Role of the mtor Pathway in Endocrine Therapy- Resistant Breast Cancer

Transcription

1 Role of the mtor Pathway in Endocrine Therapy- Resistant Breast Cancer Ana M. Gonzalez-Angulo, M.D. Associate Professor Breast Medical Oncology Systems Biology Sao Paulo, Brazil, 3/2012

2 PI3K pathway Meric-Bernstam and Gonzalez-Angulo, J Clin Oncol 2009

3 PI3K pathway adaptor RTK PTEN PIP2 PIP3 p85 p110 Ras enos p53 Mdm2 NF κb Bad IKK Forkhead AKT GSK-3 Tuberin PDK1 Hamartin Rac Bcl-XL Bim Fas-ligand p130 Rb2 p27 KIP1 Cyclin D1 Myc Rheb mtor 4E-BP1 S6K1 Ribosomal S6 Cell Survival Cell Cycle Cell Growth Protein Synthesis

4 PI3K pathway: metabolism Gonzalez-Angulo and Meric-Bernstam, Clin cancer Res 2009

5 PI3K pathway: angiogenesis Stoeltzing, Meric-Bernstam, Ellis, Cancer Cell 2006

6 PI3K Pathway: genetic target in Growth Factors breast Cancer HER2 RAS PTEN PI3K INPP4B LKB1 Gene % Mutation % Amp/Del HER AKT AMPK PIK3CA KRAS 4 TSC 1/2 PTEN 4 8 INPP4B 55 (TN) mtor AKT1 3 S6K Tumor suppressor gene Oncogene Modified from W. Sellers at SABCS 2009 Onc*Base and Beroukhim et al, Nature 2010

7 PI3K pathway: distinct cancer states Are there distinctive dependences? Modified from W. Sellers at AACR 2011

8 PIK3CA Mutations DO NOT invariable activate AKT DO NOT invariable require AKT DO require PIK3C alpha PIK3CA mutations Growth Factors HER2 PI3K RAS PTEN AKT PDK1 TSC1/2 mtor S6K Vasudevan et al, Cancer Cell 2009 Wee et al, PNAS 2008 Modified from W. Sellers at SABCS 2009

9 PTEN loss Growth Factors PTEN loss leads to Constitutive AKT activation AKT dependence (AKT1) PIK3C Beta dependence PTEN HER2 PI3K AKT RAS PDK1 TSC1/2 mtor S6K Vasudevan et al, Cancer cell 2009 Nakamura et al, MCB 2000 Jia et al, Nature 2008 Modified from W. Sellers at SABCS 2009

10 RTK activation RTK activation Leads to PIK3C Alpha dependence If HER2 signaling depends on alpha, why PTEN loss creates trastuzumab resistance? PTEN loss can convert alpha to beta dependence Zhao et al, PNAS 2008 Jia et al, Nature 2008 Wee et al PNAS 2008 Modified from W. Sellers at SABCS 2009

11 Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signaling LTED cells exhibit increased PI3K/mTOR pathway activation PI3K pathway inhibition suppresses LTED cell growth, and prevents the emergence of hormone- independent cells Miller et al, J Clin Invest 2010

12 Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signaling Miller et al, J Clin Invest 2010

13 Frequency of mutations in the PIK3CA, and AKT1 genes in 547 human breast cancers and 41 breast cancer cell lines Tumor subtype PIK3CA catalytic domain* PIK3CA other Mutation PIK3CA total AKT1 E17K All human breast tumors 73/547 (13.3%) 44/547 (8.0%) 117/547 (21.4%) 6/418 (1.4%) Human breast HR+ 48/232 (20.7%) 32/232 (13.8%) 80/232 (34.5%) 6/232 (2.6%) ER+PR+ 39/186 (21%) 22/186 (11.8%) 61/186 (32.8%) 6/186 (3.2%) ER+PR- 9/41 (22%) 10/41 (24.4%) 19/41 (46.3%) 0/41 (0%) ER-PR+ 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/5 (0%) Human breast HER2+ 13/75 (17.3%) 4/75 (5.3%) 17/75 (22.7%) 0/75 (0%) Human breast TN 12/240 (5.0%) 8/240 (3.3%) 20/240 (8.3%) 0/111 (0%) All breast cancer cell lines 7/41 (17.1%) 9/41 (22%) 16/41 (39%) 0/41 (0%) Breast cancer cell lines HR+ 1/12 (8.3%) 3/12 (25%) 4/12 (33.3%) 0/12 (0%) Breast cancer cell lines HER2+ 2/10 (20%) 4/10 (40%) 6/10 (60%) 0/10 (0%) Breast cancer cell lines TN 4/19 (21%) 2/19 (10.5%) 6/19 (31.6%) 0/19 (0%) Stemke-Hale, Gonzalez-Angulo et al, Cancer Res 2008

