Phase II Study of Fluorine-18 3'-Deoxy-3'-Fluorothymidine (F-18-FLT) in Invasive Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00572728
• Collaborator: (none)
• Enrollment: 90
• Locations: 27
• Arm: 1
• Duration (Months): 70
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well 3'-deoxy-3'-18F fluorothymidine (18F-FLT) positron emission tomography (PET)/computed tomography (CT) works in predicting response in patients receiving chemotherapy and undergoing surgery for breast cancer that has spread from where it started to nearby tissue or lymph nodes. Diagnostic procedures, such as 18F-FLT PET/CT, may help in learning how well chemotherapy works to kill breast cancer cells before surgery and help doctors plan the best treatment.

Condition or Disease	Intervention/Treatment	Phase
Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer	Procedure: CT; Drug: 18F-FLT; Procedure: PET	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To correlate the percentage change in standardized uptake value at 60 minutes (SUV60) between baseline (FLT-1) and early-therapy (FLT-2) with pathologic complete response to neoadjuvant chemotherapy of the primary tumor in patients with locally advanced breast cancer.

SECONDARY OBJECTIVES:

1. To demonstrate correlation between FLT-1 and post-therapy (FLT-3) uptake parameters and tumor proliferation markers in locally advanced breast cancer.

2. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pathologic complete response of the primary tumor and residual cancer burden (RCB).

3. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and non-response of the primary tumor (stable or progressive disease) to therapy.

4. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pathologic complete response to neoadjuvant chemotherapy in patients with regional disease in the lymph nodes in patients with locally advanced breast cancer.

5. To compare the changes of FLT-2 and FLT-3 uptake parameters to changes in tumor sizes from other serial imaging modalities such as mammograms, magnetic resonance imaging (MRI), and ultrasound.

6. To compare the changes of FLT-2 and FLT-3 uptake parameters to metabolic changes from [18F] fludeoxyglucose (FDG)-PET, as available.

7. To continue to monitor for potential safety issues and define any physiologic effects associated with 18F FLT administration.

OUTLINE:

Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: 3'-Deoxy-3'-18F Fluorothymidine PET/CT in Predicting Response To Chemotherapy Before Surgery in Patients With Locally Advanced Breast Cancer
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Diagnostic (18F-FLT) Patients undergo 18F-FLT PET /CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy.

Procedure: CT; Undergo 18F-FLT PET/CT; Other Names: CAT CAT Scan Computed Tomography Computerized Axial Tomography Computerized Tomography CT SCAN tomography ; Drug: 18F-FLT; Undergo 18F-FLT PET/CT; Other Names: Fluorothymidine F-18 3'-deoxy-3'-(18F) fluorothymidine 3'-deoxy-3'-[18F]fluorothymidine fluorothymidine F 18 ; Procedure: PET; Undergo 18F-FLT PET/CT; Other Names: Medical Imaging, Positron Emission Tomography Positron Emission Tomography PET SCAN Positron Emission Tomography Scan Positron-Emission Tomography proton magnetic resonance spectroscopic imaging

Outcome Measures

Primary Outcome Measures

1. %Change in FLT Uptake Between the Baseline (Pre-therapy) and the Early-therapy Imaging Studies to Predict Pathological Complete Response [Baseline (FLT-1) to early therapy (5-10 days after chemotherapy, FLT-2)]

   The primary statistical evaluation will be based on the percent change in FLT SUV60 between baseline (pre-therapy, FLT-1) and the early-therapy imaging (5-10 days after chemotherapy, FLT-2) studies

Secondary Outcome Measures

1. Correlation Between SUVmax and Ki-67 LI at FLT1(Baseline PET) [Baseline (FLT-1)]

   For the purposes of reporting, SUVmax @ FLT1 will be considered the outcome. the correlation is measured between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT1 . Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.

2. Correlation Between SUVmax and Ki-67 LI at FLT3 (Post-NAC) [Post-NAC (FLT3)]

   For the purposes of reporting, SUVmax @ FLT-3 will be considered the outcome. correlation between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT-3 Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.

3. SUVmax at FLT-1 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III [Baseline (FLT-1)]

   While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the Standardized Uptake Values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) at Baseline (FLT-1) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III

4. SUVmax at FLT-2 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III [early treatment (FLT2)]

   While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the uptake values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) after one cycle of NAC (FLT2) were compared for Participants with Residual Cancer Burden (RCB) 0/I vs RCB II/III

5. SUVmax at FLT-3 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III [post-NAC (FLT-3)]

   The Standard Uptake Values (max) after completion of NAC (FLT-3) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the mean of the uptake values the measurement of interest and report those values herein.

6. Change in Uptake Between FLT1 and FLT3 to Predict Pathologic Complete Response (pCR) of the Primary Tumor [Baseline (FLT-1) and post-NAC (FLT-3)]

   To evaluate the relationship between the change in uptake between FLT1 and FLT3 and pathologic complete response, an ROC curve will be estimated and the area under the curve (AUC), along with its 90% confidence interval, will be determined. For the purposes of reporting, we will consider the percent change in uptake between FLT1 and FLT3 to be the outcome. Reported values in the Outcome Measure table represent Change in uptake between FLT1 and FLT3, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT3 and pathological complete response was assessed by using ROC analysis. The Area Under the ROC Curve is reported in the Statistical Analysis section

7. %Change SUVmax From FLT1-FLT2 to Predict Lymph Node Status at Surgery [Baseline (FLT-1) and Early Therapy (FLT-2)]

   Reported values in the Outcome Measure table represent %Change in uptake between FLT1 and FLT2, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT2 and lymph node (LN) status. For the purposes of reporting, the % Change in SUV will be considered the outcome.

8. %Change SUVmax From FLT1-FLT3 to Predict Lymph Node Status at Surgery [Baseline (FLT-1) and post-NAC (FLT-3)]

   %change in SUVmax from FLT1-FLT3 will be compared by lymph node status at surgery For the purposes of reporting, %change in SUVmax from FLT1-FLT3 will be consider the outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically confirmed 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

• Locally advanced breast cancer, not stage IV, and with a tumor size >= 2 cm (as measured on imaging or estimated by physical exam)

• No obvious contraindications for primary chemotherapy

• Residual tumor planned to be removed surgically following completion of neoadjuvant therapy

• Able to lie still for 1.5 hours for PET scanning

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/ul

• Absolute neutrophil count >= 1,500/ul

• Platelets >= 100,000/ul

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance >= 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• If female, postmenopausal for a minimum of one year, OR surgically sterile, OR not pregnant, confirmed by institutional standard of care (SOC) pregnancy test, and willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation

• Able to understand and willing to sign a written informed consent document and a Health Insurance Portability and Accountability Act (HIPAA) authorization in accordance with institutional guidelines

Exclusion Criteria:

• Previous treatment (chemotherapy, radiation, or surgery) to involved breast; including hormone therapy

• 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

• Medically unstable

• Condition requiring anesthesia for PET scanning and/or unable to lie still for 1.5 hours

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to F-18 fluorothymidine

• Pregnant or nursing

• 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

• Currently on hormone therapy as the primary systemic neoadjuvant therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scottsdale Medical Imaging Limited	Scottsdale	Arizona	United States	85251
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	Morton Plant Hospital	Clearwater	Florida	United States	33756
5	Morton Plant Mease	Dunedin	Florida	United States	34695
6	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
7	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
8	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
9	Siteman Cancer Center at Washington University	Saint Louis	Missouri	United States	63110
10	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
11	Mount Sinai Medical Center	New York	New York	United States	10029
12	Mount Sinai School of Medicine	New York	New York	United States	10029
13	University of North Carolina	Chapel Hill	North Carolina	United States	27599
14	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
15	Radiology Consultants Inc	Youngstown	Ohio	United States	44512
16	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
17	American College of Radiology Imaging Network	Philadelphia	Pennsylvania	United States	19103
18	Hospital of The University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
19	University of Pennsylvania School of Medicine	Philadelphia	Pennsylvania	United States	19104
20	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
21	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
22	Medical University of South Carolina	Charleston	South Carolina	United States	29425
23	Excel Diagnostics	Houston	Texas	United States	77042
24	Westchase Oncology Center	Houston	Texas	United States	77042
25	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
26	University of Washington Medical Center	Seattle	Washington	United States	98195
27	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lale Kostakoglu, American College of Radiology Imaging Network

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Phase II Study of [(18)F]-3'Deoxy-3'-Fluorothymidine Positron Emission Tomography (FLT-PET) in The Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results From ACRIN 6688

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00572728
• Other Study ID Numbers: NCI-2009-00266; NCI-2009-00266; ACRIN 6688; 8029; N01CM27165; NCT00566293
• First Posted: Dec 13, 2007
• Last Update Posted: Dec 30, 2016
• Last Verified: Dec 1, 2016

