Association of Modifiable Risk Factors With Early Discontinuation of Adjuvant Endocrine Therapy: A Post Hoc Analysis of a Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Table 1.  Endocrine Therapy Early Discontinuation by Baseline Patient-Reported Outcomes, Adjusted for Age and Receipt of Chemotherapy
Endocrine Therapy Early Discontinuation by Baseline Patient-Reported Outcomes, Adjusted for Age and Receipt of Chemotherapy
Table 2.  Endocrine Therapy Early Discontinuation HRs by Baseline Comorbidity, Adjusted for Age and Receipt of Chemotherapy
Endocrine Therapy Early Discontinuation HRs by Baseline Comorbidity, Adjusted for Age and Receipt of Chemotherapy
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Lambert  LK, Balneaves  LG, Howard  AF, Gotay  CC.  Patient-reported factors associated with adherence to adjuvant endocrine therapy after breast cancer: an integrative review.   Breast Cancer Res Treat. 2018;167(3):615-633. doi:10.1007/s10549-017-4561-5 PubMedGoogle ScholarCrossref
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Hershman  DL, Kushi  LH, Hillyer  GC,  et al.  Psychosocial factors related to non-persistence with adjuvant endocrine therapy among women with breast cancer: the Breast Cancer Quality of Care Study (BQUAL).   Breast Cancer Res Treat. 2016;157(1):133-143. doi:10.1007/s10549-016-3788-x PubMedGoogle ScholarCrossref
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Bender  CM, Gentry  AL, Brufsky  AM,  et al.  Influence of patient and treatment factors on adherence to adjuvant endocrine therapy in breast cancer.   Oncol Nurs Forum. 2014;41(3):274-285. doi:10.1188/14.ONF.274-285 PubMedGoogle ScholarCrossref
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Wagner  LI, Zhao  F, Goss  PE,  et al.  Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03).   Breast Cancer Res Treat. 2018;169(3):537-548. doi:10.1007/s10549-018-4713-2 PubMedGoogle ScholarCrossref
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Stanton  AL, Petrie  KJ, Partridge  AH.  Contributors to nonadherence and nonpersistence with endocrine therapy in breast cancer survivors recruited from an online research registry.   Breast Cancer Res Treat. 2014;145(2):525-534. doi:10.1007/s10549-014-2961-3 PubMedGoogle ScholarCrossref
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Paranjpe  R, John  G, Trivedi  M, Abughosh  S.  Identifying adherence barriers to oral endocrine therapy among breast cancer survivors.   Breast Cancer Res Treat. 2019;174(2):297-305. doi:10.1007/s10549-018-05073-z PubMedGoogle ScholarCrossref
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Mausbach  BT, Schwab  RB, Irwin  SA.  Depression as a predictor of adherence to adjuvant endocrine therapy (AET) in women with breast cancer: a systematic review and meta-analysis.   Breast Cancer Res Treat. 2015;152(2):239-246. doi:10.1007/s10549-015-3471-7 PubMedGoogle ScholarCrossref
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    EXPAND ALL
    Endocrine therapy should be adjusted in evaluation of risk factors for early discontinuation
    Shen Tian | Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University
    Endocrine therapy should be adjusted in evaluation of risk factors for early discontinuation

    Shen Tian1*, Juan Wu1*, Ling-quan Kong1#
    * These authors have contributed equally to this work.

    Author Affiliations:
    1Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
    #Corresponding author:
    Dr. Ling-quan Kong, Department of Endocrine and Breast Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. E-mail: huihuikp@163.com Tel:+8613101380893;

    Yanez B, Gray RJ et al. reported in the post hoc analysis of TAILORx study that age older than 40 years were
    associated with a lower probability of early discontinuation of endocrine therapy (ET), and poor social well-being, poor physical well-being and comorbid depression, were significant risk factors for early discontinuation of ET.1 However there might be some limitations in the conclusion.
    According to the NCCN guidelines, premenopausal breast cancer patients with the diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative are recommended treatment of tamoxifen, ovarian suppression/ablation with tamoxifen or aromatase inhibitors (AIs), or tamoxifen followed by AIs. While postmenopausal breast cancer patients with same molecular subtype are recommended treatment of AIs or tamoxifen.2 Actually the prevalence of side effects of tamoxifen and AIs, such as vulvo-vaginal symptoms and musculoskeletal symptoms, are different3, which leads to different levels of poor physical well-being and depression. Furthermore, patients younger than 40 years, especially treated with ovarian suppression/ ablation, even suffer more severe estrogen deprivation than those only with tamoxifen and postmenopausal patients. Hence, the physical well-being or comorbid depression level attributable to ET may be varied with different ET options among patients younger than 40 years and postmenopausal patients, leading to different adherence rates.4 Therefore, in order to explore the risk factors of discontinuation of ET, the treatment protocols of ET should also be adjusted.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    June 17, 2021

