Endocrine Therapy In Advanced Breast Cancer
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Endocrine Therapy In Advanced Breast Cancer

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Endocrine Therapy In Advanced Breast Cancer Endocrine Therapy In Advanced Breast Cancer Presentation Transcript

  • Ashok K Vaid MD,DM Artemis Health Instt National Capital Region Gurgaon Endocrine Therapy in Advanced Breast Cancer Overview (Past to the present)
  • Breast cancer
    • Worldwide
      • >1.2 million new cases per year
      • 350,000 deaths per year
    • Early disease - curable
      • cure rates
        • stable from 1930 until 1990
        • slight improvement 1990s (screening, adjuvant therapy)
    • Metastatic disease - non-curable
      • concept of chronic disease
  • Advanced / Metastatic Breast Cancer 100 50 75 25 0 Stage of Disease % alive after five years
    • Approx. 40% women diagnosed
    • - Cancer spread to other parts of
    • the body
    • Five-year Survival
    • - Low due to spread of disease
    • - Incurable
    • - Treatment goals for advanced
    • disease differ from early stage
    Stage I 84% Stage II 71% Stage III 48% Stage IV 18%
  • The Lancet 11 July 1896
    • On the treatment of inoperable cases of carcinoma of the mamma - suggestions for a new method of treatment, with illustrative cases
    • By George Thomas Beatson, MD, Edinburgh; Surgeon to the Glasgow Hospital; Assistant Surgeon, Glasgow Western Infirmary; Examiner in Surgery to the University of Edinburgh
    • Dear Dr Beatson
    • The bearer is, and has been, suffering, I fear, from a malignant breast. She has been in the Royal Infirmary before she came to me. My own opinion is that nothing can be done for her, but as she is a woman of great courage you might have a look at it for my sake, and perhaps you can order her something in the way of dressing. Even this little will be accepted by her as a great deal.
    • With kindest regards, yours very truly James W Wallace
  • Advanced / Metastatic Breast Cancer
    • Beatson removed ovaries of a 33 yr old lady with advanced breast cancer in May 1895.
    • She responded to treatment for 42 months
    • The mechanism of response was unknown.
  • Ovary Pituitary gland LHRH (hypothalamus) Pre-/post- menopausal Premenopausal Gonadotrophins (FSH + LH) ACTH Adrenal glands Oestrogens Progesterone Progesterone Androgens Oestrogens Peripheral conversion ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; LH, luteinising hormone; LHRH, LH releasing hormone LHRHa Aromatase Inhibitors Hormones affecting the breast Ovary
  • Efficacy of endocrine agents in women with advanced breast cancer Rose C et al. Acta Oncol 1988 Inhibitive Therapy Response data from a comprehensive review Response rate (%) Oophorectomy Adrenalectomy Hypophysectomy Aminoglutethimide + HC Oestrogens Progestins Androgens Glucocorticoids Tamoxifen 33 32 36 31 Competitive Additive Ablative 26 29 21 25 32 HC, hydrocortisone
  • Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens (PREMENOPAUSAL) Aromatase Inhibitors (POSTMENOPAUSAL)
  • Phase III trials comparing tamoxifen with other hormonal endocrine agents in advanced breast cancer
    • Meta-analysis of 35 randomized clinical trials (n=5160)
    • 88% postmenopausal women
    • 36% ER status unknown
      • no difference in efficacy between tamoxifen and aromatase inhibitors, megestrol acetate and medroxyprogesterone
      • toxicity profile in favour of tamoxifen
    • Tamoxifen - the hormonal therapy ‘gold standard’
      • first-line therapy in the advanced setting
    Fossati R et al. J Clin Oncol 1998 ER, oestrogen receptor
  • The use of hormonal agents in advanced/metastatic disease in pre -menopausal women
  • Endocrine use in premenopausal women
    • Tamoxifen (alone or with LHRHa) is the most prescribed endocrine agent
    • But…
    • Is tamoxifen still the optimal agent for younger women?
