Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor–Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Figure 1.  Flow Diagram
Flow Diagram

CTC indicates circulating tumor cell; HR, hormone receptor.

Figure 2.  Time to Recurrence by Circulating Tumor Cell (CTC) Assay Result Among Patients With Hormone Receptor–Positive Breast Cancer
Time to Recurrence by Circulating Tumor Cell (CTC) Assay Result Among Patients With Hormone Receptor–Positive Breast Cancer

RR indicates relative risk.

Table.  Univariate and Multivariable Analyses of Association Among Presence of CTCs, Clinicopathologic Features, and Recurrence in Hormone Receptor–Positive Breast Cancer
Univariate and Multivariable Analyses of Association Among Presence of CTCs, Clinicopathologic Features, and Recurrence in Hormone Receptor–Positive Breast Cancer
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Original Investigation
December 2018

Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor–Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
  • 2Department of Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts
  • 3Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 4Department of Oncology, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
  • 5Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona
  • 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 7Department of Medicine, Division of Oncology, Stanford Cancer Center, Palo Alto, California
  • 8Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis
JAMA Oncol. 2018;4(12):1700-1706. doi:10.1001/jamaoncol.2018.2574
Key Points

Question  Are circulating tumor cells associated with late recurrence of breast cancer?

Findings  In this secondary analysis of a randomized clinical trial, circulating tumor cells were detectable in 26 of 547 patients (4.8%) with localized breast cancer 5 or more years after diagnosis and were associated with a higher risk of recurrence among patients with hormone receptor–positive breast cancer.

Meaning  Circulating tumor cells may be used to stratify for risk of late recurrence among patients with hormone receptor–positive breast cancer.

Abstract

Importance  Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor–positive breast cancer.

Objective  To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2–negative breast cancer.

Design, Setting, and Participants  This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2–negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018.

Interventions  A blood sample was obtained for identification and enumeration of CTCs.

Main Outcome and Measures  The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence.

Results  Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor–positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor–negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative).

Conclusions and Relevance  A single positive CTC assay result 5 years after diagnosis of hormone receptor–positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy.

Trial Registration  ClinicalTrials.gov identifier: NCT00433511

Introduction

Breast cancer is the most common cancer and the leading cause of death from cancer among women, accounting for 25% of all cancers and 15% of deaths from cancer worldwide.1,2 Although most patients with breast cancer present with localized disease that is potentially curable with surgery and radiation,3 recurrence in distant organs is common and incurable.4 Adjuvant systemic therapies reduce distant recurrence and breast cancer mortality.5 Adjuvant chemotherapy reduces recurrence primarily within 5 years after diagnosis,6 whereas endocrine therapy reduces recurrence during a typical 5-year treatment course and after completion of endocrine therapy because of a carry-over effect.7,8 Recurrence 5 years or more after a diagnosis is commonly referred to as late recurrence and accounts for approximately one-half of all recurrences of hormone receptor–positive breast cancer, whereas recurrence 5 years or more after diagnosis is considerably less common among patients with hormone receptor–negative disease.9,10 Continuing tamoxifen therapy beyond 5 years or switching to an aromatase inhibitor are associated with reductions in recurrence and breast cancer mortality,11-14 whereas continuing therapy with aromatase inhibitors beyond 5 years is associated with marginal effects in reducing distant recurrence risk.15-17

Biomarkers prognostic for late recurrence potentially provide more accurate stratification of recurrence risk than clinicopathologic features. Although some multiparameter gene expression assays of the primary tumor can be used to determine both early and later recurrence18-23 and the efficacy of extended adjuvant endocrine therapy beyond 5 years,24 the use of such assays is not recommended for guiding therapy beyond 5 years after diagnosis because they are associated with a modest degree of risk stratification and there is limited evidence of their clinical utility.25,26 Biomarkers that more robustly stratify risk are needed. Assays that use blood-based biomarkers such as circulating tumor cells (CTCs)27 or circulating tumor DNA28 (so-called liquid biopsies) have potential to address this unmet need but have not been evaluated for use in determining late recurrence in breast cancer. We describe here, to our knowledge for the first time, the prospective evaluation of a CTC assay used to determine late clinical recurrence of breast cancer 5 years after potentially curative local therapy and systemic adjuvant therapy.

