The Prostate Cancer Consensus: Myriad MDx Health Smarter Screening, - PowerPoint PPT Presentation

Disclosures • Consulting relationships with: • Astellas • Dendreon The Prostate Cancer Consensus: • Myriad • MDx Health Smarter Screening, Smarter Treatment • Institutional research projects: Matthew R. Cooperberg, MD, MPH @dr_coops • GenomeDx Departments of Urology and Epidemiology & Biostatistics • Genomic Health UCSF Advances in Internal Medicine • Myriad San Francisco, CA May 23/June 20, 2019 Department of Urology Outline Outline 1. Epidemiology update 1. Epidemiology update 2. The data on PSA screening 2. The data on PSA screening 3. Smarter screening 3. Smarter screening 4. Risk‐stratified treatment 4. Risk‐stratified treatment 5. Tracking quality of care 5. Tracking quality of care Department of Urology Department of Urology 1

Prostate cancer 2019 The Impact of the USPSTF “D” Recommendation Incidence Incidence Mortality Mortality Siegel et al. CA Cancer Clin 2019; 69:7 Siegel et al. CA Cancer Clin 2019; 69:7 Department of Urology Department of Urology The diagnosis at the heart of the dilemma Racial disparity has not narrowed Not “cancer”! Esserman et al. JAMA 2009; 302:1685 Kelly et al. Eur Urol 2017; 71:195 Department of Urology Department of Urology 2

All have benefited but not all equally Interactions between race and SES Change in county-level mortality rates by county-level poverty Kelly et al. Eur Urol 2017; 71:195 Siegel et al. CA Cancer Clin 2019; 69:7 Department of Urology Department of Urology Local variation in trends: stasis in SF Outline Study of US trends in 50 cities 1. Epidemiology update 1990-94 to 2005-09 2. The data on PSA screening • Mortality rate changes ERSPC, PLCO, Göteborg • Impact of the USPSTF 2012 guideline 3. Smarter screening SF: 44% mortality reduction for white men, 43% for black men 4. Risk‐stratified treatment 5. Tracking quality of care Benjamins et al. Cancer Epidemiol 2016; 44:125 Department of Urology Department of Urology 3

PSA testing in the PLCO “control” arm Here’s what we know: • ERSPC: 21‐29% relative reduction in prostate cancer mortality (Schröder et al. Lancet 2014) (very likely an underestimate) >90% of “control” patients had at least one PSA • Göteborg: 42% relative reduction in prostate cancer PLCO was not a trial of screening vs. no screening mortality (Arnsrud Godtman R et al Eur Urol 2014) • PLCO: Non‐informative with respect to the question of Traditional meta-analysis including screening vs. no screening (Andriole et al, JNCI 2012) PLCO is invalid! Shoag et al. N Engl J Med 2016; 374:1795 Department of Urology Department of Urology Reconciling PLCO and ERSPC Taking the long view on screening Short ‐ Term Long ‐ Term Lives saved 0.7 6 A guideline based on Overdiagnoses 34 42 outcomes at 8 or 10 years is not informative! Overdiagnoses/Lives 48 7 saved (13 is only marginally better) Tsodikov et al, Ann Intern Med 2017 Gulati et al. J Clin Epidemiol 64: 1412, 2011 Department of Urology Department of Urology 4

Over‐screening and under‐screening The real problems? Over‐ and under‐screening, Over‐ and under‐treatment Sammon et al. JAMA Intern Med 174:1839, 2014 Department of Urology Over‐treatment and under‐treatment Metastatic disease is rising already Weiner et al. PCAN 2016; 19:395; Hu et al. JAMA Oncol 2017; 3:705 Cooperberg et al. J Clin Oncol 2010; 28:1117 Department of Urology Department of Urology 5

Screening update: a very brief summary Too much care is by low‐volume providers • PSA might be the best biomarker in the history of oncology. We just haven’t used it properly . • Throughout the 1990s and 2000s, prostate cancer screening was implemented poorly. Older men were over‐screened, younger men were under‐screened, low‐risk disease was over‐treated, and high‐risk disease was under‐treated. • Despite all these problems, we drove down mortality rates >50%—but at the cost of too much entirely avoidable treatment and its attendant side effects. • “Screen none” was not the right solution; rather we need to screen smarter . Savage et al, J Urol 2009 182:2677 Department of Urology Department of Urology Guidelines 2019: toward consensus SDM does not have to be highly burdensome • AUA: shared decision making (SDM) for men 55‐70; no recommendation for 40‐54; recommend against for >70; no specific rec for Af‐Am • NCCN: SDM for men 45‐75, start “several years earlier” for Af‐Am men • ACS: SDM for most men starting age 50; earlier baseline (40 or 45) if risk factors including Af‐Am • USPSTF and AAFP: SDM for men 55‐69; recommend against for >70. No recs for Af‐Am. Vickers et al. Ann Intern Med 2014; 161: 441 Department of Urology Department of Urology 6

Outline How do we screen smarter? 1. Epidemiology update Our proposal (closest to NCCN): 2. The data on PSA screening 3. Smarter screening • Early baseline testing • Calculators • Secondary testing (markers, MRI) • Shared decision making 4. Risk‐stratified treatment Referral implies secondary testing not immediate biopsy, and such testing 5. Tracking quality of care could occur in primary care setting Department of Urology Department of Urology The value of establishing an early baseline The value of establishing an early baseline • If PSA <1.0 at age 60, likelihood of prostate cancer death <0.3% • 90% of prostate cancer deaths occurred in men with PSA >2.0 (top quartile) Vickers et al. BMJ 341:c4521, 2010; Vickers et al BMJ 346:f2023, 2013 Preston et al. J Clin Oncol 2016; 34:2705 Department of Urology Department of Urology 7

The value of establishing an early baseline Data from Japan Preston et al. Eur Urol 2018, epub Kato et al. AUA Annual Meeting 2019 Department of Urology Department of Urology Should African American men be screened differently? PSA should not be interpreted in a vacuum • Minimal representation in RCTs (4.5% of PLCO, ~0 in ERSPC) • Look to models, given empiric data on early progression Gulati et al. CEBP 2017; 26:222 http://riskcalc.org/PCPTRC Department of Urology Department of Urology 8

Consider secondary (reflex?) testing Prostate Cancer 2019: Decisions, decisions… Tissue • SNPs Draw PSA ? Urine Blood •PCA3 / MiPS •phi Urine • PCA3 •4K 1 st biopsy? Active Other •SelectMDx Surveillance •ExoDx • SelectMDx (HOXC6, DLX1) •ConfirmMDx •PCA3 2 nd biopsy? •phi Blood •4K •Prolaris •Decipher Pre- • phi (PSA, fPSA, ‐2proPSA) treatment •OncoType •ProMark •Decipher • 4K (PSA, fPSA, iPSA, HK2) Post-op mpMRI treatment? •Prolaris PSMA-PET/CT • ARv7, BRCA, etc? Advanced disease • GRID? Department of Urology Department of Urology PCA3 4K mRNA Detectable in urine PSA, fPSA, iPSA, HK2, together with clinical variables following DRE Improved specificity for cancer over PSA (depends on threshold) Less consistent as predictor for high‐grade disease Works best as a 2 ‐threshold test: high NPV <20 and high PPV >60 Wei et al. J Clin Oncol 2014; 32:4066 Department of Urology Department of Urology 9

4K (PSA, fPSA, iPSA, HK2) SelectMDx • Urinary assay for HOXC6 and DLX1 mRNA transcripts Men <60 • Validated in 2 multicenter cohorts across 6 centers in the Netherlands (N=519, N=386), mixed de novo and repeat biopsy Men ≥60 Calibrated for very high NPV if score is low Sjoberg et al. Eur Urol 2018; 73:941 Van Neste et al. Eur Urol 2016; 70:740 Department of Urology Department of Urology SelectMDx Multiparametric MRI It’s all about accurate assessment of risk 1. Good‐quality TRUS‐biopsy including anterior zones Power Doppler imaging can help Verification biopsy before committing to AS 2. MRI (must be multiparametric, ± endorectal coil) Highly center‐dependent. Variable quality and interpretation MRI‐fusion biopsy may be helpful in the right hands Very expensive (in the US) 3. Novel markers Tumor genomics? (OncoType DX GPS, Prolaris) Blood / urine tests? (PCA3, 4K, phi, etc) Kurhanewicz et al. Curr Opin Urol 2008; 18:71 Department of Urology Department of Urology 10

PIRADS: Massive information loss! Should mpMRI be a reflex test for elevated PSA? mpMRI exam 1,2,3,4,5 Grayscale image PACS 1‐3 4‐5 PROMIS trial take-home: Use of mpMRI as a secondary screen among men with elevated PSA could obviate ~25% of biopsies, but would miss 24% of GS ≥3+4 cancers PIRADS Dichotomized Ahmed et al. Lancet 2017; 389:815 Department of Urology Department of Urology mpMRI: The interobserver variation problem Outline 1. Epidemiology update 2. The data on PSA screening 3. Smarter screening 4. Risk‐stratified treatment • Active surveillance • Comparative effectiveness • Multimodal treatment 5. Tracking quality of care Sonn et al. Eur Urol Focus 2017 epub Department of Urology Department of Urology 11