Multi-cancer early detection (MCED) assays represent a new paradigm in cancer screening with the potential to deliver on the promise of earlier detection of many cancers with a single test. This technology is quickly moving into the mainstream, which means more patients will be asking about it. In this webinar, we will explore the results of the Pathfinder Study, which evaluated the Galleri test, and we’ll hear how practitioners are implementing this cutting-edge technology into their practices

Klein, MD, Eric

Massart, MD, PhD, Mylynda

Skoufalos, EdD, Alexis

Jefferson Digital Commons

C O L L E G E  O F  P O P U L AT I O N  H E A LT HMulti-Cancer Early Detection: Understanding the Pathfinder Study and Clinical ImplementationMylynda Massart, MD, PhDEric Klein, MDAlexis Skofalous, EdDDecember 8, 2022Today’s PresentersAlexis Skoufalos, EdD (Moderator)Associate Dean for Strategic DevelopmentProgram Director, Doctor of Health Science in Population HealthJefferson College of Population HealthEric Klein, MDEmeritus Chairman, Glickman Urological & Kidney InstituteProfessor of SurgeryCleveland Clinic Lerner College of MedicineMylynda Massart, MD, PhDMedical Director, UPMC Primary Care Precision Medicine CenterAssistant ProfessorUniversity of PittsburghThe Promise of MulticancerEarly DetectionEric A. Klein, MDEmeritus Professor and ChairGlickman Urological and Kidney InstituteCleveland Clinic Lerner College of MedicineFellow, Stanford Distinguished Careers InstituteDisclosure:I am a consultant for GRAIL, IncScreening for individual cancersScreening individuals for cancerParadigm Shift• Why is this necessary?• How is it possible?Why Early Detection is ImportantLow Tumor BurdenHigh Tumor Burden> 600,000 people die of cancer every year In the USDespite this:Why is this Necessary?USPSTF Recommendations for Cancer Screening MortalityLimitations of Current Screening ParadigmCompelling Rationale for a Paradigm Shift to Include MCED ~ 600,000 cancer deaths per year in the US despite current screening70% of all cancers are not foundUnscreened cancers account for ~70% of deathsPPV for single cancers is <10%Adherence rates are sub-optimal 5% (lung) - 80% (cervical)More likely to be diagnosed with a different cancer than those targeted by screeningCumulative false positive rates are high (40-50%)PPV for single cancers is <10%Cumulative False-Positive Rate From Single-Cancer ScreeningA 60-year-old women with a history of smoking screened for 4 cancers would have a 43.6% false positive rate (FPR)1–4Cumulative probability of a false-positive resultin the PLCO trialCroswell et al. Ann Fam Med 2009;7:212-222 Pinsky PF, et al. Ann Intern Med. 2015;162:485-491. 2. Melnikow J, et al. JAMA. 2018;320:687-705. 3. US Food and Drug Administration (FDA) premarket approval (PMA) P130017 4. Lehman CD, et al. Radiology. 2017;283:49-58.Universal Cancer Screening Improves EfficiencyAhlquist, NPJ Precision Oncol 2:23, 2018 Pan-GIUniversalEffect on NNS & PPVLiquid BiopsyKey Concepts for Understanding MCED• MCED is not about finding a particular cancertype• MCED should not be compared to tests thatscreen for individual cancers• MCED is intended as an adjunct to standardscreening tests• MCED is a screening test and requires a diagnostic evaluationCancer Signals in Blood• Methylation• Mutations• Chromosomal copy number alterations• Fragmentomics• Proteins• miRNA• Microvesicles• Multi-AnalyteJamashidi et al., Cancer Cell 2022 (in press)The targeted methylation assay underlying Galleri is based on a shared cancer signal across many cancer typesBiology of MethylationIntegration of Genomic and Epigenomic DataNormal cellCancer cellMCED Clinical WorkflowAnalysisResults ReportPublished MCED Studies• CancerSeek/DETECT-A• Circulating Cancer Genome Atlas (CCGA) • PathfinderDETECT- A StudyLennon et al., Science July 2020 • 10,000 women, ages 65 – 75 • No current or previous known cancer• 9,911 women were screened– 26 cancers were detected– Double the number of cancers detected by standard-of-care screening alone.DETECT-A: Results and Test PerformanceLennon AM et al. Science. 2020;369:eabb9601. 10203040Stage at Diagnosis, %IIIIIIIVResults of CCGA3Prospective, Case-Control, Discovery & Validation Study● Anus● Corpus uteri (2 types)● Esophagus● Exocrine pancreas● Gallbladder● Hodgkin and non-Hodgkin lymphoma● Bile duct (3 types)● Kidney● Larynx● Leukemia ● Liver● Melanoma of the skin● Malignant pleural mesothelioma● Merkel cell carcinoma > 50 cancers, including unscreened cancers such as:USPSTF Recommended screening programs● Nasopharynx● Neuroendocrine (3 types) ● Oral cavity● Oropharyngeal● Oro- and hypo-pharynx● Ovary● Plasma cell myeloma● Renal pelvis and ureter● Soft tissue sarcoma (5 types) ● Small intestine● Stomach● Testis● Urinary bladder● Vagina● VulvaBreast    |   Cervix uteri    |  Colon and rectum    | Lung | Prostate>50 Cancer types detected0.5%89%False positive rateAccuracy in predicting location of the cancer68%Sensitivity stages I-III for 12 prespecified cancers representing 2/3 of cancer mortality in USKlein EA, et al. Ann Oncol. 32:1167, 2021N = 4,077Sensitivity of Cancer Signal Detection by Cancer Type: Stage I-IIKlein EA, et al. Ann Oncol. 32:1167,2021Sensitivity> 50%PATHFINDERProspective Study in Intended Use PopulationResults returned to provider and participantPATHFINDERCancer signal was detected in 1.4% (92/6621 participants)01020304050607080Stage I or II Lack standardscreeningMCED Detected CancersPercent40%72%Consistent Results Across StudiesClinical Validation Study (CCGA3)0.5%False positive rate44%Positive predictive value89%Localization accuracyConfirmatory Intended Use Population Study (PATHFINDER)*0.5%False positive rate43%Positive predictive value 88%Localization accuracy**Refined test used commercially; **1st or 2nd location prediction Klein EA, et al. Ann Oncol. 32:1167, 2021ESMO 2022 (Schrag et al.)Galleri Commercial ExperienceConfirmed DiagnosesOut of 130 voluntarily reported “Cancer Signal Detected” cases with diagnostic resolutionVoluntary reporting of diagnostic follow up and resolution by ordering physicians to GRAILDo MCEDs Overdetect Nonlethal Cancers?Chen  et al., Clin Cancer Res 27:422, 2021 Not detectedDetectedAll StagesP < .0001Stage I Stage IIStage III Stage IVP < 0.0001 P < 0.0001P < 0.0001P < 0.00055False PositivesEligible for screening (ages 50-79): 107MHackshaw et al., Brit J Cancer (2021) 125:1432 – 1442 Pathfinder, Schrag et al., ESMO (2022)012345678910SOC SOC + MCEDMillionsAxis Title8,057,6578,592,6570.5%CostHackshaw et al., Brit J Cancer (2021) 125:1432 – 1442020406080100SOC SOC + MCEDThousands $0100200300400500SOC SOC + MCEDThousands Number of Cancers Detected Cost per Cancer DetectedCurrent SOC cost: $16.9BMCED cost: $3B189,498422,105Eligible to be screened ~107M (aged 50 – 79)$89,042$7,0602.2X increase in CDR results in a 12.6X reduction in costIntended Use• Adjunct to current screening tests• In the short term - Higher risk of cancer• Smokers• Strong family history• Known genetic carrier or syndrome (BRCA, others)• Prior history of cancer • Pediatric cancer survivors• Immunosuppressed • Worried well• In the long term- General population – adults over 50> 600,000 people die of cancer every year In the USAdding MCED has the potential...Despite thisTo achieve thisHackshaw et al., Brit J Cancer (2021) 125:1432 The Value of MCED at the Population LevelAdvantages Practical EffectsDetects cancers not currently screened for Increases overall cancer detection rateImproves efficiency of screening Improved PPVShifts diagnosis to earlier stages Lower burden of treatment &Improved cure rateReduced cost per cancer detected 2.2X increase in CDR results in a 12.6Xreduction in cost**Hackshaw et al., Brit J Cancer (2021) 125:1432MCED Implementation in the ClinicMylynda B. Massart, MD, PhDUPMC Primary Care Precision MedicineDepartment of Family MedicineClinical and Translational Science InstituteInstitute for Precision MedicineUniversity of PittsburghDisclosures:Grail Speaker BureauChallenges of Current Cancer Screening Paradigm:• Current challenges in cancer screening:• Second leading cause of death• Cancer has a huge cost burden• Screening is limited 5 cancers only 4 with USPSTF guidelines A/B• Current screening paradigms are invasive, time consuming and present significant barriers to access• Adherence to current screening