10/15/2012. Overcoming Endocrine Therapy Resistance. The Problem in ER+ Tumors is Endocrine Therapy Resistance

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1 Overcoming Endocrine Therapy Resistance Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology Slide Credits: Hope Rugo, MD The Problem in ER+ Tumors is Endocrine Therapy Resistance About 50% of hormone receptor-positive breast cancers are de novo resistant to endocrine therapy Almost all patients with advanced disease will develop acquired resistance to endocrine therapies The mechanisms of de novo and acquired resistance are likely similar, but are not completely understood Phase III Randomized Clinical Trial of Anastrozole vs Anastrozole + Fulvestrant as First-Line Therapy for MBC. SWOG S0226: Efficacy (Intent-to-Treat) Anastrozole (n = 345) Anastrozole + fulvestrant (n = 349) Hazard ratio p-value Median PFS 13.5 mos 15.0 mos Median OS 41.3 mos mos Grade 3 AE 12.2% 14.6% NS No prior adjuvant tamoxifen (n = 414) (n = 208) (n = 206) Median PFS 12.6 mos 17 mos Median OS 39.7 mos 47.7 mos Mehta RS, et al. New Engl J Med 367:435,

The PI3K/AKT/mTOR Pathway Oxygen, energy, and nutrients Ras/Raf pathway kinases S6 Cell growth and proliferation Growth factors including IGF-1, VEGF, ErbB S6K1 PTEN TSC2 TSC1 PI3K AKT mtor Protein

Apoptosis Angiogenesis Lymphocytes Homeostasis Metabolism 1. Bjornsti MA, et al. Nat Rev Cancer. 2004;34(5):335-348; 2. Crespo JL, et al. Microbiol Mol Biol Rev. 2002;66(4):579-591; 3. Huang S, et al.

2 The PI3K/AKT/mTOR Pathway Oxygen, energy, and nutrients Ras/Raf pathway kinases S6 Cell growth and proliferation Growth factors including IGF-1, VEGF, ErbB S6K1 PTEN TSC2 TSC1 PI3K AKT mtor Protein production Nutrient uptake and metabolism Estrogen receptor 4E-BP1 elf-4e Angiogenesis mtor (mammalian target of rapamycin) signaling plays a key role in Cell growth Cell proliferation Regulation of Apoptosis Angiogenesis Lymphocytes Homeostasis Metabolism 1. Bjornsti MA, et al. Nat Rev Cancer. 2004;34(5): ; 2. Crespo JL, et al. Microbiol Mol Biol Rev. 2002;66(4): ; 3. Huang S, et al. Cancer Biol Ther. 2003;2(3): ; 4. Mita MM, et al. Clin Breast Cancer. 2003;4(2): ; 5. Wullschleger S, et al. Cell. 2006;124(3): ; 6. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S. The mtor Pathway Is Active in Breast Cancer Genetic alterations result in activation of the PI3K/AKT/mTOR pathway in breast cancer Loss of PTEN protein (~30% - 48%), PTEN mutation (<5%) 1-3 PIK3CA mutation (~21% - 33%) 4-8 ~30% - 40% of breast cancer cells exhibit AKT activation 9,10 Overexpression/mutation of receptor tyrosinekinases (eg, HER-2, EGFR, FGFR) also activates the PI3K/AKT/mTOR pathway Hennessy BT, et al. Nat Rev Drug Discov. 2005;4(12): ; 2. Pérez-Tenorio G, et al. Clin Cancer Res. 2007;13(12): ; 3. degraffenried LA, et al. Ann Oncol. 2004;15(10): ; 4. Bachman KE, et al. Cancer Biol Ther. 2004;3(8): ; 5. Campbell IG, et al. Cancer Res. 2004;64(21): ; 6.Stemke-Hale K, et al. Cancer Res. 2008;68(15): ; 7. Wu G, et al. Breast Cancer Res. 2005;7(5):R609-R616; 8. Lee JW, et al. Oncogene; 2005;24(8): ; 9. Liu W, et al. Front Biosci. 2007;12: ; 10. Basu A. Breast Cancer. 2008;2:11-16; 10. Basu A. Breast Cancer. 2008;2:11-16; 11. Hynes NE, et al. Curr Opin Cell Biol. 2009;21(2): Crosstalk between ER and mtor Signaling mtorc1 activates ER in a ligand-independent fashion [1] Estradiol suppresses apoptosis induced by PI3K/mTOR blockade [2] Hyperactivation of the PI3K/mTOR pathway occurs in endocrine-resistant BC cells [3] 1. Yamnik RL, et al. J Biol Chem. 2009;284: Crowder RJ, et al. Cancer Res. 2009;69: Miller TW, et al. J Clin Invest. 2010;120:

