Breast Cancer
Conditions
Keywords
ductal breast carcinoma in situ, estrogen receptor-positive breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes. PURPOSE: This phase II trial is studying how well letrozole works in treating women with ductal carcinoma in situ.
Detailed description
Treatment with letrozole begins within 21 days of registration, and only after notification has been received from the UCSF Breast MRI Research Laboratory that the baseline MRI is acceptable. Protocol therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a MRI for disease evaluation at months 3 and 6. All patients will continue to take study drug until the day prior to surgery, whether at month 3 or at month 6 or may stop if they experience unacceptable toxicity. It is expected that decisions regarding any adjuvant treatment (eg, radiation and hormonal therapy) will be made individually based on the best practice guidelines, using informed and shared decision making between patient and provider. The primary and secondary objectives are provided below. Primary objective: 1\. To estimate the mean change in MRI tumor volume from pretreatment to completion of preoperative endocrine therapy in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS), as well as to determine whether 3-month change in volume correlates with 6-month change. Secondary objectives: 1. To assess radiographic-pathologic correlation between MRI findings and histopathology, including the prevalence of occult invasive cancer in patients undergoing neoadjuvant endocrine therapy for DCIS. 2. To compare changes in MRI maximum lesion diameter and mammographic extent at baseline and following treatment. These are two additional radiographic parameters which may also biological response to therapy. 3. To determine practice patterns of adjuvant hormonal and radiation therapy in patients who complete neoadjuvant letrozole therapy for DCIS. 4. To determine whether Ki67 is reduced with neoadjuvant letrozole treatment for DCIS, and to compare the reduction in proliferation between radiographic responders and non-responders. 5. To identify baseline IHC and expression biomarkers predictive of response to treatment, with response determined by extent of Ki67 reduction. Subsets showing the greatest reduction in Ki67 would be the most likely candidates for non-operative treatment in future studies. 6. To examine whether germline polymorphisms are associated with clinical endpoints, including treatment-related toxicity or efficacy outcomes, or with expression of biomarkers in serum or tumor. 7. To assess quality-of-life and musculoskeletal symptoms associated with neoadjuvant letrozole for ER positive DCIS. Patients will be followed up to 6 months post-surgery.
Interventions
DRUGletrozole
PROCEDUREMRI
PROCEDUREconventional surgery
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria: 1. Histologic documentation: Pathologic confirmation of ductal carcinoma in situ (DCIS) of the female breast without invasive cancer, with diagnosis rendered on core biopsy only, completed within 60 days before registration. Patients diagnosed with DCIS on the basis of surgical biopsy are not eligible for this study. 1. Patients with microinvasion on diagnostic core biopsy, defined as tumor ≤ 1 mm in greatest dimension, will be allowed to participate. 2. All patients must have a clip placed, either at the time of the diagnostic biopsy or at the time of the baseline MRI prior to the start of treatment. 2. Tissue samples: Patient has diagnostic tissue available for correlative studies. 3. Clinical stage: Tis or T1mi N0, M0 4. Hormone receptor status: DCIS must express estrogen and/or progesterone receptor, as determined by immunohistochemical methods on the diagnostic pathology sample, according to the local institution's standard protocol. Greater than or equal to 1% cells will be considered to be positive. 5. Menopausal status: Patients must be postmenopausal defined as: 1. Age ≥ 55 years and one year or more of amenorrhea 2. Age \< 55 years and one year or more amenorrhea, with an estradiol assay \< 20pg/ml 3. Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration) The use of GnRH analogs to achieve post menopausal status is not allowed. 6. Prior treatment: 1. No prior surgical excision in the index breast for current DCIS diagnosis of DCIS 2. Any exogenous hormone therapy must be completed 4 weeks prior to registration 3. Any patients with a history of tamoxifen or raloxifene use within two years of current DCIS diagnosis are not eligible 4. No prior neoadjuvant/adjuvant therapy for current DCIS diagnosis 7. Contraindication to MRI: No contraindications to breast MRI 8. Measurable disease: Mammographic extent of calcifications must be accurately measurable in at least one dimension with each lesion ≥ 1 cm and ≤ 7 cm 1. DCIS must be visible on MRI based on central review. 2. Patients with palpable DCIS or adenopathy are not eligible to participate. 3. Patients with multifocal or bilateral disease are eligible. 9. History of osteoporosis: Women diagnosed with osteoporosis may participate in this trial provided they are receiving appropriate therapy or if they have declined therapy. 10. Age: Patients ≥ 18 years of age 11. Performance Status: ECOG performance status 0 or 1 12. Pregnancy/nursing status: Not pregnant or nursing 13. Required Initial Laboratory Values: 1. ANC ≥ 1,000/μL 2. Platelet count ≥ 100,000/μL 3. Serum creatinine ≤ 1.7 mg/dL 4. Bilirubin ≤ 2.0 mg/dL 5. AST/ALT ≤ 2.5 times upper limit of normal 6. Serum estradiol level assay \< 20 pg/mL \*Required for patients \< 55 years of age and one year or more of amenorrhea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 3 (V3) | up to 3 months from start of treatment | Mean total MRI FTV change from baseline to month 3 (V3): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V3 was calculated by subtracting the total MRI FTV measured (i.e. the sum over all lesions present with MRI FTV measurements) at 3 months from the total MRI FTV measured at baseline. For V3 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests. |
| Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 6 (V6) | up to 6 months from start of treatment | Mean total MRI FTV change from baseline to month 6 (V6): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V6 was calculated by subtracting the total MRI FTV measured at 6 months from the total MRI FTV measured at baseline. For V6 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Type of Primary Surgery (Mastectomy or Lumpectomy) | up to 6 months | Rate of Mastectomy will be estimated as the number of mastectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods. Rate of Lumpectomy will be estimated as the number of lumpectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods. |
| Number of Re-excisions Required to Obtain Clear Margins | 3-months and 6-months | — |
| Extent of Residual DCIS Post Surgery | Up to 6 months post-surgery | — |
| Mean Total MRI Tumor Diameter Change From Baseline to Month 3 | 3-months | To ascertain the change in maximum tumor diameter from baseline to 3 months (D3) the same methods as in Primary outcome #1 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated. |
| Size of Margins (Smallest) at Surgery | 3-months and 6-months | — |
| Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Up to 6 months post surgery | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event at least possibly related to the study treatment are reported below. |
| Mean Total MRI Tumor Diameter Change From Baseline to Month 6 | 6 months | Mean total MRI tumor diameter change from baseline to month 6: To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary Outcome #2 will be used but on diameter instead of volume. |
| Presence of Invasive Cancer at Surgery | 3-months and 6-months | — |
| Change in Maximum Diameter at 6-months Based on Mammographic Measurement (MD6) | 6-months | Change in maximum diameter at 6-months based on mammographic measurement (MD6) will be estimated using the methods in Primary Outcome #1, but using the mammographic measurements instead. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Letrozole + MRI Protocol Therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a bilateral MRI for disease evaluation at months 3 and 6. | 68 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Cancel | 3 |
| Overall Study | Ineligible | 13 |
| Overall Study | No MRI | 9 |
| Overall Study | Noncompliance | 3 |
| Overall Study | Progression During Active Tx | 3 |
| Overall Study | Progression Prior to Beginning Tx | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Letrozole + MRI |
|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 8.03 |
| Region of Enrollment United States | 68 Participants |
| Sex: Female, Male Female | 68 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 75 / 90 |
| serious Total, serious adverse events | 2 / 90 |
Outcome results
Primary
Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 3 (V3)
Mean total MRI FTV change from baseline to month 3 (V3): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V3 was calculated by subtracting the total MRI FTV measured (i.e. the sum over all lesions present with MRI FTV measurements) at 3 months from the total MRI FTV measured at baseline. For V3 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.
Time frame: up to 3 months from start of treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 3 (V3) | -1.93 cubic centimeters |
p-value: <0.001t-test, 2 sided
Primary
Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 6 (V6)
Mean total MRI FTV change from baseline to month 6 (V6): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V6 was calculated by subtracting the total MRI FTV measured at 6 months from the total MRI FTV measured at baseline. For V6 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.
Time frame: up to 6 months from start of treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 6 (V6) | -1.82 cubic centimeters |
p-value: <0.001t-test, 2 sided
Secondary
Change in Maximum Diameter at 6-months Based on Mammographic Measurement (MD6)
Change in maximum diameter at 6-months based on mammographic measurement (MD6) will be estimated using the methods in Primary Outcome #1, but using the mammographic measurements instead.
Time frame: 6-months
Population: Patients who completed a mammogram at both time points (baseline and month 6) with measurements available were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Change in Maximum Diameter at 6-months Based on Mammographic Measurement (MD6) | -3.31 millimeters |
Secondary
Extent of Residual DCIS Post Surgery
Time frame: Up to 6 months post-surgery
Secondary
Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event at least possibly related to the study treatment are reported below.
Time frame: Up to 6 months post surgery
Population: Patients who had completed the study and had an Adverse Event Form submitted were included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Letrozole + MRI | Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Allergic reaction | 31 Participants |
| Letrozole + MRI | Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Cholesterol high | 7 Participants |
| Letrozole + MRI | Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Gastrointestinal disorder | 2 Participants |
| Letrozole + MRI | Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Hot flashes | 1 Participants |
Secondary
Mean Total MRI Tumor Diameter Change From Baseline to Month 3
To ascertain the change in maximum tumor diameter from baseline to 3 months (D3) the same methods as in Primary outcome #1 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.
Time frame: 3-months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Mean Total MRI Tumor Diameter Change From Baseline to Month 3 | -10.3 millimeters |
Secondary
Mean Total MRI Tumor Diameter Change From Baseline to Month 6
Mean total MRI tumor diameter change from baseline to month 6: To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary Outcome #2 will be used but on diameter instead of volume.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Mean Total MRI Tumor Diameter Change From Baseline to Month 6 | -16.66 millimeters |
Secondary
Mean Total MRI Tumor Diameter Change From Baseline to Month 6
To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary outcome #2 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Letrozole + MRI | Mean Total MRI Tumor Diameter Change From Baseline to Month 6 | -16.66 millimeters |
Secondary
Number of Re-excisions Required to Obtain Clear Margins
Time frame: 3-months and 6-months
Secondary
Presence of Invasive Cancer at Surgery
Time frame: 3-months and 6-months
Secondary
Size of Margins (Smallest) at Surgery
Time frame: 3-months and 6-months
Secondary
Type of Primary Surgery (Mastectomy or Lumpectomy)
Rate of Mastectomy will be estimated as the number of mastectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods. Rate of Lumpectomy will be estimated as the number of lumpectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods.
Time frame: up to 6 months
Population: Patients who underwent surgery were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letrozole + MRI | Type of Primary Surgery (Mastectomy or Lumpectomy) | Rate of Mastectomy | 7 percentage of surgeries |
| Letrozole + MRI | Type of Primary Surgery (Mastectomy or Lumpectomy) | Rate of Lumpectomy | 93 percentage of surgeries |