    • Published data shows that:
      • Combining an LHRHa and tamoxifen confers better efficacy than either agent alone in premenopausal patients with advanced disease
    Klijn et al, 2001, JCO (19); 343-353 Klijn et al. JNCI 2000; 92:903-11
  • Goserelin 3.6mg in Pre-/perimenopausal Women with Advanced Breast Cancer: Phase III Trials Reference Objective response rate (%) Median overall survival Taylor CW, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical J Clin Oncol oophorectomy 1998; 16: 994 – 9. ( n =29*) ( n =30*) ( n =69) ( n =67) 31 27 37 months 33 months Boccardo F, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical Ann Oncol or ovarian irradiation oophorectomy 1994; 5: 337 – 42. or ovarian irradiation ( n =22*) ( n =15*) ( n =24) ( n =18) 27 ( + 19) 47 ( + 25) 36 months 38 months Jonat W, et al ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg + + tamoxifen tamoxifen Eur J Cancer Part A ( n =159) ( n =159) ( n =159) ( n =159) 1995; 31A: 137 – 42. 31 38 29 months 32 months * evaluable patients
  • LHRH Agonist* + Tamoxifen in Pre-/perimenopausal Women with Advanced Breast Cancer: An EORTC Meta-analysis
    • The combination of LHRH agonist + tamoxifen is superior to LHRH agonist alone in the treatment of advanced breast cancer in hormone-sensitive pre-/perimenopausal women
    Klijn JGM, et al. J Clin Oncol 2001; 19: 343–53. Parameter LHRH agonist (n =256) LHRH agonist + tamoxifen ( n =250) Odds/hazard ratio p value OR (CR+PR) 30% 39% 0.67 0.03 PFS (median) 5.4 months 8.7 months 0.70 <0.001 OS (median) 2.5 years 2.9 years 0.78 0.02 OR = Objective response PFS = Progression-free survival OS = Overall survival Median follow-up of 6.8 years * 3 of the 4 studies used the LHRHa goserelin
  • Hormonal therapies for postmenopausal women with advanced breast cancer First-line Antioestrogens (eg tamoxifen) Second-line Aromatase inhibitors Third-line Progestins (eg megestrol acetate) Fourth-line Androgens or oestrogens Hortobagyi GN. N Engl J Med 1998
  • The use of aromatase inhibitors in metastatic disease in post -menopausal women
  • Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens PREMENOPAUSAL Aromatase Inhibitors Postmenopausal
  • The development of aromatase inhibitors
    • Non-selective (first-generation)
      • aminoglutethimide (competitive)
    • Selective - discovery late 1980s
      • Competitive Non-competitive (non-steroidal) (steroidal)
        • Fadrozole
        • Anastrazole
        • Letrozole
        • Vorozole
    • Formestane (second generation)
    • Exemestane (third-generation)
  • Development of Aromatase Inhibitors Toxicity Specificity Potency First generation Second generation Third generation Aminoglutethimide Fadrozole 4-OHA Anastrozole Exemestane Letrozole Rash, etc. No adrenal insufficiency, etc. 1,000 to 10,000 100 1
  • Aromatase inhibitors Mechanism of action X Cholesterol Cortisol Progesterone Aldosterone Oestrone Oestradiol Testosterone Aromatase inactivators and aromatase inhibitors X Pregnenolone Androstenedione
  • Inhibition (%) 85 / 92* 91 98.4 / 98.9* 96.7 / 98.1* 97.9 In vivo effect of Aromatase inhibition Lønning P. Acta Oncol 1996 Geisler J et al. Clin Cancer Res 1998 Anti-aromatase agent Formestane (intramuscular) Aminoglutethimide Letrozole Anastrazole Exemestane *Inhibition at different doses
