Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
th 18 Annual Perspectives in Breast Cancer Growth Factor Pathways in Hormone Resistant Breast Cancer Christy A Russell, MD Fight On! Tumors Classified as ER+ Have Varied Receptor Expression Profiles • ASCO/CAP recommends that a tumor specimen be considered ER+ if >1% of tumor cells test positive for ER. • Breast cancer classified as ER+ is a heterogeneous disease, based on varying – ER expression level – PR status – HER2 status • BC with strong ER expression are biologically distinct from those with weak ER expression Hormone Receptor Positive Determination Any endocrine therapy (n = 777) Allred Score* for Estrogen Receptor Score Straining Harvey et al. J Clin Oncol 1999;17:1474-1481 Proportion of malignant cells straining for ER 0 None 1 <0.01 2 0.01-0.1 3 0.1-0.33 4 0.33-0.67 5 >0.67 Intensity Allred Score of > 3 are generally considered hormone-sensitive Component of Score Average intensity of positively stained cells 0 None 1 Weak 2 Intermediate 3 Strong Compare Survival with Stable Disease (Clinical Benefit) to Survival with CR or PR with Anastrozole Use in ABC Clinical Benefit = CR + PR + Stable 24 wks Survival (%) 100 80 At Risk Deaths 60 CR or PR 2-Year Estimate 33 10 85% 40 Stable 24wk 78 23 86% 20 Other 118 35% 0 0 1 2 3 152 4 Years From Randomization Stable disease on hormone therapy provides similar benefit as CR or PR ABC = advanced breast cancer, Clinical benefit = no prognosis for > 24wks Robertson JF, et al. Breast Cancer Res Treat. 1999;58:157-162. Patients with Disease Progression on One Hormone Therapy May Respond to Another Hormone Therapy 40% 30% 25% 15% 1st Line 2nd Line 3rd Line 4th Line R E S I S T A N C E An optimal sequence of hormone therapies has not been defined Bavior C, et al. Ann Oncol 2012. Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:233-247 NCCN Guidelines Recommend Serial Endocrine Therapy for Hormone Receptor Positive, HER2- Advanced Breast Cancer, Not in Visceral Crisis NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, version 1.2012; Osborne CK, et al. Ann Rev Med 2011;62:233-247 Hormone Receptor Positive, Advanced Breast Cancer Unmet Need • With initial hormone therapy of advanced breast cancer: – About 30% will have clinical response (PR, CR) – About 50% will have clinical benefit (no progression for 24 weeks) • However, almost all will develop resistance and ultimately have disease progression Endocrine Agents for Postmenopausal Breast Cancer • SERMs • Aromatase Inhibitors Tamoxifen Anastrozole Toremifene Letrozole Raloxifene Exemestane • Estrogens • Progestins Estradiol Megestrol Acetate DES, EE2 MPA • ER-Down Regulator Fulvestrant • Androgens Fluoxymesterone Review of Trials of Hormone Therapy in First-Line Advanced Breast Cancer Selected Trials of HT in First-Line ABC Trial or Lead Author Nabholtlz Anastrozole vs tamoxifen Mouridsen Letrozole vs tamoxifen Paridaens Exemestane vs tamoxifen Howell Fulvestrant (250) vs tamoxifen S02226 Fulvestrant (250, loading) + anastrozole vs anastrozole N 1021 FACT Fulvestrant (250, loading) + anastrozole vs anastrozole 514 FIRST Fulvestrant (500) vs anastrozole 205 916 371 587 694 Mehta SABCS 2011, Abst S1-1; Bergh J Clin Oncol 2012 [Epub ahead of print]; Nabholtz Eur J Cancer 2003;39:1684-1689; Mouridsen 2003;21:2101-2109; Paridaens 2008;26:4883-4890; Howell J Clin Oncol 2004;22:1605-1613. First-Line Phase III Studies: AIs and/or Fulvestrant (250) vs Tamoxifen • AIs have improved efficacy compared with tamoxifen2-4 TTP (mo): anastrozole (10.7) vs tamoxifen (6.4)2 TTP (mo): letrozole (9.4) vs tamoxifen (6.0)3 PFS (mo): exemestane (9.9) vs tamoxifen (5.8)4 • Fulvestrant (250) has similar efficacy compared with tamoxifen5 TTP (mo): fulvestrant (8.2) vs tamoxifen (8.3) First-Line Phase III Studies Fulvestrant (250, loading )* + Anastrozole vs Anastrozole • In SWOG S0226 (n = 694), fulvestrant addition improved: PFS (mo); fulvestrant + anastrozole (15.0) vs anastrozole (13.3), P = 0.007 OS (mo): fulvestrant + anastrozole (47.7) vs anastrozole (41.3), P = 0.049 • In FACT (n=514), fulvestrant addition had: no effect on PFS or OS seen: OS (mo): fulvestrant + anastrozole (37.8) vs anastrozole (38.2), P = 1.00 Mixed results for fulvestrant 250, loading Mehta, et al. SABCS 2011, Abst S1-1 Bergh, et al. J Clin Oncol 2012;30(16):1919-25 *Fulvestrant 500 mg d 1 IM, 250 mg d 14 and 28, 250 mg every 28 days thereafter. FIRST: Fulvestrant (500) vs Anastrozole (Phase II) N = 205 PMW with previously untreated HR+ advanced breast cancer FULVESTRANT 500 mg IM days 1, 14, 28 and q28days thereafter ANASTROZOLE 1 mg QD orally Primary CBR defined as CR, PR, and SD for > 24 wks Secondary ORR, TTP, DoR FUL (500) n = 102 ANAS n = 103 HR P-value TTP (mo) 23.4 13.1 0.66 0.01 ORR (%) 36.0 35.5 1.02 0.947 CBR (%) 72.5 67.0 1.30 0.386 Robertson JRF, et al. SABCS 2010. Abstract S1-3, Robertson et al. J Clin Oncol 2009;27:4530-35 Proportion of patients alive and progression-free FIRST: TTP, Fulvestrant (500) vs Anastrozole (Phase II) 1.0 Fulvestrant 500 mg Anastrozole 1 mg 0.8 0.6 0.4 HR = 0.66 95% CI (0.47, 0.92) p=0.01 0.2 0.0 0 6 12 18 24 30 36 42 48 Time (months) Percent with progression (%) Median (months) Robertson SABCS 2010, Abst S1-3 Fulvestrant 500 mg Anastrozole 1 mg n = 102 (%) n = 103 (%) 63 (61.8) 79 (76.7) 23.4 13.1 Review of Trials of Hormone Therapy in Advanced Breast Cancer After Progression on Prior Non-Steroidal Aromatase Inhibitor Selected Trials of Fulvestrant Use After Progression on Prior NSAI* Trial EFECT Fulvestrant vs exemestane SoFEA Fulvestrant + anastrozole vs fulvestrant vs exemestane CONFIRM Fulvestrant high vs fulvestrant low N 693 750 736 Fulvestrant 250, loading Fulvestrant 500 *Non-steroidal aromatase inhibitor. EFECT: Fulvestrant (250, loading) vs Exemestane N = 693 PMW with advanced HR+ BC after failure of NSAI therapy TTP (mo) ORR (%) FULVESTRANT 500 mg IM day 1, 250 mg day 14, 28, monthly EXEMESTANE 25 mg QD FUL n = 351 EXE n = 342 3.7 7.4 3.7 6.7 Primary TTP Secondary ORR, CBR, DOR, TTR, OS, tolerability P-value 0.653 0.736 Fulvestrant (250 loading) similar to exemestane Chia S, et al. J Clin Oncol 2008;26(10):1664-1670 SoFEA: Fulvestrant (250, loading) With or Without Anastrozole vs Exemestane N = 723 Post menopausal women with advanced HR+ BC following progression on NSAI FULVESTRANT 500 mg loading dose on day 1, then 250 mg monthly + ANASTROZOLE 1 mg/daily FULVESTRANT 500 mg loading dose on day 1, then 250 mg monthly + Placebo daily Primary PFS Secondary ORR, CBR, OS, tolerability EXEMESTANE 25 mg/daily No significant differences were observed in PFS, ORR, CBR, or OS PFS (mo) Johnston S et al. EBCC-8. 