Hormone Therapy Resistance: Challenges and Opportunities Pamela. N. Munster, MD University of California, San Francisco Financial Disclosures Research Support From Merck Objectives: Understanding the current challenges in hormone sensitive breast cancer Outline novel strategies Discuss the use of estrogens in hormone therapy resistance Dosing of current agents Discuss the role of histonedeacetylaseinhibitorsin breast cancer
Reversal of Hormone Resistance the clinical challenge How to define hormone resistance? Present ER: not responding to hormone therapy De novo After progression on hormonal therapy ER+ and HER2+ tumors Absent ER: (triple negative) Current Challenges in Hormonal Therapy of Advanced Breast Cancer Almost 50% of ER+ positive breast cancers show primary hormone resistance and almost all patients with advanced disease will acquire hormone therapy resistance No additional benefits from combinations of chemotherapy and hormonal therapy No additional benefits from combinations of aromatase inhibitors and anti-estrogens Increased chemotherapy resistance of ER+ positive tumors Newer strategies for hormone positive tumors are needed EGF blockade Novel Strategies for hormone-sensitive breast cancer Mammalian Target of RAPAMYCIN (mtor) inhibition PI3Kinase/AKT pathways IGFR modulation Estrogens Histone deacetylase inhibitors
PI3Kinase/ AKT pathways Cross-Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen Plasma membrane IGFR P P P P Lapatinib EGFR / HER2 Letrozole ER Cell survival P P SOS PI3-K RAS RAF Akt P MEK P p90 RSK MAPK P P Cytoplasm P P P P ER ER p160 CBP Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S. Cross-Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen Plasma membrane IGFR P P P P Lapatinib EGFR / HER2 Letrozole ER Cell survival P P SOS PI3-K RAS RAF Akt P MEK P p90 RSK MAPK P P Cytoplasm P P P P ER ER p160 CBP Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.
First-Line Therapy With Lapatinib Combined with Letrozole vs Letrozole Alone for Postmenopausal Hormone Receptor Positive MBC: Results from the Phase III Double-Blind EGF30008 Trial Finn et al, ASCO 2008, S. Johnston et JCO 2009 Background and Biologic Rationale Activation of growth factor receptors (EGFR / HER2) is associated with endocrine resistance Dual targeting is a rational approach to overcome endocrine resistance Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC Trial Regimen Population TAnDEM 1 Phase III Osborne et al 2 Randomized, placebo-controlled phase II Cristofanilli et al 3 Randomized, placebo-controlled phase II Anastrozole +/- trastuzumab Tamoifen +/- gefitinib Anastrozole +/- gefitinib No. of patients Median PFS, mo Endocrine therapy alone Endocrine therapy + anti-erbb HER2+ 208 2.4 * 4.8 * ITT HER2+ subset 206 37 8.8 5.8 10.9 6.7 ITT 93 8.2 14.5 *Increased slightly in eploratory analysis of centrally confirmed ER status, 3.8 vs 5.6 mo. Stratum 1 of trial defined as never receiving tamoifen or completed adjuvant tamoifen > 1 year prior. 1 Mackey J, et al. Breast Cancer Res Treat. 2006;100. Abstract 3; 2 Osborne K, et al. Breast Cancer Res Treat. 2007;106. Abstract 2067; 3 Cristofanilli M, et al. J Clin Oncol. 2008;26(No 15S). Abstract 1012.
Endpoints Primary Progression-free survival (PFS) as assessed by investigator in patients with HR+, HER2+ MBC Secondary PFS in HR+ ITT population (HER2+, HER2-ve/unknown) as assessed by investigator Overall survival (OS) Overall response rate (ORR) Clinical benefit rate (CBR) Safety Progression-Free Survival: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo 3.0 8.2 Hazard ratio (95% CI) 0.71 (0.53, 0.96) p-value 0.019 Response Rate: HER2+ Population (N=219) p=0.003 48% % of Patients p=0.021 28% 29% 15% Response rates were compared using stratified Fisher s eact test.
Overall Survival: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Died 54 (50%) 50 (45%) Median OS, mo 32.3 33.3 Hazard ratio (95% CI) 0.74 (0.5, 1.1) p-value 0.113 Progression-Free Survival: ITT and HER2-negative Populations ITT HER2 negative * Letrozole Letrozole + Lapatinib (N = 644) (N = 642) Progressed or died 476 (74%) 413 (64%) Median PFS, mo 10.8 11.9 Hazard ratio (95% CI) 0.86 (0.76, 0.98) p-value 0.026 Letrozole Letrozole + Lapatinib (N=474) (N=478) Progressed or died 342 (72%) 294 (62%) Median PFS, mo 13.4 13.7 Hazard ratio (95% CI) 0.90 (0.77, 1.05) p-value 0.188 *Centrally confirmed Response Rates: ITT and HER2-negative Populations ITT Population (N=1286) p=0.096 HER2-ve Population (N=952) p=0.761 56% 58% % of Patients 51% p=0.262 30% % of Patients p=0.726 32% 33% 56 % 28% Let Let + Lap Response rates were compared using stratified Fisher s eact test.
Overview of Safety Combination of letrozole + lapatinib was manageable and predictable, with no unepected toicity First trial to evaluate long-term adverse event profile of lapatinib in trastuzumab-naïve population Letrozole N=624 Letrozole + Lapatinib N=654 Any adverse event 536 (86%) 628 (96%) Grade 3-4 adverse event 148 (24%) 251 (38%) Adverse events leading to study drug discontinuation 19 (3%) 72 (11%) All serious adverse events (SAEs) 94 (15%) 144 (22%) Treatment-related LVEF decline 7 (1%) 14 (2%) Safety: Most Common Adverse Events 60 patients with grade 3/4 diarrhea 10 (17%) discontinued drug 11 (18%) dose reduction 21 (35%) dose interruption 18 (30%) supportive measures Efficacy Summary: Lapatinib +Letrozole vs Letrozole In postmenopausal women with HR+, HER2-positive MBC improvement in median PFS from 3.0 to 8.2 months 29% reduction in risk of disease progression (p=0.019) Significant improvement in clinical benefit rate (29% to 48%; p=0.003) In postmenopausal women with HR+, HER2-negative MBC: No significant treatment benefit on PFS [HR 0.90 (0.77, 1.05; p=0.188)] 23% reduction in risk of disease progression by preplanned Co analysis [adjusted treatment HR 0.77 (0.64, 0.94; p=0.010)] Prior tamoifen eposure was a significant covariate Biomarker studies ongoing
CONFIRM:COmparisoN of FASLODEX In Recurrent or Metastatic breast cancer Phase III study of postmenopausal women with hormone receptorpositive advanced breast cancer Fulvestrant 500mg vs 250 mg/m (days 0, 14, 28) Fulvestrant 250 mg (n=374) 500 mg (n=362) TTP (m) 5.5 6.5 HR 0.80, p=0.006 CBR % (CR+PR+SD) 39.6 45.6 p=0.1 OS NS SABCS 2009: Abstract 25 Reversal of Hormone Resistance by estrogens Reviving the past? Copyright restrictions may apply. Lower-dose (6 mg Daily) versus Highdose (30 mg Daily) Oral Estradiol Therapy of Hormone-receptor-positive, Aromatase-inhibitor-resistant Advanced Breast 3Cancer: A Phase 2 Randomized Clinical Trial. Ellis, JAMA 2009
Lower-dose (6 mg Daily) versus High-dose (30 mg Daily) Oral Estradiol Therapy 2of Hormone-receptor-positive, Aromatase-inhibitor-resistant Advanced Breast 3Cancer: A Phase 2 Randomized Clinical Trial. Ellis, JAMA 2009 Biomarker Comparisons Between Study Groupsa Ellis, M. J. et al. JAMA 2009;302:774-780. Copyright restrictions may apply. Progression-Free Survival and Probability of Treatment Failure by Study Group Ellis, M. J. et al. JAMA 2009;302:774-780. Copyright restrictions may apply.