• Additional relevant MeSH terms: Breast Neoplasms; Alovudine; Dideoxynucleosides

Study Results

Participant Flow

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	90
Eligible	87
Enrolled Under Amendment 5 or Later	82
Did Not Withdraw	72
On Study	71
Completed FLT1 Scan	67
First Therapy Initiated	65
Completed FLT2 Scan	60
Second Chemotherapy Initiated	59
Second Chemotherapy Initiated After FLT2	52
Pathology Complete	51
Completed FLT3 Scan	43
LN Evaluation After NAC	38
RCB Evaluation	35
COMPLETED	51
NOT COMPLETED	39

Baseline Characteristics

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Overall Participants	90
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	51
Gender (Count of Participants)
Female	90 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 10%
Not Hispanic or Latino	75 83.3%
Unknown or Not Reported	6 6.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.1%
Asian	2 2.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	25 27.8%
White	51 56.7%
More than one race	0 0%
Unknown or Not Reported	11 12.2%
Region of Enrollment (participants) [Number]
United States	90 100%

Outcome Measures

1. Primary Outcome

Title	%Change in FLT Uptake Between the Baseline (Pre-therapy) and the Early-therapy Imaging Studies to Predict Pathological Complete Response
Description	The primary statistical evaluation will be based on the percent change in FLT SUV60 between baseline (pre-therapy, FLT-1) and the early-therapy imaging (5-10 days after chemotherapy, FLT-2) studies
Time Frame	Baseline (FLT-1) to early therapy (5-10 days after chemotherapy, FLT-2)

Outcome Measure Data

Analysis Population Description

Percent Change in Maximum Standardized FLT uptake between the baseline (pre-therapy, FTL-1) and the early-therapy imaging (5-10 days after chemotherapy, FLT-2)

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	51
Mean (Standard Deviation) [percentage change of SUVmax]	38.78 (26.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	A receiver operating characteristic (ROC) analysis was performed to assess the significance of the Area Under the Curve (AUC) under the Null Hypothesis with a one sided alpha=0.05 (95% one-sided CL): H0: AUC = 0.50 (no difference from guessing) given the alternative hypothesis: Ha:AUC >= 0.75 AUC = ROC(%ΔSUVmax| path response) where percent change (%ΔSUVmax ) was defined as (SUVmax at FLT1 -SUVmax at FLT2)/SUVmax at FLT1 x 100
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments	The Delong method was used to test if the observed AUC was significantly different than 0.5 with the one-sided p value DeLong ER, DeLong DM, Clarke-Pearson DL, Biometrics (1988)
	Method	Delong method
	Comments	one-sided p-value
Method of Estimation	Estimation Parameter	AUC
	Estimated Value	0.68
	Confidence Interval	(1-Sided) 95%; to .83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	percent change in SUVmax was computed as: %ΔSUVmax = 100*(FLT1-FLT2)/FLT1 a 90% 2-sided confidence interval was constructed from 2000 Bootstrapping estimates from which the 1-sided 95% CI was derived. Hanley SE(AUC) reported.

2. Secondary Outcome

Title	Correlation Between SUVmax and Ki-67 LI at FLT1(Baseline PET)
Description	For the purposes of reporting, SUVmax @ FLT1 will be considered the outcome. the correlation is measured between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT1 . Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.
Time Frame	Baseline (FLT-1)

Outcome Measure Data

Analysis Population Description

1 of the 73 participants did not have both FLT-1 and Ki-67 LI available data

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	72
Mean (Standard Deviation) [Standard Uptake Values (SUVmax)]	5.71 (3.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: ρ = 0; that is, there is no correlation between SUVmax @ FLT-1 and Ki-67 LI a Fisher's z Transformation was applied to adjust for bias in the Spearman Correlation Statistic
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	spearman correlation method
	Comments
Method of Estimation	Estimation Parameter	spearman correlation
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	This estimate uses the Fisher's z Transformation to adjust for bias in the Spearman Correlation Statistic

3. Secondary Outcome

Title	Correlation Between SUVmax and Ki-67 LI at FLT3 (Post-NAC)
Description	For the purposes of reporting, SUVmax @ FLT-3 will be considered the outcome. correlation between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT-3 Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.
Time Frame	Post-NAC (FLT3)

Outcome Measure Data

Analysis Population Description

43 patients who had suitable post-NAC tissue samples for correlation between surgical specimens and FLT3 SUVs

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post-NAC (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	43
Mean (Standard Deviation) [Standard Uptake Values (SUVmax)]	1.88 (1.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: ρ = 0; that is, there is no correlation between SUVmax @ FLT-3 and Ki-67 LI
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Spearman Correlation method
	Comments	we use Fisher's z Transformation to adjust for bias in the Spearman Correlation Statistic
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	this estimate uses the Fisher's z Transformation to adjust for bias in the Spearman Correlation Statistic

4. Secondary Outcome

Title	SUVmax at FLT-1 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III
Description	While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the Standardized Uptake Values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) at Baseline (FLT-1) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III
Time Frame	Baseline (FLT-1)

Outcome Measure Data

Analysis Population Description

@ Baseline: 35 patients with FLT-1 were evaluable for RCB: 14 patients with RCB 0/I and 21 patients with RCB II/III

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	35
All Data	5.9 (3.2)
RCB 0,I	6.2 (2.9)
RCB II,III	5.8 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: Mean SUVmax (RCB 0,I) = Mean SUVmax (RCB II,III) After dichotomization, Wilcoxon two-sample test was used to compare uptake values between RCB groups. In other words, we are comparing the means (of SUVmax) @ FLT1 between the RCB 0,I and the RCB II,III groups..
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	two-sided exact p value from Wilcoxon two-sample test

5. Secondary Outcome

Title	SUVmax at FLT-2 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III
Description	While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the uptake values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) after one cycle of NAC (FLT2) were compared for Participants with Residual Cancer Burden (RCB) 0/I vs RCB II/III
Time Frame	early treatment (FLT2)

Outcome Measure Data

Analysis Population Description

after one cycle of NAC (FLT2): 35 patients had FLT-2 and RCB evaluation: 14 patients with RCB 0/I and 21 patients with RCB II/III

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	35
All Data	3.3 (2.0)
RCB 0,I	3.5 (2.3)
RCB II,III	3.2 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: SUVmax (RCB 0,I) = SUVmax (RCB II,III) in other words, we are comparing the SUVmax @ FLT2 between the RCB 0,I and the RCB II,III groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	*two-sided exact p value from Wilcoxon two-sample test

6. Secondary Outcome

Title	SUVmax at FLT-3 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III
Description	The Standard Uptake Values (max) after completion of NAC (FLT-3) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the mean of the uptake values the measurement of interest and report those values herein.
Time Frame	post-NAC (FLT-3)

Outcome Measure Data

Analysis Population Description

After completion of NAC (FLT-3): only 31 patients had both FLT3 and RCB evaluation: 11 patients with RCB 0/I and 20 patients with RCB II/III

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	31
All Data (FLT3)	1.8 (1.8)
RCB 0/I (FLT3)	0.7 (0.3)
RCB II/III (FLT3)	2.4 (2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: SUVmax (RCB 0,I) = SUVmax (RCB II,III) in other words, we are comparing the SUVmax @ FLT3 between the RCB 0,I and the RCB II,III groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	two-sided exact p value from Wilcoxon two-sample test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	H0: %SUVmax FLT1-FLT3 (RCB 0,I) = %SUVmax FLT1-FLT3 (RCB II,III) A logistic regression model is used to determine if a larger percent change in SUVmax is associated with (RCB 0,I); the null hypothesis assumes that there is no association.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.76 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in Uptake Between FLT1 and FLT3 to Predict Pathologic Complete Response (pCR) of the Primary Tumor
Description	To evaluate the relationship between the change in uptake between FLT1 and FLT3 and pathologic complete response, an ROC curve will be estimated and the area under the curve (AUC), along with its 90% confidence interval, will be determined. For the purposes of reporting, we will consider the percent change in uptake between FLT1 and FLT3 to be the outcome. Reported values in the Outcome Measure table represent Change in uptake between FLT1 and FLT3, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT3 and pathological complete response was assessed by using ROC analysis. The Area Under the ROC Curve is reported in the Statistical Analysis section
Time Frame	Baseline (FLT-1) and post-NAC (FLT-3)