  • Aromatase inhibitors Phase III second-line metastatic breast cancer versus megestrol acetate No. patients CR + PR (%) CR + PR + SD > 24 weeks (%) Median TTP (months) Median survival (months) Letrozole 2.5 mg 174 vs. 189 23.6 vs. 6.4 † 34.5 vs. 31.7 5.6 vs. 5.5 25.3 vs. 21.5 Anastrozole 1 mg (31mo) 263 vs. 253 12.4 vs. 12.2 42.2 vs. 40.3 4.8 vs. 4.6 26.7 vs. 22.5 † Exemestane 25 mg (12 mo) 366 vs. 403 15.0 vs. 12.4 37.4 vs. 34.6 4.7 vs. 3.8 † NR vs. 26.7 † Buzdar A et al. Cancer 1998 Dombernowsky P et al. J Clin Oncol 1998 Kaufmann M et al. J Clin Oncol 2000 *Pooled data; † Statistical significance vs. MA; CR, complete response; MA, megestrol acetate; NR, median not reached; PR, partial response; SD, stable disease; TTP, time to progression
  • Evolution of aromatase inhibitors
    • The third-generation aromatase inhibitors have favorable efficacy and tolerability profiles compared with megestrol acetate
    • Median survival gain of 4.1 months ( Messori A et al Anticancer Drugs. 2000;11:701-6)
    • This finding triggered further research which challenged tamoxifen in the first-line adjuvant treatment of postmenopausal patients with breast cancer
  • Anastrozole versus tamoxifen as first systemic therapy for advanced disease Two large, randomized trials in North America / Europe / rest of world Postmenopausal women with ABC eligible for endocrine therapy (ER+ve and / or PgR+ve or unknown) Randomised 1:1 (double-blind, double dummy) Anastrozole 1 mg daily plus tamoxifen placebo daily Tamoxifen 20 mg daily plus Anastrozole placebo daily
    • Primary objectives
      • TTP
      • objective response
      • tolerability
    • Secondary objectives
      • TTF
      • TTP in responding patients
      • survival
    Bonneterre J et al. Cancer 2001 ABC, advanced breast cancer; ER, oestrogen receptor; PgR, progesterone receptor; TTP, time to progression TTF, time to treatment failure
  • TTP in hormone receptor-positive patients Combined analysis of two trials % not progressed Median TTP Anastrozole 10.7 months Tamoxifen 6.4 months p=0.022 TTP (months) 0 20 40 60 80 100 0 6 12 18 24 30 36 42 Anastrozole (n = 305) Tamoxifen (n=306) TTP, time to progression Bonneterre J et al. Cancer 2001
  • Anastrozole versus tamoxifen Tolerability Data (Predefined Adverse Events) Anastrozole Tamoxifen 1 mg 20 mg ( n =506) ( n =511) n % n % Depression 30 5.9 36 7.0 Tumour flare 15 3.0 18 3.5 Thromboembolic disease 27 3.6 46 9.0 Gastrointestinal disturbance 184 36.4 207 40.5 Hot flushes 139 27.5 123 24.1 Vaginal dryness 16 3.2 11 2.2 Lethargy 6 1.2 17 3.3 Vaginal bleeding 5 1.0 13 2.5 Weight gain 12 2.4 8 1.6 Bonneterre J et al. Cancer 2001
  • Phase III trial comparing Anastrazole with tamoxifen in hormone-dependant advanced breast cancer Anastrozole (n=121) Tamoxifen 40 (n=117) CR + PR (%) Median TTP (months) Dead (%) HR for TTP (95% CI) HR for survival (95% CI) 27 (56) 5.3 (7) 92 (0.56-0.91) (0.51-0.89) 34 (CBR 83) 10.6 (18) 61 0.77 0.63 - - - p<0.05 p<0.05 Milla-Santos A et al. Am J Clin Oncol 2003 CI, confidence intervals; CR, complete response; HR; hazard ratio; PR, partial response; TTP, time to progression p-value
  • Study 025 Letrozole vs. Tamoxifen
    • All treatments:
      • Double-blind
      • Given until progression
    PO = Orally; QD = Every day. Extension phase Crossover treatment if appropriate All patients followed for survival every 6 months Follow-up R A N D O M I Z E Core phase Letrozole 2.5 mg PO QD Tamoxifen 20 mg PO QD
