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Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC

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An Interactive Discussion On Key Issues Affecting Young Adult Colorectal Cancer Patients and Their Caregivers
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Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC

  1. 1. Improving Outcomes For EAO-CRC Advancing Earliest Stage Diagnosis: Recognizing Symptoms and Signs of CRC Thomas K. Weber MD FACS State University of New York Health Sciences
  2. 2. Advancing Earliest Possible Stage Diagnosis: Recognizing Symptoms & Signs of Young Adult CRC Thomas Weber, MD FACS Professor of Surgery State University of New York Health Sciences Center President, Colon Cancer Challenge Foundation
  3. 3. SATURDAY MARCH 21st, 2015 http://events.coloncancerchallenge.org
  4. 4. Siegel et al, Journal of the National Cancer Institute (2017) 109(8): • “From 1989-90 to 2012-2013 the proportion of rectal cancers diagnosed in adults younger than age 55 doubled from 14.6% to 29.2%. Compared with adults born circa 1950, those born circa 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer. As nearly one-third of rectal cancer patients are younger than age 55, screening initiation before 50 years should be considered.”
  5. 5. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “A study of initial presentation of young onset CRC patients without established risk factors found that 86% were symptomatic at the time of diagnosis” * • Siegel et al Can Epi Biomark 18(6) 1695-8
  6. 6. Let Us Not Forget “I spent a year, maybe more, going to multiple doctors with my complaints. I received lot’s of sincere “reassurance”. But I did not receive a diagnosis. I did not receive a diagnosis until someone finally did a rectal exam. That exam took 30 seconds and told me and my new doctor all we needed to know. But I lost a lot of time.” A Survivor
  7. 7. Increasing Earliest Possible Stage Diagnosis of YA CRC • Young Onset CRC is more likely to be detected at an advanced stage1 • Young Onset CRC patients are significantly more likely to present with stage III/IV disease compared with patients with older-onset disease (colon cancer 63% vs. 49%; rectal cancer 57% vs 46%) 2 1. Ahnen et al Mayo Clin Proc 2016:89:216-24 2. You YN et al Arch Int med 2012;172:287-89
  8. 8. Trends in young adults by stage at diagnosis Source: SEER 9 delay-adjusted rates, 1975-2012; 3-year moving average. 0 0.5 1 1.5 2 2.5 3 Colon Localized Regional Distant 0 0.5 1 1.5 2 2.5 3 Rectum Localized Regional Distant Incidencerateper100,000 3.6% annually, 2003-2012 3.0% annually, 2003-2012
  9. 9. Increasing Earliest Possible Stage Diagnosis of YA CRC What is the Problem? It is a complex , multifactorial problem… Rich in opportunity to improve the situation and save lives….. • Pre-symptomatic strategies • And….. • Rapid, effective response for the symptomatic patient
  10. 10. Increasing Earliest Possible Stage Diagnosis of YA CRC What is the Problem? Pre-Symptomatic Strategies Primary Strategies: Risk Assessment Driven • Family History : Lynch, MYH, FAP • Family History: First Degree Relative History of CRC and or Adenomatous Polyps • Personal History of CRC or Adenomatous Polyps • Inflammatory Bowel Disease • Take a family history! And HC Systems must be able to ACT on that information. EMR?
  11. 11. Increasing Earliest Possible Stage Diagnosis of YA CRC What is the Problem? It is a complex , multifactorial problem… Rich in opportunity to improve the situation and save lives….. • Pre-symptomatic strategies • And….. • Rapid, effective response for the symptomatic patient
  12. 12. Increasing Earliest Possible Stage Diagnosis of YA CRC What is the Problem? Strategies to Improve Timely Diagnosis For Symptomatic Patients • Provider Related Delays • Patient Related Delays
  13. 13. Delays in Diagnosis of Young-Onset CRC Patient Related Delays • “On average, symptomatic young patients wait approximately 6 months before seeking medical care” Ahnen et al • Lack of recognition • Embarrassment and fear • Denial • Lack of access to care
  14. 14. Delays in Diagnosis of Young-Onset CRC Provider Related Delays • “Once young patients do present with colorectal symptoms they may encounter physician-related delays” • Missed symptoms • Missed diagnosis • Affecting 15-50% of cases* *Ahnen et al Mayo Clin Proc 2016:89:216-24
  15. 15. Colorectal Cancer Symptoms & Signs* • Bleeding from the rectum • Blood in the stool / Dark or black stools • Change in the shape of stool • Cramping abdominal pain • Constipation and or Urgency • Decreased appetite and weight loss • Anemia * http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-signs-and-symptoms
  16. 16. Cancer Risk of Rectal Bleeding* • Rectal bleeding: Twenty-one primary studies provided PPVs on rectal bleeding as a single presenting symptom.13,14,17,18,21,22,24,27-34,36,37,39-41,43 • In more than half of these studies the risk of cancer was equal to or greater than5% 12-15,17-19,21,23-26,28-37,39-43 • Del Giudice et al Canadian Family Physician 2014 e405
  17. 17. The Clinical Significance / Cancer Risk of Rectal Bleeding • “ The rate of CRC among men and women with rectal bleeding is approximately 25 times that of the general population”* * Lawrensen R et al. Risk of colorectal cancer in general practice patients presenting with rectal bleeding Eur J Cancer Care 2006: 15:267-271
  18. 18. Liang and Church • “Rectal bleeding is a common symptom,(of CRC) especially in combination with anemia and should be thoroughly investigated. • “The presence of a second symptom doubles the absolute risk of CRC in individuals for all age groups.”
