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Joan Albanell Servicio de Oncología Médica Implicaciones clínicas de los subtipos intrínsecos de cáncer de mama.

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Presentation on theme: "Joan Albanell Servicio de Oncología Médica Implicaciones clínicas de los subtipos intrínsecos de cáncer de mama."— Presentation transcript:

1 Joan Albanell Servicio de Oncología Médica Implicaciones clínicas de los subtipos intrínsecos de cáncer de mama

2 The intrinsic breast cancer subtypes PAM50: intrinsic subtypes and ROR Studies in Hormone Receptor positive disease Studies in HER2 positive disease Studies in Triple Negative disease Summary

3 Molecular classification in breast cancer: The intrinsec subtypes Sorlie, T et al. PNAS, 2001 Perou, CM et al. Nature, 2000 Perreard, L et al. Breast Cancer Res, 2006

4 Breast cancer intrinsic subtypes vary in subsets defined by ER and HER2 Prat, A & Perou, CM. Mol Oncol 2011

5 IHC-based definition of Luminal A is ER+ and/or PR+ HER2- Ki67<14% PR>20% IHC-based definition of Luminal B is ER+ and/or PR+ / HER2- / Ki67<14% / PR<20% or ER+ and/or PR+ / HER2- / Ki67>14% or ER+ and/or PR+ / HER2+ IHC-based definition of Luminal A versus Luminal B tumors However, these definitions 1) do not fully recapitulate the intrinsic subtypes and 2) are technically challenging (i.e. precise scoring of Ki-67 and PgR), and thus the Pathology Community needs to establish scoring standards and provide controls Prat et al. J Clin Oncol 2013 Survival analyses within IHC-LumA tumors

6 The intrinsic breast cancer subtypes PAM50: intrinsic subtypes and ROR Studies in Hormone Receptor positive disease Studies in HER2 positive disease Studies in Triple Negative disease Summary

7 Extract RNA from FFPE tumor sample Run RNA & CodeSet on nCounter Analysis System Intrinsic Subtype Risk of Relapse (ROR) RESEARCH DIAGNOSTICS FDA 510(k) Prosigna test (PAM50) Adapted from Aleix Prat

8 1.The qRT-PCR assay consists of 50 genes 2.The subtype classification accuracy of the 50 genes by qRT-PCR versus 2000 genes by microarray was 93% 3.The assay works using RNA from FFPE materials or fresh frozen tissues. PAM50 Using nCounter Classifies Breast Cancer Into Intrinsic Subtypes Parker J Clin Oncol 2009

9 PAM50 Generates a Risk Of Relapse (ROR) Score Specific to Each Patient ROR is based on the similarity of the gene expression profile to intrinsic subtypes, proliferation score (i.e. mean expression prolif-related genes), nodes and tumor size. ROR ranges from 0 through 100 (ROR) indicating the probability of distant recurrence in a “training cohort” of patients with tumors representing all subtypes and patients that did not receive any adjuvant systemic therapy. Patient expression profile LumB LumA Basal-like HER2-enriched PAM50 centroids ROR = aR LumA + bR LumB + cR Her2e + dR Basal + eP+ fT Pearson’s correlation to centroids Proliferation score Tumor size Parker et al. JCO 2009; Nielsen et al. CCR 2010

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11 The intrinsic breast cancer subtypes PAM50: intrinsic subtypes and ROR Studies in Hormone Receptor positive disease Studies in HER2 positive disease Studies in Triple Negative disease Summary

12 ATAC study Postmenopausal women with invasive BC (N=9366) ATAC study Postmenopausal women with invasive BC (N=9366) Tam alone (N=3116) Arimidex alone (N=3125) Tam + Arimidex (N = 3125) TransATAC study (N=1125 blocks) TransATAC study (N=1125 blocks) ABCSG-8 study Post-menopausal women with HR+ BC (N=3714) ABCSG-8 study Post-menopausal women with HR+ BC (N=3714) Tamoxifen (N=1849) Tamoxifen (N=1849) Anastrozole (N=1865) ABCSG-8 study (N = 1478 blocks) ABCSG-8 study (N = 1478 blocks) Tam 2-years Tam 2-years 3 years PAM50 (PROSIGNA®) Validation Studies Primary Objective: Validate published observations that Prosigna/ROR Score provides additional prognostic information over and above standard clinical variables for DRFS at 10 yrs - Primary Analysis: All patients - Secondary Analysis: Node- negative, node-positive, and HER2-negative patients Secondary Objective: Validate observations that Luminal A and Luminal B patients have statistically significantly different DRFS at 10 yrs 1

13 Findings From the Combined Analysis of >2400 Patient Samples DRFS by Risk-Group for Node-negative Patients DRFS by Risk-Group for Node-positive Patients (1-3 positive nodes) Follow-Up Time (yrs) Percent Without Distance Recurrence Low-risk Intermediate-risk High-risk Follow-Up Time (yrs) Percent Without Distance Recurrence Low-risk Intermediate-risk High-risk Risk GroupN (%) Events Through 10 Yrs % Without Recurrence at 10 yrs [95% CI] Low875 (49%)3196%.2 [94.7% %] Intermediat e 551 (31%)5389.2% [86.% %] High360 (20%)7377.7% [72.8% %] Total1,786 (100%) 157 Risk GroupN (%) Events Through 10 yrs % Without Recurrence at 10 yrs [95% CI] Low24 (4%)291.7% [70.6% %] Intermediat e 211 (36%)1890.4% [85.2% %] High355 (60%)8771.8% [66.3% %] Total590 (100%) 107 Prosigna Low Risk patients remain Low Risk over 10yrs Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22): : Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):

