Management of ER+/HER2- Breast Cancer: New Options, New Insights, Coming Agents

Transcription

1 Management of ER+/HER2- Breast Cancer: New Options, New Insights, Coming Agents P. Kelly Marcom, MD Associate Professor Co-Director Breast Cancer Clinical Research NCOA August 23, 2014

2 Off-Label Use Disclosure(s) I do not intend to discuss an off-label use of a product during this activity, but will discuss ongoing clinical trials using the following agents: Paclociclib Velaparib Entinostat

3 Financial Disclosure(s) I currently have or have had the following relevant financial relations to disclose: If you have relevant relations to disclose, please list Novartis, Genentech, Abbvie Clinical Trial support

4 Overview and Recent Results Preoperative models for ER Preoperative Endocrine Therapy Recent Results NCI meta analysis Dissecting biology Coming Agents

5 Divide and Conquer: Breast Cancer Subtypes 10-15% 15-20% 65% Sørlie, T, Perou C, et al. PNAS 2001;98:

6 Major Intrinsic Subtypes and Conventional Histopathology Tubular Grade 1 Ductal Mucinous Estrogen Receptor Lobular Grade 2 Ductal HER2 Receptor Grade 3 Ductal Medullary

7 HER2 Positive Cases (CALGB 40601) Pretreatment Subtype by Hormone Receptor Status Presented By Lisa Carey at 2014 ASCO Annual Meeting

8 The Recurrence Score Result Uses Key Genes Linked to Critical Molecular Pathways 16 BREAST CANCER RELATED GENES Estrogen Proliferation HER2 Invasion Others ER PR Bcl2 SCUBE2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GRB7 HER2 Stromelysin 3 Cathepsin L2 CD68 GSTM1 BAG1 5 REFERENCE GENES Beta-actin GAPDH RPLPO GUS TFRC Paik S, et al. N Engl J Med. 2004;351:

9 Proportion without distant recurrence Oncotype DX Clinical Validation: NSABP B-14, Distant Recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% RS, Recurrence Score result Paik S, et al. N Engl J Med. 2004;351: Distant recurrence over time All Patients, n = 668 RS < 18, n = 338 RS 18-30, n = 149 RS 31, n = Years *10-Year distant recurrence comparison between low- and high-risk groups: P < Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% P <

10 Proportion distant recurrence-free Trans ATAC: Recurrence Score Value Is Prognostic in Node-Positive Patients Node+ (n = 306; both treatment arms) Log-rank P < N (%) Events Low 160 (52%) 25 Int 94 (31%) 25 High 52 (17%) Years 83% 72% 51% Dowsett M, et al. J Clin Oncol. 2010;28(11): Recurrence Score group Hazard ratio* (95% CI) High vs Low 2.7 ( ) Int vs Low 1.8 ( ) 10

11 9-Year risk of distant recurrence (%) 100 Trans ATAC: Rate of Distant Recurrence Increases with Number of Positive Nodes for All Recurrence Score Values Mean 95% CI Recurrence Score 4 Positive nodes n = Positive nodes n = 243 Node negative n = 872 Low Recurrence Score suggests a low risk of recurrence for patients with 1-3 positive nodes. Dowsett M, et al. J Clin Oncol. 2010;28(11):

12 Estrogen Production in Premenopausal and Postmenopausal Patients Hypothalamus Premenopausal Gonadotropins (FSH + LH) Pituitary Gland Premenopausal and Postmenopausal Adrenocorticotropic Hormone (ACTH) Ovary Prolactin Growth Hormone Adrenal Gland Estrogens Progesterone Corticosteroids Progesterone Androgens Estrogens

13 ATLAS: Recurrence (A) and breast cancer mortality (B) by treatment allocation for 6846 women with ER-positive disease The Lancet, Volume 381, Issue 9869, 2013,

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15 Characteristics Presented By Olivia Pagani at 2014 ASCO Annual Meeting

16 Exemestane+OFS Improved DFS Presented By Olivia Pagani at 2014 ASCO Annual Meeting

17 ER+/HER2 Breast Cancer Preoperative Endocrine Therapy

18 Trial design. IMPACT: Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen Multicenter Double-Blind Randomized Trial Smith I E et al. JCO 2005;23: by American Society of Clinical Oncology

19 IMPACT: Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen Multicenter Double-Blind Randomized Trial

20 ACOSOG 1031 Cohort A (Integrated biomarker design) Cohort B (integral) Ki67 at 2-4 weeks < 10%: Continue AI >10%: Preoperative Chemo