  19. 19. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “A study of initial presentation of young onset CRC patients without established risk factors found that 86% were symptomatic at the time of diagnosis” * • Siegel et al Can Epi Biomark 18(6) 1695-8
  20. 20. Colorectal Cancer Symptoms & Signs* • Bleeding from the rectum • Blood in the stool / Dark or black stools • Change in the shape of stool • Cramping abdominal pain • Constipation and or Urgency • Decreased appetite and weight loss • Anemia * http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-signs-and-symptoms
  21. 21. Let Us Not Forget “I spent a year, maybe more, going to multiple doctors with my complaints. I received lot’s of sincere “reassurance”. But I did not receive a diagnosis. I did not receive a diagnosis until someone finally did a rectal exam. That exam took 30 seconds and told me and my new doctor all we needed to know. But I lost a lot of time.” A Survivor
  22. 22. Risk Assessment Tool for Colorectal Cancers
  23. 23. The Development of an Ovarian Cancer Symptom Index Goff et al.
  24. 24. Professor William Hamilton University of Exeter, U.K. Clinical Practice Research Datalink: National Health Service (NHS): 64 Million Patients
  25. 25. Positive predictive values (95% confidence intervals) for colorectal cancer in men and women aged 18 to 49 years for individual risk markers and for pairs of risk markers in combination. Rectal bleeding Rectalmass Changein bowelhabit Constipation Diarrhoea Abdominal pain Nausea and/or vomiting Low haemoglobin Raised inflammatory markers Lowmean redcell volume 0.4 (0.3, 0.6) 0.6 (0.3, 1.1) 0.5 (0.2, 1.0) 0.1 (0.1, 0.2) 0.1 (0.1, 0.1) 0.1 (0.1, 0.1) 0.1 (0.1, 0.1) 0.1 (0.1, 0.1) 0.1 (0.1, 0.1) 0.1 (0.1, 0.2) PPV as a single symptom 1.8 (-) 17 (-) 0.3 (-) 5.8 (-) 0.4 (-) 0.4 (-) 1.3 (-) 13 (-) 1.4 (-) 8.0 (-) Rectal bleeding 5.6 (-) 6.3 (-) 6.1 (-) 5.1 (-) 7.0 (-) 1.3 (-) 5.6 (-) 7.0 (-) 2.9 (-) Rectal mass 1.2 (-) 0.3 (-) 6.1 (-) 0.3 (-) 0.3 (-) 5.1 (-) 0.4 (-) 2.1 (-) Change in bowel habit 0.3 (0.1, 0.7) 1.8 (-) 0.3 (0.1, 0.6) 0.5 (-) 0.4 (-) 1.0 (-) 5.1 (-) Constipation 0.1 (0.1, 0.2) 0.2 (0.1, 0.3) 0.1 (-) 0.4 (-) 0.3 (0.1, 0.6) 0.7 (-) Diarrhoea 0.2 (0.1, 0.3) 0.1 (0.1, 0.3) 0.5 (0.3, 1.2) 0.3 (0.2, 0.6) 0.7 (-) Abdominal pain 0.1 (0.1, 0.2) 0.3 (-) 0.2 (-) 0.2 (-) Nausea and/or vomiting 0.4 (0.2, 0.6) 0.2 (0.2, 0.4) Low haemoglobin 0.4 (0.2, 0.7) Raised inflammatory markers
  26. 26. Frequency of selected features in cases and controls in the whole study population Diarrhoea Abdominal pain Rectal bleeding Change in bowel habit Raised Inf markers Low Hb Raised platelets Raised white cell count Raised hepatic enzymes Low MCV Cases 3047 3040 2654 730 3115 1802 1678 1472 1392 1102 Controls 531 1534 201 65 575 572 206 488 1019 290 0 500 1000 1500 2000 2500 3000 3500 Cases Controls Positive LR (95% CI) 13.8 (12.6, 15) 4.8 (4.5, 5) 31.6 (27.5, 36.5) 26.9 (20.9, 34.6) 13 (11.9, 14.2) 7.6 (6.9, 8.3) 19.5 (16.9, 22.5) 7.2 (6.5, 8) 3.3 (3, 3.5) 9.1 (8, 10.3)
  27. 27. Young Adult Colorectal Cancer Symptom Index : Risk Score • We have the Ovarian Cancer Symptom Index model • We have the progress reported by Deborah Alsina, Bowel Cancer U.K. with Professor William Hamilton • We have a “charge” from the NCCRT to move forward as “rapidly as practical” to develop tools to identify those at increased risk and dramatically improve earliest possible stage diagnosis • FOR ADDITIONAL CONSIDERATION: We have a body of published literature confirming the cancer risk associated with prolonged rectal bleeding especially if there are symptoms & signs of anemia.