Methods
Eligibility Criteria

The study population included patients enrolled in a completed E5103 adjuvant clinical trial (Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer [NCT00433511]) that accrued 4994 patients with node-positive or high-risk node-negative human epidermal growth factor receptor 2–negative operable breast cancer between November 2007 and February 2011. The protocol stipulated adjuvant therapy including sequential doxorubicin/cyclophosphamide-paclitaxel chemotherapy alone or in combination with bevacizumab plus endocrine therapy for patients with hormone receptor–positive disease. Five-year invasive disease–free survival rates ranged from 76% to 80% and were not significantly associated with bevacizumab use.29 Trial participants were eligible to participate in a late recurrence substudy (EL112) if they were without clinical evidence of recurrence based on history and physical examination between 4.5 and 7.5 years after registration in the original E5103 trial and if they consented to participate in the substudy. Written informed consent was obtained. Data were deidentified. The parent E5103 study and EL112 late relapse substudy were reviewed and approved by the Cancer Therapy Evaluation Program, National Cancer Institute, and by the local institutional review board at each participating center. This prospective trial was designed and results were reported in accordance with the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines.30

CTC Assay

Whole blood samples were obtained in fixative-containing tubes (CellSave; Menarini Silicon Biosystems Inc) and sent to a central laboratory (Alpaugh Laboratory, Fox Chase Cancer Center, Philadelphia, PA) for CTC identification and enumeration using the CellSearch system, as described elsewhere.31,32 The assay is a clinically validated, US Food and Drug Administration–cleared blood test for enumerating CTCs in patients with metastatic breast cancer.31 Results were not reported to the treating clinician or patient because of the uncertainty regarding the prognostic information provided by the assay in this context.

Statistical Evaluation

Data analysis was performed in April 2018. An interim analysis was planned after accrual of approximately 233 patients, with further accrual to be halted if the CTC positivity rate was less than 1%, providing 90% power with a 1-sided type I error rate of 5% to distinguish between a true CTC positivity rate of 5% vs 10%. Accrual continued after the interim analysis when it was determined that the CTC positivity rate exceeded 1% and was discontinued after 3.4 years of accrual (and 5.4 years after enrollment of the last patient in the parent E5103 trial) because of slowing accrual. The primary analysis population included patients with an evaluable blood sample and no documented invasive recurrence within 30 days after or at any time before the CTC blood sample obtainment. The primary end point was time to recurrence, defined as the date of the CTC blood sample obtainment to the date of the first invasive distant, local, or regional recurrence; patients without documentation of invasive recurrence were censored at the date on which they were last known to be disease free. The Fisher exact test was used to compare groups with respect to patient characteristics. Clinical recurrences were determined by the local treating physician on the basis of clinical, radiographic, and pathologic information and were confirmed by a research coordinator in the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) data management center and the study principal investigator (K.D.M.). The Kaplan-Meier method was used to estimate time-to-recurrence distributions, and the log-rank test was used for comparison. Cox proportional hazards regression models were used to estimate hazard ratios. Recurrence rates were calculated as number of time-to-recurrence events divided by person-years of follow-up. P < .05 was considered to be statistically significant. P values were 2-sided. A positive CTC assay result was defined as at least 1 CTC per 7.5 mL of blood, and a negative CTC assay result was defined as no CTC detected in 7.5 mL of blood.

