Obesity and prostate cancer incidence and survival Elizabeth A. Platz, ScD, MPH

(1)

Obesity and prostate cancer

incidence and survival

Elizabeth A. Platz, ScD, MPH

Professor and Martin D. Abeloff, MD Scholar in Cancer Prevention

Department of Epidemiology,

Johns Hopkins Bloomberg School of Public Health;

Department of Urology and the James Buchanan Brady Urological Institute,

Johns Hopkins School of Medicine;

(2)

Body fatness and prostate cancer

incidence and mortality

(3)

(4)

(5)

Methodologic issues that arise as a result

of routine PSA-based screening

for prostate cancer

• Changing spectrum of disease due to PSA screening

– Proportion of advanced vs early disease

– Nature of the early cases (may never have become

clinically apparent)

– Use of PSA screening differs around the world

• Detection bias

– Differential opportunity to be PSA screened by exposure

status (obese vs not obese)

– Differential detection of the presence of disease due to

exposure changing PSA levels (lower PSA in obese men)

(6)

Influence of PSA screening

on the observed association

between obesity and prostate cancer risk

(7)

Death from prostate cancer by BMI,

Cancer Prevention Study II, 1982-1998

1

1.1

1.2

1.3

1.4 18.5-24.9

25.0-29.9

30.0-34.9

35.0+

BMI (kg/m

2

)

RR

Calle E et al. 2003; NEJM 348:1625-1638

(8)

Obesity and prostate cancer,

Health Professionals Follow-up Study

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9 Fatal

Incident

< 21 21-22.9 23-24.9 25-27.4 27.5-29.9 >= 30

RR

P-trend=0.03

P-trend=0.47

Giovannucci E et al. Int J Cancer 2007;121:1571-8. PMID: 17450530

BMI kg/m2

RR=1.80, 95% CI 1.10-2.93

(9)

Obesity and prostate cancer risk in the

NIH-AARP Diet and Health Study

0.5

0.7

0.9

1.1

1.3

1.5

1.7

1.9

2.1

2.3

< 25 25-29.9 30-34.9 35-39.9 >= 40 Incident Fatal

BMI (kg/m

2

₎

RR

Wright ME et al. Cancer. 2007;109:675-84

P-trend = 0.0006 P-trend = 0.02 2.12 1.08-4.15 0.67 0.50-0.89

(10)

Obesity and prostate cancer,

Melbourne Collaborative Cohort

0.5

0.7

0.9

1.1

1.3

1.5

1.7 Fatal

Nonaggressive

<23 23-24.9 25-29.9 >= 30

RR

Per 5 kg/m2_: RR=1.49, 95% CI 1.11-2.00 P-trend=0.01 Per 5 kg/m2_: RR=0.99, 95% CI 0.89-1.10 P-trend=0.83

Bassett JK et al. Int J Cancer 2012;131:1711-9. PMID: 22213024.

BMI kg/m2

RR=1.52, 95% CI 0.89-2.58

(11)

Weight gain since age 18 and prostate

cancer, Melbourne Collaborative Cohort

0.5

0.7

0.9

1.1

1.3

1.5

1.7

1.9

2.1 Fatal

Nonaggressive

<5 5-9.9 10-19.9 >=20

RR

Per 5 kg: RR=1.13, 95% CI 1.02-1.26 P-trend=0.02 Per 5 kg: RR=0.99, 95% CI 0.81-1.22 P-trend=0.77

Bassett JK et al. Int J Cancer 2012;131:1711-9. PMID: 22213024.

Weight gain since age 18 kg

RR=1.84, 95% CI 1.09-3.09

(12)

BMI and prostate cancer by grade,

Prostate Cancer Prevention Trial

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Total Low grade High grade

Q1 Q2 Q3 Q4

Gong Z et al. Cancer Epidemiol Biomarkers Prev 2006;15:1977-1983

BMI P-trend=0.03 P-trend=0.04

N=1,936 N=1,300 N=521

(13)

Meta-analyses

• Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer 2001;91:421–30

• MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control

2006;17:989–1003

• Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective

observational studies. Lancet 2008;371:569–78

• Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res 2011;4:486-501

• Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer--a dose-response meta-analysis of prospective studies. Ann Oncol 2012;23:1665-71

• Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol 2013;63:800-9

• Golabek T, Bukowczan J, Chłosta P, Powroźnik J, Dobruch J, Borówka A. Obesity and Prostate Cancer Incidence and Mortality: A Systematic Review of Prospective Cohort Studies. Urol Int. 2013 Aug 8. [Epub ahead of print].

