2018 National Academy of Medicine Annual Meeting October 15, 2018 - - PowerPoint PPT Presentation

October 15, 2018

Targeting Cancer with “Precision Prevention”

Ernest Hawk, M.D., M.P.H.

2018 National Academy of Medicine Annual Meeting

MD Anderson

What is “Precision Prevention?”

“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

“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: 793-795

“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

Targeting Cancer with Precision Prevention

Cancer Risk Groups Risk Agents Current Methods of Identification Potential Future Methods of Identification Dramatic exposures

Dose, frequency, duration

Tobacco, obesity, diet, prior chemoRx, immunosuppressives Social history Past medical history Current meds Wearable health tech devices Integrative exposure biomarkers Germline predisposition Genetic mutation Polygenic risk score Family history Genetic testing Large-scale population-based registries Subclinical neoplasia Past/present precancer or cancer Past medical history Screening test (imaging, molecular) 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 359:926-930, 2018

“Precision Prevention” Applied to Cancer

Kensler TW, et al. Cancer Prev Res. 9(1): 2–10, 2016 Rebbeck TR, et al. Cancer Discov. 8(7): 1–9, 2018

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General Population

Who Develops Colorectal Cancer (CRC) in 2018?

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General Population: Diet, Tobacco, Inactivity 40% incidence of adenomas by 60 yo ~150,000 CRC cases/yr Lifetime risk 4.2-4.5% (2018) Moderate-Risk: Precancerous Lesions

• r 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 ~ 40-100% Moderate Risk High Risk

APC Polyposis MUTYH Polyposis MLH1 / MSH2 Lynch

Targeting Cancer with Precision Prevention

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“Precision” Prevention of CRC & Related Mortality in Lynch Syndrome

Screening Significantly Improve Outcomes

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Jarvinen, et al., Gastroenterol 1995; 108: 1405-1411

Targeting Cancer with Precision Prevention

Cumulative Proportion CRC-Free

P=0.03 Screening: 6 cases of CRC (4.5%) Control: 14 cases of CRC (11.9%)

62% reduction in CRC incidence

Cumulative Proportion Surviving

P=0.087 Screening: 6 deaths total, 0 due to CRC Control: 12 deaths total, 5 due to CRC

CRC-related mortality = 0% in screened vs. 36% in control

3-year interval screening with colonoscopy or barium enema with sigmoidoscopy

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“Precision” Prevention of CRC in Lynch Syndrome

Clinical Guidelines for Mutation Carrier Identification & Surgical Intervention

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MUTYH Polyposis

Colonoscopy at age 20-25 or 2-5 yrs before earliest colon cancer if diagnosed <25 Repeat every 1-2 yrs

Deleterious LS Mutation Known in Family Genetic testing for familial mutation

Positive for familial LS Mutation Negative for familial LS Mutation Not tested

Average Risk for CRC See Guideline for CRC Screening

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 high- grade dysplasia

Segmental or extended colectomy depending on clinical scenario 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 Colonoscopy at age 20-25 or 2-5 yrs before earliest colon cancer if diagnosed <25 Repeat every 1-2 yrs

Universal screening of all CRCs recommended1

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“Precision” Prevention of Cancer in Lynch Syndrome

Medical Intervention

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APC Polyposis MUTYH Polyposis MLH1 / MSH2 Lynch

Aspirin for 2 yrs. Reduced the Incidence of CRC

Burn, et al., The Lancet 2011; 378:2081-2087

Targeting Cancer with Precision Prevention

Time to 1st Colorectal Cancer in participants randomly assigned to ASA vs. placebo

(adjusted for gender)

Time to 1st LS Cancer in participants randomly assigned to ASA vs. placebo

(adjusted for gender)

Analysis restricted to those on intervention for 2+ yrs Analysis restricted to those on intervention for 2+ yrs

& Other Lynch Syndrome Cancers

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Next Step in “Precision” Prevention of CRC in Lynch Syndrome

7 Targeting Cancer with Precision Prevention

3 MMR neoepitopes identified 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

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 frame- 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 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,

• ur 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

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“Precision” Prevention of Sporadic CRC

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Colorectal Adenomas Colorectal Cancer Consensus Molecular Subtypes Guide Treatment Consensus Molecular Subtypes May Guide Prevention & Screening

Guinney, et al., Nat Med 2015; 21(11): 1350-6

Targeting Cancer with Precision Prevention

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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

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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

Targeting Cancer with Precision Prevention

1Vogelstein B, et al., Science 339:1546-1558, 2013