14 PI3K pathway activation mtor Courtesy of S. Johnston

15 Temsirolimus Reverses TAM resistance in Akt- Expressing Breast Cancer by Restoration of Apoptotic Response Control Temsirolimus Tam Tam + Temsirolimus WT MCF-7 MyrAkt1 MCF7 De Graffenried et al, Clin Cancer Res 2004

16 Temsirolimus Reverses TAM resistance in Akt- Expressing Breast Cancer by Restoration of Apoptotic Response Control Temsirolimus Tam Tam + Temsirolimus WT MCF-7 MyrAkt1 MCF7 De Graffenried et al, Clin Cancer Res 2004

17 RAD001 Added to Letrozole Causes GI Accumulation and Increased Apoptosis Vehicle 2 54% 0.2 nm RAD001 53% 2 nm RAD001 60% MCF7 cells overexpressing aromatase enzyme Vehicle 1 66% 73% otic cells (%) Apopto p < 0.05 (Friedman test) 60% nm Let RAD001 MCF7 Cells overexpressing aromatase enzyme 100nM Let 500nM Let Adapted from S. Johnston Boulay et al. Clin Cancer Res 2005

18 Randomised Phase II study of Letrozole ± Temsirolimus in MBC Probability of Progre ession-free Survival mg TEMSR mg LET, daily schedule 30 mg TEMSR mg LET, intermittent schedule 2.5 mg LET alone, daily schedule RR CBR L 45% 69% L+10T 33% 57% L+30T 40% 80% Months to Progressive Disease/Death Baselga et al, SABCS 2005

19 Phase III Study of Letrozole ± Temsirolimus in ER+ MBC Progression- -free survival No specific patient selection! Letrozole (n=489) Letrozole + Temsirolimus (n=493) Median PFS (mo) HR (95% CI) = 0.92 (0.75, 1.13) Time (months) Chow et al. SABCS 2006, abstract 6091

20 RAD001 increases tumor p-akt in patients Phase I pharmacodynamic study weekly oral dose onon-therapy prepre-therapy daily continuous oral dose 5mg/day 10mg/day 20mg/week Tabernero et al. J Clin Oncol mg/week

21 IGF1R Feedback loop IRS1 PI3K PIP2 PIP3 PDK1 Akt PTEN TSC1 TSC2 Rheb GTP Rheb GDP mtor raptor mtor rictor S6K 4EBP1 S6 eif4e-f-g Courtesy of S. Johnston Proliferation Ki67

22 IGF1R Feedback loop IRS1 PI3K PIP2 PIP3 PDK1 Akt PTEN TSC1 TSC2 everolimus Rheb GTP Rheb GDP mtor raptor mtor rictor S6K 4EBP1 S6 eif4e-f-g Courtesy of S. Johnston Proliferation Ki67

23 Phase II neoadjuvant everolimus (RAD001) breast cancer study Newly diagnosed, untreated patients with ER + localized breast cancer likely to benefit from hormonal therapy Palpable tumor: > 2 cm diameter S C R E E N R A N D O M I Z E N = 138 N = 132 Letrozole 2.5 mg/d RAD mg/d Letrozole 2.5 mg/d Placebo 16 weeks Surgery Tumor biopsies (pretreatment) Tumor biopsies (day 15) Tumor samples (surgery) Baselga et al. J Clin Oncol 2009

24 Results: efficacy summary Overall Response (CR + PR), % Everolimus + Letrozole n = 138 Placebo + Letrozole n = 132 P Palpation (primary end point) * Ultrasound * *1-sided chi-square level of significance is 10%. Baselga et al. J Clin Oncol 2009

25 Results: Major pharmacodynamic changes at day 15 Reduction in ps6240 and ps6235 reveals everolimus-treated patients 40 ive for Ki67) Change in H Score (% Positi CyclinD1 ER PR Ki67 Everolimus + letrozole pakt ps6 235 ps Letrozole Baselga et al. J Clin Oncol 2009

26 Cell cycle response (Ki-67) correlates with clinical response: role of PIK3CA mutations Day 15 Ki-67 score correlated with clinical response Reduction in Ki-67 at Day 15 Patients with PIK3CA exon 9 mut less responsive to letrozole as sensitive to everolimus + letrozole 80 0 PIK3CA e9 PIK3CA e20 mutant only mutant only PIK3CA wt only Ki67d CR PR NC PD Everolimus + letrozole Letrozole Baselga et al. J Clin Oncol 2009

