Investigator Meeting SOFT GOCCHI August 16, 2007 BIGBIG

Tailored Treatment Investigations Premenopausal patients with endocrine- responsive disease (ER > 10% and/or PgR > 10%) Open questions related to adjuvant treatments: 1.Role of suppression of ovarian function 2.Role of AI 3.Role of chemotherapy in addition to endocrine therapies 4.Duration of GnRH analogue when combined with SERMS

SOFT: Suppression of Ovarian Function Trial (IBCSG 24-02; BIG 2-02) TEXT: Tamoxifen and Exemestane Trial (IBCSG 25-02; BIG 3-02) North American Intergroup and Breast International Group (BIG) participation Coordinating Group: International Breast Cancer Study Group (IBCSG) Pharmaceutical Partner: Pfizer STP Tailored Treatment Investigations Premenopausal patients with endocrine-responsive disease (ER > 10% and/or PgR > 10%)

SOFT Suppression of Ovarian Function Trial A Phase III Trial Evaluating the Role of Ovarian Function Suppression and the Role of Exemestane as Adjuvant Therapy for Premenopausal Women with Endocrine Responsive Breast Cancer Gini Fleming and Prue Francis

SOFT: Background EBCTCG overview: Ovarian ablation effective adjuvant therapy in women < 50 EBCTCG overview: benefit of ovarian ablation uncertain in women < 50 if also receive chemotherapy

Does Overview underestimate ovarian ablation efficacy? Some were hormone receptor negative Most women < 50 who receive adjuvant chemotherapy become menopausal Need to test ovarian function suppression in group who can benefit i.e. remain premenopausal after chemo + receptor positive cancer

Amenorrhea after Chemotherapy 80% of women > 40 yrs after CMF x 6 < 50% women < 40 yrs after CMF Less amenorrhea with AC than CMF (34% vs 69%) Prognosis after CMF better in those who get amenorrhea

Combining Tamoxifen plus ovarian function suppression In advanced breast cancer there is a survival advantage to combined endocrine treatment (GnRH + Tam) vs. single hormonal treatment in premenopausal women

Women < 35 yrs with hormone receptor positive breast cancer Do poorly after adjuvant chemotherapy alone Worse prognosis than premenopausal women > 35 Paradoxically have worse prognosis than same age group with hormone receptor negative cancer when treated with adjuvant chemotherapy

SOFT [IBCSG 24-02, BIG 2-02] Patients who remain premenopausal within 6 months after CT, or receive tamoxifen alone as adequate treatment Premeno. ER  10% and/or PgR  10% Patients with estradiol (E 2 ) in the premenopausal range either after CT or without CT CT=chemotherapy; T=tamoxifen; E=exemestane; OFS=ovarian function suppression using triptorelin x 5 years or surgical oophorectomy or ovarian irradiation RANDOMIZERANDOMIZE T x 5y OFS + T x 5y OFS + E x 5y Any CT PremenopausalPremenopausal No CT Strata Target sample size: 3000 patients * *Randomization within a 8-month evaluation period after end of CT, or within 12 weeks after definitive surgery for patients with no CT

SOFT: Eligibility (the basics) Resected Breast Cancer ER and/or PgR positive (  10% IHC) Premenopausal

SOFT: Premenopausal Estradiol within institutional premenopausal range Measured between 2 wks and 8 mos post chemotherapy Transient amenorrhea which resolves is acceptable (with premenopausal E2 level) Amenorrhea on tamoxifen acceptable if estradiol level in premenopausal range

SOFT: Treatment CHEMOTHERAPY –Completed prior to randomization or not given ADJUVANT ENDOCRINE THERAPY –OFS by randomization (investigator choice of method: Triptorelin 3.75mg IM q 28 days x 5 y OR oophorectomy OR ovarian irradiation) –Tamoxifen/Exemestane by randomization RADIOTHERAPY –Optional after mastectomy –Required after breast-conservation

SOFT: Primary Objectives Compare OFS + T vs T Compare OFS + E vs T Compare OFS + E vs OFS + T Primary endpoint: Disease-free survival

SOFT: Statistical Considerations 3 pairwise comparisons, each tested at the 2-sided alpha level Target: 25% reduction in hazard 80% power Sample Size: 3000 patients

STP: 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 (non-breast) cancers Causes of death without cancer event

SOFT: OFS Triptorelin: 3.75 mg IM q28 days for 5 years from randomization unless: –relapse or intolerance Triptorelin supplied Zoladex allowed but not supplied Irreversible OFS allowed

Adjuvant Endocrine Therapy Exemestane 25 mg po daily for 5 years Tamoxifen 20 mg po daily for 5 years Exemestane/Tamoxifen should start after adjuvant chemotherapy has been completed or at least 6 weeks after the initiation of GnRH analogue, whichever is later NB if patient ceases GnRH, exemestane ineffective

Exemestane Irreversible inactivator of aromatase Steroidal structure

TEXT Tamoxifen and Exemestane Trial A Phase III Trial Evaluating the Role of Exemestane Plus GnRH Analogue as Adjuvant Therapy for Premenopausal Women with Endocrine Responsive Breast Cancer Olivia Pagani and Barbara Walley

TEXT [IBCSG 25-02, BIG 3-02] Patients who should receive OFS from the start Premeno. ER  10% and/or PgR  10% Candidates to begin GnRH analogue (triptorelin) from the start of adjuvant therapy Strata** Any CT No CT CT=chemotherapy; GnRH analogue=triptorelin x 5 yrs, but oophorectomy or radiation is allowed after 6 months RANDOMIZERANDOMIZE GnRH + Tamoxifen* x 5y +/- CT** GnRH + Exemestane* x 5yy +/- CT** *to begin at least 6 weeks after start of triptorelin or after CT, whichever is later. **choice of +/- CT may be made by previous randomization in the PERCHE trial. Target sample size: 1845 patients

TEXT + SOFT It is prospectively planned to combine data from the arms comparing exemestane plus ovarian function suppression (OFS) versus tamoxifen plus OFS in the SOFT trial with the data from the TEXT trial.

The Quality of Life (QL) component is an integral part of the current protocols Includes core QL indices (e.g., physical well-being, mood, coping) and focus on impact of menopausal symptoms (e.g., hot flushes, loss of sexual interest) Baseline assessment prior to randomization Every 6 months for first two years Annually in years 3 to 6 (total 9 times thru 6 yrs) See protocol section 10.0 and Appendix V STP: Quality of Life Study

QL Forms One-page QL Core Form (QLC) – [LASA scales] One-page QL Module Form (QLM) – [LASA scales] For English-speaking centers: Two-page QL Supplement Form (QLS) – [Likert scales] Missing QL Form (MQL) – for patients who do not participate or whenever an assessment is missed See protocol section 10.0 and Appendix V STP: Quality of Life Study

LASA scale example Likert scale example

STP Target and Actual Accrual (through July 31, 2007)

STP Information