Download Does MX screening work?

Neubrandenburg
Sobrediagnóstico
en los programas
de cribado del
cáncer de mama:
¿diagnósticos incorrectos, obsesión o biología
tumoral??
Thomas Decker
Department of Pathology
Dietrich Bonhoeffer Medical Center
Neubrandenburg, Germany
Neubrandenburg
Neubrandenburg
Berlin
Deutsches Mammographie-Screening-Programm
Population:
82.600.000
10.325.000 Frauen (50 – 69 J.)
94
Screening-Einheiten
(1/800.000 Einw.)
o
5 Referenzzentren
Berlin
Münster
Nord
Südwest
München
o
Kooperationsgemeinschaft
Berlin
Neubrandenburg
Overdiagnosis in
breast cancer
screening:
wrong diagnoses,
overeager,
or tumour biology?.
Thomas Decker
Department of Pathology
Dietrich Bonhoeffer Medical Center
Neubrandenburg, Germany
OUTLINE
How does MX screening work?
Pathobiological features of screen-detected BCs
Definition of overdiagnosis
Pathobiological features of overdiagnosed BCs
How to avoid overtreatment
HOW DOES MX SCREENING WORK?
Does MX screening work?
History
 expectation of mortality reduction was based on the
results of two population screening trials in Sweden.
 Subsequent meta-analyses of all the relevant
screening trial data then available have indicated that
population screening was associated with a relative
mortality reduction of approximately 25 % in
women aged between 50 and 70.
Does MX screening work?
Today
much has changed since the screening trials were undertaken:
 the treatment of BC has improved considerably
 BC risk has been increasing for decades in the western world,
regardless of the effect of population screening (!)
 changes in known risk factors for breast cancer
women having their first child later
postmenopausal obesity
can explain only part of the increase in BC incidence.
 survival amongst breast cancer patients has improved greatly
in recent decades.
Does MX screening work?
The academic literature on the effectiveness of population
screening for breast cancer presents conflicting outcomes:
 substantial reduction in breast cancer mortality
vs.
 minimal effect
Why?
Does MX screening work?
Why?
Trend studies gauging the effect of screening from mortality
statistics derived from cause-of-death records are negatively
biasing the screening effect:
They are for years after the introduction of screening dominated
by cases of breast cancer detected before opportunity for
screening was given.
…therefore
 trend studies
lack in discriminatory power. The inadequacy of the outcome
parameter and the usually limited level of analyses
effectiveness of population screening mean that trend
studies cannot sufficiently support substantial conclusions.
 cohort studies or case-control studies
can show the effect of screening (if well-designed)
the effect of screening can be distinguished from the effects
of other factors influencing breast cancer mortality, such as
improved therapy and trends in the background risk of breast
cancer.
Does MX screening work?
meta-analysis of methodologically the most reliable
cohort studies in Europe:
BC mortality was 26 per cent lower in women between
50 and 70 who were invited for screening.
RR=0.74 (95% CI 0.64-0.87)
How does MX screening work?
Mammography screening: the ideal
normal
DCIS
=
preclinical
invasive BC
=
Mortality reduction through
prevention of progression to
metastatic disease
palpable
invasive BC
metastazing
invasives BC
+ (BC-related)
In theory there is no difference
between theory and practice.
In practice there is.
Yogi Berra
How does MX screening work?
1,884 Patientinnen
FinProg database,
http://www.finprog.org
Screening-detektiert
22% (n = 408)
Nicht-screening-detektiert
78% (n = 1476)
Lehtimäki et al. Breast Cancer Research 2011, 13:R134
PATHOBIOLOGICAL FEATURES OF
SCREEN-DETECTED BCS
Intrinsic factors and MX screening detection
 BC histological type and grade
 Proteomics
 Molecular subtypes
Biology of screen-detected BC (old story)
1.
Porter PL et al.: Breast tumor characteristics as predictors of mammographic detection: comparison of
interval- and screen-detected cancers. J Natl Cancer Inst 1999, 91:2020-2028.
2. Dawson SJ et al.: Molecular characteristics of screen-detected vs symptomatic breast cancers and their
impact on survival. Br J Cancer 2009, 101:1338-1344.
3. Sihto H et al. : Molecular subtypes of breast cancers detected in mammography screening and outside of
screening. Clin Cancer Res 2008, 14:4103-4110.