2012 FUL 500 n = 231 4.8 FUL + ANA n = 243 4.4 EXE 3.4 CONFIRM: Fulvestrant 250 vs 500 mg N = 736 PMW with advanced HR+ BC after failure of prior endocrine therapy PFS (mo) ORR (%) CBR (%) FULVESTRANT 500 mg IM on day 1, 14, 28, monthly FULVESTRANT 250 mg IM monthly FUL 500 n = 362 6.5 9.1 45.6 FUL 250 n = 374 5.5 10.2 39.6 Bachelot T, et al. J Clin Oncol 2012. Epub 1-7; DiLeo et al. J Clin Oncol 2010;28:4594-4600 Primary PFS Secondary ORR, CBR, DoCB, OS, Qol P-value 0.004 0.795 0.100 Mechanisms of ER Action in Breast Cancer Mechanisms of Endocrine Resistance IGF1R MoAb EGFR/HER2 TKI VEGFR P AB P P P MoAb P P SOS TKI PI3-K TKI MEK Akt CCI RAD RAS RAF p90RSK MAPK SERD AI ER T Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR Increased signaling through PI3-K pathway E2 PP P P Cytoplasm ERER p160 CBP ERE Plasma Membrane Basal Transcription Machinery ER Target Gene Transcription Nucleus Cell Growth Mechanisms of intrinsic and acquired resistance likely similar From Johnston CCR 2005 Endocrine Resistance and the PI3K/AKT/mTOR Pathway • Evidence suggests that the PI3K/AKT/mTOR pathway becomes activated in hormone resistant breast cancer • This pathway allows cells to survive despite concurrent endocrine therapy • Targeting the PI3K/AKT/mTOR pathway could provide benefit in metastatic breast cancer that is becoming resistant to the current endocrine therapy Johnston, S. Role of the mTOR Pathway in Endocrine Resistant Breast Cancer — Opportunities for Novel Combination Strategies. 2009. PI3K/AKT/mTOR Pathway http://www.cellsignal.com/reference/pathway/mTor.html Everolimus as mTOR Kinase Inhibitor • Mechanisms of Action (MOA): everolimus inhibits mTOR through allosteric binding to the mTORC1 complex • Reduces tumor angiogenesis by inhibiting VEGF and HIF-1 expression • Targets pathway known to be involved in endocrine resistance • Available as oral agent Villarreal-Garza, et al. Ann Oncol 2012 May 2 Epub ahead of print Barnett, et al. Pharmacotherapy 2012;32:383-96 Selected Trials of Hormonal Therapy Including Everolimus After Progression on Prior AI* Trial EFECT Fulvestrant (250) vs exemestane CONFIRM Fulvestrant (500) vs fulvestrant (250) SoFEA Fulvestrant + anastrozole vs fulvestrant (250) vs exemestane TAMRAD Tamoxifen + everolimus BOLERO-2 Exemestane + everolimus Fulvestrant 250 Fulvestrant 500 N 693 736 750 110 725 Everolimus Combinations *Non-steroidal aromatase inhibitor. TAMRAD: Tamoxifen + Everolimus (Phase II) Phase 2 study; N=111 PMW with advanced HR+ HER2- BC Previously treated with non-steroidal aromatase inhibitor therapy in adjuvant or metastatic setting CBR (6 mo) TTP (mo) Bachelot T, et al. J Clin Oncol 2012. Epub 1-7. Tamoxifen 20 mg/day + Everolimus 10 mg/day Tamoxifen 20 mg/d + Placebo TAM+EVE n = 54 61% 8.6 TAM n = 57 42% 4.5 Primary CBR at 6 months Secondary Safety, TTP, OS, ORR P-value 0.045 0.002 TAMRAD: Time to Progression TAM: 4.5 mo. TAM + EVE: 8.6 mo. Hazard Ratio (HR) = 0.53; 95% CI (0.35-0.81) Exploratory log-rank: P = 0.0021 Probability of Survival 1.0 0.9 TAM TAM + EVE 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Month Patients at risk TAM + RAD: n = TAM : n = Everolimus plus tamoxifen reduced time to 54 45 39 34 28 26 25 19 16 12 9 7 1 1 0 57 44 30 progression 24 22 16 13 11 by 7 47% 6 2 1 0 0 0 Bachelot T, et al. J Clin Oncol 2012.Epub 1-7 TAMRAD: Overall Survival Everolimus plus tamoxifen increased overall survival by 55% Tamoxifen With or Without Everolimus: TAMRAD: Safety The addition of everolimus resulted in an increase in the expected toxicities, including fatigue, stomatitis, rash, diarrhea, and pneumonitis (predominantly grade 1-2) Select Grade 3-4 Adverse Events Stomatitis Rash Anorexia Dose reductions due to AEs Treatment discontinuation due to AEs Bachelot et al. J CLin Oncol 2012. Epub 1-7. Tamoxifen + Everolimus (n = 54) 6 (11%) 3 (6%) 5 (9%) 15 (28%) 3 (6%) Tamoxife n (n = 57) 0 1 (2%) 2 (3.5%) 0 4 (7%) BOLERO-2: Everolimus in Postmenopausal, Hormone Receptor Positive ABC N = 724 Postmenopausal ER+ HER2breast cancer pts refractory to letrozole or anastrozole Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over