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

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The Prostate Cancer Consensus:

Smarter Screening, Smarter Treatment

Matthew R. Cooperberg, MD, MPH Departments of Urology and Epidemiology & Biostatistics

UCSF Advances in Internal Medicine San Francisco, CA May 23/June 20, 2019

@dr_coops

Department of Urology

Disclosures

• Consulting relationships with:
• Astellas
• Dendreon
• Myriad
• MDx Health
• Institutional research projects:
• GenomeDx
• Genomic Health
• Myriad

Department of Urology

• 1. Epidemiology update
• 2. The data on PSA screening
• 3. Smarter screening
• 4. Risk‐stratified treatment
• 5. Tracking quality of care

Outline

Department of Urology

• 1. Epidemiology update
• 2. The data on PSA screening
• 3. Smarter screening
• 4. Risk‐stratified treatment
• 5. Tracking quality of care

Outline

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Department of Urology

Siegel et al. CA Cancer Clin 2019; 69:7

Prostate cancer 2019

Mortality Incidence

Department of Urology

Siegel et al. CA Cancer Clin 2019; 69:7

Incidence Mortality

The Impact of the USPSTF “D” Recommendation

Department of Urology

The diagnosis at the heart of the dilemma

Esserman et al. JAMA 2009; 302:1685

Not “cancer”!

Department of Urology

Kelly et al. Eur Urol 2017; 71:195

Racial disparity has not narrowed

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Department of Urology

Kelly et al. Eur Urol 2017; 71:195

All have benefited but not all equally

Department of Urology

Siegel et al. CA Cancer Clin 2019; 69:7

Interactions between race and SES

Change in county-level mortality rates by county-level poverty

Department of Urology

Benjamins et al. Cancer Epidemiol 2016; 44:125

Local variation in trends: stasis in SF

Study of US trends in 50 cities 1990-94 to 2005-09 Mortality rate changes

SF: 44% mortality reduction for white men, 43% for black men Department of Urology

• 1. Epidemiology update
• 2. The data on PSA screening
• ERSPC, PLCO, Göteborg
• Impact of the USPSTF 2012 guideline
• 3. Smarter screening
• 4. Risk‐stratified treatment
• 5. Tracking quality of care

Outline

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Department of Urology

• ERSPC: 21‐29% relative reduction in prostate cancer

mortality (Schröder et al. Lancet 2014) (very likely an underestimate)

• Göteborg: 42% relative reduction in prostate cancer

mortality (Arnsrud Godtman R et al Eur Urol 2014)

• PLCO: Non‐informative with respect to the question of

screening vs. no screening (Andriole et al, JNCI 2012)

Here’s what we know:

Department of Urology

Shoag et al. N Engl J Med 2016; 374:1795

PSA testing in the PLCO “control” arm

PLCO was not a trial of screening vs. no screening Traditional meta-analysis including PLCO is invalid!

>90% of “control” patients had at least one PSA

Department of Urology

Tsodikov et al, Ann Intern Med 2017

Reconciling PLCO and ERSPC

Department of Urology

Short‐Term Long‐Term Lives saved 0.7 6 Overdiagnoses 34 42 Overdiagnoses/Lives saved 48 7

A guideline based on

• utcomes at 8 or 10 years is

not informative!

(13 is only marginally better)

Taking the long view on screening

Gulati et al. J Clin Epidemiol 64: 1412, 2011

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The real problems?

Over‐ and under‐screening, Over‐ and under‐treatment

Department of Urology

Sammon et al. JAMA Intern Med 174:1839, 2014

Over‐screening and under‐screening

Department of Urology

Weiner et al. PCAN 2016; 19:395; Hu et al. JAMA Oncol 2017; 3:705

Metastatic disease is rising already

Department of Urology

Cooperberg et al. J Clin Oncol 2010; 28:1117

Over‐treatment and under‐treatment

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Department of Urology

Savage et al, J Urol 2009 182:2677

Too much care is by low‐volume providers

Department of Urology

Screening update: a very brief summary

• 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.

