Prostate cancer: prognostic indicators

Travis Gerke, ScDDepartment of Cancer Epidemiology

@travisgerkeI have nothing to disclose.

Learning objectives

1. Prognostic indicators are needed to reduce overtreament resulting fromoverdiagnosis: as many as 2/3 of prostate cancers may be overdiagnosed

2. Biochemical recurrence is a commonly used endpoint for prognosticstudies, as less follow-up is required. It is not a strong surrogate for lethaldisease; however, metastasis-free survival can act as such a surrogate.

3. Watchful waiting and radical prostatectomy cohorts may identifydifferent types of prognostic markers. Discovery and validation effortsshould consider the effects of study design.

Newly diagnosed PCa: a challenge in prognostication

More men die with prostate cancer than from the diseaseOver 180,000 diagnoses annually in American menLess than 10% will die from the disease; 5-year survival: 99%

42 million latent PCa cases in the US! (2.9 million living with diagnosis)PSA screening −→ high rates of overdiagnosis and overtreatmentUp to 2/3 of prostate cancers are overdiagnosed; most are treated†

Better prognostic information: overdiagnosis 6−→ overtreatmentHence, plethora of studies seek markers of indolent vs lethal disease

† Loeb et al. Eur Urol, 2014

←− Jahn et al. Int J Cancer, 2015

What endpoint do you want to predict?

Typical studies of PCa take > 10 years to estimate markers of survival

Many studies use biochemical recurrence as an endpointMeaningful, but not a robust surrogate for metastasis/survivalOf the 20-40% with BCR within 10 years post-prostatectomy, only

20-40% will go on to develop distant metastases†

ICECaP?: metastasis-free survival is a strong surrogate for overall survival

† Schweizer et al. Ann Oncol, 2013? Xie et al. J Clin Oncol, 2017

What kind of marker do you want to find?

Conceptual ABC model†: the type of marker we find depends on designStudies vary in PSA screening intensity and treatment (WW vs RP)This has critical impact on our ability to discover/validate biomarkers0.

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0 3 6 9 12 15 18

TreatedUntreated

A: men who couldavoid treatment

B: men who benefitfrom treatment

C: men who diedespite treatment

† Pettersson∗, Gerke∗, et al. Cancer, 2017

What kind of marker do you want to find?

RCTs of RP vs WW can help guide power to detect ABC markersLimited power for B markers in RP cohorts

Biomarker PIVOT (76% PSA) SPCG-4 (5% PSA)type 12 years 12 years 18 years

A 89% 74% 62%B 6% 7% 12%C 5% 19% 26%

Risk of prostate cancer metastasis

Tumor-based biomarkers of prognosis

Goal: improve clinicopathologic risk stratification (e.g. CAPRA)Table summarizes the 3 recommended by NCCNOnly Prolaris R© has been tested in untreated cohorts: recall comment

from previous slide regarding power to detect B markers

Genomic test Oncotype DX R© Prolaris R© Decipher R©

Company Genomic Health Myriad Genetics GenomeDxmRNA signature 12 genes + 5 ref 31 genes + 15 ref 22 genesAssay QRT-PCR qPCR MicroarrayDeveloped to predict Adverse pathology

on RPProgression in bothRP/untreated

Recurrence/metspost-RP

NCCN guidelines Post-biopsy low andvery low risk w 10-20 yr life expectancy

Post-biopsy low andvery low risk w 10 yrlife expectancy

Treated w RP andadverse pathology

Table adapted from Mucci LA, GU ASCO 2017

Below are the 3 tests not currently recommended by NCCN

Genomic test Ki-67 ProMark PTENAssay IHC 8 protein multiplex IHCDeveloped to predict Mets in RT/AS Adverse pathology

on RPAdverse pathologyon RP, BCR/mets inAS/RP

Tumor-based biomarkers of prognosis: some surprises

Thus far, only mRNA-based signatures have been validatedDespite well-known heterogeneity

A notable absentee: ERG fusion status is not prognostic†

Known risk SNPS for PCa incidence are not prognostic?

† Pettersson et al. CEBP, 2012? Shui et al. Eur Urol, 2014

Opportunities

Subtypes within ERG+ and ERG− may be prognosticImpact of PTEN loss on lethal progression higher in ERG− (HR 1.8;

95% CI 1.2-2.9) compared to ERG+ (HR 1.2; 95% CI 0.7-2.2)†

Impact of obesity (per 5-unit BMI increase) on lethal progressionhigher in ERG+ (HR 2.2; 95% 1.4-3.6) vs (HR 0.8; 95% 0.5-1.2)?

AR-dependent transcriptional program varies by ERG status∗

Largely unknown how existing markers perform in non-white populationsMortality > 2 times higher in African-American compared to whiteMolecular differences abound: e.g. ERG+ 50% in EA but 25% in AASignatures of adverse pathology and BCR appear distinct by race◦

† Ahearn et al. JNCI, 2016? Pettersson et al. JNCI, 2013∗ Yamoah et al. ASTRO, 2017◦ Yamoah et al. JCO, 2015

Opportunities

Gains from refining sampling/analysis by microenvironmentSignatures of stromal behavior away from tumor are prognostic†

Increasing recognition that new markers should be highly specific?

