BALKAN MCO 2011 - T. Cufer - Hormonal therapy options/management in metastatic breast cancer

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  • As depicted in this slide, cross talk exists between ER signaling and signal transduction pathways in endocrine resistant breast cancer. Breast cancer cells that coexpress ER and ErbB2 are less responsive to Selective Estrogen Receptor Down-Regulators and Aromatase Inhibitors. Growth factor signaling via the ErbB2/MAPK pathway and the IGFR/AKT pathway activates the ER through phosphorylation and activates the coactivator A1B1. Modulating these pathways by various signal transduction inhibitors may overcome the resistance to SERDs and AI.
  • CCO would like to thank John Mackey, MD, for his permission to use this figure. CI, confidence interval; MBC, metastatic breast cancer; PFS, progression free survival (time from randomization to date of progressive disease or death). A = anastrozole A plus H = anastrozole plus trastuzumab
  • This trial presents results from the TAnDEM and Johnston studies. Once again it must be remembered that d ifferences in baseline demographics and patient characteristics, and in the local management of breast cancer at participating study cent re s, make it impossible to draw definitive conclusions from cross-trial comparisons. Mackey JR, et al. Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. San Antonio Breast Cancer Symposium 2006. Abstract 3 and presentation Kaufman B, et al. Trastuzumab + anastrozole in postmenopausal women with HER2‑positive, HR-positive MBC: results of the TAnDEM study. ESMO 2006 Johnston S, et al. Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 Trial. San Antonio Breast Cancer Symposium 2008; Abstract 46 and presentation 7 First-line metastatic
  • BALKAN MCO 2011 - T. Cufer - Hormonal therapy options/management in metastatic breast cancer

    1. 1. Hormonal Therapy of Metastatic Breast Cancer Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty, Ljubljana ESO Masterclass; Dubrovnik 2011
    2. 2. Metastatic Breast Cancer (MBC) <ul><li>The survival of pts with metastatic disease is improving </li></ul><ul><li>MBC is still: </li></ul><ul><ul><li>Incurable but highly treatable </li></ul></ul><ul><ul><li>Chronic disease </li></ul></ul><ul><li>The goal of treatment: </li></ul><ul><ul><li>Control of symptoms </li></ul></ul><ul><ul><li>Prolongation of life </li></ul></ul><ul><ul><li>Good quality of life </li></ul></ul>
    3. 3. Multidisciplinary Treatment Modalities in MBC <ul><li>Systemic therapy </li></ul><ul><ul><li>Endocrine therapy </li></ul></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Targeted systemic therapy </li></ul></ul><ul><li>Radiotherapy (bone, CNS mets) </li></ul><ul><li>Surgery (solitary lesions) </li></ul><ul><li>Palliative medicine </li></ul>
    4. 4. Systemic Therapy Selection in MBC <ul><li>Disease-related factors </li></ul><ul><ul><li>Biology of disease </li></ul></ul><ul><ul><ul><li>HR status </li></ul></ul></ul><ul><ul><ul><li>HER2 status </li></ul></ul></ul><ul><ul><li>Previous adjuvant ST </li></ul></ul><ul><ul><li>Disease-free interval </li></ul></ul><ul><ul><li>Tumor burden (number & site of mets) </li></ul></ul><ul><ul><li>Need for rapid disease control </li></ul></ul><ul><li>Patient-related factors </li></ul><ul><ul><li>PS </li></ul></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Co-morbidities </li></ul></ul><ul><ul><li>Patient’s preferences </li></ul></ul>
    5. 5. Impact of “Hormone Receptor Status ” <ul><li>Hormone receptor positivity </li></ul><ul><ul><li>P redictor of benefit to anti-hormonal agents </li></ul></ul><ul><ul><ul><li>40-60% of pts with ER+ MBC achieve measurable tumor response with 1st-line HT; TTP around 14 months </li></ul></ul></ul><ul><ul><ul><li>2nd-line agents: 30 % response, TTP around 6 months… </li></ul></ul></ul><ul><ul><li>Predictor of low response rates to chemotherapy </li></ul></ul><ul><li>Hormone receptor negativity </li></ul><ul><ul><li>Good predictor of no response to hormonal manipulations </li></ul></ul>
    6. 6. Hormone Therapy in Advanced Breast Cancer ENDOCRINE RESPONSIVE DISEASE HR-positive, long DFI, predominant non-visceral mets ENDOCRINE THERAPY HER-2 negative HER-2 positive No threatening disease ENDOCRINE THERAPY + HER2-directed therapy (Tandem; EGF30008) Courtesy F. Cardoso
    7. 7. Repeating ER/PR and HER2 Status at the Time of Progression?
