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A Case Based Approach to Hormone Therapy Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller.

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Presentation on theme: "A Case Based Approach to Hormone Therapy Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller."— Presentation transcript:

1 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 Clinical Updates Optimizing Endocrine Therapy for Early Breast Cancer

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: 1.An aromatase inhibitor (AI) for 5 years 2.Tamoxifen for 2-3 years followed by an AI for a total duration of 5 years 3.Tamoxifen for 5 years followed by discussion of extended adjuvant hormone therapy with an AI 4.Ovarian suppression or ablation with tamoxifen 5.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 E 2 > 40pg, 8 were amenorrheic > 6 months 5 with E 2 > 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 Amenorrhea Royal 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) Smith I et al, JCO 2006 * Chemotherapy-Induced Amenorrhea

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 Study Cumulative HR Overall Survival ExemestaneTamoxifen Annual Hazard Rate, % (95% CI) ITT12345 Exemestane0.8 (0.5, 1.2)1.8 (1.3, 2.5)2.2 (1.6, 2.9)3.6 (2.8, 4.5)2.3 (1.6, 3.4) Tamoxifen1.0 (0.7, 1.5)2.4 (1.8, 3.1)2.5 (2.0, 3.3)3.2 (2.5, 4.1)2.9 (2.1, 4.1) ITTER+/Unknown End of treatment 0.02 0.00 0.04 0.06 0.08 0.10 0.12 0.14 Cumulative Rate 012345 Time since randomization (years) 0.00 End of treatment 0.02 0.04 0.06 0.08 0.10 0.12 0.14 012345 Time since randomization (years) Cumulative Rate Jassem, J. et al Anticancer Drugs. 2008 Feb;19 Suppl 1:S3-7.

12 IES - Intergroup Exemestane Study Consistency of OS Across Subgroups 0.84 (0.61, 1.18) 0.75 (0.60, 0.95) 0.85 (0.67, 1.07) 0.84 (0.69, 1.02) 0.83 (0.52, 1.32) 0.83 (0.65, 1.05) 0.84 (0.63, 1.13) 1.01 (0.70, 1.47) 0.70 (0.52, 0.95) 0.90 (0.67, 1.22) 0.83 (0.69, 0.99) 0.81 (0.60, 1.09) Favors Tamoxifen Favors Exemestane OS (Adjusted)* Age >70 yrs (1153) Age 60-69 yrs (1969) Age <60 yrs (1480) Prior tam >2.5 yrs (1838) Prior tam ≤2.5 yrs (2764) ER unknown (560) ER positive (4042) Previous CT (1499) No previous CT (3103) Nodes positive (2038) Nodes negative (2384) Hazard ratio (95% CI) 0.50.60.81.01.21.5 CT=chemotherapy *Adjusted for Nodal Status, Chemotherapy Use & HRT Use ER+/Unknown p=0.04 HR (95% CI) Coombes RC et al. Lancet 2007; 369: 559-70.

13 IES n=4,274 0.76 ARNO n=979 0.62 ABCSG n=2579 0.61 ITA n=448 0.42 Results of Switch Trials exemestane anastrozole tamoxifen 1.0 AIs better TAM better HR DFS 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 ABCSG12 ANA Does Not Improve DFS vs TAM in 1800 Premenopausal Women with Early Stage Disease 100 90 80 70 60 50 40 30 20 10 0 012243648607284 Time since randomization, months Disease-free survival, % No. ofHazard ratio (95% CI) eventsvs TAMP value ANA721.096 (0.78 to 1.53).593 TAM65 No. at risk 90083471855241124312950 90384472554041125513951 TAM ANA Median follow-up = 48 months. Gnant et al, NEJM 2009 Overall: 4-year DFS = 92.4%; 4-year OS = 97.7% 30% with node positive disease

15 MA.17: Summary of Efficacy Goss et al. J Natl Cancer Inst. 2005;97:1262. DFSDistant DFSOS Node+ patients HR 0.61* (95% CI, 0.45-0.84) HR 0.53* (95% CI, 0.36-0.78) HR 0.61* (95% CI, 0.38-0.98) All patients HR 0.58; P<0.001HR 0.60; P<0.002HR 0.82 + ; P=0.3 Node– patients HR 0.45* (95% CI, 0.27-0.75) HR 0.63 (95% CI, 0.31-1.27) HR 1.52 (95% CI, 0.76-3.06)  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.

16 Tamoxifen Exemestane Test Post-meno- pause 2-3 years Yes No 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 Study Study DesignPatient PopulationQuestions SOFT (IBCSG 24-02) TAM 5y vs TAM 5 y + OFS vs EXE 5 y + OFS 2,700 pre-menopausal women with endocrine responsive disease treated with no adjuvant chemo or remain pre- menopausal after chemo Does OS add to TAM (or EXE) in pre-menopausal women not treated with chemotherapy? Does OFS add to chemo in pre- menopausal women? TEXT (IBCSG 25-02) OFS = TAM 5 y vs OFS + EXE 5 y 2,025 pre-menopausal women with endocrine responsive disease and candidates for OFS, and who may or may not receive chemo Is an AI superior to TAM in pre- menopausal women treated with OFS? ABC SG 12 OFS + TAM vs OFS + ANA 1,750 pre-menopausal women with endocrine responsive disease Is an AI superior to TAM in pre- menopausal women treated with OFS? OFS=Ovarian Function Suppression

18 ZOL Significantly Improves DFS Compared With Endocrine Therapy Alone 100 90 80 70 60 50 40 30 20 10 0 012243648607284 Time since randomization, months Disease-free survival, % No. of Hazard ratio (95% CI) events vs No ZOLP value ZOL54 0.64 (0.46, 0.91).012 No ZOL83 Median follow-up = 48 months. Gnant et al, NEJM 2009 No. at risk No ZOL 904 832 713 537 407 241 145 47 ZOL 899 846 730 555 414 257 123 54

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: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 biopsyShe 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 Therapy Replacing 5 Years of Tamoxifen as the Gold Standard AIs as Initial Therapy AIs After 2-3 Yrs of TAM AIs After 5 Years of TAM TAM X 5 Yrs AI X 5 Yrs TAM X 2-3AI X 2-3 TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs Three Strategies

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

24 BIG 1-98 Trial Mouridsen. SABCS. 2008 (abstr 13); BIG 1-98 Collaborative Group. N Engl J Med. 2005;353:2747; Coates. J Clin Oncol. 2007;25:486. SURGERYSURGERY Years TamoxifenLetrozole Tamoxifen Tam Let TamN=911 N=917 N=1548 N=1546 N=1548 N=1540 N=1828Enrolled1998-2000 N=6182Enrolled1999-2003 N=8010 025 Previous analyses show 5 yrs of upfront letrozole significantly prolongs DFS and time to distant recurrence vs upfront tamoxifen 619 patients crossed over from tamoxifen only to letrozole arm R DFS=disease-free survival.

25 BIG 1-98: Sequential Therapy TTR TTR=time to recurrence. Overall Tam Let vs Let By Nodal Status* Let Tam vs Let *42% of population is node+; 58% is node–. Overall By Nodal Status* 20202020 15151515 10 5 0 20202020 15 10 5 0 Breast Cancer Recurrence (%) 20202020 15151515 10101010 5 0 20202020 15 10101010 5 0 0 123456 Years From Randomization Breast Cancer Recurrence (%) Years From Randomization 0 123456 0 1 2345 6 0 123456 4.1 9.1 2.5 7.3 7.9 0.9 14.7 4.7 1.3 3.5 4.9 12. 4 Node+ Node– Tam Let Letrozole Letrozole Let Tam Letrozole Letrozole 2.5 2.5 7.3 7.3 4.7 3.9 1.5 0.9 3.5 3.9 12.5 12.4 Node+ Node– Mouridsen. SABCS. (abstr 13). Mouridsen. SABCS. 2008 (abstr 13).

26 Recurrences Breast Cancer Deaths More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000. Years 85.2 76.1 68.2 73.7 62.7 54.9 68% 55% 0 20 40 60 80 100 051015 TamoxifenControl 15%17% 0 20 40 60 80 100 051015 73% 64% 80.9 73.0 87.8 73.2 64.0 Years TamoxifenControl 9%18% 91.4 % of patients

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

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

29 CYP2D6 Genotype and Endoxifen Jin Y et al: J Natl Cancer Inst 97:30, 2005 CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state) P<0.001, r 2 =0.24 Plasma Endoxifen (nM)

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

31 Incidence of Moderate or Severe Hot Flashes and CYP2D6 Status Genotype% of Patients With Moderate or Severe Hot Flashes CYP2D6 *4/*4 CYP2D6 *4/WT or Wt/WT 0%20% Goetz et al J Clin Oncol. 2005;23(36):9312-8.

32 Breast Cancer and Relevant Inhibitors of CYP2D6 Strong Inhibitors Generic / Brand Names Fluoxetine Prozac® Paroxetine Paxil® Qunidine Cardioquin® Bupropion Wellbutrin® Adapted from: http://medicine.iupui.edu/clinpharm/ddis Non or weak Inhibitors Generic / Brand Names Venlavaxine Effexor® Citalopram Celexa® Escitalopram Lexapro® Sertraline Zoloft® (moderate?) Moderate Inhibitors Generic / Brand Names Diphenhydramine Benadryl® Thioridazine Mellaril® Duloxetine Cymbalta® Cimetidine Tagamet® Amiodarone Cordarone®

33 What Would I Do in This Case? She has a high risk cancer and is clearly postmenopausalShe has a high risk cancer and is clearly postmenopausal I would start with an aromatase inhibitorI would start with an aromatase inhibitor If she has significant side effects, consider changing to tamoxifen after two or three yearsIf 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: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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