is not at goal• Covid-19 has caused a dramatic drop in screening • Cancellations • De-prioritization by health systems early in pandemic• Fear of exposure by patients• Increased barriers and disparity gapsBreast CancerColon CancerLung Cancer(high-risk groups)Cervical CancerMissing Many Cancers: USPSTF Screening covers 29% of annual cancer incidence age 50-79 71% incident cancers without current screening modalityCancer Prevalence (%)USPSTF Recommended Screening Sensitivity (%)Specificity (%)Positive Predictive Value (%)Compliance with Recommended Screening (%)Breast 0.6 Biennial mammography, women ages 50-7487 89 4.4 78.3Cervical <0.1 Triennial cytology or quinquennial cytology/HPV test women ages 21-6595 85.5 <1 80Colorectal 0.65 Decennial colonoscopyTriennial stool-based screening (Cologuard)Annual Stool based screening (FIT)Ages 45-7575-93% adenomas 6mm or greater92.373.886%86.694.93.9-100 depending on study and reference (avg. 22.9%)3.78.769.7Lung 1.1 (high risk)Annual low-dose CT ages 50-80 85 87 6.9 5Prostrate 15.5 Biennial PSA testing, men 55-69 21 91 30 33Accuracy of Mammograms• Overall the sensitivity of mammography is about 87%• Mammography identifies 87% of women who have breast cancer• The chance of having a false positive result after one mammogram ranges from 7-12% depending on age.• It is estimated that over 10 years of annual mammography screening, 50% of women will experience at least one false positive recall, 17% false positive short-interval follow-up and 11% a false positive biopsy recommendation.https://health.ucdavis.edu/news/headlines/half-of-all-women-experience-false-positive-mammograms-after-10-years-of-annual-screening-/2022/03The best we have needs To be better.New Cancer Screening Paradigm• Shift cancer detection to earlier stage to hopefully increase treatability• Provide screening for cancers without previous rigorous screening optionsGoal:• Low false positives• Ability to localize the cancer with high accuracy• Limit over diagnosis (not over detect indolent cancers)• Need data from prospective studies that show that liquid biopsies deliver benefits to patients beyond being non-invasive such as increasing quality-adjusted life-years.To be successful:The Galleri Test in My Practice● Annual Physical/Wellness ● Cancer Screening Appointment ● Other● All patients 50 years or over● 50 years or over and additional risk factor ● 40y-50y with additional risk factors● Other● Pre-visit materials: videos, brochures, website● During visit: brochures, flip chart, verbal● Sample languageWhen do I discuss GalleriWho do I discuss Galleri withHow do I discuss Galleri● In office blood draw ● Kit given to patient or sent to patient’s home○ Quest, Mobile phlebotomyHow to obtain a sample● Copy of results for patient● No cancer signal detected● Cancer Signal detectedDiscussing results39The Galleri test can easily be integrated into existing clinical workflowsHCP, healthcare practitioner.Consultation & order HCP authorizes MCED  testPRIMARY CARESample collectionBlood sample drawn and sent to lab for analysisLABDetectionEVALUATION FOR CANCERDiagnostic work-up ROUTINE CARE Continue routine care and recommended age- and risk-based cancer screeningCancer Signal DetectedNo Cancer Signal DetectedResults ProvidedHCP discusses results with patient. Results indicate whether cancer signal has been detected and, if so, predicts the signal origin.10-14 dayturnaround timePRIMARY CARE40GRAIL post-positive test support for ordering providersTest orderedTest report received –10 daysMSLs can reach out for peer to peer discussion and knowledge shareCSO based Clinical ConsiderationsMSLs can reach out to referred specialist to educate on MCED and address questions about the testMSLs can share: ● Pathfinder Study case report examples when available● CSO Axis of confusion educationMCED, Multi-Cancer Early Detection 41Positive Test - Cancer Signal DetectedSample Test ReportsPage 1 only of sample test report shown.*For intended use population: Adults with an elevated risk of cancer such as those aged 50+ years. Use of Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.Negative Test - Cancer Signal Not Detected42Personalized medicine and weighing risk (SCREEN vs TEST):Pre-test Probability 1/120Post-test Probability 1/2Negative testing: how frequent to repeat?Residual risk and False negatives (0.6%): specific cancer has poor sensitivity, type of tumor Does not secrete cfDNA into blood stream at high enough levels to detectCancer is pre-detection levelDiagnostic work up is PositiveDiagnostic work up is NegativePlan for positive resultsand collaboration of care1-2% of those tested will have a positive resultsEach positive results is a post test probability of 1 out of 2 for cancerHow can we best collaborate and prepare to care for patients with a positive screen.• Support patients and their providers• Minimize invasive procedures• Minimize cost• Maximize identification of cancer in timely mannerMCED Test in My PracticeEvaluation:PATIENT CLINICAL PROFILEAge: Overall Health: Cancer Screening History:Cancer Signal Origin Prediction: Diagnostic Resolution: Reason for MCED Test: Additional Information: DISCLAIMER: Information is provided by the treating provider for educational and illustrative purposes only and does not represent GRAIL clinical data or claims.Cancer Signal Detected45None to DateMCED Test in My PracticePatient Response: Patient very relieved, had been anxious for years that a cancer was being missed.PATIENT CLINICAL PROFILEAge: 56 year old femaleOverall Health: obese, multiple fibrous cysts (pancreas, liver, abdomen, uterus)Cancer Screening History: routine screening up to date Additional Information: Reason for Test: confused about biopsy results, cancer, not cancer?No Cancer Signal DetectedDISCLAIMER: Information is provided by the treating provider for educational and illustrative purposes only and does not represent GRAIL clinical data or claims.46MCED Test in My PracticePatient Response: extremely relieved and excited to have a larger screening test that he can undergo each year given his family history and the constant stress of ”waiting for cancer”.PATIENT CLINICAL PROFILEAge: 57 year old maleOverall Health: very healthyCancer Screening History: currentAdditional Information: Reason for Test: family history significant for one or more cancers in every generation on both sides of the family including younger brother who died of cancer.No Cancer Signal DetectedDISCLAIMER: Information is provided by the treating provider for educational and illustrative purposes only and does not represent GRAIL clinical data or claims.47MCED Test in My PracticePatient Response: relieved and planning to do annual screening PATIENT CLINICAL PROFILEAge: 79Overall Health: very healthy, hx of skin cancer x1 Cancer Screening History: current Additional Information: Reason for Test: patients husband had cancer and her mom and she feels empowered to have a test that can supplement routine screening and catch cancer early if possible.No Cancer Signal DetectedDISCLAIMER: Information is provided by the treating provider for educational and illustrative purposes only and does not represent GRAIL clinical data or claims.48Early detection can help reduce disparities in late stage diagnosis and mortalityAfrican-Americans Hispanics/Latinos Native Hawaiians and Pacific IslandersAfrican Americans have the highest mortality rate of any racial or ethnic group for all cancers combined and most major cancersHispanics/Latinos are more likely to be diagnosed with advanced stages of diseaseNative Hawaiians and Pacific Islanders are 30 percent more likely to be diagnosed with cancer compared to non-Hispanic whitesNational Cancer Institute49DO NOT DISTRIBUTE: FOR TRAINING PURPOSES ONLY Thank you50Mylynda Massart, MD, PhDAssistant Professor of Family MedicineUniversity of Pittsburghmassartmb@upmc.eduTHANK YOU FOR JOINING US!Please visit our website to learn about upcoming programming:Jefferson.edu/jcphPlease fill out our survey athttps://bit.ly/MCED_12_8_2022

Multi-Cancer Early Detection: Understanding the Pathfinder Study and Clinical Implementation

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Multi-Cancer Early Detection: Understanding the Pathfinder Study and Clinical Implementation

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