Download Ovarian Cancer

Can Biomarkers be Used in
Screening for Cancer?
Professor Joe Duffy
St Vincent’s University Hospital and
School of Medicine & Medical Science,
University College, Dublin.
Approaches to Controlling Disease
 Prevention
 Develop better treatments
 Early detection by screening
Established Risk Factors for Cancer
 Smoking
 UV light
 Obesity
Approaches to Controlling Disease
 Prevention
 Develop better treatments
 Early detection by screening
Concept of Cancer Screening is
Appealing
 Catch it early
 Remove it
 Cure
“A stitch in time saves nine”
“An ounce of prevention is worth a
pound of cure”
Cancer Screening is Widely Sold
 Endorsed by celebrities
 Politicians use it to get votes
 Promoted by certain “cancer help
groups”
Cancer Screening is Superficially a
Win:Win Situation
 If test is positive: patient and doctor
feel gratified that disease was caught
early
 If negative, patient and doctor feel
reassured
 If diagnostic workup causes
complications, patients feels the price
is worth it for survival
Ransohoff D, et al. Am J Med 2002;113:663
 Three quarters of the US
population would chose a total
body CT scan over 1000$ gift
voucher
Schwartz, JAMA 2004;291:71
Screening for Cancer
 The aim of screening is to detect
early malignancy or a premalignant
condition in healthy subjects
 It is assumed that early detection
results in a better outcome
 Ideally, only tests shown to reduce
mortality in a large randomized trial
should be used in screening
Recommended Cancer
Screening Tests
Cancer
Breast
CRC
Cervical
Technique
Mammography
FOBT/colonoscopy
PAP
Survival
Yes
Yes
Yes
Advantages of Biomarkers as
Cancer Screening Tests
 Biomarkers can be measured in
biological fluids (blood, urine) that can
be obtained with minimal
inconvenience. This in turn should lead
to high compliance rates.
 For many biomarkers, automated
assays are available, allowing the
processing of large numbers of
samples in a relatively short period of
time.
Advantages of Biomarkers as
Cancer Screening Tests
 Tests for biomarkers provide
quantitative results with
objective endpoints.
 Assays for biomarkers are
relatively cheap.
Biomarkers Investigated for
Cancer Screening
 PSA: prostate cancer
 CA 125: ovarian cancer
 FOBT: colorectal cancer
PSA as a Screening Test for PCa
 Vast majority of cancers detected
via PSA screening are organconfined
 Use of PSA has potential to detect
PCa up to 10 years before clinical
evidence of disease
PSA as a Screening Test for PCa
 PCa detected with PSA screening
have lower stage and are more
differentiated than those detected
outside of screening
 Since the introduction of PSA
screening, death rates from PCa
have declined
PCa Screening is Controversial
 PSA alone is less than an ideal
screening test for PCa
 Screening may lead to overdiagnosis
and thus overtreatment
 Definitive therapy for localised PCa
unclear
 Unknown if screening for PCa reduces
mortality
Prevalence of PCa in Relation to
PSA level
PSA level (ug/L)
% PCa
<0.5
6.6
0.6-1.0
10.1
1.1-2.0
17
2.1-3.0
23.9
3.1-4.0
26.9
Thompson, N Engl J Med 2005;350:2239
Prevalence of High Grade PCa in
Relation to PSA level
PSA level (ug/L)
% High Grade PCa
<0.5
12.5
0.6-1.0
10.0
1.1-2.0
11.8
2.1-3.0
19.1
3.1- 4.0
25.0
Thompson, N Engl J Med 2005;350:2239
Prevalence of PCa in Relation to
PSA level
 Only approximately 1 in 4 men
with a PSA level 4-10 ug/L will
have a positive biopsy
Overdiagnosis
 Term used when a condition is
diagnosed that would otherwise not go
on to cause symptoms or death
 May result from 2 possibilities:
a) cancer never progress or may regress
b) cancer progresses so slowly that the
patient dies of other causes before
cancer becoming symptomatic
Overdiagnosis
 Overdiagnosis is a particularly serious
problem for PCa because of the
disparity between the histological
evidence of disease and deaths from
the disease
Overdiagnosis
 > 50% of men > 50 yr have
histological evidence of prostate
cancer
 Approx 16% diagnosed with the
disease
 Life-time risk of dying from the disease
is 3%
Overdetection of PCa by PSA
Screening
For a single screen
 At 55 yrs of age: Overdetection rate,
27%
 At 75 yrs of age, Overdetection rate,
56%
For annual screening between 55-67 yr:
 Overdetection rate: 50% and
 Lifetime risk of PCa diagnosis
increased by 80%
Draisma et al. JNCI 2003;95:868
 Definite or best therapy for men
with localised PCa is unknown
Treatment: Implications of
Screening
A prerequisite for any disease
screening programme is that
there should be effective and
definitive treatment for the
screened disease
Treatment Options for PCa
 Radical prostatectomy
 Radiotherapy,
 Brachytherapy
 Androgen deprivation
 Observation/Active
surveillance
Side Effects of Treatments for Early
PCa (ERSPC)
Radical prostatectomy
80-90% erectile dysfunction
39-49% urinary incontinence
Radiotherapy
41-55% erectile dysfunction
6-7% incontinence
30-35% bowel problems
Madalinska et al, J Clin Oncol 2001:19:1619
Radical Prostatectomy vs Watchful
Waiting
 RP reduced formation of
metastasis by 6.7%
 RP reduced death rates from PCa
by 5.4%
 Reduction in metastasis and death
confined to men <65 years of age
 Overall mortality was not
significantly different
Bill-Axelson et al. JNCI 2008;17:1797
RADICAL PROSTATECTOMY vs
WATCHFUL WAITING: Side Effects
 Erectile dysfunction (80 vs 45%) and
urinary leakage (49 vs 21%) more
common after RP whereas urinary
obstruction (28 vs 44%) was less
common.