  • Randomization Tamoxifen 20 mg od Letrozole 2.5 mg od Tamoxifen 20 mg od Letrozole 2.5 mg od Treatment until progression or discontinuation for any other reason, then cross over to alternative treatment if suitable for further endocrine treatment Treatment until progression Follow-up for survival Mouridsen H et al. J Clin Oncol 2001 Phase III cross-over trial comparing Letrozole with tamoxifen in advanced breast cancer
  • Study 025 - Median TTP Letrozole 9.4 months Tamoxifen 6.0 months p=0.0001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time, months 0 3 6 9 12 15 18 21 24 Progression-free Log-rank P < .0001 Letrozole Tamoxifen Events, Wald N n (%) HR 95% CI P value 453 308 (68) 0.70 0.60 - 0.82 < .0001 454 350 (77)
  • Time to progression of advanced breast cancer for first-line Letrozole or tamoxifen 0.0 0.2 0.4 0.6 0.8 1.0 Start 3 6 9 12 15 18 21 24 Time (months) Proportion of patients progression-free Mouridsen H et al. J Clin Oncol 2001 Median TTP Letrozole 9.4 months Tamoxifen 6.0 months p=0.0001 TTP, time to progression Letrozole (n=453) Tamoxifen (n=454)
  • Exemestane versus tamoxifen as first-line treatment for metastatic breast cancer Randomized Phase II trial Exemestane (n=61) Tamoxifen (n=59) Objective response (%) (CR + PR) Clinical benefit (%) (CR + PR + SD >24 weeks) Median duration of response (months) 95% CI 41 57 16 11-38 17 42 22 12-36 Paridaens R et al. Ann Oncol 2003 CR, complete response; PR, partial response; SD, stable disease; CI, confidence intervals
  • Correlation between TTP and hormone receptor status for non-steroidal AIs and tamoxifen 1 Bonneterre J et al. J Clin Oncol 2000 2 Bonneterre J et al. Cancer 2001 3 Mouridsen H et al. J Clin Oncol 2001 4 Milla-Santos A et al. Am J Clin Oncol 2003 5 Nabholtz JM et al. J Clin Oncol 2000 A 1 A 2 L 3 L 3 A 2 0 20 40 60 80 100 -1 0 1 2 3 4 5 6 % receptor-positive difference in TTP A 4 A 5 % receptor-positive Difference in TTP between AI and tamoxifen (months) A, anastrozole AI, aromatase inhibitor L, letrozole TTP, time to progression
  • Recent Meta analysis AI’s vs. tamoxifen for Survival Mauri D et al. JNCI 2006; 98: 1285 – 91.
  • In postmenopausal patients with HR +ve advanced disease Aromatase Inhibitors as first line hormonal therapy have an overall better therapeutic index than tamoxifen
  • Sequential use of Hormonal Agents in Postmenopausal Women with Metastatic Breast Cancer: Role of the novel anti-estrogen Fulvestrant
  • Fulvestrant: unique mechanism of action
    • A new type of oestrogen receptor (ER) antagonist with no oestrogen agonist activity
    • Removing cellular ER may impact the onset of hormone resistance that occurs via cross-talk between growth factor signalling pathways and the ER
    Competitively inhibits binding of oestradiol to the ER Impaired dimerisation, destabilisation and degradation of the ER  transcription of ER-regulated genes, including the PgR ER = oestrogen receptor; PgR = progesterone receptor
  • Fulvestrant vs. Anastrozole: Trial Design Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trial 0020: International, randomised 1:1, open, parallel-group Trial 0021: North American, randomised 1:1, double-blind, double-dummy, parallel-group Anastrozole 1mg daily orally Trial 0020: ( n =229) Trial 0021: ( n =194) Fulvestrant 250mg i.m. once monthly Trial 0020: 1 x 5ml ( n =222) Trial 0021: 2 x 2.5ml ( n =206) Analysis after 340 events (progression or death prior to progression) Trials 0020 and 0021: Recruitment between May 1997 and August 1999 Robertson JFR et al. Cancer 2003; 98: 229–238.
