Download Tissue confirmation of disease recurrence in breast cancer patients

Tissue confirmation of disease
recurrence in breast cancer patients:
pooled analysis of two large
prospective studies
E. Amir, M. Clemons, O.C. Freedman,
N. Miller, R.E. Coleman, C. Purdie,
L. Jordan, P. Quinlan, A.M. Thompson
Disclosures
• Eitan Amir and Orit Freedman declare they have
received honoraria from AstraZeneca.
• Mark Clemons declares honoraria, research funding and
advisory board involvement with AstraZeneca, Roche
and Novartis pharmaceuticals.
• Alastair Thompson, Colin Purdie, Phil Quinlan and Lee
Jordan declare they have received research funding
from AstraZeneca.
Treatment of Recurrent Breast Cancer
Primary
breast cancer
Months/years
Recurrent
breast cancer
Months/years
ER
PgR
HER2
Tumor Characteristics
and treatment
options assumed to
be the same
Progression
Current knowledge
• Receptor discordance between primary and
recurrence:
– Mostly retrospective.
– Utilized pathology reports – did not re-analyze
samples.
– Rates of discordance for receptor determination:
• Hormone receptors 15 - 40%
• HER2 7 - 26%
• Relative uniformity of hormone receptor
expression between different metastatic sites.
Wu et al. Clin Cancer Res 2008 14; 1938-46.
Is discordance important?
• Discordance may be associated with poorer survival.
Suggested reasons include:
– Inappropriate use of targeted therapies
– Selection of tumors with higher propensity for resistance to
systemic therapy
Concordant
receptors
Discordant
receptors
Liedke et al. Ann Oncol 2009; 20: 1953–1958.
Limitations of Retrospective Studies
Inconsistent techniques
Inter-laboratory variability
Inter-observer variability
Variability in patient/sample
collection
No assessment of impact on
clinical management
Feasibility & patient
acceptability not assessed
Important questions
• Is discordance “real”?
– A change in biology or manifestation of
measurement “error”?
Barry et al. J Clin Oncol 2010; 28: 2198-2206.
Weigelt et al. Lancet Oncol 2010; 11: 339-349
• Is the source of discordance important?
– Clinicians use receptor status to plan therapy.
– Discordance important irrespective of its
underlying etiology?
Study Designs
• DESTINY Study:
– Single center study,
Toronto Canada
– ER/PgR by IHC using
ASCO guidelines
– HER2 FISH
– Re-analysis of primary
• BRITS Study
– Multi-center study, UK
– ER/PgR by IHC using
quantitative and Allred
methods
– HER2 FISH
– Re-analysis of primary
Suspected recurrence or
progression
Written informed consent
Oncologist: pre-biopsy questionnaire
BIOPSY OF
RECURRENCE
Central pathology review
Evaluation of ER/PgR/HER2
Oncologist: post-biopsy questionnaire
Endpoints
• Primary Endpoint:
– The proportion of patients in whom the results of the
recurrence biopsy led to a change in management.
• Secondary Endpoint:
– Discordance rates in ER, PgR and HER2 between
primary and recurrence.
• Exploratory Analysis:
– Evaluate the effect of baseline tumor characteristics
and time on both receptor status and change of
management.
Patient Demographics n=271
Factor
Age (years)
Median
Range
Duration from breast cancer diagnosis to recurrence
biopsy (months)
Median
Range
Primary tumor
ER/PgR+ & HER2ER/PgR+ & HER2+
ER-/PgR-/HER2+
ER-/PgR-/HER2-
n (%)
61
28-87
79
0-332
182 (70.5%)
20 (7.8%)
12 (4.7%)
44 (17.1%)
Location of biopsies
DESTINY
n
BRITS
n
Total
n (%)
29
103
132 (48.7%)
1
1
16
3
8
63
5
18
0
17
64 (23.6%)
6 (2.2%)
34 (12.5%)
3 (1.1%)
25 (9.2%)
Distant recurrence
92
47
139 (51.3%)
Lymph node
Liver
Bone
Skin
Other*
17
19
20
5
31
11
4
0
9
23
28 (10.3%)
23 (8.5%)
20 (7.4%)
14 (5.2%)
54 (19.9%)
121
150
271 (100%)
Loco-regional recurrence
Ipsilateral breast
Contralateral breast
Ipsilateral skin/soft tissue
Contralateral skin/soft tissue
Lymph node
Total
* Soft tissue, paracentesis, lung, bone marrow, CNS
Change in therapy
• Among 271 patients:
–
–
–
–
41 (15.1%) had a change in therapy
1 change in systemic therapy for every 6.6 biopsies
95% CI = 11.1 – 20.0%
P <0.0001
P Value
17.0%
Loco-regional recurrence
<0.0001
13.8%
Distant recurrence
<0.0001
Whole study population
0
10%
20%
30%
Change in therapy
• Common reasons for change in
management:
– Changes in HER2.
– Gain of hormone receptor.
– Identification of benign disease or second
malignancy.
Receptor Concordance
• There are 2 different criteria for defining
positivity among ER and PgR:
– ASCO suggest any staining in >1% of cancer cells is
positive.
– St. Gallen (Europe) suggest staining in >10% of
cancer cell is positive.
• Discordance was defined as:
– A change from positive to negative (or vice versa).
– NOT a quantitative change in receptor expression.
Receptor Concordance
Recurrent
Breast Cancer
Receptors
concordant with
primary
61.2%
4 cases
Receptors
discordant with
primary
38.8%
ER discordance
12.6%
PgR discordance
34.1%
HER2 discordance
5.4%
Gain 8/57 (14.0%)
Loss 21/174 (12.1%)
Gain 16/100 (16.0%)
Loss 63/132 (47.7%)
Gain 9/197 (4.6%)
Loss 3/24 (12.5%)
Absolute change in receptor expression
Increase in receptor
expression from
primary to recurrence
Decrease in receptor
expression from
primary to recurrence
Receptors concordant
Receptors discordant
Re-analysis of primary
• Receptor discordance in:
– ER - 5.8%,
– PgR - 11.5%,
– HER2 - 3.8%
Exploratory Analyses
• Rate of receptor discordance in triple
negative tumors is very low (6.8% v
44.9%).
• Duration between primary and recurrence
biopsies does not appear to influence
receptor discordance.
– t-test 0.917, p=0.360
Potential Harms
• Experience from a single institution (n=121):
– Median delay to treatment was 15 days (range 2-56).
– One procedure-related serious adverse event:
• Uncontrollable bleeding from a skin punch biopsy site.
– Patient reported outcomes:
• Anxiety - 34.4%
• Pain - 58.9%
– 87.8% stated they would recommend a biopsy of
their recurrence to other patients.
Conclusions
• Variability in receptor staining is well
recognized.
• Largest prospective analysis of receptor
status in matched primary and recurrent
breast cancer.
• Substantial discordance in receptors:
– Most common in hormone receptors;
– Less common in HER2;
– Least common in triple negative.
Taucher et al. Endocr Relat Cancer 2003 10; 91-98.
Weigelt et al. Lancet Oncol 2010; 11: 339-349.
Conclusions
• The number needed to biopsy to alter
immediate patient management was 6.6.
• Biopsy should be considered to confirm
disease recurrence in breast cancer.
Acknowledgements
DESTINY Study
BRITS Study
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Christine Simmons
Htway Maung
Aurora De Borja
Farrah Kassam
Julie Napolskikh
Bill Geddie
George Dranitsaris
CBCF-Ontario
Colin Purdie
Lee Jordan
Phil Quinlan
Tayside Tissue Bank
Breast Cancer Research
(Scotland)
• AstraZeneca (UK)