21 Preoperative Endocrine Therapy: ACOSOG1031 Ellis, JCO, 29: 2342, 2011

22 Preoperative Endocrine Therapy

23 Context- PREOPERATIVE THERAPY DEVELOPMENTS: NEOALTTO/ALTTO

24 Slide 3 Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

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29 First results from the phase III ALTTO trial (BIG 02-06; NCCTG 063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L + T) in the adjuvant treatment of HER2-positive <br />early breast cancer (EBC) Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

30 Slide 5 Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

31 Primary Endpoint Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

32 DFS BY Hormone Receptor Status Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

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41 POETIC: Trial of Perioperative Endocrine Therapy - Individualizing Care N=5400 patients Accrual completed April, 2014

42 All Rights Reserved, Duke Medicine 2007 A011106: ALTERNATE

43 Reading the Biology CLINICALLY RELEVANT MARKERS

44 PI3K/Akt/mTOR Pathway

45 Cell Cycle Control And Breast Cancer

46 Significantly mutated genes and correlations with genomic and clinical features. DC Koboldt et al. Nature 000, 1-10 (2012) doi: /nature11412

47 Key cancer pathway components altered in luminal breast tumours. MJ Ellis et al. Nature 000, 1-8 (2012) doi: /nature11143

48 A Crossplatform Comparison of Genomic Signatures and OncotypeDx Score Aim: Use full genome expression data to examine association of OncotypeDx score to: 1) Other Prognostic signatures 2) Pathway signatures 3) Single gene probesets Materials/Methods: 104 breast cancer cases with banked frozen cores and clinically obtained Oncotype assay. RNA expression on Affymetrix U133plus2.0 arrays COMBAT algorithm used to normalize 6 batches Above 3 comparisons using Published models generating RS score from Affymetrix data (Haibe-Keinse and Fan) and R scripts for generating PAM50 and ROR scores from Affymetrix data GenePattern Software ScoreSignatures module, Single probest expression data using simple linear regression and the Benjami- Hochberg method to account for multiple testing (controlling at 1% level for false discovery rate)

49 Single Affymetrix Probesets With a 5% FDR-adjusted cutoff, 1104 features (<3% of the genome) are significant; and the top 23 (table below) pass the conservative Bonferroni threshold of a 5% family-wise error rate (FWER), indicating that there are substantial associations to Oncotype DX score.

50 Signatures of Mutational Processes Alexandrov, Nature 500: 415, 2013

51 APOBEC3B mutagenesis in cancer Kuong, Nature Genetics, 45: 964, 2013

52 APOBEC3B is an enzymatic source of mutation in breast cancer Burns, Nature 494: 366, 2013

53 S6-05: High levels of APOBEC3B, a DNA deaminase and an enzymatic source of C-to- T...AM Sieuwerts, SABCS, 2013

54 Metastatic Disease NEW AGENTS- NEW MARKERS?

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56 Bolero-2 Kaplan Meier Plot of Progression-free Survival. Exemestane aromatase inhibitor +/- Everolimus mtor inhibitor Baselga J et al. N Engl J Med 2012;366:

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58 BOLERO-2: No identified molecular predictors Hortobagyi, ASCO Annual Meeting,

59 PALOMA-1 Trial Phase II trial: Randomized First-line treatment ER+/HER2- metastatic breast cancer Letrozole +/- PD (palbociclib) (cdk 4/6 inhibitor) Arm PFS HR N=165 Palbo + Let Letrozole 20.2 mo (95% CI 0.319, 0.748) 10.2 mo 1-sided p Finn, SABCS, 2012 Finn, AACR, 2014

60 PALOMA-1 Arm Part 1 Pablo + Let Let Part 2 Pablo + Let Let PFS ER+/HER mo 5.7 mo And Cyclin D amp or p16 loss 18.1 mo 11 mo

61 CONSORT diagram. Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor Yardley D A et al. JCO 2013;31: by American Society of Clinical Oncology

62 Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS). Yardley D A et al. JCO 2013;31: by American Society of Clinical Oncology

63 Poly (ADP-ribose) polymerase (PARP) PARP inhibitors- Breast PARP Inhibitors in Development: Olaparib (KuDos Pharmaceuticals; Astra Zeneca) Velaparib (Abbott) Iglehart and Silver, NEJM :

64 FOLFIRI + velaparib Phase I BRCA 2 related disease Patient 10/2010 8/2011

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66 Conclusions ER positive disease: the original targeted therapy. ER status not a mutation event (at least directly) New therapies targeting relevant biology looking very promising Markers: Not so much Preoperative Models: Rethink