Baselga J, et al. N Engl J Med 2012;366(6):520-9. Primary PFS Secondary OS ORR Bone Markers Safety PK BOLERO-2: Baseline Characteristics Everolimus + Exemestane Placebo + Exemestane (N = 485), % (N = 239), % 62 (34, 93) 61 (28, 90) Caucasian 74 78 Asian 20 19 Performance status 0 60 59 Liver involvement 33 30 Lung involvement 29 33 Measurable disease* 70 68 Characteristic Median age (range), years Race *All other patients had ≥ 1 bone lesion. Baselga J, et al. N Engl J Med 2012;366(6):520-9. BOLERO-2: Prior Therapy Everolimus + Placebo + Exemestane Exemestane Therapy (N = 485), % (N = 239), % Sensitivity to prior hormonal therapy 84 84 Last treatment: LET/ ANA 74 75 Adjuvant 21 16 Metastatic 79 84 Prior tamoxifen 47 49 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 24 Number of prior therapies: ≥ 3 54 53 Last treatment Baselga J, et al. N Engl J Med 2012;366(6):520-9. BOLERO-2 Primary Endpoint: PFS Central Assessment Probability of Event (%) 100 HR = 0.36 (95% CI: 0.27-0.47) Log rank P value = 3.3 x 10 -15 80 EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 60 40 20 Everolimus + Exemestane (E/N=114 / 485) Placebo + Exemestane (E/N=104 / 239) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Time (weeks) Everolimus plus exemestane increased progression-free survival by 64% Baselga J, et al. N Engl J Med 2012;366(6):520-9. 78 BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment 40 Everolimus + Exemestane 35 Placebo + Exemestane 33.4% 30 P < 0.0001 25 18.0% 20 P < 0.0001 15 10 9.5% 5 0.4% 0 Response Baselga J, et al. N Engl J Med 2012;366(6):520-9. Clinical Benefit 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 56 8 0 11 1 0 Fatigue 33 3 <1 26 1 0 Dyspnea 18 4 0 9 1 <1 Anemia 16 5 <1 4 <1 <1 Hyperglycemia 13 4 <1 2 <1 0 AST 13 3 <1 6 1 0 Pneumonitis 12 3 0 0 0 0 Baselga J, et al. N Engl J Med 2012;366(6):520-9. BOLERO-2: Overall Survival • As of PFS interim analysis: 83 deaths • 10.6% in everolimus arm • 13.0% in placebo arm • OS interim analysis after 173 events • OS final analysis at 392 events • 80% power to detect 26% reduction in hazard ratio (0.74) Baselga J, et al. N Engl J Med 2012;366(6):520-9. BOLERO-2: Clinical Implications • The PFS of HR+ MBC patients who took everolimus + exemestane had a significantly higher PFS than those who took exemestane alone • Everolimus may slow progression of MBC in patients who initially became resistant to endocrine therapy alone Other Mechanisms of Resistance PI3K Compensatory Pathways PI3K Compensatory Pathways Rapalogs Activate Akt IGFR-1 Phase I Everolimus Study Tumor pAkt IRS PIP3 PDK1 Tuberin Rheb TORC1 S6K S6 on-therapy Akt PTEN pre-therapy PI3K 10mg/day 50mg/week 4EBP1 Tabernero A, et al. J Clin Oncol. 2008;26(10):1603-1610 PI3K Compensatory Pathways PI3K Inhibitors Activate ERK Pathway via Enhanced RTK Signaling IGFR1 HER2 P P P P PTEN EGFR P P P P P P PI3K Ras PIP3 Raf Akt PDK1 Tuberin MEK Erk Rheb TORC1 Rsk P P [TITLE] Conclusions • The effectiveness of ET is limited by high rates of de novo and acquired endocrine resistance. – Resistance to ET is a step-wise progression of BC cells that renders them estrogen-independent – Bidirectional crosstalk between the ER and growth factor receptor signaling pathways, such as the PI3K/AKT/mTOR pathway, is implicated in resistance to ET – Under the pressure of ET, dynamic interplay between ER and growth factor receptor expression exists that can alter BC cell phenotype • Overcoming endocrine resistance remains critical to enhancing further the benefit of existing endocrine therapies.