Breast CancerNCT02010021
Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer.
A study testing Letrozole in people with Breast Cancer, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2014to 8 Dec 2017
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 9Show fewer
- 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.
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
About this study
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.
Read more
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
- Being tested
- Letrozole
- Keywords
- breast cancer, postmenopausal, letrozole, RAD001, Everolimus
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetrozoleDrug
Also called Femara
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline and surgery, approximately 30 days
Secondary outcomes (1)
Percentage of Ki67 Score
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
Measured: baseline and surgery, approximately 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2013 (estimated)
- Study startJan 2014
- Primary completion8 Dec 2017
- Study completion8 Dec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Dartmouth-Hitchcock Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Gary Schwartz, Dartmouth-Hitchcock Medical Center
- Investigators
- Gary Schwartz, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02010021
- Sponsor's protocol ID
- D13236
- Status last verified
- Jan 2019
- First submitted
- 22 Nov 2013
- Last updated
- 17 Jan 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 29507656
Study at a glance
From the registry record, last updated by the sponsor on 17 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer.
- ClinicalTrials.gov ID
- NCT02010021
- Acronym / sponsor ID
- D13236
- Conditions
- Breast Cancer
- Keywords
- breast cancer, postmenopausal, letrozole, RAD001, Everolimus
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Dartmouth-Hitchcock Medical CenterUniversity, hospital or other
- Study start
- Jan 2014
- Primary completion
- 8 Dec 2017 (actual)
- Study completion
- 8 Dec 2017 (actual)
- First posted
- 12 Dec 2013 (estimated)
- Results
- Posted 19 Dec 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- 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).
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: LetrozolePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (3 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LetrozoleAlso: FemaraPatients 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-presurgical |
Primary outcome
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.
1 secondary outcome
Percentage of Ki67 Score
Time frame: baseline and surgery, approximately 30 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jan 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 29507656Yang 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gary Schwartz, MD principal investigator
Dartmouth-Hitchcock Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Letrozole in people with Breast Cancer, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Dec 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02010021, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2019.