 Subjective quality of life was similar in
the 2 groups.
Steinbeck et al, N Eng J Med 2002;347:790
 Unknown if screening for PCa
reduces mortality
PSA as a Screening Test for PCa:
Way Forward
 Perform a large prospective
randomised trial comparing
patient outcome and quality of
life in screened and control
groups.
 Trial would require approx
200,000 men and a time period of
approx 10 yr
Randomized Trials Evaluation PSA
in Screening for PCa, in Progress
 European Randomized Screening
for Prostate Cancer (ERSPC)
 Prostate, Lung, Colorectal and
Ovarian Cancer (PLCO)
 End of 2001, >215,000 subjects
randomized.
de Koning et al. IJC 2002;97:237
PCa Screening: PLCO Cancer
Screening Trial
 77, 000 men randomized to
screening or no screening
 Annual PSA testing for 6 yr and
DRE for 4 yr
 After 7-10 yr follow-up, similar
rates of death in 2 groups
Andriole et al, NEJ Med 2009;13:1310
Cumulative deaths from prostate cancer in the intervention and
control arms from year 1 to year 13.
Andriole G L et al. JNCI J Natl Cancer Inst 2012;104:125-132
PCa Screening: ERSPC
 182 000 men randomized to
screening or no screening
 PSA testing every 4 yr, on
average
 PSA screening reduced rate of
death from prostate cancer by
20%
Schroder et al, NEJ Med 2009;360:1320
PCa Screening: ERSPC
 To prevent one death from PCa, 1410 men
would have to be screened and 48
patients treated
Schroder et al, NEJ Med 2009;360:1320
ERSPC Trial: Follow-up, 11 yr
PSA screening decreased rate of
death from PCa by 21%
No difference in all-cause mortality
between screened and control
groups
Schroder et al, N Engl J Med 2012;366:981
Screening for Prostate Cancer:
Systematic Review and Meta-analysis
 Systematic review of the literature
identified 6 randomized prospective
controlled trials of PCa screening
 Total no of patients: 387,286
 Screening was associated with a
significant increase probability (46%)
of being diagnosed with PCa
Djulbegovic et al. BMJ 2010;341
Screening for Prostate Cancer:
Systematic Review and Meta-analysis
 Screening had no significant
impact on deaths from PCa
 Screening had no significant
impact on overall mortality
Djulbegovic et al. BMJ 2010;341
Complications of Prostate
Biopsy
Complication
% Affected
Pain
44
Fever
18
Haematuria
66
Hematochezia
37
Haemoejaculate
93
Rosario et al, BMJ 2012;344:d7894
PSA Population-Based Screening:
Recommendation by Expert Panels








American Cancer Society: Yes
American Urological Society: Yes
European Urological Society: Yes
European Group on Tumor Markers: No
European Society of Med Oncology: No
Nat Academy of Clin Biochemistry: No
Nat Institute of Clinical Excellence: No
US Preventive Service Task Force: No
Screening for Prostate Cancer:
ASCO PCO
 In men with a life expectancy < 10 yr,
screening should be discouraged as
harms seem to outweigh benefits
 In men with a life expectancy of > 10
yr, doctors should discuss with their
patients if PSA testing is appropriate.