    Association of Modifiable Risk Factors With Early Discontinuation of Adjuvant Endocrine Therapy: A Post Hoc Analysis of a Randomized Clinical Trial

    Author Affiliations
    • 1Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 2Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Biostatistics Center, Dana Farber Cancer Institute, Boston, Massachusetts
    • 3Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
    • 4Department of Radiology, University of Michigan Comprehensive Cancer Center, Ann Arbor
    • 5Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia
    • 6Center for Statistical Sciences, Brown University, Providence, Rhode Island
    • 7Canadian Cancer Trials Group, McMaster University, Hamilton, Ontario, Canada
    • 8Department of Medicine, Stanford Cancer Center Palo Alto, Stanford, California
    • 9Department of Social Sciences and Health Policy, Wake Forest University Health Sciences, Winston Salem, North Carolina
    JAMA Oncol. 2021;7(8):1196-1202. doi:10.1001/jamaoncol.2021.1693
    Key Points

    Question  What risk factors are associated with early discontinuation of endocrine therapies among women with breast cancer in the Trial Assigning Individualized Options for Treatment?

    Findings  In this post hoc analysis of a randomized clinical trial, including 954 women with breast cancer, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies.

    Meaning  Patient-reported outcomes can identify patients at increased risk for early discontinuation of endocrine therapies and select intervention targets.

    Abstract

    Importance  Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment.

    Objective  To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids.

    Design, Setting, and Participants  This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021.

    Main Outcomes and Measures  Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors.

    Results  A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003).

    Conclusions and Relevance  In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET.

    Trial Registration  ClinicalTrials.gov Identifier: NCT00310180

    Introduction

    Endocrine therapy (ET) has been associated with up to a 50% reduction in breast cancer recurrence, a reduction in contralateral breast cancer, and approximately 30% reduction in breast cancer mortality.1-4 Endocrine therapy is typically recommended for at least 5 years, or longer in those at higher risk of recurrence,5-7 but nonadherence to a prescribed course is common.2,8,9 In a retrospective analysis, nonadherence to tamoxifen was 52.2% and nonadherence to anastrozole was 47% after 3 years.10 These findings were confirmed in a systematic review of 29 studies of patients with breast cancer as well as additional studies.8,9 Nonadherence (ie, not taking the medication daily) and early discontinuation (ie, a subtype of nonadherence in which the medication is discontinued before the prescribed duration) are therefore problematic.

    Studies on nonadherence to ET have largely focused on demographic and clinical characteristics as factors associated with nonadherence.9,11-16 Age, out-of-pocket cost of ET, and experiencing ET-related adverse effects have been associated with nonadherence.11-16 The association between polypharmacy and nonadherence is not well established, with some studies revealing a positive association between the number of additional oral medications and adherence, and other studies reporting that fewer medications at study baseline was associated with higher adherence.9,17 Class of concurrent non-ET medications may also be an important factor associated with adherence.17 Lipid-lowering drugs and antihypertensive drugs have been associated with favorable adherence, and frequent use of opioid-containing analgesics, anxiolytics or antipsychotics, and antidepressants have been associated with lower odds of adherence.18

    Modifiable factors associated with nonadherence can reveal screening and intervention targets. Limited research in this area has found that poor health-related quality of life (HRQoL) and depression are associated with nonadherence.6,17 Establishing definitive conclusions about factors associated with nonadherence to ET is challenging owing to methodological variability in published studies. For example, some studies limited their assessment of ET adherence within the first 1 to 2 years from initiation, not capturing patients who might discontinue later treatment.19-21 Other studies have been limited to a cross-sectional design, inclusion of only 1 type of ET, or reliance on retrospective and subjective patient self-reported adherence.22,23 Longitudinal study designs that incorporate objective measures of adherence to ET are needed to better evaluate risk factors of nonadherence.17,19

