2. Treatment Options for Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Ongoing Studies This program is supported by an educational grant from Pfizer and Clinical Care Options

3. Treatment Options for Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Edith A. Perez, MD Mayo Clinic

4. Ongoing Clinical Trials of Aromatase Inhibitors in Premenopausal Women

5. clinicaloptions.com/oncology Ongoing Studies Issues for Premenopausal Patients With Hormone Receptor–Positive Breast Cancer  Tamoxifen is standard therapy  Ongoing clinical trials are evaluating the strategy of ovarian suppression in combination with aromatase inhibitors  The long-term toxicity of adjuvant therapies is a particular concern  The implications of possible fertility impairment and premature menopause require consideration when discussing adjuvant therapy

6. clinicaloptions.com/oncology Ongoing Studies Suppression of Ovarian Function Trial (SOFT): Study Design Randomization Target accrual: 3000 Enrolled as of 3/06: 499 Eligibility: Premenopausal Estradiol (E2) in the premenopausal range either after or without chemotherapy ER ≥ 10% and/or PgR ≥ 10% 5 Years *OFS = ovarian function suppression using triptorelin 3.75 mg by injection every 28 days for 5 years from randomization x 5 years or surgical oophorectomy or ovarian irradiation. OFS* + tamoxifen OFS + exemestane 25 mg/day Study Chairs: Prudence Francis, MD, and Gini Fleming, MD Tamoxifen 20 mg/day

7. clinicaloptions.com/oncology Ongoing Studies SOFT: Background  Women < 35 years of age with ER+ breast cancer have a worse prognosis when treated with adjuvant chemotherapy than similarly aged women with ER- breast cancer  Women < 35 years of age are less likely to become postmenopausal as a result of chemotherapy  Ovarian function suppression is effective adjuvant therapy for women aged < 50 years when compared with CMF chemotherapy –Efficacy after chemotherapy not clearly established  Aromatase inhibitors may offer some advantages over tamoxifen in the adjuvant setting, but they have not demonstrated safety or efficacy in premenopausal women

8. clinicaloptions.com/oncology Ongoing Studies SOFT: Exemestane  Exemestane is an oral irreversible inactivator of aromatase  Depletes plasma estrogen by > 90% and whole body aromatization by 98%; unlike reversible aromatase inhibitors, it cannot be displaced from the aromatase enzyme  Therapy with exemestane has demonstrated efficacy in postmenopausal women with hormone receptor–positive breast cancer  It is postulated that premenopausal women who undergo ovarian function suppression may derive the same benefits from aromatase inhibition

9. clinicaloptions.com/oncology Ongoing Studies SOFT: Objectives  Primary endpoint: disease-free survival  Secondary endpoints –Overall survival –Systemic disease-free survival –Quality of life –Sites of first treatment failure –Late side effects of early menopause –Incidence of second (nonbreast) cancers –Causes of death without cancer event

10. clinicaloptions.com/oncology Ongoing Studies SOFT: Eligibility  Estradiol within institutional premenopausal range –Measured between 2 weeks and 6 months after completing chemotherapy –Transient amenorrhea which resolves is acceptable (with premenopausal estradiol level)  Amenorrhea on tamoxifen acceptable if estradiol level in premenopausal range

11. clinicaloptions.com/oncology Ongoing Studies SOFT: Eligibility (cont’d)  Negative margins –Either axillary lymph node dissection, negative sentinel node biopsy, or pN1mi with randomization on a clinical trial evaluation microscopically positive sentinel nodes  Baseline chest x-ray, chemistries, CBC required

12. clinicaloptions.com/oncology Ongoing Studies SOFT: Expected Toxicity  Tamoxifen: hot flashes, irregular menses, vaginal discharge, thromboembolic disease, endometrial cancer  Ovarian function suppression: hot flashes, amenorrhea, osteoporosis, fertility impairment, decreased libido, vaginal dryness  Exemestane: hot flashes, possible osteoporosis

13. clinicaloptions.com/oncology Ongoing Studies SOFT: Follow-up  Patients will be followed by physical exam  Year 1: every 3 months  After Year 1: every 6 months for 5 years  After Year 5: yearly until death

14. clinicaloptions.com/oncology Ongoing Studies SOFT: Statistical Analysis  3 pair-wise comparisons, each tested at the 2-sided alpha level 0.0167  Target: 25% reduction in hazard  80% power  Sample size: 3000 patients

15. clinicaloptions.com/oncology Ongoing Studies Tamoxifen and Exemestane Trial (TEXT): Study Design Randomization Target accrual: 1845 Enrolled as of 3/06: 768 Eligibility: Premenopausal ER ≥ 10% and/or PgR ≥ 10% Candidates to begin GnRH analogue from the start of adjuvant therapy 5 Years *GnRH = triptorelin 3.75 mg by injection every 28 days x 5 years, but oophorectomy or radiation is allowed after 6 months. GnRH ± chemotherapy + exemestane Study Chairs: Barbara Walley, MD, and Olivia Pagani, MD GnRH* ± chemotherapy + tamoxifen

16. clinicaloptions.com/oncology Ongoing Studies TEXT: Objectives  Compare the disease-free and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with triptorelin and exemestane vs triptorelin and tamoxifen  Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens  Compare the sites of first treatment failure in patients treated with these regimens  Compare the incidence of second (nonbreast) malignancies in patients treated with these regimens

17. clinicaloptions.com/oncology Ongoing Studies TEXT: Eligibility  Premenopausal patients with histologically proven, resected breast cancer –Pathology material should be available  Randomization 12 weeks after definitive surgery  Hormone receptor–positive tumors  Tumor confined to breast and axillary lymph nodes without detected distant metastases –Exception: tumor detected in internal mammary chain nodes by sentinel node biopsy  Tumor confined to breast and axillary lymph nodes without detected distant metastases

18. clinicaloptions.com/oncology Ongoing Studies TEXT: Statistical Analysis  Primary endpoint: disease-free survival  Target: 25% reduction in hazard with exemestane compared with tamoxifen  2-sided alpha level 0.05; 80% power  Sample size: 1845 patients

19. clinicaloptions.com/oncology Ongoing Studies PERCHE (IBCSG 26-02, BIG 4-02): Study Design Premenopausal ER ≥ 10% and/or PgR ≥ 10% Patients for whom CT is considered to be a randomized option (lower risk) OFS = ovarian function suppression using triptorelin x 5 years or surgical oophorectomy or radiation; TEXT, randomized trial comparing tamoxifen vs exemestane. OFS + any chemotherapy + TEXT x 5 years or tamoxifen or exemestane Stratified by type of chemotherapy Type of OFS TEXT or tamoxifen or exemestane Target sample size: 1750 patients Study Chairs: M. Laura Nasi, MD, and Edith A. Perez, MD Randomization OFS + TEXT x 5 years or tamoxifen or exemestane

20. clinicaloptions.com/oncology Ongoing Studies PERCHE: Patient Population  Premenopausal women (E2) with histologically proven, resected breast cancer with ER- and/or PgR-positive tumors for whom there is an uncertain role for adding chemotherapy to the adjuvant treatment program

21. clinicaloptions.com/oncology Ongoing Studies PERCHE: Study Rationale  Role of endocrine manipulation as a central aspect of adjuvant therapy in premenopausal women deserves careful evaluation  Current data suggest that adjuvant combination chemotherapy plus tamoxifen may improve results over single modality treatments  The independent benefit of chemotherapy for premenopausal women with endocrine responsive disease who undergo ovarian ablation with tamoxifen or an AI is unclear  Endocrine therapy alone, with ovarian function suppression and tamoxifen or an AI, may be sufficient to achieve excellent outcomes without chemotherapy, especially for patients at low risk of recurrent disease

22. clinicaloptions.com/oncology Ongoing Studies PERCHE: Treatment Arms  Chemotherapy –≥ 2 months if anthracycline-containing regimen –≥ 4 months if nonanthracycline-containing regimen  Adjuvant endocrine therapy –OFS –Triptorelin 3.75 mg IM q 28 days x 5 years, or –Oophorectomy, or –Ovarian irradiation –Tamoxifen/exemestane: TEXT  Radiotherapy optional after mastectomy

23. clinicaloptions.com/oncology Ongoing Studies PERCHE: Statistical Analysis  Primary endpoint: disease-free survival  Target: 30% reduction in hazard by adding chemotherapy to combined endocrine therapy  2-sided alpha level 0.05 and 80% power  Sample size: 1750 patients

24. clinicaloptions.com/oncology Ongoing Studies Clinical Implications  Tamoxifen is the current standard of care; OFS considered an alternative option by some investigators  Adjuvant endocrine therapy may be as important as chemotherapy in premenopausal women with ER+ breast cancer  The long-term toxicity of adjuvant therapies, particularly regarding future fertility and premature menopause, require consideration when discussing adjuvant therapy  Ongoing clinical trials are evaluating the strategy of ovarian suppression in combination with aromatase inhibitors

25. clinicaloptions.com/oncology Ongoing Studies For more information on this important clinical topic, go online to: www.clinicaloptions.com/premenopausal  Free CME-certified virtual presentations with narration by the experts and more downloadable slidesets –Hope S. Rugo, MD: An Overview –Edith A. Perez, MD: Ongoing Studies  Sign up for a free CME-certified teleconference and present your questions to the experts!