“Results: The evidence from the prospective cohort studies linking obesity with PCa incidence has not been consistent. However, cumulative data is compelling for a strong positive association between obesity and fatal PCa.”

(14)

Discacciati A et al. Ann Oncol 2012;23:1665-71.

Literature search to Oct 2011.

Meta-analysis:

BMI and prostate

cancer risk, by

localized and

advanced disease

(15)

Meta-analysis:

BMI and fatal prostate cancer

Cao Y and Ma J. Cancer Prev Res 2011;4:486-501. PMID: 21233290.

(16)

Cause versus bias?

Hypotheses based on published results

• Obesity



– Risk (causation)

•  Risk of death from prostate cancer

•  Risk of nonaggressive prostate cancer

– Detection bias

•  PSA (lower production, hemodilution)

•  Prostate volume

Freedland SJ, Platz EA Epidemiol Rev 2007;29:88-97; Freedland SJ et al. Cancer Causes Control 2006;17:5-9; Freedland SJ et al. J Urol 2006;175:500-504;

(17)

If causal, what pathways mediate the

obesity-prostate cancer association?

• Metabolic and hormonal perturbations secondary

to obesity?

– Insulin regulation (and IGF-axis)

– Sex steroid hormones

– Others?

• Bioactive factors secreted by adipocytes?

– Energy regulation

– Inflammatory mediators

– Others?

• Obesity’s influence on the detectability of prostate

cancer via these same pathways?

(18)

Is obesity associated with poor outcome

after prostate cancer diagnosis?

• Emerging support that the extent of body

fatness and weight gain

– Before diagnosis

– Circa diagnosis

• are risk factors for recurrence and prostate

cancer death in men with prostate cancer.

• Excellent review: Cao Y and Ma J. Cancer Prev Res

2011;4:486-501. PMID: 21233290.

(19)

Meta-analysis:

BMI and death from prostate cancer

in men with the diagnosis

(20)

Meta-analysis: BMI and prostate

cancer recurrence after treatment

(21)

Literature is not perfectly consistent

for obesity and prostate cancer

recurrence

• Publications since Cao and Ma’s meta-analysis

– No association between obesity and recurrence

• Lee SE et al. BJU Int 2011;107:1250-5. PMID: 20880194.

[Korea]

• Narita S et al. Prostate Cancer Prostatic Dis 2013;16:271-6. PMID:

23752230.

[Japan]

• Tomaszewski JJ et al. Urology 2013;81:992-6. PMID: 23453649.

– Positive association between obesity with recurrence

• Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID:

21325564.

[also weight gain]

• Asmar R et al. Prostate Cancer Prostatic Dis 2013;16:62-6. PMID:

22907512.

(22)

Men who gain weight have a higher risk

of prostate cancer recurrence after

prostatectomy, JHH

Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID: 21325564.

Adjusted for weight 5 years before surgery, height, physical activity 1 year after surgery, age, race/ethnicity, family history, year of surgery, stage, grade, and smoking status.

Maintenance <2.2kg Weight Gain >2.2 kg Weight Loss >2.2 kg P for trend 0.02

Weight change from 5 years before to 1 year after surgery 0 1 2 3 4

OR

RR

(23)

Considerations (fully or partially)

specific to prostate cancer

outcomes

• To confirm or refute associations observed

thus far

(24)

Consideration 1

• What is the optimal prostate cancer outcome to

capture biology and import?

– Biology and import: Progression to metastasis or death

from prostate cancer (rather than biochemical

recurrence).

– Nature of outcome that can be studied may depend on

the type of treatment, though.

• Especially when studying men with clinically localized

prostate cancer (patients selected for curability  few

deaths)

– Surgery - biochemical recurrence

(25)

Consideration 2

• Confounding - Body fatness appears to be a risk

factor for advanced stage and high-grade prostate

cancer AND stage and grade are prognostic factors

– Thus, must take into account stage and grade in the

analysis to determine whether body fatness/weight gain are

associated with poor outcome in men with prostate cancer

Body fatness / weight gain Advanced stage / high-grade prostate cancer Recurrence / death from prostate cancer

(26)

Consideration 3

• Etiologically relevant measurement - Timing of body

fatness / weight gain relative to the diagnosis /

treatment of prostate cancer

– Pre-diagnostic

– At diagnosis / treatment

– Post diagnosis / treatment

Normal Precursors Organ-confinedProstate cancer Limited_{Extraprostatic} Disseminated Fatal

Body fatness / weight gain Body fatness / weight gain Body fatness / weight gain Body fatness / weight gain

(27)

How can body fatness influence

outcomes after treatment, especially

after prostatectomy?