4. Crosier M et al. : Differences in Ki67 and c-erbB2 expression between screen-detected and true interval
breast cancers. Clin Cancer Res 1999, 5:2682-2688.
5. Groenendijk RP et al: Screen-detected breast cancers have a lower mitotic activity index. Br J Cancer
2000, 82:381-384.
6. Dong W et al.: Prognostic role of detection method and its relationship with tumor biomarkers in breast
cancer: the University of Texas M.D. Anderson Cancer Center experience. Cancer Epidemiol Biomarkers
Prev 2008,17:1096-1103.
7. Ernst MF et al.: Breast cancers found by screening: earlier detection, lower malignant potential or both?
Breast Cancer Res Treat 2002, 76:19-25.
8. Gabriel H et al: Breast cancer in women 65-74 years old: earlier detection by mammographic screening.
AJR Am J Roentgenol 1997, 168:23-27.
9. Anttinen J, et al.: Her-2/neu oncogene amplification and protein over-expression in interval and screendetected breast cancers. Anticancer Res 2003, 23:4213-4218.
10. Klemi PJ et al.: Mammography screening interval and the frequency of interval cancers in a
populationbased screening. Br J Cancer 1997, 75:762-766.
Proteomics and MX screening detection
Markers of „good“ prognosis
 Estrogen receptors
- provide growth stimulating effect of
estrogens
- marker of high differentiation
- predictive for response to hormonal
monal treatment
 Progesteron receptors
- induced by estrogen
- predictive for response to hormonal
monal treatment
Proteomics and MX screening detection
Markers of bad prognosis
 p53 – mutation
- P53 = protein product of tumor suppressor
gen TP53, normally instabel
- accumulation in case of DNA damage
- funktion: tumor suppression (DNAreparation, stops cell cycle)
- mutation → unlimited cell division even in
case of DNA damage in tumor cells
 c-erbB2 (HER2)
- Group of growth hormon receptors
 Ki67 expression
- protein specific for the active phases of cell
cycle (G(1)-, S-, G(2)-, and M)
- marker for cells still able to divide
- measure of the growth fraction of a cell
population
BC Proteomics
screen-detected vs. intervall-cancers
% pos. cells
Scatterplot: immunhistochemical expression
Crosier M et al. Clin Cancer Res 1999;5:2682-2688
Molecular subtypes and prognosis
Metastasenfreies Überleben
luminal A
luminal B
Claudin-low
basal-like
HER2-enriched
P. Eroles et al. Cancer Treat Rev 2012; 38: 698–707
acc. to UNC337 database (J.S. Parker et al. J Clin Oncol 2009;27: 1160–1167)
Molecular subtypes – new insights
Luminal A tumours
 high expression of ER and
related gene networks
 lower proliferation rates
 tend to be of low
histological grade
 have the best prognosis
Molecular subtypes – new insights
Luminal B tumours
 show lower expression of
ER networks
 more often of higher
histological grade
 Higher proliferation rates
and
 worse prognosis than
luminal A tumours.
Molecular subtypes – new insights
HER2 tumours
 usually no expression of
ER and related gene
networks
 over-expression and
amplification of HER2
(17q11)
 typically aggressive clinical
behaviour
 a significant proportion of HER2-positive tumours is ER
positive, and clusters with the luminal B subgroup.
Molecular subtypes – new insights
Basal-like tumours
 no expression of ER / HER2
 Gene expression similar to
that of normal basal cells of
the breast (CK 5/6, 14, Pcadherin, nestin and EGFR
 pushing borders, central
necrosis, lymphocytic
infiltration
 high histological grade
 High and proliferation
 typically aggressive clinical
behaviour
Molecular subtypes and MX screening detection
1610 screen-detected BCs, The Netherlands
Brouckaert Ann. Oncol. 2013
Molecular subtypes and MX screening detection
Sihto H et al.
Clin Cancer Res 2008;14:4103-4110
S J Dawson, et al. Br J Cancer. 2009 October 20;101(8):1338-1344
Intrinsic factors and detection in MX screening
Characteristic features of screen detected BC
(up to 80%):





Histological grade 1
Low proliferation (MAI <10, ki67 „low“)
Positive ER- and PR- status
no Her2 overexpression
Luminal A subtype
Pathobiological features
of screen-detected BCs
Spain
Pathobiological features
of screen-detected BCs
Characteristic features of screen detected BC
(up to 80%):





Histological grade 1
Low proliferation (MAI <10, ki67 „low“)
Positive ER- and PR- status
no Her2 overexpression
Luminal A subtype
all these represent a lower aggressiveness!
!
Sojourn Time
 is the duration of a disease before clinical symptoms become
apparent but during which it is detectable by a screening test.
Clinical relevance:
 it represents the duration of the temporal window of
opportunity for early detection.
 Is relevant for overdiagnosis !
Statistical relevance:
 estimation of the mean sojourn time of a screened
population, taking into account the sensitivity of the screening
test
Tubular BC
NST BC (ductal) G1
Fall 22
NST (ductal) BC G3
Sojourntime for different types and grades
Histological type
Sojourn-Time
(median) (years)
medullary
1.2
lobular
2.3
screen-detected BCs
mucinous
2.9
ductal G2
3.0
patients
60. – 69. y.
ductal G3
3.1
DCIS
5.1
tubular
7.1
duktal G1
7.7
Chen et al. J Epidemiol Biostat 1997
Type, grade, and sojourn time
100
clin. detection
MED
IL
MUC
NST G3
NST G2
DCIS
NOS G1
TUB
MX detection
0
0
0
2
4
6
8 years
Tabar et al. Int J. Cancer 1996
Type, grade and MX screening detection
Detection model based on Swedish data (Tabar 1996)
100
Klin. Detektion
Med
NOS G1
MX Detektion
0
0
0
2
4
6
8 Jahre
Tabar et al. Int J. Cancer 1996
Mammography screening: the reality part 1
normal
DCIS
Mortality reduction through prevention of
progression to metastatic disease
=
preclinical
invasive BC
=
Metastazing in preclinical stage
NO
Mortality reduction
palpable
invasive BC
metastazing
invasives BC
+ (CA)
Mammography screening: the ideal
normal
DCIS
=
preclinical
invasive BC
=
…is working for the typical
screen-detected BCs
Mortality reduction through
prevention of progression to
metastatic disease
palpable
invasive BC
metastazing
invasives BC
+ (BC-related)
Pathobiological features of screen-detected BCs
1. Pathobiological features of BC (histological type, grade,
molecular subtype, clinicopathological subtype) have
impact on cancer detection in MX screening
2. Mortality reduction in MX screening is based on
 is based on early detection of luminal type breast cancers
before they metastasise
 preferably detection of slowly growing tumors (these is the
vast majority of cancers in 50-70 years old patients)
Definition of overdiagnosis in MX screening
 diagnosis of breast cancer that will never cause symptoms or
death during a patient's lifetime
 may lead to treatments that do no good and perhaps do harm
 detected abnormalities meet the pathologic definition of cancer
(under the microscope)
overdiagnosis ≠ wrong diagnosis
Estimation of overdiagnosis in MX screening
 Overdiagnosis is only certain when an individual remains
untreated, never develops symptoms of the disease and dies of
something else.
 Rapidly rising rates of BC in the setting of stable rates of the BC
related death are highly suggestive of overdiagnosis.
 Most compelling is evidence from randomized MX screening
trials:
A persistent excess of BC in the attending group years after the
trial is completed provides the best evidence that overdiagnosis
has occurred.
BUT: this has to be adjusted to:
AGE and BC RISK
Estimation of overdiagnosis rate
w / wo adjustment to breast cancer risk and lead time
(10) Zahl PH et al., BMJ 2004
(11) Jonsson H et al. Int J Cancer 2005
(12) Olsen AH et al., Breast J 2006
(12) Paci E et al., Breast Cancer Res 2006
(13) Waller M et al., Cancer Epidemiol
Biomarkers Prev 2007
(14) Jørgensen KJ & Gotzsche P, BMJ 2009
(15) Puliti D et al., Eur J Cancer 2009
(16) Jørgensen KJ et al., BMC Women’s Health
2009
(17) Duffy SW et al. J Med Screen 2010
(18) Martinez-Alonso M et al., Breast Cancer
Res 2010
(19) de Gelder R et al., Epidemiol Rev 2011
50%
40%
30%
20%
10%
Modifiziert nach Putili et al. J Med Screen 2012;19 Suppl1:42–56
Sojourn-Time-Estimation
by tumor shrinkage time after PCT as surrogate for tumor doubeling time
Grey zone:
Detection in MX screening
Sojourn times for different
tumours:
 Main group:
> 1 year
 Slow growing BCs
(near the lower border of
95% CI): 3 - 6 years
 Extremely slow growing
BCs:
10 – 20 years
Johnson AE, Bennett MH, Cheung CWD et al. The management of individual breast cancers. The Breast 1995;4:100–11
Mammography screening: the reality part 2
normal
DCIS
=
+ (non CA)
Präklinisches
Invasives Ca.
+ (non CA)
Palpables
Invasives Ca.
+ (non CA)
=
=
Metastasiertes
Invasives Ca.
+ (CA)
no prevention of
progression to
metastatic
disease
→
no mortality
reduction
=
OVERDIAGNOSIS
Overdiagnosis
…is an extreme variant of „lead time bias“
Lead Time
Definition of lead time in English:
lead time
Line breaks: lead time
Pronunciation: /ˈliːdtʌɪm
noun
the time between the initiation
and completion of a production
process:
PATHOBIOLOGICAL FEATURES OF
OVERDIAGNOSED BCS
70-Gen-Signature prognosis
(MammaPrint™)
Esserman L. J. et al. Breast Cancer Resaerch and Treatment 2011
70-Gen-Signature in MX screening
Esserman L. J. et al. Breast Cancer Resaerch and Treatment 2011
70-Gen-Signature in MX screening
„historic“
„modern“
Esserman L. J. et al. Breast Cancer Resaerch and Treatment 2011
70-Gen-Signature in MX screening
Identification of
a “ultralow risk”
Subgroup:
70-GenSignature - Index
score :
additional
cut off = 0.6).
Esserman L. J. et al. Breast Cancer Resaerch and Treatment 2011
70-Gen-Signature in MX screening
G1
ER+ Luminal A
PR+
Her2 –
Low proliferation
Esserman L. J. et al. Breast Cancer Resaerch and Treatment 2011
Molecular subtypes and screening
… two sides of a coin
Pathobiological features of screendetected BCs
1. Pathobiological features of BC (histological type, grade,
molecular subtype, clinicopathological subtype) have
impact on cancer detection in MX screening
2. Mortality reduction in MX screening is based on
 is based on early detection of luminal type breast cancers
before they metastasise
 preferably detection of slowly growing tumors (these is the vast
majority of cancers in 50-70 years old patients)
BUT:
– Even almost all of the overdiagnosed cancers are
Luminal A Tumors.
CONSEQUENCES OF OVERDIAGNOSIS:
OVERTREATMENT
… AND HOW TO AVOID IT BY
PROTEOMIC BASED PATHOLOGICAL
SUBTYPING
Screen-detected BCs in Neubrandenburg
St. Gallen Subtypes
2011 + 1. Q
1.-3. Q 2012 2.+3.Q 2012
2012
N27
N16
2010
2011
N28
N44
Luminal A
61%
52%
55%
77%
88%
Luminal B HER2 -
21%
25%
25%
15%
6%
Luminal B HER2 +
7%
9%
9%
4%
0%
HER2+
4%
5%
4%
0%
0%
Triple negative
7%
9%
7%
4%
6%
St. Gallen Suptype
N55
Conclusion
Up to 88% of patients with screen-detected BC will
have an excellent prognosis and do not need
chemotherapy.
Adjuvant therapy in screen-detected BC
Avoidable (over)treatment in MX screening
 Mastectomy ( by stage – small tumors)
 Axillary dissection or SLNB (by stage – node negative tumors)
 Chemotherapy in Luminal A tumores with mit 0 – 3 LN mets
Preconditions:
1. standardised pathology reports with accurate measurement
for staging, exact typing and grading, and clinicopathological
subtyping (proteomics – immunohistochemistry)
2. active involvement of a competent dedicated breast
pathologist in MDT for therapeutic decision making
Overdiagnosis in
breast cancer
screening:
wrong diagnoses?
overeager?
or tumour biology?
NO
NO
YES
Thanks to: