How Changes in Central Cancer Registries are Impacting Cancer Research

Transcription

1 How Changes in Central Cancer Registries are Impacting Cancer Research Presented by: Thomas C. Tucker, PhD, MPH Director, Kentucky Cancer Registry University of Kentucky Kentucky Cancer Registry 29 th Advanced Cancer Registrars Workshop Louisville, KY September 10-11, 2015

2 Topics to be covered A very short history of the Kentucky Cancer Registry The importance of population-based cancer research Internal Validity External validity How population-based cancer registries can improve cancer research Providing a Population-Based Sample Frame Making Rapid Case Ascertainment Possible Serving as a Virtual Tissue Repository Measuring the last Phase of Translational Research The Kentucky model for moving evidence-based research into the population An example of the potential impact of implementing evidencebased research in the population

3 The importance of population-based cancer research

4 Two important concepts Internal validity External validity

5 Animal Studies genetically identical mice Exposed Animals Unexposed Animals Developed Disease A C Did not Develop Disease B D Relative Risk = (A/A+B)/(C/C+D)

6 Randomized Clinical Trial Randomized trial (Prospective) Study Outcome Occurred Did not Occur Random Allocation Exposure or Intervention No Exposure or Intervention A C B D Relative Risk = (A/A+B)/(C/C+D)

7 Internal Validity When differences between the experimental (exposed) group and the control group are completely accounted for, the study is said to have internal validity and causal inferences can be made. In other words, it is possible to determine whether the exposure causes some outcome (disease, etc.). Many have argued that randomization was the most important scientific advance of the 20 th century. Why is it that the findings from randomized clinical trials with internal validity almost never have the same effect when they are applied to general populations?

8 External Validity When the findings from a research project or study can be generalized to some defined population, they are said to have external validity. Epidemiology (population science) provides the tools to explore external validity and many argue that moving from studies with strong internal validity to studies with strong external validity is the next step in advancing our scientific understanding. The continuum from research with strong internal validity to studies with strong external validity is also part of Translational Research.

9 Population-based Central Cancer Registries Can Enhance Cancer Research in Several Important Ways.

10 1. As a Population-Based Sample Frame Geographic Area Covered by the Population-Based Cancer Registry Cancer cases occurring each year Information gathered on each cancer case The Population-Based Cancer Registry Cancer research with strong external validity (the ability to generalize the findings to the underlying population) A scientific sample of data from cancer patients representing the population covered by the registry is provided to the researcher

11 Intimate Partner Violence and Cancer Disparities A novel population-based cohort study Research Question: Is IPV associated with delayed screening, late stage Dx or poor survival among women diagnosed with breast, colorectal or cervical cancer in Kentucky? Design: Population-based prospective cohort study Methods: KCR recruitment Population-based Sample: n=1,850 Results: IPV (37% lifetime) Partner Interference (13%) Indirect Pathway Poverty, Risk behaviors, Access to care, Low education, Co-morbidity IPV & Partner Interference with Cancer Treatment Direct Pathway Later Stage at Diagnosis Suboptimal Treatment Poorer Quality of Life Poorer Survival

12 2. For Rapid Case Ascertainment Geographic Area Covered by the Population-Based Cancer Registry Pathology Labs Cancer research with strong external validity (the ability to generalize the findings to the underlying population) Electronic Path (EPath) Reports for Cancer Patients Sent Automatically at the Time of Diagnosis The Population-Based Cancer Registry Receives EPath Reports for 95% of All New Cancer Cases Diagnoses each Year Biospecimens collected A population-based sample of cancer cases provided to the researcher

13 High Arsenic, Chromium and Radon Levels and High Lung Cancer Rates in Appalachian Kentucky (Top) Arsenic content and coal field locations in Kentucky; (Bottom) Incidence of lung cancer in the Appalachian versus Non-Appalachian region of Kentucky.

14 Environmental Exposure and Lung Cancer A population-based lung cancer case-control study By Drs. Arnold, Orren, Mellon, and Huang Lung Cancer Rate per 100, Arsenic PPM Appalachia Study Area Epi, Blood, Urine, Hair, Toenails, Radon level, Tap water, Soil, GPS Hypothesis: Lung cancer incidence is higher than expected from smoking alone and is associated with exposure to environmental carcinogens

15 Environmental Exposure and Lung Cancer A population-based lung cancer case-control study By Drs. Arnold, Orren, Mellon, and Huang Live lymphocytes

16 3. As a Population-Based Virtual Tissue Repository Geographic Area Covered by the Population-Based Cancer Registry Pathology Labs Cancer research with strong external validity (the ability to generalize the findings to the underlying population) The Population-Based Cancer Registry Formalin fixed paraffin imbedded tissue samples are collected from the labs by the Registry for a populationbased sample of cases A population-based sample of cancer case data and tissue are provided to the researcher

17 1. A retrospective cohort study using the registry as a virtual tissue repository to explore 5 distinct proteins associated with breast cancer recurrence Purpose of the Study Determine whether female breast cancer patients who were disease-free following surgery but subsequently had a recurrence of their breast cancer within five years had altered levels or activity of one or any combination of five proteins compared to women who were diseasefree and did not have a recurrence.

18 The Five Proteins Par-4: pro-apoptotic tumor suppressor protein downregulated during breast cancer recurrence Wnt/β-catenin: signaling pathway induces epithelial-mesenchymal transition (EMT) and promotes metastasis SNAIL, TWIST: transcription factors, promote EMT promote cancer progression (metastasis) elevated in metastatic and recurrent tumors c-abl, Arg: tyrosine kinases, oncoproteins promote survival, proliferation, and metastasis activity levels measured by pcrkl activity

19 A Retrospective Cohort Study Using the Registry, all female breast cancer patients treated surgically between 2000 and 2007 at UK for their 1 st Ca. and determined to be disease free were identified. Tissue blocks from the initial surgery were obtained for all of these patients, TMAs were constructed and stained to determine activity levels for each protein. This cohort was then traced forward in time to determine which patients recurred and which did not. (479 patients met the study criteria). Identify the study Population Comparisons were made between activity levels of each protein among the primary tumors of recurrent patients (62) and the non-recurrent patients (417). Did Not Recur Recurred For patients that recurred, comparisons were made between the tumor tissue at first surgery (the primary tumor) and the tissue taken at the time of recurrence. Tissue at the time of recurrence was only available for 22 patients. Tissue at the time of recurrence

20 Preliminary Results PROTEIN EXPRESSION IN PRIMARY TUMORS FROM RECURRENT VS. NON-RECURRENT PATIENTS Intensity Allred Score Intensity X Percent TWIST SNAIL PAR4 β-catenin pcrkl HER2+ (n=36) HER2-/ER+/PR+ (n=282) H L HER2-/ER-/PR+ (n=32) HER2-/ER-/PR- (n=75) HER2+ HER2-/ER+/PR+ H L HER2-/ER-/PR+ HER2-/ER-/PR- HER2+ HER2-/ER+/PR+ H L HER2-/ER-/PR+ HER2-/ER-/PR- H: Significantly high in the primary tumor of recurrent patients L: Significantly low in the primary tumor of recurrent patients

21 Preliminary Results PROTEIN EXPRESSION IN RECURRENT VS. PRIMARY TUMORS Intensity Allred Score Intensity x Percentage TWIST SNAIL PAR4 β-catenin pcrkl H H H H: Significantly high at the time of recurrence in the tissue sample of patient who recurred compared to their primary tumors

22 Preliminary Results pcrkl EXPRESSION IN RECURRENT VS. PRIMARY TUMORS

23 Conclusions Elevated levels of Twist, and low or not activated c-abl/arg (pcrkl) in HER2 - /ER + /PR + breast tumors may potentially serve as a novel biomarker for the recurrence of breast cancer. c-abl/arg was activated and over expressed in the tumors of patients at the time of recurrence. Inhibiting c-abl/arg activation may potentially prevent recurrence. It is difficult to imagine doing this study without using the Cancer Registry as a virtual tissue repository.

24 2. Pre-Invasive Cervical Cancer HPV Genotyping Study: Research Questions Are the HPV genotypes different for non-appalachian white women diagnosed with pre-invasive cervical cancer (CIN-3) compared to Appalachian white women? Are the HPV genotypes different for non-appalachian white women diagnosed with pre-invasive cervical cancer (CIN-3) compared to non-appalachian black women? Are the HPV genotypes different for white women diagnosed with CIN-3 compared to white women diagnosed with AIS?

25 Study Population All Kentucky women age 18 or older diagnosed with CIN-3 or AIS between January 1, 2009 and December 31, 2012 were available for this study. The cases were divided into four strata (non-appalachian white women, non-appalachian black women, Appalachian white women and AIS cases). A total of 4903 pre-invasive cervical cancer cases fell into one of these strata were non-appalachian white women diagnosed with CIN were non-appalachian black women diagnosed with CIN were Appalachian white women diagnosed with CIN were white women diagnosed with AIS. The recruitment goal was to obtain tissue specimens from a random sample of 150 cases in each strata (for a total of 600 cases). A random sample of 200 cases was drawn from each strata except AIS to allow replacement for cases for which tissue could not be obtained.

26 Study Procedures The Kentucky Cancer Registry (KCR) served as the Honest Broker for this study. KCR solicited the required tissue blocks from each of 48 the labs where the tissue was stored. Tissue blocks were sent directly to KCR, the blocks were anonymized and given a unique code. The coded blocks were cut by the Markey Cancer Center, Biospecimens and Tissue Procurement Research Lab and the tissue specimens sent to CDC for genotyping. The original blocks were returned to the contributing lab by KCR. All of the HPV genotyping was done at CDC. The HPV genotype or types for each specimen and the associated unique code were then returned to KCR and linked with other data in the preinvasive cervical cancer surveillance database to create a research data set.

27 Pre-Invasive Cervical Cancer HPV Genotyping Study: # and % of Cases Currently Available for Analysis Groupings Frequency + (% of 421) Available for study 421 (100%) Appalachian white 121 (28.7%) Non-Appal white 113 (26.8%) Non-Appal black 105 (24.9%) AIS white 82(19.5%)

28 Pre-Invasive Cervical Cancer HPV Genotyping Study: Research Question 1 Are HPV genotypes different for Appalachian white vs non-appalachian white females? HPV Genotype Region % with genotype Any oncogenic HPV except 16 & 18 Non-Appalachian 34% p-value Appalachian 22%

29 Pre-Invasive Cervical Cancer HPV Genotyping Study: Research Question 2 Are HPV genotypes different for non-appalachian white vs non-appalachian black females? HPV Genotype RACE % with genotype p-value 16 (alone or White 61.1% with any other HPV) Black 44.8% 16 alone White 46.9% Black 29.5% 35 (alone or White 2.7% with any other HPV) Black 13.3% 35 alone White 1.8% Black 9.5% Any oncogenic HPV White 33.6% except 16 & 18 Black 46.7%

30 Pre-Invasive Cervical Cancer HPV Genotyping Study: Research Question 3 Are HPV genotypes different for white females with CIN-3 vs white females with AIS? HPV Genotype CIN-3 Vs. AIS % with genotype p-value 18 (alone or CIN-3 3.0% < with any other HPV) AIS 39.0% 18 alone CIN-3 1.7% < AIS 32.9% 31 (alone or CIN % with any other HPV) AIS 0.0% 31 alone CIN-3 7.3% AIS 0.0% 52 (alone or CIN-3 6.8% with any other HPV) AIS 1.2% 52 alone CIN-3 3.4% AIS 0.0% 33 (alone or CIN-3 0.0% with any other HPV) AIS 4.3%

31 Preliminary Conclusions HPV oncogenic types other than 16 and 18 were more common among non-appalachian white women diagnosed with CIN-3 compared to Appalachian white women HPV 16 alone or with any other HPV type was more common among white women diagnosed with CIN-3 compared to black women. HPV 35 alone or with any other HPV type was more common among black women diagnosed with CIN-3 compared to white women. HPV 18 alone or with any other HPV type was more common among white women diagnosed with AIS compared to white women diagnosed with CIN-3.

32 The final step in translational research is the broad based implementation of cancer research findings in the genral population and measuring the impact of these interventions.

33 From the Laboratory to the Population Genes Cells Animals Humans Populations Basic Science Clinical Science Translational Research Epidemiology

34 EXAMPLE Quercitrin, a natural product from apple peel, is tested in an animal model to determine if it prevents UV exposure induced skin cancer Randomized trials in human populations Broad application of the findings to the general population

35 From the Population to the Laboratory And back again Genes Cells Animals Humans Populations Basic Science Clinical Science Epidemiology Translational Research

36 Example Cell line and animal studies are conducted to determine if exposure to arsenic and chromium contributes to the onset of colon cancer. Epidemiologic studies show that colorectal cancer is excessively high in the Appalachian area of Kentucky and this same population has high exposure to arsenic and chromium.

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38 Example Cell line and animal studies are conducted to determine if exposure to arsenic and chromium contributes to the onset of colon cancer. Human trials Epidemiologic studies show that colorectal cancer is excessively high in the Appalachian area of Kentucky and this same population has high exposure to arsenic and chromium.