Escaped prostate cancer cells Nascent bony mets Prostate cancer focus No prostate, no prostate cancer focus Recurrence / death from prostate cancer Prostatectomy

Body fatness

Body fatness Body fatness Body fatness

(28)

Consideration 4

• Does the influence of weight gain on outcome differ by

starting body fatness?

– Lean, gain weight

– Obese, gain weight

– Lean, no weight gain

– Obese, no weight gain

• Considerations 3 and 4 coupled: Full evaluation of body

fatness and weight gain over the life course.

– Requires prospective study of men without the diagnosis, followed

to diagnosis (and treatment), and then followed to death

– Requires repeated measures of body fatness, including circa the

diagnosis /treatment

(29)

Consideration 5

• Confounding and modifying effects by factors

that are highly correlated with body fatness

– Physical inactivity

– Diabetes

– Energy intake

– Smoking

• Statistical analyses

Obesity Poor outcome

Smoking RR_obs < RR_true

+

-Obesity Poor outcome

Physical inactivity RR_obs > RR_true

+ +

(30)

Consideration 6

• Alternative explanations to biology

• Greater technical difficulty when treating obese men

relative to lean men (e.g., positive surgical margins)

– Lower likelihood of cure unrelated to prostate cancer

biology

(31)

Consideration 6

• Greater technical difficulty when treating obese men

relative to lean men (e.g., positive surgical margins)

(32)

Consideration 6

• Alternative explanations

• Different choice of treatment by obese and

non-obese men

– Where the treatment may have a different likelihood of cure

irrespective of extent of body fatness

(33)

Consideration 7

• Hormonal therapy for men with metastatic prostate

cancer causes central adiposity and metabolic

perturbations.

– What is the influence of this milieu on prostate cancer

death (beyond obvious increase in risk of death from other

causes)?

(34)

Consideration 8

• Surveillance for the early recurrence (e.g.,

post-prostatectomy)

– What is the influence of body fat on PSA produced by

cells that have escaped from the prostate?

•  PSA (lower production, hemodilution) in men who are obese

compared with lean

– Detection bias - time to recurrences would be falsely

LONGER in obese compared with lean men

(35)

BMI and risk of biochemical recurrence

after prostatectomy, JHH

Freedland SJ et al. J Urol 2005;174:919-22. PMID: 16093988.

At the time of surgery

(36)

Pre-diagnostic obesity and prostate

cancer death in men with prostate cancer,

Physicians’ Health Study

Ma J et al. Lancet Oncol 2008;9:1039-47. PMID: 18835745. Unadjusted

(37)

Pre-diagnostic body mass index and

prostate cancer death in men with

prostate cancer, PHS

1

1.2

1.4

1.6

1.8

2 < 25

25.0-29.9

30.0+

BMI (kg/m

2

₎

RR*

Ma J et al. Lancet Oncol 2008;9:1039-47. PMID: 18835745.

P-trend=0.0042 *Adjusted for age at diagnosis, baseline

smoking status, time interval from BMI

measurement to prostate-cancer diagnosis,

clinical stage, and Gleason grade.

BMI 30+ vs < 25 kg/m2_:

Adj excluding for stage/grade – RR=2.66 Adj including for stage/grade – RR=1.95

Body fatness / weight gain Advanced stage / high-grade prostate cancer Recurrence / death from prostate cancer Body fatness / weight gain Advanced stage / high-grade prostate cancer Recurrence / death from prostate cancer

(38)

Men who gain weight have a higher risk

of prostate cancer recurrence after

prostatectomy, JHH

Adjusted for weight 5 years before surgery, height, physical activity 1 year after surgery, age, race/ethnicity, family history, year of surgery, stage, grade, and smoking status.

Maintenance <2.2kg Weight Gain >2.2 kg Weight Loss >2.2 kg P for trend 0.02

Weight change from 5 years before to 1 year after surgery 0 1 2 3 4