  28. 28. Young Adult Colorectal Cancer Symptom Index : Risk Score • Take action based on the data we have including the NHS data. • Provider Education initiatives: Medical Schools, Residency, CME • HCS (Health Care Systems) Quality of Care Metrics. If 80% of your YA CRC patients are diagnosed at Stage III & IV – NOT acceptable • NCCRT: Progress with the Family Health History & Early Age Onset Task Group: Special Satellite Session November 2017 NCCRT Annual Meeting. Move forward as “rapidly as practical” to develop tools to identify those at increased risk and dramatically improve earliest possible stage diagnosis • Explore complimentary research on the critical symptoms and signs for Young Adult CRC – as Decision Support for HC Providers. • Case & Control data sets in the U.S. setting as well as the Patient Survey Concept
  29. 29. Advancing Prevention & Earliest Possible Stage Diagnosis: What “Action Steps” Can We Take NOW! To Reduce YA CRC Diagnosis And Improve Survival
  30. 30. Advancing Prevention & Earliest Possible Stage Diagnosis • Consumer & Provider Awareness of YA CRC • Risk Assessment and Evidence Based Action: Family Health History • Adaptation of the Screening Guidelines to the Current Reality • Assessing SYMPTOMS is not Screening. It is DIAGNOSIS • Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs • What is driving these dramatic increases? The “Epi Challenge”
  31. 31. Constructive Next Steps  The application and utilization of current evidence- based, risk-driven CRC surveillance and screening guidelines would save lives. Nb 74% age 40-49. This includes improving the use of family history documentation; the “Forgotten Question.”  Research and validation of a YA CRC Symptoms & Signs Index. Barbara Goff’s Ovarian Cancer Symptom index.  The identification of suitable patient cohorts for the study of suspected and novel etiologic drivers of these incidence trends. Nb CDC enhanced comorbidity Cancer Registries program. 1. Chang et al. Mod Path 2012;25:1128-39
  32. 32. Advancing Prevention & Earliest Possible Stage Diagnosis • Consumer & Provider Awareness of YA CRC • Risk Assessment and Evidence Based Action: Family Health History • Adaptation of the Screening Guidelines to the Current Reality • 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or 45 year old NOW equal to that of a 50 year old in 1990? • Assessing SYMPTOMS is not Screening. It is DIAGNOSIS • Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs • What is driving these dramatic increases? The “Epi Challenge”
  33. 33. 0 10 20 30 40 50 60 70 80 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 Colon 40-44 years 45-49 years 50-54 years 55-59 years 0 5 10 15 20 25 30 35 40 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 Rectum 40-44 years 45-49 years 50-54 years 55-59 years Colon and Rectal Cancer Incidence Trends by Age and Birth Cohort R. Siegel et al
  34. 34. Siegel et al, Journal of the National Cancer Institute (2017) 109(8): “Beginning screening at age 45 years is not supported by a recent review of the evidence for CRC screening (49,50) (USPSTF) and would add approximately 20 million people to the screening-eligible population. Yet it is worth noting that in 2013 there were about 10 400 new CRCs diagnosed in adults age 40 to 49 years and 12 800 cases in adults age 50 to 54 years, similar to the total number of cervical cancers (12 300) (51), for which screening of 95 million women age 21 to 65 years is recommended (52). Moreover, Cancer Intervention and Surveillance Modeling Network (CISNET) researchers recently reported that beginning screening at age 45 years is “more effective and provided a more favorable balance between life-years gained and screening burden than starting at age 50 years” (49). Endoscopic screening could be particularly useful in stemming the tide of tumors in the distal colon and rectum (53), which are preponderant in young patients.”