    8. 8. Treatment of Recurrent Breast Cancer Amir E, ASCO 2010, Ab 1007 . ? Several small retrospective studies shown receptor disordance between primary and recurrent tumor Rate of discordance: - H R 15-40% - HER2 7-26%
    9. 9. ASCO 2010: Significant Rate of Discordancy Between Primary and Metastases Discussion ASCO 2010: Richardson AL Studies #1007 Amir et al. N=271 #CRA 1008 Locatelli et al. N=255 #1009 Karlsson et al. N=477 prospective retrospective (liver) retrospective ER+ primary with loss in recurrence 21/174 (12%) 22/197 (11%) 123/336 (36%) ER- primary with gain in recurrence 8/57 (14%) 15/58 (25%) 32/141 (22%) Overall ER discordance rate 12% 14.5% 32% Overall PR discordance rate 34% 48% 43% HER2- primary with gain in recurrence 9/197 (4.6%) 7/118 (5.9%) n.d. HER2+ primary with loss in recurrence 3/24 (12.5%) 17/54 (31.5%) n.d. Change in management from results of recurrence biopsy 15% 12% n.d.
    10. 10. Optimal First-line Endocrine Therapy for MBC <ul><li>Changed substantially along the time </li></ul><ul><li>Premenopausal patients </li></ul><ul><ul><li>Tamoxifen </li></ul></ul><ul><ul><li>OAS +/- Tamoxifen </li></ul></ul><ul><li>Po st menopausal patients </li></ul><ul><ul><li>AI or fulvestrant </li></ul></ul>
    11. 11. Combined Tamoxifen and LHRH Agonist vs LHRH Agonist Alone in Premenopausal Advanced Breast Cancer: A Meta-Analysis of Four Randomized Trials LHRH+TAM LHRH Klijn , et al . J Clin Oncol 2001 ; 19 . End Point LHRH agonist alone N=256 LHRH agonist + Tamoxifen N=250 HR 95%CI p Median survival, years 2.5 2.9 0.78 0.63-0.96 0.02 Median PFS, months 5.4 8.7 0.70 0.58-0.85 0.0003 Objective response % 29.7 38.8 0.67 0.46-0.96 0.03
    12. 12. Randomized Phase III Trials of AIs vs Tamoxifen as First-line Treatment of MBC ORR = overall response rate; CBR = clinical benefit rate; TTP = time to progression; PFS = progression free survival; ER = estrogen receptor *Statistically significant difference 1. Nabholtz JM, et al. J Clin Oncol. 2000;18:3758. 2. Bonneterre J, et al. J Clin Oncol. 2000;18:3748. 3. Mouridsen H, et al. J Clin Oncol. 2003;21:2101. 4. Paridaens R, et al. J Clin Oncol. 2008;26:4883. Anastrozole 1 Anastrozole 2 Letrozole 3 Exemestane 4 No. patients 170 vs 182 340 vs 328 453 vs 454 182 vs 189 ORR, % 21 vs 17 33 vs 33 32 vs 21* 46 vs 31* CBR, % 59 vs 46* 56 vs 56 50 vs 38* 66 vs 49* TTP or PFS, months 11 vs 6* 8 vs 8 9 vs 6* 10 vs 6* ER status unknown, % 11 vs 11 56 vs 54 34 vs 33 15 vs 11
    13. 13. AIs vs TAM First-Line MBC Disease-free Survival in ER+ Population 0 12 18 24 30 36 42 6 Time in months 48 6 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 TAM AI 1. Nabholtz JM, et al. J Clin Oncol. 2000;18:3758. 2. Bonneterre J, et al. J Clin Oncol. 2000;18:3748. 3. Mouridsen H, et al. J Clin Oncol. 2003;21:2101. 4. Paridaens R, et al. J Clin Oncol. 2008;26:4883. TTP median P LETR 9.4 <.0001 TAM 6.0 ANASTR 10.7 .022 TAM 6.4 EXEMEST 10.5 .028 TAM 5.5