Gleason and stage, for example, are highly sensitive

0.0 0.2 0.4 0.6 0.8 1.0

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AUC = 0.847pAUC(0,0.2) = 0.0824

0.0 0.2 0.4 0.6 0.8 1.0

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Gleason + genes

1 − Specificity

Sen

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AUC = 0.932pAUC(0,0.2) = 0.141

Refining existing clinicopathologic variables can still be helpful!Baseline PSA measured in midlife predict lethal PCa∗

Gleason may be more/less prognostic, depending on categorization◦

Designs with metastasis as surrogate endpoint can expedite progress

† Tyekucheva et al. Nat Commun., 2017? Gerke et al. AUA, 2014∗ Preston et al. JCO, 2016

◦ Fankhauser et al. EAU, 2017

References (1/3)

1. Jahn, JL, Giovannucci, EL, Stampfer, MJ (2015). The high prevalence ofundiagnosed prostate cancer at autopsy: implications for epidemiology and treatmentof prostate cancer in the Prostate-specific Antigen-era. Int. J. Cancer, 137,12:2795-802.

2. Loeb, S, Bjurlin, MA, Nicholson, J, Tammela, TL, Penson, DF, Carter, HB, Carroll,P, Etzioni, R (2014). Overdiagnosis and overtreatment of prostate cancer. Eur. Urol.,65, 6:1046-55.

3. Schweizer, MT, Zhou, XC, Wang, H, Yang, T, Shaukat, F, Partin, AW,Eisenberger, MA, Antonarakis, ES (2013). Metastasis-free survival is associated withoverall survival in men with PSA-recurrent prostate cancer treated with deferredandrogen deprivation therapy. Ann. Oncol., 24, 11:2881-6.

4. Xie, W, Regan, MM, Buyse, M, Halabi, S, Kantoff, PW, Sartor, O, Soule, H, et al.(2017). Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in LocalizedProstate Cancer. J. Clin. Oncol., 35, 27:3097-3104.

5. Pettersson, A∗, Gerke, T∗, Fall, K, Pawitan, Y, Holmberg, L, Giovannucci, EL,Kantoff, PW, Adami, HO, Rider, JR∗, Mucci, LA∗ (2017). The ABC model ofprostate cancer: A conceptual framework for the design and interpretation ofprognostic studies. Cancer, 123, 9:1490-1496.

6. Mucci LA. Genomic tests in active surveillance and the role of hereditary testing.In: Genitourinary Cancers Symposium: 2017 Feb 16-18; Orlando, FL.

References (2/3)

7. Mohler, JL, Armstrong, AJ, Bahnson, RR, D’Amico, AV, Davis, BJ, Eastham, JA,Enke, CA, et al. (2016). Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw,14, 1:19-30.

8. Pettersson, A, Graff, RE, Bauer, SR, Pitt, MJ, Lis, RT, et al. (2012). TheTMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: acohort study and meta-analysis. Cancer Epidemiol. Biomarkers Prev., 21, 9:1497-509.

9. Shui, IM, Lindstrom, S, Kibel, AS, Berndt, SI, Campa, D, Gerke, T, Penney, KL, etal. (2014). Prostate cancer (PCa) risk variants and risk of fatal PCa in the NationalCancer Institute Breast and Prostate Cancer Cohort Consortium. Eur. Urol., 65,6:1069-75.

10. Ahearn, TU, Pettersson, A, Ebot, EM, Gerke, T, Graff, RE, Morais, CL, Hicks, JL,et al. (2016). A Prospective Investigation of PTEN Loss and ERG Expression inLethal Prostate Cancer. J. Natl. Cancer Inst., 108, 2:11.

11. Pettersson, A, Lis, RT, Meisner, A, Flavin, R, Stack, EC, Fiorentino, M, Finn, S,et al. (2013). Modification of the association between obesity and lethal prostatecancer by TMPRSS2:ERG. J. Natl. Cancer Inst., 105, 24:1881-90.

12. Yamoah K, Rounbehler RJ, Takhar M, Gerke T, Park J, Awasthi S, Erho NG,Davicioni E, Cleveland JL, Berglund AE. Distinct AR-dependent transcriptionalprogram in TMPRSS2-ERG fusion negative tumors in African-American men withprostate cancer. In: Proceedings of the American Society for Radiation Oncology(ASTRO): 2017 Sep 24–27; San Diego, CA.

References (3/3)

13. Yamoah, K, Johnson, MH, Choeurng, V, Faisal, FA, Yousefi, K, Haddad, Z, Ross,AE, et al. (2015). Novel Biomarker Signature That May Predict Aggressive Disease inAfrican American Men With Prostate Cancer. J. Clin. Oncol., 33, 25:2789-96.

14. Tyekucheva, S, Bowden, M, Bango, C, Giunchi, F, Huang, Y, Zhou, C, Bondi, A,et al. (2017). Stromal and epithelial transcriptional map of initiation progression andmetastatic potential of human prostate cancer. Nat Commun, 8, 1:420.

15. Gerke T, Tyekucheva S, Penney K, Sweeney C, Lis R, Nuttall I, Loda M, StampferM, Parmigiani G, Mucci L. Discovering a gene expression signature of prostate cancerprognostication by focusing on indolent tumors. In: American Urological AssociationAnnual Meeting: 2014 May 16-21; Orlando, FL.

16. Preston, MA, Batista, JL, Wilson, KM, Carlsson, SV, Gerke, T, Sjoberg, DD, etal. (2016). Baseline Prostate-Specific Antigen Levels in Midlife Predict LethalProstate Cancer. J. Clin. Oncol., 34, 23:2705-11.

17. Fankhauser C, Wilson K, Rider J, Penney K, Peisch S, Fiorentino M, Kanto P,Moch H, Mucci L, Gerke T. Do more granular Gleason categorizations lead to betterprognostic accuracy over time? In: Annual European Association of Urology Congress:2017 Mar 24-28; London, England.