3 Signature of PI3K activation predicts poor response to adjuvant endocrine therapy Miller et al., JCI 2010 Phase III Study: Temsirolimus with Letrozole in Postmenopausal Women with Locally ABC/mBC Key endpoints Primary: Progression free survival (PFS) (eg, time to emergence of endocrine resistance) Secondary: Overall survival, Safety, prognostic and pharmacogenomics analysis N = 992 Postmenopausal No prior therapy R Let 2.5 mg/day + Tem 30 mg/day for 5 days every 2 wks (n = 493) Let 2.5 mg/day + Placebo for 5 days every 2 wks (n = 499) LABC = locally advanced breast cancer 1 Chow LWC, et al. Breast Cancer Res Treat. 2006;100(suppl 1):Abstract 6091; 2 accessed March 28, Phase III Study of Temsirolimus with Letrozole in Advanced Breast Cancer Trial was closed on the basis of data from a planned interim analysis that demonstrated a lack of benefit for the combination Characteristic Median PFS, months (95% CI) LET+TEM (n = 493) 92mo 9.2 ( ) LET alone (n = 499) 92mo 9.2 ( ) Objective response rate* 24% 24% Clinical benefit 40% 43% Progressive disease as best response 14% 18% Potential reasons for lack of benefit include high frequency of dose reductions, incorrect dose or schedule, potency of agent, patient population *[(CR + PR)/n] x 100; modified RECIST criteria CR + PR + SD ( 24 weeks) Chow LWC, et al. Breast Cancer Res Treat. 2006;100(suppl 1):Abstract

Neoadjuvant Phase II Letrozole ± Everolimus Primary end point: RR at 16 weeks (palpation) Secondary: RR (ultrasound), biomarkers, safety, pharmacokinetics 270 Postmenopausal women with ER+ early BC,

4 Neoadjuvant Phase II Letrozole ± Everolimus Primary end point: RR at 16 weeks (palpation) Secondary: RR (ultrasound), biomarkers, safety, pharmacokinetics 270 Postmenopausal women with ER+ early BC, measurable disease Biopsy at baseline, 14 days, and surgical specimen R Everolimus 10 mg/day A Letrozole 2.5 mg/day N D O Surgery M I Placebo Z Letrozole 2.5 mg/day E Results: Higher RR: Palpation: 68% vs 59% (P = 0.062), ultrasound: 58% vs 47% (P = 0.035) Greater antiproliferative response: Ki67 by 57% vs 30% (P < 0.01) RR = response rate. Baselga J, et al. JCO. 2009;27: TAMRAD: a Randomized Phase II trial of Everolimus with Tam vs Tam alone in HR+ MBC with Prior Exposure to AIs Randomized Phase II, 111 PM women with MBC Prior exposure to AI, prior adj tam or chemo ok A : Tamoxifen, 20 mg/d (TAM) B : Tamoxifen 20 mg/d + RAD mg/d (TAM + RAD) Stratification: Primary or secondary hormone resistance Primary: Relapse during adjuvant AI, progression within 6 months of starting AI treatment in metastatic setting Secondary: Late relapse ( 6 months) or prior response and subsequent progression to metastatic AI treatment No crossover planned Median follow-up 22 months, median age Bachelot et al, JCO 2012 TAMRAD (Phase II): Tamoxifen ± Everolimus in Advanced BC ogression Probability of Pro HR = 0.54 Log-rank P = TAM: 4.5 mos TAM + EVE: 8.6 mos Months AI = aromatase inhibitor; BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; TAM = tamoxifen Bachelot et al, JCO

Time to Progression As a Function of Intrinsic Hormone Resistance Primary hormone resistance (n = 54) TAM: 3.9 mo. TAM + RAD: 5.4 mo. HR = 0.74 (0.42 1.3) Probability of Survival P TAM TAM + RAD 1.

5 Time to Progression As a Function of Intrinsic Hormone Resistance Primary hormone resistance (n = 54) TAM: 3.9 mo. TAM + RAD: 5.4 mo. HR = 0.74 ( ) Probability of Survival P TAM TAM + RAD Months Secondary hormone resistance (n = 56) TAM: 5.0 mo. TAM + RAD: 17.4 mo. HR = 0.38 ( ) Probability of Survival Months Phase III BOLERO-2 Trial: Exemestane +/- Everolimus in Advanced BC N = 724 Postmenopausal ER+ R Unresectable locally advanced or metastatic BC 2:1 Recurrence or progression after letrozole or anastrozole EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, QOL, safety, bone markers, PK BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; EXE = exemestane; ORR, overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; QOL = quality of life. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7), Baselga, NEJM 2011 BOLERO-2: Prior Therapy Therapy Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Sensitivity to prior hormonal therapy Last treatment: LET/ ANA Last treatment Adjuvant Metastatic Prior tamoxifen Prior fulvestrant Prior chemotherapy for metastatic BC Number of prior therapies: LET: letrozole, ANA: anastrozole Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 5

BOLERO-2 (12 mo f/up): PFS Local ity (%) of Event Probabil 100 80 60 40 20 0 Number of patients still at risk EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239) HR = 0.44 (95% CI: 0.36-0.

