A phase III trial evaluating the role ofcontinuous letrozole versusintermittent letrozole following 4 to 6years of prior adjuvant endocrine therapyfor postmenopausal women withhormone-receptor positive, node-positiveearly stage breast cancer

S LEBackground• Current standard duration of adjuvant endocrinetherapy for breast cancer (either SERMs or AIs)is 5 years.• Improved DFS observed for:– Patients who receive extended adjuvantletrozole for 5 years following 5 years oftamoxifen compared with 5 years oftamoxifen alone. (MA.17)– Switching from tamoxifen to an AI after 2 to3 years of tamoxifen to complete five yearsof endocrine therapy. (EIS)– 5 years of initial AI compared with 5 yearsinitial tamoxifen. (ATAC, BIG 1-98)

S LEHypothesisIntroducing 3-month treatment-free intervalsduring the course of five years of extendedadjuvant letrozole will improve disease-freesurvival.Hypothesis is based on the theory that letrozolewithdrawal for 3 months will permit someestrogenic stimulation which will make residualresistant disease susceptible to letrozolereintroduction.

S LEPatient Population• Postmenopausal• Disease-free after 4 and 6 years ofprior adjuvant endocrine therapy(SERM and/or AI)• Endocrine-responsive breast cancerat diagnosis• Node-positive breast cancer atdiagnosis

SLEStratifyInstitutionPrior ET:SERMAIBothRANDOMIZEContinuous letrozole x 5 yrsIntermittent letrozole over 5 yrs9 mos. 9 mos. 9 mos. 9 mos. 12 mos.0 6 12 18 24 30 36 42 48 54 60Extended Adjuvant Endocrine TherapyA: Continuous letrozole 2.5 mg daily for 5 yearsB: Intermittent letrozole 2.5 mg daily for the first 9months of years 1 through 4, followed by 12months in year 5

SLEEnd Points• Primary: Disease-free survival (DFS)• Time from randomization to first occurrence of:– Local relapse (including invasive recurrencerestricted to the breast after breastconservingtreatment)– Regional relapse– Distant relapse– Contralateral breast cancer– Appearance of a second (non-breast)malignancy– Death from any cause

S LEEnd Points• Secondary:– Overall survival (OS)– Distant disease-free survival (DDFS)– Breast cancer free interval (BCFI)– Sites of first failure– Second (non-breast) malignancies– Deaths without prior cancer events– Adverse events

SLEStatistical Considerations• Hypothesize 20% reduction in risk of a DFSevent (HR = 0.80) with intermittent letrozolevs. continuous letrozole• Assumes 4-year DFS = 90% for continuousletrozole (based on N+ cohort in MA.17)• 2 interim and 1 final analysis at 647 DFSevents• 80% power; two-sided 0.05 level test ofsignificance• Target=4800 patients• 1600 patients per year for 3 years, 5 years ofadditional follow-up; one year start-up timeanticipated

SLEEligibility: PostmenopausalDefinitive confirmation of postmenopausal status isrequired.• Any age with bilateral oophorectomy (includingradiation castration AND amenorrheic for > 3months)• Age 56 or older: If the patient has any evidence ofovarian function, biochemical evidence of definitepostmenopausal status (defined as estradiol, LH,and FSH in the postmenopausal range) is required• Age 55 or younger must have biochemical evidenceof postmenopausal statusNote: Patients who have received prior LHRHanalogue within the last year are eligible if theyhave biochemical evidence of postmenopausalstatus

SLEEligibility: Disease Characteristics• At randomization: Patients must be clinicallydisease-free• No previous or concomitant malignancy EXCEPTadequately treated: basal or squamous cellcarcinoma of the skin, in situ carcinoma of thecervix or bladder, contra- or ipsilateral in situbreast carcinoma.• No bilateral breast cancer• At diagnosis– Operable, non-inflammatory breast cancer– Steroid hormone receptor positive tumor (ERand/or PgR) determined by IHC– Node-positive (axillary or IM nodes)

SLEEligibility: Prior/Concurrent Treatment• Proper local treatment including surgery withor without radiotherapy for primary breastcancer with no known clinical residual locoregionaldisease.• Completed 4 to 6 years of prior adjuvantendocrine therapy with SERMs, AIs, or asequential combination of both.• Stopped prior endocrine SERM/AI therapy• Randomized within 12 months of the last doseof prior SERM/AI• No restriction on other prior adjuvant therapies• Stopped HRT, bisphosphonates (except fortreatment of bone loss), or any investigationalagent at randomization.

SLEEligibility• Pathology material from the primary tumormust be available for submission for centralreview as part of the quality control measuresfor this protocol• No bone fractures due to osteoporosis at anytime during the 4-6 years of prior endocrineSERM/AI therapy• Adequate hepatic function• Trial and tissue informed consent

SLEPatient Visit Schedule• All patients will be followed every6 months for years 1 to 5, andthereafter yearly for assessment ofdisease status and for survivaldata collection.

SLEQL Substudy• Selected centers• 5 assessment timepoints• Standard LASA and patientreportedsymptom checklist• Target enrollment=744

SLEQL SubstudyContinuous letrozole x 5 yrsIntermittent letrozole over 5 yrs9 mos. 9 mos. 9 mos. 9 mos. 12 mos.0 6 12 18 24 30 36 42 48 54 60QL Assessments: LASA and Symptom Checklist

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