  35. 35. Siegel et al, Journal of the National Cancer Institute (2017) 109(8): • “From 1989-90 to 2012-2013 the proportion of rectal cancers diagnosed in adults younger than age 55 doubled from 14.6% to 29.2%. Compared with adults born circa 1950, those born circa 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer. As nearly one-third of rectal cancer patients are younger than age 55, screening initiation before 50 years should be considered.”
  36. 36. Advancing Prevention & Earliest Possible Stage Diagnosis • Consumer & Provider Awareness of YA CRC • Risk Assessment and Evidence Based Action: Family Health History • Adaptation of the Screening Guidelines to the Current Reality • 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or 45 year old NOW equal to that of a 50 year old in 1990? • 2. Can we better inform “risk”? If you are 42 years old and your BMI is 42, you have diabetes, smoke and do not exercise – YOUR CRC risk at 42 might well equal that of the standard (new normal) 50 year old. We need to know. This is a CISNET modeling problem – that has an answer. • Assessing SYMPTOMS is not Screening. It is DIAGNOSIS • Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs • What is driving these dramatic increases? The “Epi Challenge”. “Why?”
  37. 37. Advancing Prevention & Earliest Possible Stage Diagnosis • Consumer & Provider Awareness of YA CRC • Risk Assessment and Evidence Based Action: Family Health History • Adaptation of the Screening Guidelines to the Current Reality • 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or 45 year old NOW equal to that of a 50 year old in 1990? • 2. Can we better inform “risk”? If you are 42 years old and your BMI is 42, you have diabetes, smoke and do not exercise – YOUR CRC risk at 42 might well equal that of the standard (new normal) 50 year old. We need to know. This is a CISNET modeling problem – that has an answer. • Assessing SYMPTOMS is not Screening. It is DIAGNOSIS! • Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs. • What is driving these dramatic increases? The “Epi Challenge”. “Why?”
  38. 38. Advancing Prevention & Earliest Possible Stage Diagnosis of Young Adult CRC : A Strategic Outline • Consumer & Provider Awareness of YA CRC • Risk Assessment and Evidence Based Action: Family Health History • Adaptation of the Screening Guidelines to the Current Reality: • 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or 45 year old NOW equal to that of a 50 year old in 1990? (It’s close - see • 2. Can we better inform “risk”? If you are 42 years old and your BMI is 42, you have diabetes, smoke and do not exercise – YOUR CRC risk at 42 might well equal that of the standard (new normal) 50 year old. We need to know. This is a CISNET modeling problem – that has an answer. • Assessing SYMPTOMS is not Screening. It is DIAGNOSIS! • Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs. • What is driving these dramatic increases? The “Epi Challenge”. “Why?” T. Weber MD for the Young Adult CRC Research Consortium
  39. 39. The COVINA Group March 11th, 2017 NYC T. Weber MD for the Young Adult CRC Research Consortium
  40. 40. The “Other Agenda” For EAO CRC 2017: Based on the Covina Group Discussions • To come to a consensus on the top priority Action Items: Screening Guidelines : Family Health History : Earlier Diagnosis of the Symptomatic Patient : The Causes – “The Epi Challenge” • To lay out a road map of the constructive “Next Steps we plan to take. • Build on the unique to date awareness prompted by Rebecca Siegel’s article and the media attention it has received e.g. NY Times article • Launch the formation of the Young Adult CRC Research Consortium. • The COVINA Declaration? • Support tools for patients and their Care Givers: The Provider Buddy “App” for Patients, Care Givers & Providers T. Weber MD for the Young Adult CRC Research Consortium
  41. 41. Early Age Onset Colorectal Cancer A 21st Century Cancer Control Challenge: Summary • Early Age Onset CRC is a significant and growing national and international cancer control challenge. • Characterized by delayed, late stage diagnosis and poor outcomes. • The reasons for the global increase in EAO CRC are unknown but not unknowable. • Risk clarification and stratification will save lives. FAMILY HEALTH HISTORY. National Health Care System Issue / Challenge! • Symptom recognition and ACTION is essential. SURVEY > RISK INDEX > A Health Care Provider and Consumer / Patient Issue / Challenge! • 75% of EAO CRC in 40-49 age group. Revision of Screening Guidelines to incorporate additional risk factors e.g. Obesity, Diabetes, Smoking etc. • EAO CRC presents an opportunity for the Lombardi Cancer Center Care Community to help lead efforts to understand, prevent and effectively treat as early as possible, a leading cause of young adult cancer death.
  42. 42. FUTURE TRENDS: US COLON & RECTAL CA BY AGE GROUP A Colon Cancer Rectal Cancer
  43. 43. Improving Outcomes For EAO-CRC Advancing Earliest Stage Diagnosis: The Genetics of Early Age Onset CRC Tumor Testing: Improving Access to Targeted Molecular Therapies and Clinical Trials Julia A. Smith MD PhD Laura and Isaac Perlmutter Cancer Center
  44. 44. Julia A. Smith, M.D., Ph.D. • Clinical Director, Cancer Screening Program Laura and Isaac Perlmutter Cancer Center • Director, NYU and Bellevue Lynne Cohen Foundation & Caring Together Project for Woman with Increased Risk for Cancer
  45. 45. Hereditary CRC Syndromes Why bother understanding your risk?
  46. 46. 25% of CRC are associated with a Family History • 10% are associated with a well recognized genetic syndrome • Data accumulating • HNPCC, FAP, MYH polyposis, PJS • Bloom’s syndrome, HPS, JPC, 1307K APC
  47. 47. First, Know Your Risk • Contributing Factors - overview – Family History/Genetics – Personal Medical History • Associated Medical Diseases • Personal History of Exposure – Lifestyle • Diet • Exercise • Cigarettes • Alcohol
  48. 48. Factors Suggestive of Hereditary Cancer • Young age at diagnosis • Red flags or unusual cancers – Ovarian, male breast, pancreatic, melanoma, sarcoma, gastric, brain • Multiple primaries in same individual • Family clustering of certain cancers – Colon/endometrial, breast/ovarian, melanoma/pancreatic • Multiple colorectal adenomas in same family • Ancestry – Specific at risk population – Relative of a known mutation carrier
  49. 49. @ 50 y/o: • Population lifetime risk: 1.8% • With 1 affected relative: 3.4% • With 2 or >: 6.9%
  50. 50. Hereditary Colorectal Cancer Syndromes • Nonpolyposis – HNPCC : CRC +/- EC • CRC: 25% by age 50, 80% by age 70 • EC: 20% by age 50, 60% by age 70 • Red flag – early onset EC esp. w/ fhx CRC or EC – Other HNPCC associated cancers • Gastric, ovarian • Renal, biliary, small bowel, pancreas, brain, sebaceous adenoma • Red flag – onset at <50 of 2 or > HNPCC related cancers
  51. 51. Hereditary Colorectal Cancer Syndromes • Polyposis: 3 syndromes, degree & type – FAP • CRC risk 93% by age 50, >99% by age 70 – AFAP • Lifetime risk of CRC 80-100% – MAP – MYH associated polyposis • Specific penetrance/risk not known
  52. 52. Hereditary CRC Syndromes Risk of 2nd Cancer • HNPCC – 30% within 10 yr of initial diagnosis – 50% within 15 yrs (CRC, EC, 2nd CRC) • FAP – duodenal or periampullary ca: 4-12% risk – Thyroid, pancreatic, gastric, bile duct, adrenal, CNS (medulloblastoma): increased but small (2%) – 1.6% risk hepatoblastoma in children < 5 y/o
  53. 53. Lynch Syndrome Increases Risk of Second Cancer 0 20 40 60 Within 10 yrs Within 15 yrs General Population Lynch RiskofCancer(%) 3.5% 30% 5% 50%
  54. 54. Lynch Syndrome Increases CRC and Endometrial Cancer Risks 0 20 40 60 80 100 CRC by age 50 CRC by age 70 EC by age 50 EC by age 70 General Population Lynch RiskofCancer(%) 0.2% >25% 2% Up to 80% 0.2% 20% 1.5% Up to 71%
  55. 55. Assessment • Family history – Expanded pedigree – Types of cancer – Polyp history – Age at diagnosis – Medical record documentation • Detailed medical and surgical history – Personal history of cancer – Previous colon history including polyp number and type – Past medical illnesses – Carcinogen exposure • Focused physical exam – Gyn for women including endometrail/ovarian – Dermatologic – Head/neck (including thyroid) – Cononoscopy/EGD
  56. 56. Risk Counseling Educate, Assess risk, Manage risk • Provide accurate information on genetic, biologic, environmental risk • Provide understanding of the genetic basis to allow participation in decision making • Formulate options and recommendations for prevention and screening • Psychosocial support to adjust to risk assessment and adhere to recommendations • Must be tailored to individual’s age, education, level of risk, personal exposure to the disease, social environment
