Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer.

• ClinicalTrials.gov Identifier: NCT02010021
• Recruitment Status: Completed
• First Posted: December 12, 2013
• Results First Posted: December 19, 2018
• Last Update Posted: January 17, 2019
• Sponsor: Dartmouth-Hitchcock Medical Center
• Information provided by (Responsible Party): Gary Schwartz, Dartmouth-Hitchcock Medical Center

Study Description

Brief Summary:

Some tumors use estrogen in the body to assist with growth. Letrozole is a drug that is prevents cells from producing estrogens. This should assist with the slowing of growth of tumor cells. Letrozole also promotes cell destruction by inhibiting a cellular destruction pathway.

The objectives of this study will look at the differences between the cellular destruction pathway before and after letrozole use, and the differences in the cellular destruction pathway in participants that have received letrozole versus those who did not. The study will also look at a gene in all participants called Ki67. This gene is associated with the rate of tumor cell growth. The study will measure the levels of Ki67 and compare them to the amount of activation of the cellular destruction pathway.

Participants in this study will have undergone a diagnostic biopsy of their breast tissue.

In order to meet these objectives, one group of participants (Arm A) will not receive letrozole. Tissue leftover from their diagnostic biopsy will be treated with everolimus (RAD001) in the laboratory and the effects of this drug on the cellular destruction pathway will be studied.

The other group of participants (Arm B) will take letrozole for a minimum of 10 and maximum of 21 days. They will have a second tumor sample taken as part of their surgical procedure completed to remove the tumor tissue. Any differences in the cellular destruction pathway before and after exposure to letrozole will be measured.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Letrozole	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

10 subjects received no presurgical therapy, and then 7 subjects received presurgical letrozole.

This is a sequential model because the results from Arm A determined the sample size for Arm B. Tumors from each of the 10 untreated patients in Arm A showed induction of AKT activation with RAD001 treatment. Based on these results, we determined that a sample size of seven patients from Arm B would be adequate to detect a significant effect (p≤0.05) of presurgical Letrozole on RAD001-induced changes in phospho-AKT levels with 80% power (calculated using uncorrected chi-squared statistic).

• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer.
• Study Start Date: January 2014
• Actual Primary Completion Date: December 8, 2017
• Actual Study Completion Date: December 8, 2017

Arms and Interventions

Arm	Intervention/treatment
No Intervention: No drug treatment; Post-menopausal women with stage I-III breast cancer will have surgical resection of tumor and tumor tissue will be used to study cell growth signaling pathways ex-vivo.
Active Comparator: Letrozole-presurgical; Patients will receive Letrozole for 10-21 days prior to surgical resection of tumor tissue. This tissue will be used ex-vivo to study cell growth signaling pathway. The results will be compared to arm of the study with no intervention.	Drug: Letrozole; Patients will receive Letrozole for 10-21 days prior to surgical resection of tumor tissue. This tissue will be used ex-vivo to study cell growth signaling pathway. The results will be compared to arm of the study with no intervention.; Other Name: Femara

Outcome Measures

Primary Outcome Measures :

1. Change in Insulin Receptor Substrate 1 (IRS-1) / Phosphoinositide 3-kinase (PI3K) / Serine-threonine Protein Kinase (AKT) Pathway Activation [ Time Frame: baseline and surgery, approximately 30 days ]
   The Primary Endpoint is to determine the effect of ex vivo mTORC1 inhibition with everolimus (RAD001) on IRS-1/PI3K/AKT pathway activation (as measured by phospho-AKT-T308 and phospho-AKT-S473) in ER+/human epidermal growth factor receptor 2 (HER2)- breast tumors treated with presurgical letrozole compared to ER+/HER2- breast tumors not treated with presurgical therapy.

Secondary Outcome Measures :

1. Percentage of Ki67 Score [ Time Frame: baseline and surgery, approximately 30 days ]

   The Secondary Endpoint is to compare tumor cell proliferation as measured with the Ki-67 assay in breast cancer specimens taken before and at the time of surgery, comparing specimens of patients treated with presurgical letrozole and specimens of patients who did not receive presurgical letrozole. The secondary endpoint is Ki67 score, as determined by the percentage of Ki67+ tumor cells identified by immunohistochemistry.

   Whole slides were scanned at 40x (Aperio AT2, Leica Biosystems), and automated Ki67 analysis (percent positive nuclei) was determined using the Aperio ImageScope (v12.3.1.60002, Leica Biosystems) nuclear v9 algorithm. As recommended by the International Ki67 in Breast Cancer Working Group, 3 high-power microscopic fields were selected for analysis to represent the spectrum of staining present on the whole tissue section, and a minimum of 500 malignant invasive cells were score

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologic Documentation of invasive breast cancer by core needle or incisional biopsy. Excess baseline biopsy tumor tissue sufficient to make three 5-micron sections must be available for molecular analyses as part of this study.
• The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining present in greater than 50% staining of invasive cancer cells by IHC.
• The invasive cancer must be human epidermal growth factor receptor 2 (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. Tumor must be ≥ 2cm to provide adequate tissue.
• Patients with multi-centric or bilateral disease are eligible if the target lesions meet the other eligibility criteria. Samples from all available tumors are requested for research purposes.
• Women ≥ age 18, for whom adjuvant treatment with an aromatase inhibitor would be clinically indicated. Women must be either post-menopausal, or pre-menopausal having undergone oophorectomy.
• Patients must meet the following clinical laboratory criteria:

Absolute neutrophil count (ANC)≥ 1000/mm3 and platelet count ≥ 75,000/mm3. Total bilirubin ≤ 1.5 X the upper limit of 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.
• Systemic drug treatment to induce ovarian suppression if woman is pre-menopausal.
• Any other neoadjuvant therapy for breast cancer (i.e., treatment with any other anti-cancer agent besides Letrozole (10-21)days before surgical resection of the primary tumor).

Contacts and Locations

Locations

United States, New Hampshire

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, United States, 03756

Sponsors and Collaborators

Dartmouth-Hitchcock Medical Center

Investigators

• Principal Investigator: Gary Schwartz, MD; Dartmouth-Hitchcock Medical Center

  Study Documents (Full-Text)

Documents provided by Gary Schwartz, Dartmouth-Hitchcock Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] November 17, 2015

More Information

Publications of Results:

Yang W, Schwartz GN, Marotti JD, Chen V, Traphagen NA, Gui J, Miller TW. Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer. Oncotarget. 2018 Jan 15;9(10):8810-8822. doi: 10.18632/oncotarget.24256. eCollection 2018 Feb 6.

• Responsible Party: Gary Schwartz, Associate Professor of Medicine, Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT02010021
• Other Study ID Numbers: D13236
• First Posted: December 12, 2013
• Results First Posted: December 19, 2018
• Last Update Posted: January 17, 2019
• Last Verified: January 2019

Keywords provided by Gary Schwartz, Dartmouth-Hitchcock Medical Center:

breast cancer; postmenopausal; letrozole; RAD001; Everolimus

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Letrozole; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs