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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 • • • • • • • • • • • • • 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)