  57. 57. Genetic Testing • Selection based on personal and familial characteristics that determine probability of carrying a mutation • Psychosocial readiness to receive results • Review of possible genetic test results – True-positive (carrier) – True-negative (not carrier but identified in family member) – Indeterminate (neg & family members neg or unk) – Inconclusive (MUS) • Decision made on multifactorial grounds – Level of risk – Cost – Perceived risk-benefit ratio
  58. 58. HNPCC Surveillance Guidelines • Colon – Colonoscopy: Starting at age 20-25 every 1-2 yr After age 40 every year • EC/Ov – Endometrial aspiration, TVUS, CA-125: Starting at age 25-35 every 1-2 yrs
  59. 59. Adenomatous Polyposis Syndromes Surveillance Guidelines • Colon/rectum (FAP) – Sigmoidoscopy annually starting age 10-12 • Colon/rectum (AFAP) – Colonoscopy q 1-3 yr begin late teens or early 20s • Stomach/duodenum (FAP/AFAP) – EGD q 1-3 yr begin age 20-25 or time of dx
  60. 60. Management of CRC • Surgical prevention • Enhanced surveillance • Chemoprevention ? ASA NSAIDs OCP
  61. 61. Lifestyle Modification • Some data: cigs weight control healthy diet exercise
  62. 62. Remember • Think • Plan • Advocate • Team work • It’s never too late • And get your colonoscopy
  63. 63. Improving Outcomes For EAO-CRC Advancing Earliest Stage Diagnosis: New and “In the Pipeline” Treatments for CRC Joshua Raff MD White Plains Hospital Center for Cancer, Director, Digestive Cancer Program
  64. 64. Joshua P. Raff, M.D. Director, Digestive Cancer Program New and ‘In the Pipeline’ Therapies March 12, 2017,
  65. 65. Treatment Overview for Early Stage Surgery Adjuvant Chemo NeoAdjuvant Chemo +Radiation Surgery Adjuvant Chemo Rectal Cancer Colon Cancer
  66. 66. Treatment Overview for Advanced Disease Chemo Biologics Occasional Surgery Occasional Radiation Palliative Therapies
  67. 67. Drugs Used For CRC in the US 5 Fluorouracil Capecitabine 5Fu LV Capecitabine Oxaliplatin 5fu LV Oxaliplatin Capecitabine Irinotecan Cetuximab Panitumumab Bevacizumab Ramucirumab Ziv-Aflibercept Regorafenib Trifluridine +Tipiracil NeoAdjuvant (Rectal Only) Adjuvant (Both) Advanced (Both)
  68. 68. Drugs Used For CRC in the US 5 Fluorouracil Xeloda 5Fu LV Xeloda Eloxatin 5fu LV Eloxatin Xeloda Camptosar Erbitux Vecitbix Avastin Cyramza Zaltrap Stivarga Lonsurf NeoAdjuvant (Rectal Only) Adjuvant (Both) Advanced (Both)
  69. 69. Colorectal Cancer Host Immune Response Genetics Cell Signal Pathways Gut Microbe Milieu
  70. 70. Host Immune Response Cell Signal Pathways
  71. 71. Overview of cellular signaling pathways involved in colorectal cancer J Natl Cancer Inst (2009) 101 (19): 1308-1324.
  72. 72. Molecularly Targeted Approaches VEGF – Bevacizumab, Ramucirumab, Zif-Aflibercept EGFR – Cetuximab, Panitumumab Regorafenib - a multi-target inhibitor: VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET, Raf-1 MTOR, MEK IDO, BRAF WnT, PDGFR FGFR These – and many more – currently being studied
  73. 73. Types of Immunotherapies in GI Ca Immune Checkpoint Inhibition Monoclonal Antibodies Cancer Vaccines Adoptive Cell therapy Oncolytic Virus therapy Adjuvant Immunotherapies Cytokines
  74. 74. Mismatch Repair (MMR) & MicroSatellite Instability (MSI) • Mismatch Repair enzyme system - recognize and repair errors which occur during DNA replication • Impaired or deficient mismatch repair genes (MMR-D) leads to inconsistent DNA patterns of certain areas of chromosomes, called microsatellites • Normal State is MMR-P (proficient), and MS Stable • Micro Satellite Instability-High (MSI-H) is the condition of DNA inconsistency resulting from impaired MMR genes • MSI caused by MMR-D represents a distinct pathway of carcinogenesis, ie cancer formation.