    The Trial Assigning Individualized Options for Treatment (TAILORx) trial demonstrated that ET was noninferior to chemotherapy followed by ET (chemoendocrine therapy) in women with a midrange 21-gene recurrence score (RS) of 11 to 25.24 The unique design of the TAILORx trial, in which participants were provided with information on their 21-gene RS, can provide novel insights into factors associated with early discontinuation of ET among women who have received personalized information on their risk of breast cancer recurrence. The goal of this post hoc exploratory study was to investigate modifiable factors associated with early discontinuation across the course of ET treatment within the TAILORx trial. Because HRQoL is a multidimensional construct, we sought to identify which domains of cancer-related HRQoL predict early discontinuation. In addition, we explored the association between polypharmacy, including class and type of additional medications, and early ET discontinuation.

    Methods
    Study Design

    This study is a post hoc analysis of the TAILORx data set. The Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (ClinicalTrials.gov Identifier NCT00310180) coordinated patient enrollment into the TAILORx study (trial protocol in Supplement 1).24 This study was approved by the Montefiore Medical Center institutional review board. After obtaining written study consent, 10 273 patients with breast cancer were enrolled from April 7, 2006, to October 6, 2010; the study was amended in January 2010 to incorporate a patient-reported outcomes (PRO) substudy. Participants comprised a subgroup of 954 women who were enrolled in the PRO substudy of TAILORx (eFigure 1 in Supplement 2). Additional information on the TAILORx study has been previously published.24

    Participants

    Participants were women between the ages of 18 and 75 years who had a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer. Per TAILORx study requirements, all participants met the National Comprehensive Cancer Network guidelines for recommendation of adjuvant chemotherapy based on tumor size grade and Eastern Cooperative Oncology Group performance status of 0 or 1. All study participants initiated ET within 1 year of study entry.

    Study Outcome

    Early discontinuation of ET, defined as discontinuation less than 4 years from initiation of ET for reasons other than death or recurrence, was assessed via clinician report. Initiation for women randomized to ET began after baseline, whereas ET initiation for women randomized to chemoendocrine therapy began after completion of chemotherapy. Study participants who were still receiving ET at the last study follow-up were counted as ET persistent.

    HRQoL as a Factor Associated With Early Discontinuation

    Health-related quality of life was measured using the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system.25,26 The Functional Assessment of Cancer Therapy (FACT) scale was used to assess domains of physical well-being, functional well-being, emotional well-being, and social/family well-being.27 Fatigue was measured by the FACIT fatigue scale and endocrine symptoms were measured by the FACIT endocrine symptoms scale. Higher scores on these scales indicate better cancer-related HRQoL. The FACIT scales can be found online.26,28 Health-related quality of life measures were administered at study baseline, which occurred at the time of study enrollment and randomization.

    Medical Covariates

    Information on patient characteristics, medical comorbidities, and polypharmacy were collected at study baseline. As part of the TAILORx protocol, clinical research associates were provided with a medication study form to collect current medical covariates, including depression, as well as non-ET medications being taken at study baseline. This form was completed using patient interviews and medical records. A list of medical comorbidities and additional medications is included in eTable 1 in Supplement 2.

    Statistical Analysis

    Statistical analysis took place from January 15, 2020, to April 6, 2021. Kaplan-Meier estimates were used to calculate the rate of discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET and patient-level factors. Analyses were conducted in the intent-to-treat population. Patient-level factors included age, race/ethnicity, treatment type, Oncotype DX Breast RS (Genomic Health Inc), insurance status, medical comorbidities, polypharmacy, and HRQoL. Hazard ratios (HRs) and 95% CIs are reported. Health-related quality of life scores were categorized into 3 groups by tertile for analysis; the group with the lowest HRQoL was the reference group. Polypharmacy was defined as having frequent use of 1 to 3 medication classes, 4 to 7 medication classes, or more than 7 medication classes, compared with no frequent use of any non-ET medication. Only non-ET medications used by 5 or more participants were included in the analyses. The Benjamini-Hochberg method was used to decrease the false discovery rate in all analyses focusing on HRQoL, medical comorbidities, and polypharmacy. A false discovery rate of 5% was selected, all P values were from 2-sided tests, and P ≤ .006 was considered statistically significant.