Results
Study Population

Of the 4994 patients enrolled in the parent E5103 trial, a total of 547 patients (9.1%) (mean [SD] age, 51.9 [9.4] years) without clinical evidence of recurrence and with an evaluable CTC assay result were included in the late recurrence substudy analysis between February 25, 2013, and July 29, 2016 (Figure 1). There were no significant differences in the demographic and clinical characteristics of the substudy population and the population enrolled in the E5103 parent trial (eTable 1 in the Supplement). Twenty-six of 547 patients (4.8% [95% CI, 3.1%-6.9%]) had positive CTC assay results, with no significant differences noted in the characteristics of the CTC-positive and CTC-negative patients (eTable 2 in the Supplement). Of the 26 patients with a positive CTC assay result, 12 (46%) were 50 years or older at the time of diagnosis and registration for the E5103 parent study, 16 (62%) had a primary tumor size larger than 2 cm in diameter, 21 (81%) had at least 1 positive axillary node metastasis, 18 (69%) had hormone receptor–positive disease, and 12 (46%) had high-grade histologic findings. There were no significant differences in characteristics between the CTC-positive and CTC-negative groups. There were also no significant differences in the demographic and clinical characteristics of the late relapse substudy population and the patients enrolled in the parent trial who did not enroll in the substudy (eTable 2 in the Supplement).

Recurrence in the Study Population

At the time of the analysis, the median follow-up after the CTC assay was performed was 2.6 years (range, 1.6-4.4 years), and 24 of 547 patients had experienced clinical recurrence (4.4% [95% CI, 2.8%-6.5%), including 23 patients whose primary tumor was hormone receptor–positive at the original diagnosis and 1 patient with a hormone receptor–negative tumor at the original diagnosis. Twenty-two of 24 patients had recurrences that were in distant sites (including 2 patients with concurrent local regional recurrence), and 2 patients had recurrences that were in a local or regional site without distant recurrence (including the only patient in this study with hormone receptor–negative disease who experienced relapse). Recurrence occurred in 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) with hormone receptor–positive disease, but it occurred in only 1 of 193 patients (0.5% [95% CI, 0%-2.9%]) with hormone receptor–negative disease. In the entire population, a positive CTC assay result was associated with a 12.7-fold higher risk of recurrence (95% CI, 4.7-34.7; P < .001) in multivariate analysis (eTable 3 in the Supplement). Because there was only 1 recurrence in the hormone receptor–negative population, all subsequent analyses evaluating the association between CTC status and recurrence are restricted to the hormone receptor–positive population.

CTCs and Recurrence in the Hormone Receptor–Positive Population

Seven of 18 patients (38.9% [95% CI, 17.3%-64.3%]) with hormone receptor–positive disease and a positive CTC assay result had a recurrence. A positive CTC assay result was associated with a 10.82-fold higher risk of recurrence (95% CI, 4.42-26.47; P < .001) (Figure 2). As shown in the Table, in multivariable models that include clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%) with hormone receptor–positive disease and recurrence had a positive CTC assay result before recurrence. The median time to recurrence was 2.8 years (range, 0.1-2.8 years) among the CTC-positive patients. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively.

Among the 330 patients for whom information regarding endocrine therapy use at the time of registration was available, most patients in both the CTC-negative group (272 of 313 [86.9%]) and CTC-positive group (15 of 17 [88.2%]) were receiving endocrine therapy. Among 23 patients with hormone receptor–positive disease who had a clinical recurrence, 18 were receiving endocrine therapy after study registration at the time that the CTC assay was performed (including 5 of 7 CTC-positive patients and 13 of 16 CTC-negative patients), and 5 of 7 patients with a positive CTC assay result and clinical recurrence experienced relapse while receiving endocrine therapy.

CTC Burden and Recurrence in the Hormone Receptor–Positive Population

The association between CTC burden and recurrence in 18 patients with hormone receptor–positive disease and a positive CTC assay result is depicted in eFigure 1 in the Supplement. The median CTC count was 1 per 7.5 mL of blood (range, 1-15 per 7.5 mL blood) among all 18 patients, 9 per 7.5 mL blood (range, 1-15 per 7.5 mL blood) among the 7 patients with recurrence, and 1 per 7.5 mL blood (range, 1-14 per 7.5 mL blood) among the 11 patients without recurrence. Recurrence occurred in 16 of 335 patients (4.8% [95% CI, 2.8%-4.8%]) with a CTC count of 0 cells per 7.5 mL blood, 2 of 12 patients (16.7% [95% CI, 2.1%-48.4%]) with a CTC count of 1 per 7.5 mL blood, and 5 of 6 patients (83.3% [95% CI, 35.9%-99.6%]) with a CTC count of 2 or more per 7.5 mL blood, which suggests that a numerically higher recurrence risk is associated with higher CTC burden.