  75. 75. MMR / MSI, & Hereditary Syndromes • The hereditary syndromes involving mutations of mismatch repair enzymes (MLH1, MSH2, MSH6, and PMS2) is often referred to as Lynch syndrome, but other classifications exist including HNPCC (Hereditary Non- Polypotic Colon Cancer) – 5% of CRC • MSI-H Associated more with: Right Side colon cancer, poorly differentiated tissue, Crohn's-like host response, Tumor Infiltrated Lymphocytes, • MSI-H cancer appears to be more antigenic than MSS malignancies and has a special susceptibility to immunotherapeutic strategies.
  76. 76. T Cell Inhibition http://www.genscript.com/immune-checkpoint-inhibitors.html
  77. 77. Immune Checkpoint Inhibition http://www.genscript.com/immune-checkpoint-inhibitors.html Pembrolizumab Nivolumab Atezolimumab Ipilimumab
  78. 78. J Clin Oncol 34, 2016 (suppl; abstr 103); J Clin Oncol 35, 2017 (suppl 4S; abstract 519) 28 patients MMR-D / MSI-H At least 2 prior Chemos 25 patients MMR-P At least 2 prior Chemos Pembrolizumab PD-1 Inhibitor (Keytruda) 10mg/kg q 3wk RR SD PFS OS 50% 39% N/R N/R 0% 16% 2.4 6m o 74 patients MMR-D / MSI-H At least 1 prior Chemo Nivolumab PD-1 Inhibitor (Opdivo) 3mg/kg q 2wk RR SD PFS OS 31% 37% 9.6 N/R PD-1 Inhibitors in Metastatic CRC with MMR / MSI
  79. 79. Atezolimimab + Bevacicumab in MSI-H • Ph Ib study Atezolimumab 1200 mg q3w plus Bev 15 mg/kg q3w • Ten MSI-high mCRC pts; 2L; median follow-up of 11.1 mo. • Confirmed ORR was 30%; dCR 90%; Median OS had not been reached • One AE led to discontinuation of Atezo and 3 AEs led to d/c of bev J Clin Oncol 35, 2017 (suppl 4S; abstracts 673, 676, 767 ) Pertuzumab + Trastuzumab in HER2+ • ph IIA study HER2+ heavily treated mCRC; 2L, med 4 prior • standard doses of pertuzumab + trastuzumab only NO CHEMO • 34 patients; median follow-up of 5.2 mo • 12 patients had PR; 3 with SD for >4 months Activated T cells with chemotherapy • 17 patients with mCRC ; first-line chemoimmunotherapy. • XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes • mPFS 15.2 months; Immunotherapy-assoc toxicity minimal • ORR 70%: CR = 23.5%, PR = 47.1%, SD = 29.4% PD = 0
  80. 80. J Clin Oncol 35, 2017 (suppl 4S; abstracts 660, 673, 676, 677, 767 ) • MABp1 (Xilonix; IL-1a Ab) • Cobimetinib (anti-MEK)+ Atezolimumab • Napabucasin (Stemness Inhibitor) • Nindetanib (anti VEGFR, PDGFR and FGFR) • Vemurafenib – for BRAFV600 mutated and extended RAS wild-type mCRC • Anti-KRAS siRNA nanoparticles (preclinical) Other Agents Showing Promise
  81. 81. Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy • Retrospectively analyzed the composition and the function of • 1,388 colorectal cancer tumors from three independent cohorts • Prospectively validated findings using immunohistochemistry. • Found four distinct subclasses based upon molecular and tumor micro-environment features Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066
  82. 82. Immune and stromal signatures of the four molecular subgroups of colorectal cancer. Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066©2016 by American Association for Cancer Research
  83. 83. Immune and stromal signatures of the four molecular subgroups of colorectal cancer. CMS1 characterized by overexpression of genes specific to cytotoxic lymphocytes. CMS2 (canonical ) and CMS3 (metabolic ) subtypes have intermediate prognosis exhibit low immune and inflammatory signatures : target cellular pathways, and or strategies to up- regulate immune response CMS4 is a poor-prognosis mesenchymal subgroup, expresses markers of lymphocytes and of cells of monocytic origin. The mesenchymal subgroup also displays an angiogenic, inflammatory, and immunosuppressive signature Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066
