Disclosures

1. 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

2. 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.

3. Recurrentbreast cancer Progression Months/years Months/years Tumor Characteristics and treatmentoptions assumed to be the same Treatment of Recurrent Breast Cancer Primarybreast cancer ER PgR HER2

4. 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.

5. 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 Is discordance important? Liedke et al. Ann Oncol 2009; 20: 1953–1958.

6. 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

7. 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?

8. 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 Study Designs

9. 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.

10. Patient Demographics n=271

11. Location of biopsies

12. 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 • 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

13. Change in therapy • Common reasons for change in management: • Changes in HER2. • Gain of hormone receptor. • Identification of benign disease or second malignancy.

14. 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.

15. Receptor Concordance 4 cases

16. 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

17. Re-analysis of primary • Receptor discordance in: • ER - 5.8%, • PgR - 11.5%, • HER2 - 3.8%

18. 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

19. 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.

20. 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.

21. 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.

22. DESTINY 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) Acknowledgements