    14. 14. Hormonal Therapy in MBC; the Place of Aromatase Inhibitors <ul><li>All three AIs showed higher RR and longer TTP compared to Tam in first line setting; no differences in long term OS ( Mouridsen et al JCO 2003; Bonneterre et al Cancer 2001, Paridaens et al, ASCO 2004 ); </li></ul><ul><li>The efficacy of AIs after Tam is comparable to the efficacy of Tam after AIs ( Thurlimann et al, EJCancer 2003) </li></ul><ul><li>All three AIs seem to be equally effective with slight differences in untoward effects ( Rose et al ASCO 2002, Cameron et al , ASCO 2004 , Mayordomo et al, ASCO 2006 ) </li></ul><ul><li>Steroid inactivator exemestane is effective after failure to nonsteroidal AIs, nonsteroidal AIs are effective after failure to exemestane (Thurlimann et al, EJCancer 1997, Bertelli G , et al. Oncology. 2005) </li></ul>
    15. 15. Sequences of Aromatase Inhibitors <ul><li>Clinical benefit with E xemestane in 43.5% and median TTP of 5.1 months in patients progressing on nonsteroidal Ais </li></ul><ul><li>Clinical benefit with N onsteroidal AI in 55.6% and median TTP of 9.3 months in patients progressing on exemestane </li></ul>Bertelli G, et al. Oncology. 2005;69:471.
    16. 16. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 Time to progression (months) Proportion not progressed F ulvestrant 5.5 months Anastrozole 4.1 months Hazard ratio: 0.95 (95% CI 0.82 to 1.10) p=0.48 Howell , et al . 2001 . Faslodex 250 mg Anastrozole 1 mg Faslodex vs Arimidex as Second - Line Time to Progression Pooled data from 2 trials
    17. 17. CONFIRM: Fulvestrant 250 mg vs 500 mg After Prior Endocrine Therapy HR (95% CI) = 0.84 (0.69 - 1.03) P = .091 Time (Months) Proportion alive Di Leo A , et al. SABCS 2009;Abstract 25. TTP OS Fulvestrant 500 Fulvestrant 250 % Progressed 82 85.8 Median TTP (months) 6.5 5.5 Fulvestrant 500 Fulvestrant 250 % died 48.3 54.3 Median OS (months) 25.1 22.8
    18. 18. FIRST: Fulvestrant 500 mg vs Anastrozole as First - Line CI = confidence interval; HR = hazard ratio; TTP = time to progression 0.0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 24 Time (months) 30 36 42 48 Fulvestrant 500 mg Anastrozole 1 mg Proportion of patients alive and progression-free HR = 0.66 (95% CI: 0.47-0.92) P = .01 Number of patients at risk: Fulvestrant 500 mg Anastrozole 1 mg Robertson JF, et al. Cancer Res. 2010;70: Abstract S1-3. 102 103 74 69 65 55 52 39 45 30 34 21 20 8 6 2 0 0
    19. 19. FIRST: Response to First Subsequent Endocrine Therapy Robertson JF, et al. Cancer Res. 2010;70: Abstract S1-3. Number (%) of patients Fulvestrant Anastrozole No. patients who progressed 63 79 Patients who received subsequent endocrine breast cancer therapy 34 50 Complete response 0 0 Partial response 3 (8.8) 7 (14.0) Total responders 3 (8.8) 7 (14.0) Stable disease ≥24 weeks 11 (32.4) 14 (28.0) Total with Clinical Benefit 14 (41.2) 21 (42.0) Stable disease <24 weeks 10 (29.4) 16 (32.0) Progressive disease 3 (8.8) 8 (16.0) Not evaluable 7 (20.6) 5 (10.0)