CTC Burden in the Hormone Receptor–Negative Population

None of 8 patients with hormone receptor–negative disease and a positive CTC assay result had a recurrence (0% [95% CI, 0%-37.0%]). Seven patients had a CTC count of 1 per 7.5 mL blood, and 1 patient had 2 per 7.5 mL blood. The median follow-up time after a positive CTC assay result was 2.8 years (range, 0-2.9 years).

Discussion

Late recurrence accounts for at least one-half of all cases of recurrence among patients with localized hormone receptor–positive breast cancer. Among 62 923 patients with hormone receptor–positive breast cancer who completed 5 years of endocrine therapy evaluated in the Early Breast Cancer Collaborative Trialists Group database, the ensuing 5-year risk of distant recurrence for patients with 0, 1 to 3, and 4 to 9 positive axillary nodes was approximately 6%, 10%, and 22%, respectively.33 We prospectively evaluated, for the first time to our knowledge, the association between the presence of CTCs determined using an analytically validated blood-based assay at 5 or more years after diagnosis and late clinical recurrence of operable breast cancer. All patients received primary surgical therapy and participated in a prospective clinical trial that included adjuvant systemic chemotherapy and at least a 5-year course of endocrine therapy if the breast cancer expressed hormone receptors. Consistent with earlier reports, late recurrence occurred predominantly among patients with hormone receptor–positive breast cancer who received similar adjuvant chemotherapy and endocrine therapy.10 The result of the CTC assay was positive for approximately 5% of patients with hormone receptor–positive breast cancer and was associated with an approximately 13-fold higher risk of clinical recurrence compared with a negative CTC assay result. Nearly one-half of patients with hormone receptor–positive disease who had a recurrence had a positive CTC assay result before clinical recurrence, with a median time between a positive CTC assay result and recurrence of 2.8 years (range, 0.1-2.8 years). The recurrence rates per person-year of follow-up among CTC-positive and CTC-negative groups were 21.4% and 2.0%, respectively. For patients with hormone receptor–negative disease, although the CTC positivity rate was similar to that in the hormone receptor–negative group, it was not associated with late recurrence. However, only 1 of 193 patients with hormone receptor–negative disease (0.5%) had a late clinical recurrence at the time of the analysis.

Critical features supporting the use of biomarkers for directing cancer therapy include analytic validity, clinical validity, and clinical utility.34 With regard to analytic validity, the CTC assay used in this study is a clinically validated, US Food and Drug Administration–cleared blood test for enumerating CTCs that provides prognostic information for patients with metastatic breast, prostate, and colorectal cancer.31,32 With regard to clinical validity, this prospectively conducted study offers a high level of evidence supporting the association between a positive CTC assay result and risk of clinical recurrence.35 This study was designed and is reported in accordance with established evidence-based guidelines for biomarker validation30 and identified an approximately 13-fold higher residual risk of late clinical recurrence of hormone receptor–positive breast cancer among patients with a positive CTC assay result. This level of risk stratification surpasses the 2-fold higher late recurrence risk observed with multiparameter gene expression assays of the primary tumor and a poor risk signature, including the HOXB13 (OMIM 604607) to IL17BR (OMIM 605458) 2-gene ratio24 and the ESR1 RNA score.19

Earlier studies have evaluated the prognostic information provided by the same CTC assay for breast cancer at diagnosis. Lucci et al36 detected CTCs in 24% of 302 patients with stage I-III breast cancer at the time of primary surgery; after a median follow-up of 2.9 years, a positive CTC assay result was associated with a 4.6-fold increased risk of recurrence. Likewise, among 2026 patients with stage I-III breast cancer, Rack et al37 reported a 2.1-fold higher risk of recurrence after a median follow-up of 2.9 years among the 22% of patients who had a positive CTC assay result before or after adjuvant chemotherapy. A pooled analysis of individual data from 3173 patients with stage I–III breast cancer, including the 2 earlier reports, likewise showed that CTCs were detected in 20.2%, and the presence of CTCs was an independent prognostic factor in multivariate analysis for distant recurrence and breast cancer mortality.38 However, the CTC assay is currently not recommended to guide adjuvant therapy,26 largely because of the modest degree of risk stratification and lack of effect on clinical management associated with the assay.

