutation Known Repeat every 1-2 yrs Mutation Segmental or extended colectomy in Family depending on clinical scenario Genetic testing Negative for Average Risk for CRC for familial See Guideline for CRC Screening familial LS Adenomas mutation Complete endoscopic polypectomy Mutation with f/u colonoscopy every 1-2 yrs Colonoscopy at age 20-25 or Not tested 2-5 yrs before earliest colon Adenomas not amenable cancer if diagnosed <25 MUTYH to resection or high- Polyposis Repeat every 1-2 yrs grade dysplasia Segmental or extended colectomy depending on clinical scenario Universal screening of all CRCs recommended 1 with f/u of remaining mucosa every 1-2 yrs Source: NCCN Guidelines Ver 1.2018, Lynch Syndrome 1 EGAPP Working Group. Genetic Medicine 2009; 11: 35-41
Targeting Cancer with Precision Prevention MD Anderson 6 “Precision” Prevention of Cancer in Lynch Syndrome Medical Intervention Aspirin for 2 yrs. Reduced the Incidence of CRC & Other Lynch Syndrome Cancers Time to 1 st Colorectal Cancer in participants Time to 1 st LS Cancer in participants randomly randomly assigned to ASA vs. placebo assigned to ASA vs. placebo (adjusted for gender) (adjusted for gender) Analysis restricted to those on Analysis restricted to those on intervention for 2+ yrs intervention for 2+ yrs APC MUTYH Polyposis Polyposis MLH1 / MSH2 Lynch Burn, et al., The Lancet 2011; 378:2081-2087
Targeting Cancer with Precision Prevention MD Anderson 7 Next Step in “Precision” Prevention of CRC in Lynch Syndrome 3 MMR neoepitopes identified Cancer vaccine has been proposed, based on an understanding of the mechanisms of DNA mismatch Lynch syndrome (LS) is a cancer predisposition disorder wherein patients have a 70–80% lifetime risk of developing colorectal cancers (CRC). Finding germline mutations in predisposing genes allows for risk assessment of CRC repair and the immune system, to development. Here we report a germline heterozygous frame-shift mutation in the mismatch repair MLH1 gene which was identifed in members of two unrelated LS families. Since defects in DNA mismatch repair genes generate frame- treat or delay the onset /relapse of shift mutations giving rise to highly immunogenic neoepitopes, we postulated that vaccination with these mutant peptide antigens could ofer promising treatment options to LS patients. To this end we performed whole-exome and LS-CRC RNA seq analysis on the blood and tumour samples from an LS-CRC patient, and used our proprietary neoepitope prioritization pipeline OncoPeptVAC to select peptides, and confirm their immunogenicity in an ex vivo CD8+ T cell activation assay. Three neoepitopes derived from the tumour of this patient elicited a potent CD8+ T cell response. Furthermore, analysis of the tumour-associated immune infltrate revealed CD8+ T cells expressing low levels of activation markers, suggesting mechanisms of immune suppression at play in this relapsed tumour. Taken together, our study paves the way towards development of a cancer vaccine to treat or delay the onset/relapse of LS-CRC. Scientific Reports 8:12122; DOI:10.1038/s41598-018-30466-x, Published online, Aug 14, 2018
Targeting Cancer with Precision Prevention MD Anderson 8 “Precision” Prevention of Sporadic CRC Colorectal Adenomas Colorectal Cancer Consensus Molecular Subtypes Consensus Molecular Subtypes May Guide Prevention & Screening Guide Treatment Guinney, et al., Nat Med 2015; 21(11): 1350-6
Targeting Cancer with Precision Prevention MD Anderson How Can We Advance “Precision” Cancer Prevention? • Systematic, personal characterization of exposures, germline genetics, precancers at the population level to better identify and quantify cancer risk • Pursue molecular mechanisms of precancer development and progression – Precancer Genome Atlas (PCGA; National Cancer Moon Shot; -Omics applied to precancerous lesions) • Evaluate “prevention endpoints” in treatment trials, especially of targeted agents or immunotherapies – Synchronous precancers – Metachronous precancers/cancers in post-therapeutic surveillance • Analyze prevention trials re: “dramatic responders” or “dramatic non-responders” to improve our mechanistic insights
Targeting Cancer with Precision Prevention MD Anderson Top 5 Actions to Prevent More Cancers, Sooner 1. Advance a national culture of prevention as ‘Plan A’ 1 • Develop a national cancer control plan with a national coordinator • Collaborate across sectors 2. Address disparities across the cancer continuum • Leverage our youths’ commitment to equity 3. Enhance consistent support of the CDC and its leadership in cancer control 4. Standardize data collection & surveillance re: family history, behaviors, and social determinants of health at an actionable level, across time 5. Commission and support NCI-designated cancer centers as responsible stewards and “change agents” to address the cancer burden of their catchment area populations • Encourage a network of ECHO partnerships connecting cancer centers to frontline providers 1 Vogelstein B, et al., Science 339:1546-1558, 2013
Recommend
More recommend
