Neoadjuvant Letrozole for the Treatment of Stage I-III Estrogen Receptor Positive Breast Cancer, The NAOMI Study

Status: closed to accrual

This phase II trial tests whether letrozole works to shrink tumors before surgery (neoadjuvant) in patients with stage I-III estrogen receptor positive breast cancer. Estrogen receptor positive breast cancer is "estrogen-sensitive", which means that the hormone estrogen helps the cancer to grow. Letrozole is a type of drug called an “aromatase inhibitor” that can help block the growth of these types of tumors by lowering the amount of estrogen in the body. This trial may help researchers learn how an estrogen-blocking medication (letrozole) affects the cancer cells and their interaction with surrounding breast fat cells before surgery.

Inclusion Criteria

Histologic documentation of invasive breast cancer by core needle or incisional biopsy. Excess baseline biopsy tumor tissue sufficient to make ten 5-micron sections must be available for research use as part of this study
The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining present in greater than 50% of invasive cancer cells by immunohistochemistry (IHC)
The invasive cancer must be HER2-negative (IHC 0-1+, or with a fluorescence in situ hybridization [FISH] ratio of < 1.8 if IHC is 2+ or if IHC has not been done)
Clinical stage I-III invasive breast cancer with the intent to treat with surgical resection of the primary tumor. Baseline tumor must be >= 1 cm to provide adequate tissue
Patients with multicentric or bilateral disease are eligible if the subject is a candidate for clinically indicated neoadjuvant endocrine therapy. Samples from all available tumors are requested for research purposes
Women over 18 years of age, for whom neoadjuvant treatment with an aromatase inhibitor would be clinically indicated. Women must be post-menopausal, defined as last menstrual period (LMP) > 2 years (yrs) prior to registration or > 1 yr prior to registration with FSH and estradiol in post-menopausal range
Absolute neutrophil count (ANC) >= 1,000/mm^3
Platelet count >= 75,000/mm^3
Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
Ability to give informed consent

Exclusion Criteria

Prior endocrine therapy for any histologically-confirmed cancer is not allowed * Prior endocrine therapy that was administered >= 5 years ago for the prevention of breast cancer in patients with no history of breast cancer is allowed
Any other neoadjuvant therapy for breast cancer. Bisphosphonate treatment for bone symptoms is allowed
Women who are pregnant or lactating

PRIMARY OBJECTIVE:

I. Determine whether residual cancer cells exhibit upregulation of CPT1-alpha (compared to baseline) following neoadjuvant endocrine therapy in patients with estrogen receptor (ER)+ breast cancer.

SECONDARY OBJECTIVES:

I. Determine the proportion of subjects who experience clinical response, defined as a >= 50% decrease in the longest dimension of the primary tumor.

II. Determine whether residual cancer cells exhibit markers of altered mitochondrial and fatty acid metabolism compared to baseline tumors.

EXPLORATORY OBJECTIVES:

I. Determine whether residual cancer cells are enriched for genetic alterations implicated in endocrine resistance compared to baseline tumors.

II. Determine whether residual cancer cells exhibit a transcriptional profile reflecting increased fatty acid oxidation compared to baseline tumors.

III. Determine changes in tumor cell type abundance induced by neoadjuvant endocrine therapy.

IV. Determine whether duration of neoadjuvant letrozole treatment is correlated with changes in markers of altered mitochondrial and fatty acid metabolism.

OUTLINE:

Patients receive letrozole orally (PO) once daily (QD) for 4-16 weeks up to the day of surgery in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

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Neoadjuvant Letrozole for the Treatment of Stage I-III Estrogen Receptor Positive Breast Cancer, The NAOMI Study

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