    20. 20. EFECT: Fulvestrant 250 mg vs Exemestane After Progression on Nonsteriodal AI Chia S, et al. J Clin Oncol. 2008;26:1664. Median, months 3.7 3.7 HR = 0.963, 95% CI (0.819, 1.133), P = .6531 Cox analysis, P = .7021
    21. 21. FACT: Fulvestrant plus Anastrozole vs Anastrozole 0.1 0 6 12 18 24 30 36 42 48 54 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.0 Time, months Number at risk: Anastrozole 256 148 108 57 31 16 10 5 4 1 Anastrozole + Fulvestrant 258 149 107 55 40 20 6 2 1 0 Proportion of Patients Progression-Free Fulvestrant + Anastrozole Anastrozole n = 258 n = 256 Number progressed (%) 200 (77.5%) 200 (78.1%) Median TTP (months) 10.8 10.2 Hazard Ratio (95% CI) 0.99 (0.81-1.20) P value .91 TTP per protocol analysis (unadjusted model) F+A vs A Hazard Ratio (95% CI) n = 175 / 175 P value .70 Bergh J, et al. Cancer Res. 2009;69: Abstract 23.
    22. 22. Hormonal Therapy in MBC : Place of Fulvestrant <ul><li>Fulvestrant 500 mg showed higher RR and longer TTP compared to fulvestrant 250 mg, with a safety profile consistent to fulvestrant 250 mg -> r ecommended dose of fulvestrant is 500 mg. </li></ul><ul><li>First-line fulvestrant 500 mg was associated with longer TTP compared to anastrozole. </li></ul><ul><li>The efficacy of fulvestrant 250 mg is comparable to the efficacy of AIs. </li></ul><ul><li>There is no advantage of adding fulvestrant to anastrozle in first-line therapy. </li></ul><ul><li>Patients progressing on fulvestrant remain sensitive to subsequent endocrine therapy. </li></ul>
    23. 23. Cross-talk Between Signal Transduction and Endocrine Pathways Johnston SRD , Clin Cancer Res. 2005;11:889. p90 RSK Cell Survival Cytoplasm Nucleus Cell Growth Plasma Membrane EGFR/HER2 IGFR TANDEM EGF30008 TA MRAD SOS RAS RAF Basal Transcription Machinery p160 ERE ER Target Gene Transcription ER CBP P P P P ER P Akt P MAPK P Tam ER AI P13-K P P P P P P MEK P Growth Factor Estrogen Tamoxifen
    24. 24. Targeted Therapies Suggesting Improvement in Combination with Endocrine Therapy <ul><li>Anastrozole + Trastuzumab (TANDEM) 1 </li></ul><ul><li>CB 28 v 43%; PFS 2.4 v 4.8 months </li></ul><ul><li>Letrozole + Lapatinib (EGF30008) 2 </li></ul><ul><li>CB 29 v 48%; PFS 3.0 v 8.2 months </li></ul><ul><li>Tamoxifen + Everolimus (TAMRAD) 3 </li></ul><ul><li>CB 42 v 61%; TTP 4.5 v 8.5 months </li></ul><ul><li>Kaufman , et al . J Clin Oncol 27 2009 . </li></ul><ul><li>Johnston , et al . J Clin Oncol 27 2009 . </li></ul><ul><li>Bachelot, SABCC 2010. </li></ul>
    25. 25. TANDEM: Evaluation of Anastrozole + /- Trastuzumabin HER2+/HR+ MBC n = 103 48 31 17 14 13 11 9 4 1 1 0 0 A + H n = 104 36 22 9 5 4 2 1 0 0 0 0 0 A Progression-Free Survival (%) 100 80 60 40 20 0 5 10 15 20 25 30 35 40 45 50 55 60 0 2.4 months Kaufman , et al. J Clin Oncol 2009 . Months Outcome A (n = 104) A + H (n = 103) P Value Events, n 99 87 Median PFS, mos (95% CI) 2.4 (2.0-4.6) 4.8 (3.7-7.0) .0016
