Breast Cancer
Conditions
Keywords
stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer
Brief summary
RATIONALE: New imaging procedures, such as diffuse optical spectroscopy imaging, may help measure a patient's response and allow doctors to plan better treatment. PURPOSE: This clinical trial studies diffuse optical spectroscopy imaging in monitoring and predicting response in patients with locally advanced breast cancer undergoing chemotherapy before surgery.
Detailed description
OBJECTIVES: Primary * To determine whether the percentage change in the diffuse optical spectroscopy imaging (DOSI) measurement of the tumor/normal (T/N) tissue optical index (TOI) from baseline to mid-therapy is predictive of the final pathologic response of the primary tumor in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy. Secondary * To investigate whether change of TOI measurements from baseline to post-therapy are predictive of the final pathologic response in these patients treated with this regimen. * To investigate whether baseline TOI measurements are associated with final pathologic response in patients treated with this regimen. * To investigate whether TOI measurements at baseline, change from baseline to mid-therapy, and change from baseline to post-therapy correlate with available MRI volumetric imaging measurements. * To investigate whether changes on TOI measurements from baseline to mid-therapy, and from baseline to post-therapy, correlate with other standard-of-care imaging and/or any MRI-imaging measurements. * To explore whether additional optical endpoints and indices obtained during DOSI measurements can be used to predict final pathologic response in patients treated with this regimen. * To determine a cutpoint for the percent change of TOI from baseline to mid-therapy that is predictive of pathological complete response in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients undergo diffuse optical spectroscopy imaging (DOSI) at baseline, 5-10 days after initiation of neoadjuvant chemotherapy, during early- and mid-neoadjuvant therapy, and within 21 days after completion of neoadjuvant therapy. Results are compared to standard-of-care imaging (e.g., MRI, ultrasound, mammography). Patients then undergo surgery.
Interventions
PROCEDUREDOSI
Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, tissue oxygen saturation (StO2), and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant chemotherapy (NAC) treatment.
Sponsors
National Cancer Institute (NCI)
American College of Radiology Imaging Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed diagnosis of invasive breast cancer, determined to be a candidate for primary systemic (neoadjuvant) therapy and for surgical resection of residual primary tumor following completion of neoadjuvant therapy; 2. Tumor size \>2cm, measured on imaging or estimated by physical exam; 3. No contraindications for primary chemotherapy; 4. Planned definitive breast surgery (mastectomy or lumpectomy/breast conservation) following completion of neoadjuvant therapy; 5. Age 18 years or older; 6. ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%; see Appendix II); 7. Normal organ and marrow function as follows: * leukocytes ≥ 3,000/μl; * absolute neutrophil count ≥ 1,500/μl; * platelets ≥ 100,000/μl; * total bilirubin within normal institutional limits; * AST(SGOT)/ALT(SGPT) ≤ 2.5 times the institutional upper limit of normal; * creatinine within normal institutional limits; OR * creatinine clearance ≥ 30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal; 8. If female, postmenopausal for a minimum of one year, OR surgically sterile, OR not pregnant, confirmed by a pregnancy test as per institutional Standard of Care (SOC), and willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation; 9. Able to understand and willing to sign a written informed consent document and a HIPAA authorization in accordance with institutional guidelines;
Exclusion criteria
1. Previous treatment (chemotherapy, radiation, or surgery) to involved breast; including hormone therapy; 2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; 3. Medically unstable; 4. Under age 18; 5. Pregnant or nursing; 6. Previous malignancy, other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix, from which the patient has been disease free for less than 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict Pathologic Response (pCR +/-) | From baseline to mid-therapy | This measure will look at the Accuracy of % change in DOSI measured Tumor Optical Index (TOI) from baseline to mid therapy to predict pathologic response (pCR+ v pCR-) Pathologic response (dichotomized into responders (pCR+) and non-responders (pCR-) based pathologic assessment) will be used as the reference standard and Accuracy will be determined using receiver operating characteristic (ROC) analysis to determine the ROC Area Under the Curve (AUC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) | baseline to mid-therapy | Pathologic Complete response vs Non-Complete response, by PR status Progesterone Receptor Status (positive, negative, unknown ) is determined at pathological assessment of the tumor sample. %change in TOI is evaluated from baseline to mid-therapy. |
| Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02) | baseline to mid-therapy | subset analysis, subjects were stratified using the median tumor StO2 %change TOI Between Baseline and Mid-therapy dichotomized at -40% stratified by the set evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median). Accuracy will be determined using ROC analysis to determine the ROC Area Under the Curve (AUC). |
| Estimate the Optimal Cutpoint for %Change in TOI From Baseline to Mid-therapy to Predict pCR | baseline to mid-therapy | Determine the optimal cutpoint (aka Youden-index) for %Change in TOI ratio (T/N) to maximize sensitivity and specificity in the predication of pCR |
Countries
United States
Participant flow
Recruitment details
Seven institutions were approved to enroll a total of 60 female breast cancer patients: Enrollment began in June 2011 and completed in June 2013. All institutions activated concurrently, except MD Anderson Cancer Center and Boston University, which joined the study in January and May 2013, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Diffuse Optical Spectroscopy Imaging (DOSI) Participants undergo approximately four assessments of breast health using the DOSI technology during treatment and prior to surgery for breast cancer.
DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant Chemotherapy (NAC) treatment. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Central Path not Available | 1 |
| Overall Study | DOSI not performed/not eval | 12 |
| Overall Study | Normal Breast TOI not available | 10 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Diffuse Optical Spectroscopy Imaging (DOSI) |
|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 10.7 |
| Areolar tumor Areolar tumor | 17 Participants |
| Areolar tumor Nonareolar tumor | 17 Participants |
| cell division marker (Ki67) status Negative | 2 Participants |
| cell division marker (Ki67) status Positive | 17 Participants |
| cell division marker (Ki67) status Unknown | 15 Participants |
| estrogen receptor (ER) status Negative | 7 Participants |
| estrogen receptor (ER) status Positive | 24 Participants |
| estrogen receptor (ER) status Unknown | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| fluorescence in situ hybridization (FISH) status Amplified | 7 Participants |
| fluorescence in situ hybridization (FISH) status Non amplified | 14 Participants |
| fluorescence in situ hybridization (FISH) status Unknown/not available | 13 Participants |
| Histologic findings Ductal Carcinoma In Situ (DCIS)/ILC | 11 Participants |
| Histologic findings IDC/ILC | 2 Participants |
| Histologic findings Invasive (infiltrating) ductal carcinoma (IDC) | 16 Participants |
| Histologic findings Invasive lobular carcinoma (ILC) | 3 Participants |
| Histologic findings Other/not available | 2 Participants |
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): 0 - HER2-negative | 4 Participants |
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): 1 - HER2-negative | 8 Participants |
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): 2 - equivocal | 8 Participants |
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): 3 - HER2-positive | 4 Participants |
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): unknown/not available | 10 Participants |
| progesterone receptor (PR) status Negative | 12 Participants |
| progesterone receptor (PR) status Positive | 19 Participants |
| progesterone receptor (PR) status Unknown | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 34 |
| other Total, other adverse events | 0 / 34 |
| serious Total, serious adverse events | 0 / 34 |
Outcome results
Primary
Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict Pathologic Response (pCR +/-)
This measure will look at the Accuracy of % change in DOSI measured Tumor Optical Index (TOI) from baseline to mid therapy to predict pathologic response (pCR+ v pCR-) Pathologic response (dichotomized into responders (pCR+) and non-responders (pCR-) based pathologic assessment) will be used as the reference standard and Accuracy will be determined using receiver operating characteristic (ROC) analysis to determine the ROC Area Under the Curve (AUC).
Time frame: From baseline to mid-therapy
Population: Bedside DOSI images of the tissue concentrations of TOI (ctHHb x tH2O/lipid) acquired on both breasts at baseline and mid-therapy during neoadjuvant chemotherapy (NAC) treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diffuse Optical Spectroscopy Imaging (DOSI | Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict Pathologic Response (pCR +/-) | 0.60 probability |
Comparison: This analysis will look at the ability of the % change in DOSI measured tumor Optical Index (TOI) from baseline to mid-therapy to predict pathologic response using logistic regression.~Pathologic response (dichotomized into responders and non-responders) will be used as the reference standard and %change in TOI ratio (dichotomized at -40%) will be used to estimate pCR (+/-)= alpha + beta1(%change TOI)p-value: 0.05995% CI: [0.95, 23.04]Regression, Logistic
Secondary
Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02)
subset analysis, subjects were stratified using the median tumor StO2 %change TOI Between Baseline and Mid-therapy dichotomized at -40% stratified by the set evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median). Accuracy will be determined using ROC analysis to determine the ROC Area Under the Curve (AUC).
Time frame: baseline to mid-therapy
Population: evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median) and %change TOI dichotomized at -40%
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diffuse Optical Spectroscopy Imaging (DOSI | Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02) | 0.38 probability |
| PR- Participants | Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02) | 0.83 probability |
p-value: 0.04395% CI: [1.09, 250.15]Regression, Logistic
p-value: 0.40695% CI: [0.24, 33.9]Regression, Logistic
Secondary
%Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown )
Pathologic Complete response vs Non-Complete response, by PR status Progesterone Receptor Status (positive, negative, unknown ) is determined at pathological assessment of the tumor sample. %change in TOI is evaluated from baseline to mid-therapy.
Time frame: baseline to mid-therapy
Population: Analysis population consists of the 34 participants with both baseline and mid-therapy TOI measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diffuse Optical Spectroscopy Imaging (DOSI | %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) | -29.874 percentage change | Standard Deviation 31.349 |
| PR- Participants | %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) | -14.605 percentage change | Standard Deviation 107.425 |
| PR? Participants | %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) | -45.701 percentage change | Standard Deviation 25.237 |
Comparison: The Null is that the odd ratio is the same in both the PR+ and PR- subjects fro the model including %change in TOI form baseline to mid-therapy (dichotomized at \<=-40%), PR status (+/-) and the interaction between them.p-value: 0.8193Regression, Logistic
Secondary
Estimate the Optimal Cutpoint for %Change in TOI From Baseline to Mid-therapy to Predict pCR
Determine the optimal cutpoint (aka Youden-index) for %Change in TOI ratio (T/N) to maximize sensitivity and specificity in the predication of pCR
Time frame: baseline to mid-therapy
Population: participants having TOI ratio (T/N) using tumor breast normal at baseline and mid-therapy and have pathologic response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diffuse Optical Spectroscopy Imaging (DOSI | Estimate the Optimal Cutpoint for %Change in TOI From Baseline to Mid-therapy to Predict pCR | -32.527 percentage change in TOI |