Outcome Measure Data

Analysis Population Description

43 patients who had both FLT1 and FLT3 scans

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET /CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. CT: Undergo 18F-FLT PET/CT 18F-FLT: Undergo 18F-FLT PET/CT PET: Undergo 18F-FLT PET/CT
Measure Participants	43
All Data	38.8 (26.1)
pCR	52.7 (22.8)
no-pCR	35.8 (26.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	ROC analysis was used to compute the AUC and evaluate if %ΔSUVmax FLT1-FLT3 is predictive of pCR with alpha=0.05. The Null Hypothesis assumes that the P(%ΔSUVmax FLT1-FLT3|pCR)= 1 - P(%ΔSUVmax FLT1-FLT3|non-pCR) that is: H0: AUC =0.5 (guessing)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Delong 1-sided p-value (alpha=0.05)
	Method	Delong Method
	Comments	The Delong-Delong Clark-Pearson method using modified U-statistics was used to evaluate the AUC
Method of Estimation	Estimation Parameter	AUC
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 90%; .72 to .94
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	%Change SUVmax From FLT1-FLT2 to Predict Lymph Node Status at Surgery
Description	Reported values in the Outcome Measure table represent %Change in uptake between FLT1 and FLT2, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT2 and lymph node (LN) status. For the purposes of reporting, the % Change in SUV will be considered the outcome.
Time Frame	Baseline (FLT-1) and Early Therapy (FLT-2)

Outcome Measure Data

Analysis Population Description

Data on 38 patients having FLT1 and FLT2 were available for histopathological LN evaluation after NAC: 14 with negative nodes, 15 with 1-3 LN metastases and 9 with >3 LN metastases

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	38
All Data	44.9 (26.0)
0 Positive Nodes	47.7 (29.0)
1-3 Positive Nodes	43.8 (23.8)
3+ Positive Nodes	42.6 (27.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments	Kruskal-Wallis one-way ANOVA was used to test whether there was a difference in %SUVmax (FLT1-FLT2) among LN statuses. H0: no difference between the 3 LN status.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Kruskal-Wallis
	Comments	two-sided p value from Kruskal-Wallis one-way ANOVA

9. Secondary Outcome

Title	%Change SUVmax From FLT1-FLT3 to Predict Lymph Node Status at Surgery
Description	%change in SUVmax from FLT1-FLT3 will be compared by lymph node status at surgery For the purposes of reporting, %change in SUVmax from FLT1-FLT3 will be consider the outcome.
Time Frame	Baseline (FLT-1) and post-NAC (FLT-3)

Outcome Measure Data

Analysis Population Description

Data on 30 patients with FLT3 were available for histopathological LN evaluation after NAC: 11 with negative nodes, 13 with 1-3 LN metastases and 6 with >3 LN metastases

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
Measure Participants	30
All Data	71.4 (29.1)
0 Positive Nodes	65.2 (42.2)
1-3 Positive Nodes	77.6 (18.1)
3+ Positive Nodes	69.5 (19.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diagnostic (18F-FLT)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments	two-sided p value from Kruskal-Wallis one-way ANOVA
	Method	Kruskal-Wallis
	Comments

Adverse Events

Arm/Group Title	Diagnostic (18F-FLT)
Arm/Group Description	Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy. Fluorothymidine F-18: Undergo 18F-FLT PET/CT Positron Emission Tomography: Undergo 18F-FLT PET/CT Computed Tomography: Undergo 18F-FLT PET/CT Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Diagnostic (18F-FLT)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Diagnostic (18F-FLT)
	Affected / at Risk (%)	# Events
Total	0/90 (0%)
Other (Not Including Serious) Adverse Events
	Diagnostic (18F-FLT)
	Affected / at Risk (%)	# Events
Total	8/90 (8.9%)
Gastrointestinal disorders
Gastrointestinal pain	1/90 (1.1%)	1
Nausea	1/90 (1.1%)	1
Diarrhea	1/90 (1.1%)	1
Mucositis oral	1/90 (1.1%)	1
General disorders
Flushing	2/90 (2.2%)	3
Paresthesia	2/90 (2.2%)	2
Peripheral sensory neopathy	2/90 (2.2%)	2
Fever	1/90 (1.1%)	1
Wound Infenction	1/90 (1.1%)	1
Nail discoloration	1/90 (1.1%)	1
Pain in extremity	1/90 (1.1%)	1
Allergic rhinitis	1/90 (1.1%)	1
Infections and infestations
Generalized muscle weakness	1/90 (1.1%)	1
Psychiatric disorders
Fatigue	1/90 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Insomnia	1/90 (1.1%)	1
Upper respiratory infection	1/90 (1.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.