39 From the Laboratory or the Population Genes Cells Animals Humans Populations Basic Science Clinical Science Epidemiology Translational Research

40 The ultimate goal of translational cancer research is the adoption and wide-spread use of evidencebased research findings that significantly reduce the cancer burden in the population. This includes the wide-spread implementation of evidence-based cancer control interventions.

41 The Kentucky Model for Moving Evidence-based Cancer Research Findings into to the Population Kentucky Cancer Consortium (KCC) Kentucky Cancer Program (KCP) Lung Cancer by Area Development District in KY, High School Current Age- Age- Area Kentucky Education Cancer Smokers Registry Adjusted (KCR) Adjusted Incidence Mortality Development District Percent Rank Percent Rank Rate Rank Rate Rank Overall Rank Kentucky River Big Sandy Cumberland Valley Gateway Buffalo Trace Barren River Lake Cumberland Fivco Green River Pennyrile Lincoln Trail Purchase Northern Kentucky Kipda Bluegrass

42 Source: Kentucky Cancer Registry (KCR)

43 Source: Kentucky Cancer Registry (KCR)

44 Combining Data from Multiple Sources Demographic Characteristics Contribute to Risk Factors Contribute to Incidence and Late Stage DX Contribute to Cancer Mortality Logic Model

45 What are the common sources of data that can be used for defining the cancer burden? Demographic data (Census U.S) Risk factor data (BRFSS) Incidence data (KCR) Mortality data (State Vital Records)

46 Area Development District Lung Cancer by Area Development District in KY, High School Education (%) Poverty Rate (%) Smoking Rate (%) Age-Adjusted Incidence Number Rate Late Stage Incidence % Age-Adjusted Mortality Number Rate U.S , , Kentucky Barren River Big Sandy Bluegrass Buffalo Trace Cumberland Valley Fivco Gateway Green River Kentucky River Kipda Lake Cumberland Lincoln Trail Northern Kentucky Pennyrile Purchase

47 High School Education ( ) vs Smoking Rate ( ) 40 High School Education vs Smoking Rate in Linear (High School Education vs Smoking Rate in R² = Percent Smoker Percent High School Education

48 Smoking ( ) vs Lung Cancer Incidence ( ) 140 Smoking ( ) vs Lung Cancer Incidence 130 Lung Cancer Incidence R² = Percent Smoker ( )

49 Lung Cancer Incidence vs Mortality ( ) Lung Cancer Incidence versus Mortality Linear (Lung Cancer Incidence versus R² = Mortality Rate Lung Cancer Incidence

50 Lung Cancer by Area Development District in KY, Area Development District High School Education, Current Smoker, Age- Adjusted Incidence Age- Adjusted Mortality Percent Rank Percent Rank Rate Rank Rate Rank Overall Rank Kentucky River Big Sandy Cumberland Valley Gateway Buffalo Trace Barren River Lake Cumberland Fivco Green River Pennyrile Lincoln Trail Purchase Northern Kentucky Kipda Bluegrass

51 An Example In 2001, Kentucky had the highest colorectal cancer incidence rate in the U.S. compared to all of the other states

52 In 2001, it was also noted that Kentucky was ranked 49 th in colorectal cancer screening compared to all other states with the second to the lowest rate (34.7% of the age eligible population).

53 Using the process previously described, data about the burden of colorectal cancer was assembled and presented to each of the 15 District Cancer Councils. Following these presentations, all 15 of the District Cancer Councils implemented evidence based cancer control intervention programs aimed at increasing colorectal cancer screening for age eligible people living in their District. What happened following the implementation of these colorectal cancer screening programs?

54 70% 65% 60% Colorectal Cancer Screening in Kentucky 65.70% 63.70% 63.70% 58.60% 55% 50% 47.20% 45% 43.90% 40% 35% 30% 34.70% th 23rd Source: accessed August 2014

55 Kentucky Colorectal Cancer Incidence ( ) Rate Year P<.05 Source: Accessed January 2014

56 Kentucky Colorectal Cancer Mortality ( ) Rate Year P<.05 Source: Accessed January 2014

57 A 24% reduction in colorectal cancer incidence and a 28% reduction in colorectal cancer mortality is a significant public health success. It is important to note that we would not have seen this problem without data from our population-based Cancer Registry and we could not have measured the impact of our interventions without data from our population-based Cancer Registry

58 Kentucky Cancer Registry Thank You! Questions?