2 months 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (weeks) Everolimus Placebo 485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0 239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0

6 BOLERO-2 (12 mo f/up): PFS Local ity (%) of Event Probabil Number of patients still at risk EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239) HR = 0.44 (95% CI: ) Log rank P value: <1 x EVE + EXE: 7.4 months PBO + EXE: 3.2 months Time (weeks) Everolimus Placebo Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) BOLERO-2 (12 mo f/up): PFS in Subgroups Favors Everolimus + Exemestane Favors Placebo + Exemestane Subgroups (N) All (724) Age <65 (449) 65 (275) Hormonal sensitivity YES (610) NO (114) Visceral metastasis YES (406) NO (318) YES (523) Baseline ECOG PS 0 (435) 1, 2 (274) Prior chemotherapy YES (493) NO (231) No. of prior therapies 1 (118) 2 (217) 3 (389) Non-NSAI hormonal therapy YES (398) NO (326) PgR status positive YES (523) NO (184) Hazard Ratio PFS = progression-free survival; PgR = progesterone receptor; NSAI = nonsteroidal aromatase inhibitor; ECOG PS = Eastern Cooperative OncologyGroup performance status. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) BOLERO-2 (12 mo f/up): Response & Clinical Benefit 60 Everolimus + Exemestane 50 Placebo + Exemestane 50.5% t Percent % P < % Response 25.5% Clinical Benefit P < Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 6

7 BOLERO-2 (12 mo f/up): Overall Survival As of July 8, 2011: 137 deaths 17.2% in everolimus arm 22.7% in placebo arm OS final analysis at 392 events 80% power to detect 26% reduction in risk OS = overall survival; PFS = progression-free survival. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) BOLERO-2 (12 mo f/up): Most Common Adverse Events Everolimus + Exemestane (n = 482), % Placebo + Exemestane (n = 238), % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Stomatitis <1 0 Rash Fatigue 36 4 < Diarrhea 33 2 <1 19 <1 0 Appetite decreased <1 0 Nausea 29 <1 < Non-infectious Pneumonitis* Hyperglycemia* 14 5 <1 2 <1 0 *Adverse Events of clinical interest Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) Signal Transduction: PI3K/Akt Pathway PI3K Inhibitors XL147 PX866 GDC0941 CAL101 GSK BKM120 SF1126 AKT Inhibitors MK2207 SR13668 GSK GSK Perifosine mtor Inhibitors Sirolimus Temsirolimus Everolimus Ridaforolimus Deforolimus OSI-027 PI3K + mtor Inhibitors XL765 PI103 BEZ235 BGT226 SWOG adjuvant AI +/- everolimus trial in high risk ER+ disease 7

Prostate Ca: Reciprocal Feedback regulation of PI3K and AR Following benefit then progression on AI + mtor inhibitor, ER blockade, PI3K blockade, or both?

8 Prostate Ca: Reciprocal Feedback regulation of PI3K and AR Following benefit then progression on AI + mtor inhibitor, ER blockade, PI3K blockade, or both? Carver et al, Cancer Cell 2011 ERα and IGF Signaling ERα function is enhanced by IGF receptor activation In primary breast cancer, ERα and IGF1R are frequently co-expressed ASCO abs #3008 8

9 ASCO abs #3008 ASCO abs #3008 Di Cosimo, et al ASCO abs #3008 9

10 Lack of Benefit for Tam in ER+ Breast Cancer in Tumors with VEGFR2 (IHC) VEGFR2 grade 0 to 2 tumors VEGFR2 grade 3 tumors Ryden, L. et al. J Clin Oncol; 23: CALGB 40503: First-line Endocrine Rx +/- Bevacizumab: Closed to Accrual ER or PR+ MBC 1st line Rx +/- Measurable Post-Menopausal or Ovarian suppression Endocrine therapy + Bevacizumab (15mg/kg IV q3wks) Endocrine therapy + Placebo Endocrine Therapy: Tamoxifen or Aromatase Inhibitor (letrozole) Double-blind, placebo-controlled Primary Endpoint: Progression-free Survival Circulating tumor and endothelial cells measured during treatment PI: Dickler Summary Activation of PI3K pathway common in ER+ breast cancer mtor inhibition with tamoxifen or AI of benefit in AIpretreated pts not in primary resistant disease?? Does mtor inhibition sensitize to subsequent endocrine therapy? Adjuvant everolimus + AI trial high risk ER+ breast cancer planned Anti-VEGF and anti-igf1r agents under evaluation 10

Mechanisms of hormone drug resistance

Mechanisms of hormone drug resistance Ljiljana Stamatović Institute for Oncology and Radiology of Serbia Tenth UMOS Conference, Belgrade, 16-17 th May 2015. Hormone receptor-positive breast cancer (HR+