27 TAMRAD Schema Randomized Phase II Metastatic patients with prior exposure to AI 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 Bachelot M, et al SABCS 2010

28 Time to Progression of Survival Probability TAM: 4.5 mo. TAM + RAD: 8.6 mo Hazard Ratio (HR) = 0.53; 95% CI ( ) 0.81) Exploratory log-rank: P = TAM Month TAM + RAD Patients at risk TAM + RAD: n = TAM : n = Bachelot M, et al SABCS 2010

29 Time to Progression as a Function of Intrinsic Hormone Resistance TAM Primary hormone resistance (n = 54) TAM: 3.9 mo. TAM + RAD: 5.4 mo. HR = 0.74 ( ) Pr robability of Survival TAM + RAD Months Secondary hormone resistance (n = 56) TAM: 5.0 mo. TAM + RAD: 17.4 mo. HR = 0.38 ( ) 0.71) Probability of Survival Months Bachelot M, et al SABCS 2010

30 Adverse Events Incidence, n (%) TAM n = 57 TAM + RAD n = 54 Grade Any 3/4 Any 3/4 Most Common Adverse Events (AE) Fatigue Stomatitis Rash Anorexia Diarrhea Nausea Vomiting Pneumonitis Thromboembolic Pain 30 (52.6) 4 (7.0) 3 (5.3) 10 (17.5) 5 (8.8) 19 (33.3) 7 (12.3) 2 (3.5) 4 (7.0) 48 (84.2) 6 (10.5) 0 1 (1.8) 2 (3.5) (3.5) 2 (3.5) 4 (7.0) 11 (19.3) 40 (74.1) 28 (51.9) 21 (38.9) 24 (44.4) 21 (38.9) 18 (33.3) 9 (16.7) 9 (16.7) 7 (13.0) 42 (77.8) 3 (5.6) 6 (11.1) 3 (5.6) 5 (9.3) 1 (1.9) 2 (3.7) 0 1 (1.9) 3 (5.6) 5 (9.3) Dose reduction due to AE 0 (0) 15 (28) Treatment discontinuation due to AE 4 (7.0) 3 (5.6) Bachelot et al SABCS 2010

31 BOLERO-2 Schema N = 724 Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole 2 1 Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-overover Baselga et al. N Engl J Med 2012

32 BOLERO-2 Primary Endpoint: PFS 100 Local Assessment HR = 0.43 (95% CI: ) 0.54) Log rank P value = 1.4 x Probability of Event (%) EVE + EXE: 6.9 months PBO + EXE: 2.8 months 0 Everolimus + Exemestane (E/N=202/485) Placebo + Exemestane (E/N=157/239) Time (weeks) Everolimus Placebo Baselga et al. N Engl J Med 2012

33 BOLERO-2 Primary Endpoint: PFS 100 Central Assessment HR = 0.36 (95% CI: ) 0.47) Log rank P value = 3.3 x of Event (%) Probability EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 0 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) Time (weeks) Everolimus Placebo Baselga et al. N Engl J Med 2012

34 BOLERO-2: Most Common G3/4 AEs Everolimus + Exemestane (N = 482), % Placebo + Exemestane (N = 238), % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Stomatitis Fatigue 33 3 < Dyspnea <1 Anemia 16 5 <1 4 <1 <1 Hyperglycemia 13 4 <1 2 <1 0 AST 13 3 < Pneumonitis Baselga et al. N Engl J Med 2012

35 Subgroups (N) BOLERO-2 PFS in Subgroups All (724) Age <65 (449) 65 (275) Hormonal sensitivity YES (610) NO (114) Visceral metastasis YES (406) NO (318) 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 NSAI hormonal therapy YES (398) NO (326) PgR status positive YES (523) NO (184) Favors Everolimus + Exemestane Hazard Ratio Favors Placebo + Exemestane Baselga et al. N Engl J Med 2012

36 BOLERO-2: Response & Clinical Benefit 60 Everolimus + Exemestane 50 Placebo + Exemestane 50,5% ,0% Response 1,3% P < ,5% Clinical Benefit Baselga et al. N Engl J Med 2012

37 BOLERO-2: Bone Markers 6 weeks 12 weeks % Change From Ba aseline BSAP P1NP CTX BSAP P1NP CTX Δ27% Δ56% Δ36% Δ22% Δ67% Δ41% Hortobagyi et al. SABCS EVE + EXE PBO + EXE

