Letrozole in Treating Postmenopausal Women Who Have Received Hormone Therapy for Hormone Receptor-Positive Breast Cancer

OBJECTIVES:

Primary

- Determine whether or not prolonged adjuvant hormonal therapy comprising letrozole vs
placebo will improve disease-free survival of postmenopausal women with estrogen
receptor-positive and/or progesterone receptor-positive breast cancer who have completed
5 years of hormonal therapy with 5 years of an aromatase inhibitor (AI) or 5 years of a
combination of up to 3 years of tamoxifen citrate followed by an AI.

- Compare the disease-free survival of patients treated with these regimens.

Secondary

- Compare overall survival of patients treated with these regimens.

- Compare breast cancer-free interval of patients treated with these regimens.

- Compare distant recurrence in patients treated with these regimens.

- Compare the incidence of osteoporotic-related fractures (e.g., Colles', hip, and spine)
in these patients treated with these regimens.

- Compare the incidence of arterial thrombotic events in patients treated with these
regimens.

OUTLINE: This is a double-blind, multicenter, placebo-controlled, randomized study. Patients
are stratified according to pathologic nodal status (negative vs positive), adjuvant
tamoxifen citrate therapy (yes vs no), and lowest bone mineral density T score for
lumbosacral spine, total hip, or femoral neck (> -2.0 vs ≤ -2.0 standard deviation). Patients
are randomized to 1 of 2 treatment arms.

- Group I: Patients receive oral placebo once daily.

- Group II: Patients receive oral letrozole once daily.

In both arms, treatment continues for up to 5 years in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed annually.

PROJECTED ACCRUAL: A total of 3,840 patients will be accrued for this study.

Eligibility Criteria

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 or 1 (0 = fully active, able to carry on all pre-disease performance without
restriction; 1 = restricted in physically strenuous activity but ambulatory).

- Patients must be postmenopausal at the time of randomization. (Note: Premenopausal or
perimenopausal women requiring therapy with luteinizing hormone-releasing hormone
[LHRH] analogs to suppress ovarian function are not eligible.) For study purposes,
postmenopausal is defined as: age 56 or older with no spontaneous menses for at least
12 months prior to study entry, or age 55 or younger with no spontaneous menses for at
least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy)
AND with a documented estradiol level in the postmenopausal range according to local
institutional/laboratory standards, or a prior documented bilateral oophorectomy.

- The patient must have remained disease-free from the time of initial breast cancer
diagnosis until the time of randomization.

- The patient must have had histologically-confirmed invasive carcinoma of the breast by
diagnostic core needle biopsy or by final pathologic evaluation of the surgical
specimen.

- Patients who received neoadjuvant chemotherapy must have been clinical Stage I, II, or
IIIA. For patients who received adjuvant chemotherapy, the primary tumor must have
been T1-3 on pathologic evaluation and ipsilateral nodes must have been pN0, pN1
(pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b.

- The primary tumor must have been estrogen receptor (ER)-positive and/or progesterone
receptor (PgR)-positive. (Patients who had a tumor that was considered to be
borderline for hormone receptor positivity and who were treated with tamoxifen and/or
an aromatases inhibitor (AI) are eligible for this study.)

- Patients must have undergone either a lumpectomy with axillary nodal staging followed
by breast radiotherapy or a total mastectomy with axillary nodal staging. (Acceptable
axillary nodal staging procedures include sentinel node biopsy alone, if sentinel
nodes were negative on hematoxylin and eosin (H&E) staining.)

- The duration of the patient's hormonal therapy following breast cancer diagnosis must
have been 57-63 months from the first dose regardless of the number of missed doses.
Hormonal therapy must have consisted of an AI or a combination of up to 3 years of
tamoxifen followed by an AI. Tamoxifen may not have been given during years 4 and 5 of
the 5 years of adjuvant hormonal therapy. (Note: Patients must discontinue their
adjuvant AI therapy at the time of randomization.)

- Optional Letrozole Registration Program for patients who have not yet completed 5
years of hormonal therapy. (Note: As of September 5, 2008, the optional NSABP B-42
Registration Program closed to patient enrollment. Accrual and data collection for the
NSABP B-42 randomized treatment trial continues as planned.) In order to have a
predominantly letrozole-treated population for B-42 study entry, patients who have had
a minimum of 2 years of hormonal therapy and who are currently on tamoxifen (for up to
3 years) or an AI may be offered letrozole at no cost until they complete 5 total
years of initial adjuvant hormonal therapy.

- B-42 randomization must be within 6 months following completion of 5 years (57-63
months) of initial adjuvant hormonal therapy.

- At the time of randomization, the patient must have had the following: history and
physical exam within 3 months demonstrating no findings suggestive of recurrent breast
cancer; bilateral mammogram within 1 year (unilateral if patient had a mastectomy);
mammogram not required if patient had a prophylactic contralateral mastectomy; bone
mineral density (BMD) testing within 1 year; and fasting lipid profile (total
cholesterol, LDL-C, HDL-C, and triglycerides) with a total cholesterol value less than
or equal to grade 1 (according to CTCAE v3.0), with or without cholesterol-lowering
therapy.

- within 1 year if the patient has a history of hypercholesterolemia controlled
with cholesterol-lowering therapy and/or therapeutic lifestyle changes or if the
patient has a history of one or more of the following risk factors for future
cardiovascular events: diabetes, hypertension, obesity, tobacco use,
hypertriglyceridemia, documented coronary artery disease, or family history of
premature coronary heart disease.

- within 2 years for all other patients.

Ineligibility Criteria

- Patients with one or more of the following conditions will be ineligible for this
study:

- History of non-traumatic osteoporotic fracture of wrist, hip, or spine.

- Diagnosis of bilateral breast cancer including ductal carcinoma in situ
(DCIS)[(synchronous or metachronous].

- Other malignancies unless the patient is considered to be disease-free for 5 or more
years prior to randomization, and is deemed by their physician to be at low risk for
recurrence. Patients with the following cancers are eligible if diagnosed and treated
within the past 5 years: carcinoma in situ of the cervix, colon carcinoma in situ,
melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

- Sex hormonal therapy, e.g., estrogen- or progesterone-replacement therapy or oral
contraceptives. These patients are eligible only if this therapy is discontinued prior
to randomization.

- Therapy with any hormonal agent such as raloxifene for management of osteoporosis.
Patients are eligible only if these medications are discontinued prior to study entry.

- Administration of any investigational agent within 30 days before study entry.