  • Fulvestrant vs. Anastrozole: Time to progression Hazard ratio (95.14% CI): 0.95 (0.82 – 1.10); p=0.48 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 Median follow-up 15.1 months Time to progression (months) Median TTP: Fulvestrant = 5.5 months Anastrozole = 4.1 months Fulvestrant 250 mg Anastrozole 1 mg Robertson JFR et al. Cancer 2003; 98: 229–238 Proportion not progressed
  • Duration of response from randomisation to progression (responding patients) Median follow-up 22.1 months 0 6 12 18 24 30 36 42 Fulvestrant 250 mg Anastrozole 1 mg Duration of response (months) 0.0 0.2 0.4 0.6 0.8 1.0 Median DoR: Fulvestrant = 16.7 months Anastrozole = 13.7 months Proportion responding Robertson JFR et al. Cancer 2003; 98: 229–238
  • Duration of response – without or with visceral metastases Duration of objective response (days) 0 200 400 600 800 1000 Fulvestrant 250 mg (n=52) Anastrozole 1 mg (n=45) 0.0 0.2 0.4 0.6 0.8 1.0 Without visceral metastases Proportion with objective response 0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0 Fulvestrant 250 mg (n=30) Anastrozole 1 mg (n=25) With visceral metastases Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233
  • Fulvestrant vs. Anastrozole: Overall survival 0 60 66 0.0 0.2 0.4 0.6 0.8 1.0 Overall survival (months) Proportion alive 54 48 42 36 30 24 18 12 6 Median survival: Fulvestrant = 27.4 months (n=428) Anastrozole = 27.7 months (n=423) Hazard ratio (95% CI): 0.98 (0.84 – 1.15); p=0.81 Median follow-up 27.0 months Fulvestrant 250 mg Anastrozole 1 mg Howell, A et al. Cancer 2005 ; 104: 236–9.
  • Fulvestrant vs. Anastrozole: Tolerability: predefined adverse events Gastrointestinal disturbances Hot flushes Urinary tract infection Joint disorders Thromboembolic disease Vaginitis Weight gain Withdrawn due to adverse event Number of adverse events (%) Anastrozole (n=423) Fulvestrant (n=423) p-value Robertson JFR et al. Cancer 2003; 98: 229–238 0.53 0.91 0.06 0.0036 0.68 0.51 0.35 Robertson JFR et al. Cancer 2003; 98: 229–238 196 89 31 23 15 11 4 12 (46.3) (21.0) (7.3) (5.4) (3.5) (2.6) (0.9) (2.8) 185 87 18 45 17 8 7 8 (43.7) (20.6) (4.3) (10.6) (4.0) (1.9) (1.7) (1.9)
  • Indirect comparison of clinical benefit rates in second-line hormonal treatment trials CB ( CR + PR + SD ≥ 24 weeks) rate (%) Fulvestrant 1 Anastrozole 1 Anastrozole 2 Letrozole 2 Exemestane 3 1 Robertson et al. Cancer 2003; 98: 229–238; 2 Rose et al. Eur J Cancer 2003; 39: 2318-2327 3 Kaufman et al. J Clin Oncol 2000; 18: 1399-1411 ; 4 Buzdar et al. J Clin Oncol 2001; 19: 3357-3366 5 Dombernowsky et al. J Clin Oncol 1998; 16: 453-461 ; 6 Buzdar et al. Cancer 1998; 83: 1142-1152 0 10 20 30 40 50 Megestrol acetate 3 Letrozole 4 Megestrol acetate 4 Letrozole 5 Megestrol acetate 5 Anastrozole 6 Megestrol acetate 6 40% vs 42% 32% vs 35% 30% vs 30% 35% vs 37% 23% vs 27% 41% vs 44%
  • Important Factors for Sequencing of Endocrine Therapies
    • Lack of cross-resistance
      • Different mechanisms of action
    • Efficacy benefits
      • Most effective agent should be used first
    • Tolerability benefits
    • Maintaining sensitivity to subsequent endocrine therapy
    • What is known about:
      • Fulvestrant and other endocrine agents following anastrozole?
      • Activity of other agents following fulvestrant?