Other blood-based biomarkers, such as circulating MUC-1 antigen assays (eg, CA15-3 and CA 27.29), have been evaluated for active surveillance with the goal of early detection of recurrent breast cancer, although not specifically for late recurrence. Sensitivity ranged from approximately 40% to 60%, the lead time between a positive assay result and clinical recurrence ranged from 3 to 6 months, and survival was not improved for those who underwent active surveillance.39-42 Despite the limitations associated with these assays and the diagnostic imaging and therapeutic interventions available at the time, evidence from other randomized trials suggests that early intervention based on active surveillance using circulating MUC-1 antigen assays may delay clinical evidence of recurrence.43-45 The high degree of risk stratification for late recurrence associated with the CTC assay and longer lead time between a positive assay result and clinical recurrence, in addition to the more effective therapies for advanced hormone receptor–positive breast cancer that are currently available, such as CDK4/6 inhibitors46-50 or oral selective estrogen receptor downregulators,51 raise the possibility of testing new treatment approaches in prospective clinical trials that include populations enriched for high risk of late recurrence by a positive CTC assay result without clinical evidence of recurrence; such trials would need to screen a large number of individuals to identify enough at high risk. Evaluation of biomarker panels, such as CTC count combined with single-cell genomics,52 circulating MUC-1,53 or circulating tumor DNA,54 represents other potential screening approaches.

Limitations

There are several limitations of this study. The sample size was small, resulting in wide confidence intervals for the various point estimates examined. The median follow-up time of 2.6 years is relatively short for hormone receptor–positive breast cancer, and more recurrences among the CTC-negative group with longer follow-up could result in a lower degree of risk stratification. Most patients were receiving endocrine therapy before the blood samples were obtained for the CTC assay, and the study was not designed to determine whether a negative CTC assay result could identify patients who could be effectively spared continued endocrine therapy because of a low risk of late recurrence. The study also excluded patients with human epidermal growth factor receptor 2–overexpressing disease, who are also at risk for late recurrence if they are hormone receptor positive.55 The CTC assay was performed at only a single time point between approximately 4.5 and 7.5 years after diagnosis, resulting in knowledge gaps about serial use of the assay or use before or after those time points for active surveillance. The CTC assay was not evaluated in the context of other assays, including commercial tumor antigen assays or emerging technologies, such as tests to determine circulating tumor DNA.56 The CTC assay results were unknown to the clinician and patient and did not trigger imaging studies if they were positive, which could impact the sensitivity and specificity of assay results and the lead time between a positive assay result and cancer recurrence.

Conclusions

The results of this study provide proof of concept supporting further study of blood-based biomarker tests such as the CTC assay for early detection of late clinical recurrence and for identifying subjects at low risk of late recurrence. Notwithstanding proof of concept, further evaluation is required to confirm the clinical validity and determine the clinical utility of performing the CTC assay in this context.

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Article Information

Accepted for Publication: May 2, 2018.

Corresponding Author: Joseph Sparano, MD, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1695 Eastchester Rd, Bronx, NY 10561 (jsparano@montefiore.org).

Published Online: July 26, 2018. doi:10.1001/jamaoncol.2018.2574

Author Contribution: Dr Sparano had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sparano, Sledge, Miller.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sparano, Wolff.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: O'Neill.

Obtained funding: Sparano, Sledge, Miller.

Administrative, technical, or material support: Sparano, Dang, Sledge, Miller.

Supervision: Sparano, Northfelt, Miller.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants CA180820, CA180794, CA180790, CA180791, CA180795, CA180802, CA180816, CA180821, and CA189859 from the National Cancer Institute, National Institutes of Health, and by Breast Cancer Research Foundation and Susan G. Komen Foundation (Dr Sparano).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Additional Contributions: This study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (Peter J. O'Dwyer, MD, and Mitchell D. Schnall, MD, PhD, group co-chairs).

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