  84. 84. Colorectal Cancer - Summary • Clarify best pre- and post-operative regimens • Shift focus on to molecular and immuno therapies • Genetic Counseling & DNA testing – more routine • Testing of tumor tissue is now routine • MMR, MSI – to predict respone from Immune Checkpoint Inhibitors • KRAS, NRAS, – to predict response from Cetuximab, Panitumumab • BRAF – for prognostic and possible Vemurafenib response • Pembrolizumab or Nivolumab for MMR-D/MSI-H: - Very promising ! • Many other molecular and immuno therapies, alone or in combinations – showing promise • Integrated Tumor Analysis – to predict subclasses and refine therapeutic strategies
  85. 85. A New Hope for ColoRectal Cancer Refine Genomic & Molecular Analysis Target Cellular Processes Alter the Tumor Micro- Environment Zhuzh up Host Immune Response
  86. 86. Improving Outcomes For EAO-CRC Advancing Earliest Stage Diagnosis: What Are We Going To Do To Advance The Cause? Jacen Roberts CRC Survivor and Advocate Daniella Burgess Fight Colorectal Cancer
  87. 87. Jacen Roberts CRC Advocate
  88. 88. News 12 Video • http://longisland.news12.com/news/study-colon-rectal- cancers-on-the-rise-for-millennials-1.13195725#autoplay=true
  89. 89. Jacen’s Story • Diagnosed with Stage IV rectal cancer in January of 2014 after 6-7 years of irregular bowel movements and constipation. • He has undergone 8 FOLFOX treatments, 25 radiation treatments and a lower anterior resection in 2014 along with a liver resection in 2015. • After having genetic testing performed in early 2016, Jacen was confirmed to be Lynch positive. As of October 2016, his bi-annual CT scans and annual scopes have ALL come back clean and he is in remission. • Attended the Early Age Onset Colorectal Cancer (EAO CRC) Summit for the past two years and become a vocal member of the CCCF Community. • Recently begun his journey as a CRC Advocate by telling his story to News 12 Long Island. He is dedicated to sharing his story with as many people under the age of 50 as possible – and SAVING LIVES. • Jacen lives in North Babylon, NY loves music, cooking and comes from a close knit family.
  90. 90. Where do we go from here? • Where do go from here? – Patient Education • Signs and Symptoms • Personal advocacy – Physician Education • AMA
  91. 91. Fight Colorectal Cancer get behind a cure.®
  92. 92. About Me! • Two-time survivor • Diagnosed at age 17 with stage III in 2001 • Diagnosed at age 25 with stage I in 2008 • Dx Lynch in 2013
  93. 93. ABOUT FIGHT CRC • National nonprofit advocacy organization founded in 2005. • Focus on 4 areas: – Advocacy/policy – Research – Awareness – Patient Education
  94. 94. ADDRESSING “UNDER 50” THE ORG ROLE 1 Multidisciplinary task force to be convened in summer 2017 2 Collaborations across the community Continue funding early-onset research3 Share real life stories4
  95. 95. ADDRESSING “UNDER 50” THE ADVOCATE ROLE 1 Share your story to raise awareness and educate others 2 Discuss your family history and encourage others to do so as well Participate in clinical trials to continue the research for treatment & survivorship care 3 Advocate for more research funding4 Support the growing body of evidence that will influence guidelines in the future 5
  96. 96. NEXT STEPS
  97. 97. POLICY CHANGE • Advocate on March 15 through Virtual Lobby Day • Become a policy advocate year-round – Blue Star States – August Recess Challenge – Call-on Congress • Sign up at FightCRC.org/Advocate
  98. 98. CRC RESEARCH • Participate in a clinical trial • Volunteer for focus groups soliciting patient feedback • RATS group for those interested in the science
  99. 99. AWARENESS • Add your story to the One Million Strong community at FightCRC.org/OneMillionStrong • Engage on social media! Tag us at @FightCRC
  100. 100. PATIENT EDUCATION • Share the free resources - both digital and print materials. Get them at FightCRC.org/Resources • Educate yourself during webinars. Sign up on our website at FightCRC.org/SignUp
  101. 101. JOIN THE FIGHT! FightCRC.org
  102. 102. Interested in Attending the 4th Annual EAO CRC Summit in 2018? Join our mailing list by visiting http://coloncancerchallenge.org

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