14 Knowledge of Luminal Status May Improve Disease Management DRFS by Risk-Group for Node-Negative Patients Risk Group N (%) Events Through 10 yrs % Without Recurrence at 10 yrs [95% CI] Luminal A % [93.1% – 95.8%] Luminal B % [77.7% – 85.3%] Total1, Risk Group N (%) Events Through 10 yrs % Without Recurrence at 10 yrs [95% CI] Luminal A % [83.5% – 90.8%] Luminal B % [60.4% – 75.0%] Total56193 DRFS by Risk-Group for Node-Positive Patients (1-3 Positive Nodes) Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22): : Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):

15 JCO 2013 Discordance between ROR and RS groups of 43% at the individual level

16 Prospective study of the impact of the Prosigna® assay on adjuvant clinical decision-making in an unselected population of women with ER+, HER2-negative, node-negative breast cancer: a GEICAM study

17 JNCI 2013 TransATAC study OncotypeDX RS, PAM50 ROR and IHC4 (Ki67, PgR, ER, HER2 status)

18 Ivana Sestak Jack Cuzick, Mitch Dowsett, Martin Filipits, Peter Dubsky, J. Wayne Cowens, Sean Ferree, Carl Schaper, Christian Fesl, Michael Gnant Centre for Cancer Prevention, Wolfson Institute of Prevention Medicine, Queen Mary University, London, UK Academic Department of Biochemistry, Royal Marsden Hospital, London, UK Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria NanoString Technologies, Seattle, WA, USA MyRAQA, Redwood Shores, CA, USA San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013 Prediction of late distant recurrence after 5 years of endocrine treatment: A combined analysis of 2137 patients from the ABCSG-8 and transATAC studies using the PAM50 Risk of Recurrence (ROR) score

19 Luminal A vs Luminal B HR (95% CI)P-value Luminal A (N=1530 (71.6%))-- Luminal B (N=542 (25.4%))2.89 ( )< San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013 Sestak et al. SABCS 2013 and JCO Follow-up time [years] Luminal B Luminal A Distant recurrence (%) 4.1% 12.9%

20 San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013 Risk groups – ROR score (N=2137) HR (95% CI) Low (N=1183 (55.4%))- Intermediate (N=538 (25.2%))3.26 ( ) High (N=416 (19.5%))6.90 ( ) 2.4% 16.6% 8.3% Follow-up time [years] Low Intermediate High Distant recurrence (%) Sestak et al. SABCS 2013

21 The intrinsic breast cancer subtypes PAM50: intrinsic subtypes and ROR Studies in Hormone Receptor positive disease Studies in HER2 positive disease Studies in Triple Negative disease Summary

22 The HER2-enriched subtype is associated wit higher responses and improved survival outcomes in HER2+ breast cancer in the NOAH study Chemotherapy: AT x 3  T x 4  CMF x (46.7%) pre-treatment samples were PAM50 profiled. HER2+HER2+/HR- Prat et al. Clin Cancer Res 2014 Note: interaction test between HER2E subtype and treatment was not statistically significant.

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24 The intrinsic breast cancer subtypes PAM50: intrinsic subtypes and ROR Studies in Hormone Receptor positive disease Studies in HER2 positive disease Studies in Triple Negative disease Summary

25 Prat et al. BJC 2014

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28 Summary The PAM50 assay provides better intrinsic subtype molecular (Luminal A and B, HER2-enriched and Basal-like) classification than current pathology-based surrogate definitions. PAM50 ROR provides robust prognostic information in ER+/HER2- early breast cancer and influenced systemic treatment recommendations in a prospective clinical impact study. PAM50 ROR and classification of luminal A vs B tumors may also help to estimate the risk of late recurrences (> 5 years) in ER+ disease. HER2+ disease includes all the intrinsic subtypes (i.e. not just Luminal B and HER2-enriched). HER2+enriched tumors appear to benefit the most from anti- HER2 treatments in combination with chemotherapy in the neoadjuvant setting. The role of HER2+ subtyping may vary by disease burden (neoadjuvant, micrometastasis, overt metastasis) and type of regimen. Within TNBC, distinguishing Basal-like vs. Other subtypes predicted benefit from chemotherapy and docetaxel vs. carboplatin benefit.

29 GEICAM 9906 (Martin, BCRT 2013) FEC vs FEC-T (n=820) ABCSG8 (Gnant, SABCS 2012) Tam-Tam vs Tam-AI (n=1478) CALGB 9741 (Liu, SABCS 2012) q2 AC-T vs q3 AC-T (n=1311) TransATAC (Dowsett, JCO 2013) Tam vs AI (n=1007) PAM50 Subtype Testing in Phase III Clinical Trials (n=5,486) NCIC MA.5 (Cheang, CCR 2012) CMF vs CEF (n=475) NCIC MA.12 (Chia, CCR 2012) Chemo vs Chemo+Tam (n=395) LumA LumB

30 PAM50 HER2-enriched phenotype as a predictor of early-response to neoadjuvant lapatinib plus trastuzumab in Stage I to IIIA HER2-positive breast cancer (PAMELA TRIAL) PIs: Dr. Llombart, Dr. Cortés and Dr. Prat

31 Predicted risk of distant recurrence by number of positive nodes (TransATAC) Dowsett et al. J Clin Oncol 2013 Nodal statusROR range Risk categorization Node- negative 0-40Low 41-60Intermediate High Node- positive (1-3 nodes) 0-15Low 16-40Intermediate High Node- positive (> 4 nodes) 0-100High 10-year probability of distant recurrence of < 10% is considered low risk 10-year probability of distant recurrence of > 20% is considered high risk PAM50 (PROSIGNA®)

32 Survival Outcomes of the Intrinsic Subtypes within HER2+ disease METABRIC dataset (no trastuzumab) Clinical HER2 status Prat et al. JNCI 2014


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