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

NCT02010021 | Completed Results DMC

• 1 other identifier: D13236
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Cancer

Keywords

breast cancer; postmenopausal; letrozole; RAD001; Everolimus

Outcome Measures

Primary Outcomes (1)

• Change in Insulin Receptor Substrate 1 (IRS-1) / Phosphoinositide 3-kinase (PI3K) / Serine-threonine Protein Kinase (AKT) Pathway Activation

  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.

  baseline and surgery, approximately 30 days

Secondary Outcomes (1)

• Percentage of Ki67 Score

  baseline and surgery, approximately 30 days

Study Arms (2)

No drug treatment

NO INTERVENTION

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.

Letrozole-presurgical

ACTIVE COMPARATOR

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

Interventions

Letrozole DRUG

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.

Also known as: Femara

Letrozole-presurgical

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (1)

• 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.

  PMID: 29507656 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Gary N. Schwartz, MD
• Organization: Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center

gary.n.schwartz@hitchcock.org

(603) 653-6181

Study Officials

• Gary Schwartz, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: 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).

Study Record Dates

• First Submitted: November 22, 2013
• First Posted: December 12, 2013
• Study Start: January 1, 2014
• Primary Completion: December 8, 2017
• Study Completion: December 8, 2017
• Last Updated: January 17, 2019
• Results First Posted: December 19, 2018

Record last verified: 2019-01

Locations

US (1)