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A Case Based Approach to Hormone Therapy

Clinical Updates Optimizing Endocrine Therapy for Early Breast Cancer . A Case Based Approach to Hormone Therapy. Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA. Case 1.

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A Case Based Approach to Hormone Therapy

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  1. Clinical Updates Optimizing Endocrine Therapy for Early Breast Cancer A Case Based Approach to Hormone Therapy Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

  2. Case 1 • A healthy 48 year old woman discovers a mass in the central right breast while showering. A mammogram 6 months before showed dense breasts without focal mass. • Exam: 2 cm central breast mass, no palpable axillary nodes • Ultrasound: 1.8 cm ill-defined hypoechoic mass • Ultrasound guided core biopsy reveals a grade II invasive ductal carcinoma with lymphovascular invasion

  3. Case I (cont.) • Lumpectomy and sentinel lymph node biopsy reveals a 2.1 cm grade II invasive ductal cancer that is ER+, PR+ and HER2 1+ (negative) by IHC, one sentinel lymph node is positive for 0.8 cm of invasive cancer • Completion axillary lymph node dissection reveals 1 additional positive node for a total of 2/15 positive nodes • She is well with no medical problems and is seeing you to discuss adjuvant therapy • She is premenopausal, although she notes skipped menses every few months for the last year

  4. Question • The patient receives adjuvant chemotherapy and has completed radiation. Her last menstrual period was the month before starting chemotherapy. • You recommend: • An aromatase inhibitor (AI) for 5 years • Tamoxifen for 2-3 years followed by an AI for a total duration of 5 years • Tamoxifen for 5 years followed by discussion of extended adjuvant hormone therapy with an AI • Ovarian suppression or ablation with tamoxifen • Ovarian suppression or ablation with an AI

  5. Important Points to Consider • How to choose the best hormone therapy for your patient? • When is a woman in menopause? • When are AIs safe to give to perimenopausal women? • Should ovarian suppression be used routinely?

  6. What Hormone Therapy? • Premenopausal at treatment start • Amenorrheic after chemotherapy does not mean menopause • Safest approach upfront is tamoxifen • Options include • Tamoxifen for 5 years followed by an AI • Tamoxifen for 2-3 years to guarantee menopause, then AI to complete 5 years of therapy • Tamoxifen with ovarian suppression if ovaries recover

  7. Estradiol, FSH and Amenorrhea Following Chemotherapy for Breast Cancer • Braverman et al, 2002 • 16 women with amenorrhea • 10 with E2 > 40pg, 8 were amenorrheic > 6 months • 5 with E2 > 40pg but FSH > 40 • Ovarian function may persist for months, and possibly years after chemotherapy induced amenorrhea • Amenorrhea is not menopause • AIs stimulate ovarian function! • Beware of AIs in young women with chemotherapy induced amenorrhea

  8. AIs Stimulate Gonadotropin Production in Women Whose Ovaries are Still Active; Resulting in Ovarian Stimulation and Follicle Growth De Ziegler et al, J Steroid Biochem and Biol, 2005

  9. Chemotherapy-induced AmenorrheaRoyal Marsden Experience - Case Series 45 women with CIA* on AIs (16 upfront, 20 switching, 9 extended) Median age: 47 (range 39-52) 33 biochemically confirmed ovarian suppression before therapy 12 (27%) recovered ovarian function menses [10], pregnancy without menses [1], biochemical assay without menses [1] Median duration of amenorrhea before recovering ovarian function 12 months (range 4-59) * Chemotherapy-Induced Amenorrhea Smith I et al, JCO 2006

  10. Criteria for Determining Menopause (NCCN v.2.2008) Prior bilateral oophorectomy Age > 60 y Age < 60 y and amenorrheic for 12 or more months in the absence of CT, Tam, toremifene or ovarian suppression and FSH and estradiol in the post-menopausal range If taking tamoxifen or toremifene, and age < 60 y, then FSH and plasma estradiol level in post-menopausal ranges • It is not possible to assign menopausal status in women receiving LHRH agonist or antagonist • In women pre-menopausal (by hormonal status and/or with menses) at the beginning of adjuvant therapy CT-induced amenorrhea is not a reliable indicator of menopausal status

  11. IES - Intergroup Exemestane StudyCumulative HROverall Survival 0.14 0.12 0.10 0.08 Cumulative Rate 0.06 0.04 0 1 2 3 4 5 0 1 2 3 4 5 0.02 0.00 Time since randomization (years) ITT ER+/Unknown Tamoxifen Exemestane End of treatment End of treatment 0.14 0.12 0.10 0.08 Cumulative Rate 0.06 0.04 0.02 0.00 Time since randomization (years) Jassem, J. et al Anticancer Drugs. 2008 Feb;19 Suppl 1:S3-7.

  12. IES - Intergroup Exemestane StudyConsistency of OS Across Subgroups Favors Tamoxifen Favors Exemestane ER+/Unknown HR (95% CI) Nodes negative (2384) 0.84 (0.61, 1.18) Nodes positive (2038) 0.75 (0.60, 0.95) 0.85 (0.67, 1.07) No previous CT (3103) 0.81 (0.60, 1.09) Previous CT (1499) ER positive (4042) 0.84 (0.69, 1.02) 0.83 (0.52, 1.32) ER unknown (560) 0.83 (0.65, 1.05) Prior tam ≤2.5 yrs (2764) 0.84 (0.63, 1.13) Prior tam >2.5 yrs (1838) 1.01 (0.70, 1.47) Age <60 yrs (1480) 0.70 (0.52, 0.95) Age 60-69 yrs (1969) 0.90 (0.67, 1.22) Age >70 yrs (1153) 0.83 (0.69, 0.99) OS (Adjusted)* p=0.04 0.5 0.6 0.8 1.0 1.2 1.5 Hazard ratio (95% CI) CT=chemotherapy *Adjusted for Nodal Status, Chemotherapy Use & HRT Use Coombes RC et al. Lancet 2007; 369: 559-70.

  13. Results of Switch Trials HR DFS 1.0 AIs better TAM better exemestane anastrozole tamoxifen Boccardo, F et al Ann Oncol. 2006 Jun;17 Suppl 7:vii10-4, Jakesz, R. et al Lancet. 2005 Aug 6-12;366(9484):455-62.

  14. ABCSG12ANA Does Not Improve DFS vs TAM in 1800 Premenopausal Women with Early Stage Disease TAM 900 834 718 552 411 243 129 50 ANA 903 844 725 540 411 255 139 51 100 90 80 70 60 Overall: 4-year DFS = 92.4%; 4-year OS = 97.7% 30% with node positive disease 50 Disease-free survival, % 40 No. of Hazard ratio (95% CI) events vs TAM P value ANA 72 1.096 (0.78 to 1.53) .593 TAM 65 30 20 10 0 0 12 24 36 48 60 72 84 No. at risk Time since randomization, months • Median follow-up = 48 months. • Gnant et al, NEJM 2009

  15. MA.17: Summary of Efficacy • Extended adjuvant letrozole significantly decreased overall risk of recurrence by 42% (4.2% absolute reduction) and risk of developing distant metastases by 40% compared with placebo. *Statistically significant benefit of letrozole. +Absolute increase of 0.4% for letrozole. HR = hazard ratio; CI = confidence interval. Goss et al. J Natl Cancer Inst. 2005;97:1262.

  16. Test Post-meno-pause Yes Exemestane Tamoxifen No Tamoxifen 2-3 years 2-3 years Peri-menopausal Women Assessment and Therapy Switch to AI in peri-menopausal patients is an option but only if close monitoring of ovarian function is performed

  17. Adjuvant Endocrine Therapy Trials In Hormone-responsive Pre-menopausal Breast Cancer Patients OFS=Ovarian Function Suppression

  18. ZOL Significantly Improves DFS Compared With Endocrine Therapy Alone 100 90 80 70 60 50 Disease-free survival, % 40 No. of Hazard ratio (95% CI) events vs No ZOL P value ZOL 54 0.64 (0.46, 0.91) .012 No ZOL 83 30 20 10 0 0 12 24 36 48 60 72 84 Time since randomization, months No. at risk No ZOL 904 832 713 537 407 241 145 47 ZOL 899 846 730 555 414 257 123 54 Median follow-up = 48 months.Gnant et al, NEJM 2009

  19. What Would I Do? • Hormonal therapy • This patient is likely to recover some degree of ovarian function • I would use tamoxifen upfront followed by an AI when clearly menopausal, similar to the sequencing used in the IES trial • Duration of therapy • Based on MA.17, I would consider extending the duration of AI therapy to 5 years if given following a course of tamoxifen • This patient would also be eligible for ongoing trials evaluating duration of AI therapy • Consider bisphosphonate trials……

  20. Case 2 • A 62 year old healthy postmenopausal woman is diagnosed with: • 1.5 cm infiltrating ductal carcinoma • Grade II, KI-67 20% • ER-positive (50%)/PR-negative (5%) • HER-2 negative by FISH • She undergoes lumpectomy and sentinel lymph node biopsy • Margins of resection are negative • One sentinel node is positive for carcinoma • Completion axillary dissection reveals a total of 4 out of 20 nodes positive

  21. Question She is treated with an anthracycline and taxane chemotherapy regimen and radiation You then recommend: • 5 years of tamoxifen • 5 years of an aromatase inhibitor • 2 years of tamoxifen followed by 3 years of an aromatase inhibitor • 2 years of an aromatase inhibitor followed by 3 years of tamoxifen • 5 years of tamoxifen followed by 5 years of an aromatase inhibitor • Use of CYP2D6 testing to help in the decision of what hormonal therapy to use

  22. Breast Cancer Adjuvant TherapyReplacing 5 Years of Tamoxifen as the Gold Standard Three Strategies AIs After 2-3 Yrs of TAM AIs as Initial Therapy AIs After 5 Years of TAM AI X 5 Yrs TAM X 5 Yrs TAM X 5 Yrs TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs TAM X 2-3 AI X 2-3

  23. Relative Reductions in DFS EventAs Reported in Eight AI Adjuvant Trials Anastrozole Letrozole Exemestane 70 ITA 52 m 60 58% MA.17 30 m 50 ABCSG-6 60 m B-33 30 m 40 42% Percent IES 56 m 36% ABCSG/ ARNO 72 m 30 32% ATAC 100 m BIG 76 m TEAM 2.75 y 24% 20 18% 15% 12% 10 11% 0 After 5 yrs of TAM After 2-3 yrs of TAM Up-Front ATAC trialists’ group. Lancet Oncol 2008 Mouridsen H, et al. SABCS 2008 Jones S, et al: SABCS 2008 Goss et al. JNCI 2005 Jakesz et al. ASCO 2005 Mamounas et al. JCO 2008 Boccardo et al. ASCO 2005 Coombes RC et al. ASCO 2006 Jakesz et al. SABCS 2008

  24. BIG 1-98 Trial Tamoxifen Tamoxifen Letrozole Tam Let Tam Let N=1828 Enrolled 1998-2000 N=911 SURGERY N=917 R N=8010 N=1548 N=6182 Enrolled 1999-2003 N=1546 Letrozole N=1548 N=1540 619 patients crossed over from tamoxifen only to letrozole arm 0 2 5 Years Previous analyses show 5 yrs of upfront letrozole significantly prolongs DFS and time to distant recurrence vs upfront tamoxifen DFS=disease-free survival. Mouridsen. SABCS. 2008 (abstr 13); BIG 1-98 Collaborative Group. N Engl J Med. 2005;353:2747; Coates. J Clin Oncol. 2007;25:486.

  25. BIG 1-98: Sequential Therapy TTR TamLet vs Let Tam Let Tam Let Let Tam vs Let Let Tam Let Tam Overall By Nodal Status* 20 20 14.7 Letrozole Letrozole 15 15 Node+ 9.1 12.4 10 10 7.9 *42% of population is node+; 58% is node–. Breast Cancer Recurrence (%) Breast Cancer Recurrence (%) 4.9 4.1 4.7 5 5 7.3 1.3 3.5 Node– 2.5 0 0.9 0 0 0 1 2 3 4 5 6 1 2 3 4 5 6 Years From Randomization Years From Randomization Overall By Nodal Status* 20 20 Letrozole 12.5 Letrozole 15 15 Node+ 12.4 10 10 7.3 Breast Cancer Recurrence (%) Breast Cancer Recurrence (%) 4.7 5 5 3.9 2.5 7.3 3.9 3.5 1.5 Node– 2.5 0 0.9 0 0 2 3 4 5 1 2 3 4 5 6 0 1 6 Years From Randomization Years From Randomization TTR=time to recurrence. Mouridsen. SABCS. 2008 (abstr 13).

  26. More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Recurrences Breast Cancer Deaths 15% 17% 9% 18% 100 100 91.4 85.2 80.9 76.1 80 80 73.0 87.8 68.2 73% 68% 73.7 73.2 64% 60 60 55% 62.7 64.0 % of patients % of patients 54.9 40 40 Tamoxifen Control Tamoxifen Control 20 20 0 0 0 5 10 15 0 5 10 15 Years Years Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.

  27. NSABP B-42Trial Evaluating Adjuvant AI Duration Postmenopausal, Disease-free, Stage I, II, or III invasive BC at diagnosis ER-positive and/or PgR-positive Letrozole X 5 yrs AI X 5 yrs Placebo X 5 yrs AI X 3-2 yrs TAM X 2-3 yrs Other Duration Trials: NCIC MA.17R Sole – intermittent dosing Planned Accrual: 3,840

  28. Decreased Tamoxifen Metabolism X Non-compliance Inhibitory Influences Enzymatic Repression Adapted from: Stearns, V et al. J Natl Cancer Inst. 2003 Dec 3;95(23):1758-64.

  29. CYP2D6 Genotype and Endoxifen P<0.001, r2=0.24 Plasma Endoxifen (nM) CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state) Jin Y et al: J Natl Cancer Inst 97:30, 2005

  30. RFS According to CYP2D6 (*4)Metabolizer Status in Women Receiving TAM as Adjuvant Therapy n=171 EM (n=115) IM (n=40) % PM (n=16) 2-year RFS EM 98% IM 92% PM 68% Log rank P=0.009 Multivariate HR (PM+IM/EM)=1.74 P=0.017 Years after randomization E: Extensive I: Intermediate P: Poor M: Metabolizer Goetz M et al. Breast Cancer Res Treat 101:113-121, 2007

  31. Incidence of Moderate or Severe Hot Flashes and CYP2D6 Status Goetz et al J Clin Oncol. 2005;23(36):9312-8.

  32. Breast Cancer and Relevant Inhibitors of CYP2D6 Adapted from: http://medicine.iupui.edu/clinpharm/ddis

  33. What Would I Do in This Case? • She has a high risk cancer and is clearly postmenopausal • I would start with an aromatase inhibitor • If she has significant side effects, consider changing to tamoxifen after two or three years • The optimal duration of hormonal therapy has not yet been defined, however: • Several trials are evaluating the impact of longer duration AI therapy • When this patient is five years out from start of hormone therapy, additional data should be available • For patients on therapy now, consider tolerance of hormone therapy, co-morbidiity and risk of relapse in your recommendation regarding treatment duration

  34. Conclusion • The future for hormone receptor positive breast cancer is very exciting and will help us to understand the pathways responsible for resistance to hormone therapy – and then use appropriate targeted agents to prevent recurrence and improve the treatment of advanced disease.

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