    26. 26. TANDEM: Evaluation of Anastrozole + /- Trastuzumab in HER2+/HR+ MBC N=207 Median age 55 years Visceral disease 1/3 Prior chemo 1/2 Anastrozole Cross-over 70% 6,8% Response rate 20,3% 2,4m Median PFS. 4,8m p 0.0016 23,9m Median O.S. 28,5m 32,1m Median O.S. 41,9m if no liver mets p 0.03 Mackey , et al. SABC 06 ; abst.03 . Adapted from M. Piccart Anastrozole + Trastuzumab Trastuzumb added to anastrozole  RR, PFS (and possibly OS if no liver mets) IMPORTANCE OF STARTING BIOLOGICAL AGENT SOON
    27. 27. EGF300 0 8: Evaluation of Letrozole +/- Lapatinib in HR+ MBC: PFS in HER2+ Population Johnston , et al . J Clin Oncol 2009 . 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
    28. 28. 1. Kaufman , JCO 2009 . 2 . Johnston , et al. JCO 2009 . 3. Di Leo , et al. Clin Oncol 2008;26:5544 . 4 . Slamon , et al. N Engl J Med 2001;344:783 . 5 . Smith , et al. Anticancer Drugs 2001;12 Suppl 4:S3–10 . 6 . Marty , et al. J Clin Oncol 2005;23:4265 . Efficacy of HER2-directed Therapy Plus Endocrine / Chemot herapy in MBC Trial Treatment ORR (%) PFS (months) OS (months) TanDEM, 2006 1 Anastrozole 1 mg daily + trastuzumab 2 mg/kg qw 20.3 4.8 28.5 Johnston, 2008 2 Letrozole 2.5 mg daily + lapatinib 1500 mg daily 28 8.2 33.0 Di Leo et al. 2008 3 (ErbB2+ patients only) Lapatinib 1500 mg qd + paclitaxel 175 mg/m 2 q3w 63 8.5 24.0 Slamon et al. 2001 4 ; Smith et al. 2001 5 Trastuzumab 2 mg/kg qw + paclitaxel 175 mg/m 2 q3w 50 7.4 25.1 Marty et al. 2005 6 Trastuzumab 2 mg/kg qw + docetaxel 100 mg/m 2 q3w ×6 61 11.7 31.2
    29. 29. TAMRAD: Tamoxifen +/- Everolimus as Second - Line After AIs Failure CI = confidence interval; HR = hazard ratio; RAD = RAD001; TAM = tamoxifen Patients at risk: TAM + RAD: n = TAM: n = 54 57 53 55 51 53 49 50 49 44 45 38 38 30 26 22 14 9 6 4 0 0 TAM TAM + RAD Hazard Ratio (HR) = 0.32 (95% CI: 0.15-0.68) Exploratory log-rank: P = .0019 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of survival Months Bachelot T, et al. Cancer Res. 2010;70: Abstract S1-6. 0 3 6 9 12 15 18 21 24 27 30 33 36
    30. 30. Metastatic Breast Cancer <ul><li>Management of MBC is complex and multi-disciplinary, main goal of therapy is palliation </li></ul><ul><li>Hormonal therapy is the preferred option for HR + MBC, unless there is concern or prove of endocrine resistance </li></ul><ul><li>Beyond progression on first line endocrine therapy patients remain sensitive to subsequent endocrine therapies </li></ul><ul><li>HER-2+/HR+ MBC is a separate disease and should be treated with HER2 -directed agents in addition to chemotherapy or endocrine therapy </li></ul><ul><li>Whenever possible a biopsy of metastatic lesion should be performed for HR and HER2 status re-determination . </li></ul>NEED: New agents but also rational use of available agents (TREATMENT TAILORING – Biological markers)

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