Grade 3 and Higher Toicities and the Incidence of Serious Adverse Events by Study Group Ellis, M. J. et al. JAMA 2009;302:774-780. Copyright restrictions may apply. Treatment Response by Study Group and Contingency for Interaction Between the Presence of a Positive FDG-PET/CT Estradiol Stimulation Test and Response to Estradiol Treatment Ellis, M. J. et al. JAMA 2009;302:774-780. Copyright restrictions may apply. Reversal of Hormone Resistance by estrogens Randomized clinical trial of diethylstilbestrol versus tamoifenin postmenopausal women with advanced breast cancer. Ingle et al. N Engl J Med. 1981 Jan 1;304(1):16-21 Randomized trial of diethylstilbestrol vs. tamoifen in postmenopausal women with metastatic breast cancer. An updated analysis. Peethambaram et al. Breast Cancer Res Treat. 1999 Mar;54(2):117-22.
Reversal of Hormone Resistance by Estrogens 14.5 y F/U DES Tamoifen Regression rate 41% 33% P=0.31 TTP 142 d 171 d Median Duration of Response 11.8 m 9.9 m P=0.32 Median Survival 3.0 y 2.4 y NS 5-year survival 35% 16% 0.039 Reversal of Hormone Resistance HDAC inhibitors HDAC inhibitors Histone Deacetylases and Histone AcetylTransferases (HATs) modulate gene epression by the removal or the addition of acetyl groups to lysine residues of histones or other non-histone targets.
Minucci S (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer Nat. Rev. Cancer. 6: 38 51 doi:10.1038/nrc1779 Rationale for Combination Many estrogen receptor-positive tumors show primary or acquired resistance to anti-estrogen therapy Histone deacetylases (HDAC) and their inhibitors play a central role in transcriptional regulation and may restore sensitivity to anti-hormonal therapy by modulation of estrogen and progesterone receptors. Study Design of associated clinical trial - Single Arm Phase II Study at UCSF and Moffitt Cancer Center and Affiliate Network - Patients with estrogen receptor-positive metastatic breast cancer who progressed on prior therapy with aromatase inhibitors, recurredon adjuvant tamoifen and up to three chemotherapy regimens - Primary Objective: Overall Response Rate Cycle 1 (4 weeks) Cycle 2 (4 weeks) Tamoifen (20 mg/d) Vorinostat (400 mg/day) Toicity visit Clinical Assessment CBC, CMP, TM PBMC Staging Studies
PATIENT CHARACTERISTICS AND TREATMENT PATIENT CHARACTERISTICS AND TREATMENT No of patients evaluable for response Age median (range) Gender female / male Hormone Receptor Status ER+/ PR- ER+/ PR unknown ER- / PR- 25 24 56 (35-71) 24 / 1 14 (56%) 10 (40%) 1 ( 4%) 0 (0%) Therapy prior- adjuvant tamoifen prior adjuvant chemotherapy prior metastatic chemotherapy 17 (68%) 19 (76%) 13 (52%) Med Number of cycles 2 (1-13) RESPONSE Objective response, CR/PR: 8/ 40 (20%) Stable Disease >12 mo 4/ 40 ( 10%) Stable Disease > 3 mo 8 / 40 (20%) Preliminary Response Data Complete/Partial Response 8 / 40 (20%) Stable Disease > 6 mo 8 / 40 (20%) Response Characteristics Partial Response: Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Pt 8 Hormone Receptor Status ER+ / PR - HER2 Status Prior AI Letrozole Anastrozole, Eemestane Anastrozole, Eemestane Letrozole, Eemestane Anastrozole Letrozole, Eemestane Anastrozole, Eemestane Letrozole Prior Tamoifen No Yes Yes No No Yes No Yes
CONCLUSIONS The combination between HDAC inhibitors and tamoifen appears synergistic HDAC inhibitors affect both ER and PR The select depletion of HDAC2 potentates the effects of tamoifen in ER positive cells The first clinical trial combining an HDAC inhibitor and tamoifen promising HDAC2 may deserve further consideration as a biomarker and therapeutic target Thank you