E. Amir, M. Clemons, O.C. Freedman, N. Miller, R.E. Coleman, C. Purdie,

L. Jordan, P. Quinlan, A.M. Thompson

Tissue confirmation of disease recurrence in breast cancer

patients: pooled analysis of two large prospective studies

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

ER

PgR

HER2

Months/years Recurrent breast cancer

ProgressionMonths/years

Tumor Characteristics and treatment

options assumed to be the same

• 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.

Current knowledge

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

Liedke et al. Ann Oncol 2009; 20: 1953–1958.

Concordant receptors

Discordant receptors

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”?

• Is the source of discordance important?– Clinicians use receptor status to plan

therapy.– Discordance important irrespective of its

underlying etiology?

Barry et al. J Clin Oncol 2010; 28: 2198-2206.Weigelt et al. Lancet Oncol 2010; 11: 339-349

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

BIOPSY OF RECURRENCE

Central pathology reviewEvaluation of ER/PgR/HER2

Oncologist: post-biopsy questionnaire

Oncologist: pre-biopsy questionnaire

Written informed consent

Suspected recurrence or progression

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=271Factor n (%) Age (years) Median Range

61

28-87 Duration from breast cancer diagnosis to recurrence biopsy (months) Median Range

79 0-332

Primary tumor ER/PgR+ & HER2- ER/PgR+ & HER2+ ER-/PgR-/HER2+ ER-/PgR-/HER2-

182 (70.5%)

20 (7.8%) 12 (4.7%)

44 (17.1%)

Location of biopsies DESTINY

n BRITS

n Total n (%)

Loco-regional recurrence

29 103 132 (48.7%)

Ipsilateral breast 1 63 64 (23.6%) Contralateral breast 1 5 6 (2.2%) Ipsilateral skin/soft tissue 16 18 34 (12.5%) Contralateral skin/soft tissue 3 0 3 (1.1%) Lymph node 8 17 25 (9.2%)

Distant recurrence

92 47 139 (51.3%)

Lymph node 17 11 28 (10.3%) Liver 19 4 23 (8.5%) Bone 20 0 20 (7.4%) Skin 5 9 14 (5.2%) Other* 31 23 54 (19.9%)

Total

121 150 271 (100%)

* 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

0

Loco-regional recurrence13.8%

10% 20% 30%

<0.0001

<0.0001

P Value17.0%

Distant recurrence

Whole study population

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.

Recurrent Breast Cancer

Receptors concordant with

primary61.2%

Receptors discordant with

primary38.8%

ER discordance12.6%

PgR discordance34.1%

HER2 discordance5.4%

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%)

Receptor Concordance

4 cases

Absolute change in receptor expression

Receptors concordant

Receptors discordant

Increase in receptor expression from primary to recurrence

Decrease in receptor expression from primary to recurrence

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.

AcknowledgementsDESTINY Study• Christine Simmons• Htway Maung• Aurora De Borja• Farrah Kassam• Julie Napolskikh• Bill Geddie• George Dranitsaris• CBCF-Ontario

BRITS Study• Colin Purdie• Lee Jordan• Phil Quinlan• Tayside Tissue Bank• Breast Cancer Research

(Scotland)• AstraZeneca (UK)