Department of Urology

• 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
• r 45) if risk factors including Af‐Am
• USPSTF and AAFP: SDM for men 55‐69; recommend against

for >70. No recs for Af‐Am.

Guidelines 2019: toward consensus

Department of Urology

SDM does not have to be highly burdensome

Vickers et al. Ann Intern Med 2014; 161: 441

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Department of Urology

• 1. Epidemiology update
• 2. The data on PSA screening
• 3. Smarter screening
• Early baseline testing
• Calculators
• Secondary testing (markers, MRI)
• Shared decision making
• 4. Risk‐stratified treatment
• 5. Tracking quality of care

Outline

Department of Urology

Our proposal (closest to NCCN):

Referral implies secondary testing not immediate biopsy, and such testing could occur in primary care setting

How do we screen smarter?

Department of Urology

Vickers et al. BMJ 341:c4521, 2010; Vickers et al BMJ 346:f2023, 2013

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)

Department of Urology

Preston et al. J Clin Oncol 2016; 34:2705

The value of establishing an early baseline

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Department of Urology

Preston et al. Eur Urol 2018, epub

The value of establishing an early baseline

Department of Urology

Kato et al. AUA Annual Meeting 2019

Data from Japan

Department of Urology

Gulati et al. CEBP 2017; 26:222

Should African American men be screened differently?

• Minimal representation in RCTs (4.5% of PLCO, ~0 in ERSPC)
• Look to models,

given empiric data

• n early progression

Department of Urology

PSA should not be interpreted in a vacuum

http://riskcalc.org/PCPTRC

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Department of Urology

Prostate Cancer 2019: Decisions, decisions…

Draw PSA?

• SNPs

1st biopsy?

• PCA3 / MiPS
• phi
• 4K
• SelectMDx
• ExoDx

2nd biopsy?

• ConfirmMDx
• PCA3
• phi
• 4K

Pre- treatment

• Prolaris
• Decipher
• OncoType
• ProMark

Post-op treatment?

• Decipher
• Prolaris

Advanced disease

• ARv7, BRCA, etc?
• GRID?

mpMRI PSMA-PET/CT

Active Surveillance

Tissue Blood Urine Other

Department of Urology

Consider secondary (reflex?) testing

Urine

• PCA3
• SelectMDx (HOXC6, DLX1)

Blood

• phi (PSA, fPSA, ‐2proPSA)
• 4K (PSA, fPSA, iPSA, HK2)

Department of Urology

mRNA Detectable in urine following DRE Improved specificity for cancer

• ver PSA (depends on threshold)

Less consistent as predictor for high‐grade disease

Wei et al. J Clin Oncol 2014; 32:4066

PCA3

Works best as a 2‐threshold test: high NPV <20 and high PPV >60

Department of Urology

4K

PSA, fPSA, iPSA, HK2, together with clinical variables

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Department of Urology

Sjoberg et al. Eur Urol 2018; 73:941

4K (PSA, fPSA, iPSA, HK2)

Men ≥60 Men <60

Department of Urology

• Urinary assay for HOXC6 and

DLX1 mRNA transcripts

• Validated in 2 multicenter

cohorts across 6 centers in the Netherlands (N=519, N=386), mixed de novo and repeat biopsy

Van Neste et al. Eur Urol 2016; 70:740

SelectMDx

Calibrated for very high NPV if score is low

Department of Urology

SelectMDx

Department of Urology

Kurhanewicz et al. Curr Opin Urol 2008; 18:71

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)

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Department of Urology

PIRADS: Massive information loss!

1‐3 4‐5

Dichotomized mpMRI exam

Grayscale image

PACS

1,2,3,4,5

PIRADS

Department of Urology

Ahmed et al. Lancet 2017; 389:815

Should mpMRI be a reflex test for elevated PSA?