38 PI3K pathway: markers vs. targets INPP4B LKB1 Modified from McAuliffe P et al. Clin P et al. Clin Breast Cancer 2010

39 Fulvestrant in ER positive breast cancer with GDC-0941 and GDC-0980 Inhibitors PIK3CA/PTEN Results PIK3CA/PTEN analysis Randomization Stratification Arm A - GDC-0941 (Daily) Registration Arm C Placebo (Daily) Arm B - GDC-0980 (Daily) Fulvestrant 500mg Fulvestrant 500mg Fulvestrant 500mg/Q4w Fulvestrant 500mg/Q4w screening run-in D1-D28 D28 D1-D28 D28 D-28 C1D1 C1D15 C2D1 C3D1

40 Phase III Randomized, placebo-controlled controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- everolimus in patients with high-risk, node- positive, hormone receptor-positive positive and HER2-neu normal breast cancer Node-positive HR-positive and HER2-negative breast cancer Number of positive nodes? 1-3 positive Patients consent to study-sponsored sponsored RS testing if not already done 4+ positive RS 25 RANDOMIZATION Chemotherapy vs. No Chemotherapy RECURRENCE SCORE evaluated Low risk 1-3 positive nodes and RS 25 RS > 25 Chemotherapy; endocrine therapy No Chemotherapy; endocrine therapy Current RxPONDER trial Adjuvant or neoadjuvant chemotherapy RANDOMIZATION Post-chemotherapy (stratification by number of lymph nodes and timing of chemotherapy) Everolimus vs. Placebo 1-3 positive nodes and RS > 25 or 4+ positive nodes New adjuvant trial Everolimus + Endocrine Therapy Placebo + Endocrine Therapy

41 A phase II neoadjuvant trial of BEZ-235 in combination with endocrine therapy in post- menopausal patients with operable hormone receptor-positive positive breast cancer 2 weeks 22 weeks Postmenpausal Breast Cancer T1-3/N0 3/N0-1 ER or PR+/HER2 Post-menopausal PI3K pathway aberration (core biopsy) Ki-67 TUNEL P-Akt, etc. microarrays RPPA FDG-PET Arm 1: Letrozole BEZ235 2:1 randomization Arm 2: Letrozole Placebo Biopsy Ki-67 TUNEL P-Akt, etc microarrays RPPA FDG-PET Letrozole BEZ235 Surgery Letrozole Placebo Path CR Clin Response (US, Mammo) Breast Cons Surgery Ki-67 TUNEL P-Akt, etc microarrays RPPA

42 Conclusions The PI3K pathway is one of the most important active signaling pathways in cancer growth through various mechanisms Modulation of signal transduction pathway may modulate activity of endocrine therapy and influence outcome Assuming of course that the tumor is addicted to the intended target!! PI3K pathway activation is an important component in all subtypes of breast cancer, both in cancer growth and in therapy resistance The PI3K pathway is a common mechanism of endocrine therapy resistance. Benefit is impressive. Will be studied in the adjuvant setting Toxicities? Patient selection (awaiting correlatives) Clinical trials to evaluate the role PI3K pathway inhibitors at different levels of the pathway are ongoing and should have extensive correlative components to be able to decipher the best use of these drugs according to the molecular aberrations of the tumors

43 Mentorship G.N. Hortobagyi G.B. Mills F. Meric-Bernstam Gonzalez-Angulo s Lab S. Liu X. Meng C. Phan H. Chen E. Tarco Meric-Berstam s Lab A. Akcakanat G. Singh Funding By NIH MDACC Physician-Scientist Start up Funds Komen for the Cure BCRF Texas Fed of Business and Professional Women Commonwealth Foundation for Cancer Research AACR SU2C Dream Team ACS Clayton Foundation Acknowledgements Collaborators MDACC Systems Biology Bioinformatics K. Hale K. Coombes J. Mendelsohn Y. Ji Transcriptional Profiling Z. Ju L. Pusztai W. Liu W.F. Symmans Biostatistics Tumor Bank D. Berry A. Sahin K. Do BMO X. Lei L. Hsu T and H&N Surgical Oncology G. Blumenschein E. Mittendorf Phase I Razelle Kurzrock PI of Investigator Initiative Trials with Novartis, BMS, GSK, Abraxis, Roche Dx, Genomic Health Inc, Merck. Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, EMD Serono, Genentech, Bayer Collaborators Outside MDA C. Perou, L. Carey I. Krop R. Bernards, H. Horlings A. Lluch, J. Ferrer C. Arteaga J. Baselga J. Tabernero, J. Rodon J. Gray M. Ellis C. Hudis, N. Rosen C. Sotiriou P. Lorusso AL. Borresen-Dale F. Andre M. Pollak

44 Thank you!!!!