  • Postmenopausal Patients with ER+ Advanced Breast Cancer and hormonal options after Non-steroidal AI 1st treatment 2nd treatment 4th treatment 3rd treatment Non-steroidal AI Fulvestrant/Tamoxifen? Exemestane? Exemestane Fulvestrant Tamoxifen Tamoxifen Tamoxifen Exemestane or Fulvestrant
  • Exemestane after non-steroidal AIs
    • Phase II, multicentre trial in postmenopausal patients with ABC (second- to fourth-line)
    • Patients had received a non-steroidal AI as their last treatment
    • Overall CB rate: 24.3%; overall RR : 6.6%
    Aminoglutethimide (n=136) Exemestane (n=241) CB 27% Anastrozole (n=46), letrozole (n=40) or vorozole (n=19) CB 20% Lønning et al. J Clin Oncol 2000;18:2234-2244
  • NCCTG study – efficacy of fulvestrant following failure of an AI and tamoxifen
    • Overall CB rate: 35.0%, overall response rate: 14.3%
    • Median duration of response: 11.4 months
    • Median survival: 20.2 months
      • 1-year survival rate: 70.5%
    Tamoxifen Fulvestrant (n=56) AI Tamoxifen AI Adjuvant Advanced Tamoxifen AI Tamoxifen AI CB 28.6% OR 8.9% AI CB 52.4% OR 28.6% Fulvestrant (n=21) Ingle et al. J Clin Oncol 2006; 24: 1052-1056
  • Prior non-steroidal AI therapy Fulvestrant LD* + 250 mg / month + placebo for exemestane (n =330 ) Exemestane 25 mg po od + placebo for fulvestrant ( n =330) *LD, loading dose regimen (500 mg d ay 0 + 250 mg day 14 and day 28 and 250 mg/month thereafter)
    • Endpoints
      • primary  TTP
      • secondary  OR rate  duration of response  CB rate  survival  quality of life
        •  pharmacokinetics  safety
    • Eligibility
      • histological confirmation
      • postmenopausal status
      • progression or recurrence on prior AI therapy
      • ER+ and / or PgR+
      • measurable disease
      • performance status 0–2
    Gradishar W et al. SABCS 2006
  • EFECT: Time to progression (ITT) Proportion of patients progression-free Months At risk: Fulvestrant Exemestane HR = 0.963, 95% CI (0.819, 1.133), p=0.6531 Cox analysis, p=0.7021 Fulvestrant Exemestane 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 351 195 96 50 25 12 4 2 342 190 98 41 21 12 8 6 0 1 0 0 Fulvestrant 3.7 Exemestane 3.7 Median (months) Gradishar W et al. SABCS 2006
  • EFECT: Objective response and clinical benefit rate (evaluable for response population) * Analyses are not adjusted for baseline covariates OR rate (CR + PR) CB rate (OR + SD ≥ 24 wks) Fulvestrant 7.4% (20/270) 32.2% (87/270) Exemestane 6.7% (18/270) 31.5% (85/270) Odds ratio* (95% CI) 1.120 (0.578, 2.186) 1.035 (0.720, 1.487) p-value 0.7364 0.8534 Gradishar W et al. SABCS 2006
  • EFECT: Duration of response (from randomisation) Proportion of patients responding Months At risk: Fulvestrant Exemestane Fulvestrant Exemestane 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 20 20 16 11 8 3 0 0 18 18 15 10 5 4 3 3 0 0 3 3 Fulvestrant 13.5 Exemestane 9.8 Median (months) Gradishar W et al. SABCS 2006
  • EFECT: Adverse events Patient had an AE Drug-related AE Withdrawal due to AE AE of grade 3 or higher Serious AE Drug-related SAE Death due to AE Death due to drug-related AE Fulvestrant n=351 Exemestane n=340 88.9% 45.9% 2.0% 21.7% 11.4% 1.1% 0.9% 0% 88.8% 48.8% 2.6% 22.6% 12.4% 0.6% 0.9% 0% Gradishar W et al. SABCS 2006
  • EFECT Summary
    • The first phase III trial in this population
    • Confirmed efficacy of Fulvestrant in patients who have progressed on a NSAI
    • Similar efficacy seen on both treatment arms
    • No differences were seen in reported AEs between Fulvestrant and Exemestane
    Gradishar W et al. SABCS 2006
  • Recent Evidence with Trastuzumab (Herceptin) plus Anastrozole (Arimidex) in Advanced Breast Cancer in post-menopausal women: TAnDEM Study TrAstuzumab in Dual HER2-positive Metastatic breast cancer ESMO 2006
  • TAnDEM: Study Design HER2-positive, HR-positive MBC (n=208) R Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose  2 mg/kg qw until disease progression Anastrozole 1 mg daily until disease progression ESMO 2006
  • TAnDEM: Progression-Free Survival PFS = time from randomisation to date of progressive disease or death 103 48 31 17 14 13 11 9 4 1 1 0 0 A + H 104 36 22 9 5 4 2 1 0 0 0 0 0 A Probability 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 0.0 No. at risk 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 Median PFS 4.8 months 2.4 months Events 87 99
  • TAnDEM: Conclusions
    • The combination of A+H in first-line treatment of women with HER2-positive hormone-dependent MBC leads to significant improvements in :
    • PFS 4.8 vs. 2.4 months; p=0.0016
    • CBR 42.7% vs. 27.9%; p=0.026
    • ORR 20.3% vs. 6.8%; p=0.018
    • OS was longer in the A+H arm (28.5 vs. 23.9 months, p=0.325) despite crossover by patients in the A arm to receive H upon PD.