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

Department of Urology

mpMRI: The interobserver variation problem

Sonn et al. Eur Urol Focus 2017 epub

Department of Urology

• 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

Outline

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Department of Urology

Risk stratify before treatment

Goal: inform physician‐patient decisions about

• ptimal initial treatment approach and timing

Active surveillance Early local therapy Multimodal therapy Systemic therapy

Department of Urology

We can tell the rabbits from the turtles

Updated from Cooperberg JNCI 2009

C-index = 0.85

CAPRA score (0-10) Age (0-1) PSA (0-4) Gleason score (0-3) cT stage (0-1) % cores positive (0-1) Likelihood of cancer mortality ranges from ~0% to >65% by 15 years PSA Density Extent of pattern 4 Subtypes of pattern 4

Department of Urology

And can do even more with genomic tests

Prolaris cell cycle progression score (Myriad) OncoType Genomic Prostate Score (Genomic Health) Decipher genomic classifier (GenomeDx)

• Based on RNA expression of gene sets derived from FPE

biopsy tissue

• All shown and validated to improve multivariable model

performance for post‐treatment endpoints (adverse path, BCR, mets, CSM)

Department of Urology

Risk distribution in a vulnerable population

Porten et al. J Urol 2010; 184:1931

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Department of Urology

Chen et al. J Clin Oncol 2016 34:2182; Sanda et al. J Urol 2018; 199:683

2019: Active surveillance is standard of care

“For most men with low-risk Gleason score ≤6 localized prostate cancer, AS is the recommended management strategy”

• No mention of tumor volume
• Caveats for younger men, African Americans, and high-volume disease
• WW may be preferred for men with limited life expectancy

Department of Urology

Cooperberg and Carroll. JAMA 2015 314:80

40% is still too low, but this is rapid progress

Surveillance is gaining in the real world UCSF does not overtreat low‐risk disease!

Department of Urology

Auffenberg et al. JAMA Surg 2017; 152:978

AS use increasing but variable

Department of Urology

Treatment by risk in AQUA

N=97,294

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Department of Urology

AS use increasing but variable

Department of Urology

Minimum 30 cases per practice

Use of AS/WW for low‐risk disease by practice

Minimum 20 cases

Department of Urology

Minimum 30 cases per practice

Use of AS/WW for low‐risk disease by provider

Minimum 20 cases

Department of Urology

(And check out Sweden!)

Loeb et al. JAMA Oncol 2017; 3:1393

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Department of Urology

Luckenbaugh et al. J Urol 2017; 197:621

(But how well is surveillance done?)

% with at least 3 PSAs and 1 biopsy within 2 years

Department of Urology

One big caveat for a safety‐net hospital

Osterberg et al. Urol Oncol 2017; 35:663

Department of Urology

• 1. Epidemiology update
• 2. The data on PSA screening
• 3. Smarter screening
• 4. Risk‐stratified treatment
• 5. Tracking quality of care

Outline

Department of Urology

Assessing harms: details matter

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Department of Urology

Track practices and outcomes systematically

Department of Urology

Urology practices signed up with AQUA

Size of circle indicates number of providers

48 states 3 territories 447 practices 2798 providers

AQUA: a truly national urology registry

Department of Urology

Practice pattern in AQUA

N=80,117

Department of Urology

Sorted by prostate cancer patient volume, minimum 30 cases

Practice pattern in AQUA

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Department of Urology

In the US, MIPS reporting is theoretically public Going forward, urologists will report on their choice of measures via AQUA to CMS, who may choose to publicize results. Neither AQUA nor any other US registry includes any public reporting (yet).

Should registry data be reported publicly?

Department of Urology

https://www.baus.org.uk/patients/surgical_outcomes/radical_prostatectomy/default.aspx

Check out BAUS!

• Offer screening to healthy men with good life expectancy
• Tailor intensity based on race/family history and baseline PSA
• Nearly all low risk disease should

be managed by AS

• Treatment must be high quality
• Ongoing quality collaborative

including primary care, urology, and patients/community

“Smarter Screening and Smarter Treatment” (S3T)

Developed in a multidisciplinary collaboration among UCSF Internal Medicine, Primary Care, and Urology, catalyzed by SF-CAN

Department of Urology

Prostate cancer early detection efforts save lives, and the ratio of benefits to harms can be improved through smarter screening and appropriate, high‐quality treatment. In 2019 we have an opportunity, finally, to “get it right” for all men at risk for prostate cancer.

Conclusions