 PSA testing may save lives but is
associated with harm, including
complications from unnecessary
biopsy, surgery, or radiation
Basch et al, JCO 2012
Screening for Prostate Cancer:
ASCO PCO
 It is recommended that
information written in lay
language be available to
clinicians and their patients to
facilitate the discussion of the
benefits and harms associated
with PSA testing before the
routine ordering of a PSA test.
Basch et al, J Clin Oncol 2012
Ovarian Cancer
 > 70% diagnosed with advanced
disease
 5-yr survival for women with advanced
disease: 20-30%
 For women diagnosed with early
disease: 5-yr survival: 80%
Traditional View of Ovarian
Cancer
 Referred to as “the silent
disease”
 Prevailing view was that there
were usually no symptoms until
advanced disease was present, ie,
when prognosis was dire
Ovarian Cancer is not so Silent:
Ovarian Cancer Symptom Index
 Pelvic pain/Abdominal pain
 Urinary urgency/Urinary frequency
 Increased abdominal size/bloating
 Difficulty in eating/feeling full
Index positive: if any of those 6
symptoms occurred >12 times per mo
for < 1 yr
Goff et al. Cancer 2007:109:221
Screening for Ovarian Cancer
 UKCTOCS Trial
 PLCO Trial (USA)
Screening for Ovarian Cancer
(UKCTOCS Trial)
Involves CA 125 and TVU
> 200,000 women randomized
Sensitivity for ovarian cancer: 89%
Specificity for ovarian cancer:
99.8%
 PPV for ovarian cancer: 35%
 Approx 50% of cancer detected had
early disease
Menon et al. Lancet Oncol 2009




PLCO Screening Trial for Ovarian
Cancer
 78,216 women randomised to screening
or usual care
 Screened group had annual CA 125
measurements for 6 yr & TVU for 4 yr
 Median follow-up: 12 .4 yr
Buys et al. JAMA 2011;305:2295
Effect of Screening on Disease
Stage at Diagnosis
Stage
Screened (no, %) Controls (no, %)
I
32 (15%)
18 (10%)
II
15 (7%)
20 (11%)
111
120 (57%)
83 (47%)
IV
43 (20%)
54 (31%)
Buys et al, JAMA 2011;305:2295
Effect of Screening on Cumulative Cases and Deaths
Buys, S. S. et al. JAMA 2011;305:2295-2303
Complications Resulting from
Screening
 False positive screening tests: 3285
 Resulting surgeries: 1080
 Serious complications: 163
Buys et al. JAMA 2011;305:2295
CA 125 in Women with Symptoms
Suggestive of Ovarian Cancer
 Measure serum CA125 in primary
care in women with symptoms that
suggest ovarian cancer
 If serum CA125 > 35 IU/ml,
arrange an US scan of the abdomen
and pelvis.
 If US suggests ovarian cancer, refer
woman urgently for further
investigation.
NICE Guidelines 2011
Tumor Markers in Early
Diagnosis of Ovarian Cancer
 Measure serum CA125 in secondary
care in all women with suspected
ovarian cancer, if this has not already
been done in primary care.
 In women under 40 with suspected
ovarian cancer, measure levels of AFP
beta-hCG as well as serum CA125, to
help identify women with germ cell
tumours.
NICE Guidelines, 2011
Does Early Referral Affect
Outcome?
 1318 women with symptoms of
ovarian cancer presented to a
medical practitioner:
 50% within 1 mo
 70% within 2 mo
 90% within 6 mo
 10% after 6 mo
Nagle et al, J Clin Oncol 2011;29:2253
Does Early Referral Affect
Outcome?
 No significant relationship found
between time to diagnosis and
stage of disease at diagnosis or
survival
Nagle et al, J Clin Oncol 2011;29:2253
Attempts at Early Diagnosis of
Ovarian Cancer
1455 patients with symptoms of
ovarian cancer
22 gynecological cancers detected
11/22 were ovarian cancer (ie, a
prevalence of 1 in 132 (0.7%)
Gilbert et al, Lancet Oncol 2012
Characteristics of Ovarian Cancers
Detected
Tumor
Trial
patients
Clinic
patients
P value
Stage 1 &2
4 (36%)
17 (23%)
NS
Stage 3 & 4
7 (65%)
58 (77%)
NS
CA 125 level
(Median)
72
888
<0.01
High grade
serous
9 (82%)
51 (89%)
NS
Gilbert et al, Lancet Oncol 2012
 FOBT in screening for colorectal
cancer
Status of CRC Screening
 43 organized schemes were identified,
based in 24 different countries
 Of 35 in operation for > 1 yr, 26 were
population-based screening
programmes, 9 pilot
Benson et al, IJC 2012;130;122:2961
CRC Screening: Available Tests
 Bowel visualisation
 Colonoscopy,
 Computed tomographic colonography,
 Flexible sigmoidoscopy
 Biochemical
 FOBT
 Stools DNA
 Serum markers
Screening Tests Being Used
Across the World
 gFOBT: 16
 FIT: 9
 Endoscopy: 9
Benson et al, IJC 2012;130;122:2961
Advantages of FOBT vs Bowel
Visualisation Tests
 Safe, non-invasive
 No bowel preparation necessary
 Less expensive to perform
 Can be done in privacy of ones home
 Best validated CRC screening test
Impact of CRC Screening with
FOBT in Reducing Mortality
 4 large prospective randomized trials
performed
 Involved > 320,000 subjects
 Meta-analysis: 16% reduction in
mortality in the screened group
 When corrected for non-attendance,
reduction in mortality was 25%
Cochrane Systematic Review, 2007
Types of FOBTs
 Guaiac-based (gFOBT) which detects
the pseudoperoxidase activity of the
haem moiety in haemoglobin
 Faecal immunochemical test (FIT or
iFOBT) which detects the globin
moiety in intact human haemoglobin
or its early degradation products
gFOBT vs FIT: Advantages of FIT
 FITs have increased analytical sensitivity
and specificity
 Use of FITs leads to higher uptake rates
 FITs can be automated
 FITs are quantitative or semi-quantitative
 FITs provide an adjustable cut-off point
 With FITs, no dietary or medication
restriction
Duffy et al. Int J Cancer 2011;128:3
gFOBT vs FIT: Disadvantages of
FIT
 FITs are more expensive to
perform
 Samples for FITs less stable after
collection of stools
 FITs are less well clinically
validated
EGTM Recommendations for FOBT
in CRC Screening
 A quantitative FIT with an
adjustable cut-off point is
recommended
Duffy et al, Int J Cancer 2011;128:3
FIT vs Colonoscopy in Screening for
CRC
Criteria
Colonoscopy
FIT
P value
Uptake
24.6%
34.2%
< 0.001
Cancer
detection
0.5%
0.3%
NS
Adv adenoma
detection
9.7%
2.4%
< 0.001
Eary adenoma
detection
22.1%
1.1%
<0.001
Complications
0.5%
0.1%
<0.001
Quintero et al. N Engl J Med 2012;366:697
Markers Under Evaluation or Previously
Evaluated for Cancer Screening
Cancer
Marker(s)
Neuroblastoma
HCC*
Prostate
Ovarian
Stomach
Colorectal
VMA/HVA
AFP
PSA
CA 125
Pepsinogen
FOBT
Survival
No
Yes
?
?
?
Yes
*In patients infected with hepatitis B or C
 Thank you
US vs European Trial
Parameter
USA trial
PSA assay
Beckman
European
trial
Beckman
Cut-off
4 ug/L
3 ug/L (most)
Frequency
Annual X 6 yr Every 4 yr
DRE
Yes
No (most)
fPSA
No
Only at 1 site
PLCO PCa Screening Trial: Possible
Reasons for Negative Findings
 Cut-off point of 4 ug/L too high
 PSA screening in control group
negating impact on test group
 Excess PSA screening had
occurred prior to start of study
Andriole et al, N Eng J Med 2009;360:13
PLCO PCa Screening Trial: Possible
Reasons for Negative Findings
 Improvement in therapy resulted
in fewer deaths in both groups
and blunted a potential benefit of
screening
 Follow-up might not have been
long enough to see a benefit of
early detection in the screened
group
Andriole et al, N Eng J Med 2009;360:13
Prostate Cancer Screening: The
Reality
 Doubles the risk of a lifetime
diagnosis of prostate cancer with little
of any decrease in the risk of dying
from the disease
Prostate Cancer Screening: The
Reality
 In 1985 before PSA screening in the
US, a man had an 8.7% lifetime risk of
being diagnosed with PCa and a 2.5%
risk of dying from the disease
 In 2005, he had a 17% lifetime risk of
being diagnosed with PCa and a 3%
risk of dying from it
Boyle et al. CA C J Clin 2009;59:220
ERSPC Trial Results:
Implications
 Screening doubled the risk if being
diagnosed with PCa
 Decreased the probability of dying
from PCa by 20%, ie, from 3% to
2.4%
Boyle et al. CA Cancer J Clin 2013;59:220