  • Endocrine Therapy in MBC Summary
    • Many options available for metastatic breast cancer; hence individual patient and tumor characteristics are important in treatment decisions.
    • Clinical studies continue to clarify roles of endocrine therapy, chemotherapy, and biologic therapy, results are very promising.
    • For post-menopausal patients with hormone receptor-positive disease, several endocrine agents are available including AI’s (anastrozole, exemestane, and letrozole), SERM’s (tamoxifen) and the selective ER down-regulator, fulvestrant.
    • - Hormonal agents can be used sequentially in post-menopausal women
    • In pre-menopausal women (HR+ve tumour), tamoxifen or tamoxifen plus LHRHa may be a useful option
    • The potential effect of all of these endocrine, chemotherapeutic, and biologic treatments on quality of life is an important consideration.
  • Thank You
  • Back-up Slides
  • Many signal pathways target ER EGFR, HER2 Raf MEK1/2 Ras ERK 1/2 p90rsk AKT GRB2 SOS PI3 Kinase Cbl p110 p85 p160 ER CBP Basal Transcription Machinery ERE Target gene P P P Rac1 cdc42 MLK3 MKK3/6 MEKK1 P38 Inflammatory cytokines TNF  ,IL-1 IGFR Cytokines stress
    • Targets HER2 protein
    • High affinity and specificity
    • 95% human, 5% murine
      • Decreases potential for immunogenicity
      • Increases potential for recruiting immune effector mechanisms
    Trastuzumab (Herceptin): Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 .
  • The HER Family Adapted from Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25. The epidermal growth factor family of receptors comprises 4 transmembrane proteins, each with different properties but all involved in the regulation of cell proliferation Extracellular Intracellular
  • Prognosis for HER2 Positive Patients
    • HER2 positivity is an independent predictor of poor prognosis
    • HER2 positivity also correlates with other clinical pathologic variables
      • Short disease-free interval
      • Tumor size
      • Positive nodal status
      • Ductal rather than lobular histology
      • High S-phase fraction
      • High nuclear grade
      • Mutated p53
      • Decreased estrogen and progesterone receptor expression
    Berger et al. Cancer Res . 1988;48:1238. Chazin et al. Oncogene . 1992;7:1859. Hynes and Stern. Biochim Biophys Acta . 1994;1198:165. O’Reilly et al. Br J Cancer . 1991;63:444. Paik et al. J Clin Oncol . 1990;8:103. Press et al. J Clin Oncol . 1997;15:2894. Slamon et al. Science. 1987;235:177. van de Vijver et al. N Engl J Med . 1988;319:1239.
