2018 National Academy of Medicine Annual Meeting

Transcription

1 2018 National Academy of Medicine Annual Meeting October 15, 2018 Targeting Cancer with Precision Prevention Ernest Hawk, M.D., M.P.H.

2 What is Precision Prevention? The concept of precision medicine prevention and treatment strategies that take individual variability into account is not new --from Collins & Varmus, N Engl J Med 2015; 372;9: Precision medicine is health care that is based on you as an individual. It takes into account factors like where you live, what you do, and your family health history. Precision medicine s goal is to be able to tell people the best ways to stay healthy. --from All of Us Research Program website Cancer Risk Groups Risk Agents Current Methods of Identification Dramatic exposures Dose, frequency, duration Germline predisposition Tobacco, obesity, diet, prior chemorx, immunosuppressives Genetic mutation Polygenic risk score Precision Prevention Applied to Cancer Precision medicine, sometimes referred to as personalized medicine, is broadly defined as treating patients based on characteristics that distinguish them from other patients with the same disease. --from AACR Cancer Progress Report 2018 Social history Past medical history Current meds Family history Genetic testing Subclinical neoplasia Past/present precancer or cancer Past medical history Screening test (imaging, molecular) Kensler TW, et al. Cancer Prev Res. 9(1): 2 10, 2016 Rebbeck TR, et al. Cancer Discov. 8(7): 1 9, 2018 Potential Future Methods of Identification Wearable health tech devices Integrative exposure biomarkers Large-scale population-based registries Liquid biopsies from tissues (or blood?) Martignetti JA, et al. Cold Spring Harb Mol Case Stud, online Oct 9, 2018 Heitzer E, et al. npjprec Onc 1:36; 1-9, 2017 Cohen JD, et al. Science 359: , 2018

3 Who Develops Colorectal Cancer (CRC) in 2018? 3 General Population Moderate Risk General Population: Diet, Tobacco, Inactivity 40% incidence of adenomas by 60 yo ~150,000 CRC cases/yr Lifetime risk % (2018) APC Polyposis High Risk MLH1 / MSH2 Lynch MUTYH Polyposis Moderate-Risk: Precancerous Lesions or Prior Cancer Current/prior adenoma(s), cancer survivor Lifetime risk ~ 10-20% High-Risk: Germline Mutations Familial Adenomatous Polyposis (FAP), Lynch Syndrome (LS) Lifetime risk ~ %

4 4 Precision Prevention of CRC & Related Mortality in Lynch Syndrome Screening Significantly Improve Outcomes Cumulative Proportion CRC-Free Cumulative Proportion Surviving P=0.03 Screening: 6 cases of CRC (4.5%) Control: 14 cases of CRC (11.9%) P=0.087 Screening: 6 deaths total, 0 due to CRC Control: 12 deaths total, 5 due to CRC 3-year interval screening with colonoscopy or barium enema with sigmoidoscopy 62% reduction in CRC incidence Jarvinen, et al., Gastroenterol 1995; 108: CRC-related mortality = 0% in screened vs. 36% in control

5 5 Precision Prevention of CRC in Lynch Syndrome Clinical Guidelines for Mutation Carrier Identification & Surgical Intervention Deleterious LS Mutation Known in Family Genetic testing for familial mutation Positive for familial LS Mutation Negative for familial LS Mutation Not tested Colonoscopy at age or 2-5 yrs before earliest colon cancer if diagnosed <25 Repeat every 1-2 yrs MUTYH Polyposis Universal screening of all CRCs recommended 1 Average Risk for CRC See Guideline for CRC Screening Colonoscopy at age or 2-5 yrs before earliest colon cancer if diagnosed <25 Repeat every 1-2 yrs No pathologic findings Continued Surveillance Colorectal Adenocarcinoma Segmental or extended colectomy depending on clinical scenario Adenomas Complete endoscopic polypectomy with f/u colonoscopy every 1-2 yrs Adenomas not amenable to resection or highgrade dysplasia Segmental or extended colectomy depending on clinical scenario with f/u of remaining mucosa every 1-2 yrs Source: NCCN Guidelines Ver , Lynch Syndrome 1 EGAPP Working Group. Genetic Medicine 2009; 11: 35-41

6 Precision Prevention of Cancer in Lynch Syndrome Medical Intervention 6 Aspirin for 2 yrs. Reduced the Incidence of CRC & Other Lynch Syndrome Cancers Time to 1 st Colorectal Cancer in participants randomly assigned to ASA vs. placebo (adjusted for gender) Analysis restricted to those on intervention for 2+ yrs Time to 1 st LS Cancer in participants randomly assigned to ASA vs. placebo (adjusted for gender) Analysis restricted to those on intervention for 2+ yrs APC Polyposis MUTYH Polyposis MLH1 / MSH2 Lynch Burn, et al., The Lancet 2011; 378:

7 7 Next Step in Precision Prevention of CRC in Lynch Syndrome 3 MMR neoepitopes identified 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 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 frameshift 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 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: /s x, Published online, Aug 14, 2018 Cancer vaccine has been proposed, based on an understanding of the mechanisms of DNA mismatch repair and the immune system, to treat or delay the onset/relapse of LS-CRC

8 Precision Prevention of Sporadic CRC Colorectal Adenomas Colorectal Cancer 8 Consensus Molecular Subtypes May Guide Prevention & Screening Consensus Molecular Subtypes Guide Treatment Guinney, et al., Nat Med 2015; 21(11):

9 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

10 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: , 2013