  • Trastuzumab Combination (with CT) Pivotal Trial: Time to Progression Slamon et al. N Engl J Med. 2001;344:783. Median TTP was significantly longer for the Herceptin + CT arms (7.4 months) than for the CT arms (4.6 months; p < 0.001). H + CT 235 152 63 15 CT 234 103 25 6 1.0 0.8 0.6 0.4 0.2 0.0 p < 0.001 Median follow-up: 35 mo Herceptin + CT (n = 235) CT alone (n = 234) 0 5 10 15 20 25 30 Progression-free survival Months No. at risk:
  • Treatment paradigm for patients with metastatic breast cancer First-line Second-line Third-line Antioestrogen or non- steroidal AI Non-steroidal AI or anti- oestrogen If response, steroidal AI - exemestane, progestin Fourth-line If response, androgen No response Postmenopausal Premenopausal Antioestrogen or LHRH agonist Chemotherapy Response, ovarian ablation Response, non-steroidal AIs If response, steroidal AI - exemestane If response, progestin If response, androgen AI, aromatase inhibitor LHRH, luteinising hormone-releasing hormone
  • Phase III trials of second- and third- generation aromatase inhibitors versus tamoxifen in the advanced setting Superiority in favour of Endpoint(s) Nabholtz JM et al. J Clin Oncol 2000 Bonneterre J et al. Cancer 2001 Mouridsen H et al. J Clin Oncol 2001 Fadrozole versus tamoxifen Anastrozole versus tamoxifen Letrozole versus tamoxifen Formestane versus tamoxifen Tamoxifen Anastrozole Letrozole Tamoxifen TTP, time to progression; TTF, time to treatment failure TTP / TTF TTF TTP TTP
  • Anastrozole vs letrozole in open-label trial: FEM-INT-01 Second-line treatment of metastatic breast cancer Postmenopausal women with ER+ and/or PgR+ve or receptor unknown metastatic breast cancer who have progressed on tamoxifen Anastrozole 1mg Randomise Letrozole 2.5mg Rose, C et al. Eur J Cancer 2003; 39:2318–27
    • Secondary endpoints:
    • Objective response rate
    • Response duration
    • Survival
    • Primary endpoints:
    • TTP
  • Anastrozole vs letrozole Median TTP (months) Median TTF (months) Median OS (months) Objective response (CR+PR) (%) Letrozole ( n =356) 5.7 5.6 22.0 19.1 Anastrozole ( n =357) 5.7 5.6 20.3 12.3 0.920 0.761 0.624 0.013 Overall population p value OS, overall survival; TTF, time to treatment failure Rose, C et al. Eur J Cancer 2003; 39:2318–27
  • Overall tumour response by hormone receptor status Overall population ER+ve and/or PgR+ve Unknown Letrozole 30/173 (17.3) 38/183 (20.8) Anastrozole 28/167 (16.8) 16/190 (8.4) No. CR+PR/Total no. pts (%) Receptor status Rose, C et al. Eur J Cancer 2003; 39:2318–27
  • FEM-INT-01: summary of adverse events No. patients (%) Adverse event >2% bone pain dyspnoea nausea vomiting abdominal pain Any serious adverse event Discontinuations due to adverse event Letrozole ( n =356) Anastrozole ( n =357) 47 (13) 40 (11) 39 (11) 19 (5) 20 (6) 63 (18) 28 (8) 53 (15) 37 (10) 28 (8) 23 (7) 15 (4) 68 (19) 28 (8) Rose, C et al. Eur J Cancer 2003; 39:2318–27
  • Effect of aromatase inhibition in premenopausal women
    • Oestradiol levels not in postmenopausal range
    • Feedback mechanism increases FSH + LH
    • Follicular hyperplasia / hypertrophy possible
    • Use of AIs in premenopausal women only in combination with LHRH analogues (eg. goserelin)
      • or after surgical or radiological ovarian ablation
  • Goserelin plus anastrozole: trial design
    • 16 premenopausal women
    Goserelin + tamoxifen Goserelin + anastrozole Disease progression* *Advanced disease Forward et al 2004; BJC 90; 590-594
  • Oestradiol suppression with Goserelin + anastrozole Forward et al 2004; BJC 90; 590-594 0 50 100 150 200 250 Baseline Goserelin + tamoxifen Goserelin + Arimidex Mean serum oestradiol (pmol/L) p<0.0001 p<0.0001
  • Goserelin plus anastrozole: clinical effects
    • Clinical result
      • objective response / static disease at 6 months in 12 (75%) patients
      • median duration of remission >17 months
    Forward DP et al. Br J Cancer 2004; 90: 590-4
  • Summary: LHRHa/AI combination therapy
    • There is a good scientific rationale for combining an LHRHa (goserelin) with an AI in premenopausal women
    • The addition of an AI to an LHRHa substantially suppresses plasma oestrogen levels in premenopausal patients compared with an LHRHa alone
    • Treatment guidelines are increasingly recognising the potential for this combination