    Results

    A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. There were 106 cases with early termination of ET in the cohort of 954 patients, for an overall 4-year nonadherence rate of 11.4% (95% CI, 9.5%-13.6%). In the initial sample size of 954 participants, there were 106 early termination events and 62 censored durations (ie, off study while still receiving ET). eFigure 2 in Supplement 2 displays the Kaplan-Meier curve.

    In an initial joint model, receipt of chemoendocrine therapy (vs receipt of ET only; HR, 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. These covariates were included in all subsequent models. eTable 2 in Supplement 2 contains demographic characteristics within the study sample, and data from the initial joint model establishing factors associated with early discontinuation.

    After adjusting for receipt of chemotherapy and age, worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002) and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were significantly associated with a higher probability of early discontinuation of ET (Table 1). After adjusting for receipt of chemotherapy (vs receipt of ET only) and age, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005) was the only medical comorbidity that was associated with early discontinuation of ET (Table 2).

    After adjusting for receipt of chemotherapy and age, the number of additional non-ET medications at study baseline was not associated with early discontinuation of ET. However, use of antidepressants at study baseline, compared with no use of antidepressants at study baseline, was associated with early discontinuation of ET (HR, 1.87; 95% CI, 1.23-2.84; P = .003) (eTable 3 in Supplement 2).

    Discussion

    Findings from a sample of patients with breast cancer enrolled in the TAILORx PRO substudy indicate that modifiable characteristics are potential risk factors for early discontinuation of ET. To our knowledge, results from this trial may be among the first to report on factors associated with early discontinuation among women who have received personalized information on their 21-gene Oncotype DX RS used to guide their treatment.

    Data from the FACT subscales provide a more nuanced understanding of the HRQoL domains that are associated with early discontinuation of ET. Specifically, after adjustment for multiple comparisons, poor social well-being and physical well-being were associated with early discontinuation of ET. Our findings, similar to other studies, revealed a significant association between poor HRQoL and early discontinuation of ET.29 Several studies have suggested benefits associated with perceived social support for ET adherence. For example, poor HRQoL was associated with early discontinuation within 2 years of ET initiation19 and depressive symptoms have been associated with early discontinuation of ET.21,23,30,31 Mean HRQoL scores in our study sample were higher than the population norms for patients with cancer,32 and the rate of ET discontinuation may have been higher if the mean HRQoL scores in this study sample had been worse. Combined, our findings suggest that depression and poor scores on select domains of HRQoL may confer risk for early discontinuation even before breast cancer ET treatment initiation.

    Although depression at study baseline was associated with early discontinuation of ET, more general emotional well-being was not significantly associated with early discontinuation in this study. The FACT emotional well-being subscale does not focus solely on depressive symptoms but also assesses worry about cancer, feeling nervous, and satisfaction with coping. Previous research has documented a positive association between anxiety symptoms and nonadherence to ET.33 Our findings, combined with previous findings in the literature on anxiety and early discontinuation of ET, suggest that while depression may be predictive of early discontinuation, fear of recurrence and symptoms of anxiety that are captured in the FACT emotional well-being subscale may differently predict early discontinuation of ET. Although a history of an anxiety diagnosis was not assessed in the TAILORx trial, additional research can further elucidate how comorbid anxiety and depression differentially predict early discontinuation of ET.

    Our findings regarding age are consistent with several studies that have reported an association between young age and early discontinuation of ET.2,10,34 One possible explanation for this finding is that women of reproductive age may be more likely to discontinue ET if they are trying to conceive after breast cancer treatment. In the present study, receipt of chemotherapy was associated with a lower probability of early discontinuation. It is possible that patients in the trial who received chemotherapy may have perceived themselves at high risk for recurrence and were more motivated to be adherent to ET. Our findings regarding chemotherapy use are not consistent with a previous study that reported no significant association with receipt of chemotherapy and adherence to ET.19 Oncotype DX RS was also not associated with early discontinuation, which is consistent with 1 additional study that investigated the association between RS and early discontinuation.35 Finally, our findings did not reveal an association between the number of additional medications and early ET discontinuation. However, antidepressant use at study baseline was associated with early ET discontinuation, which affirms our findings pertaining to baseline depression and early discontinuation. Unlike the study by Calip et al,18 which found that frequent opioid use was associated with nonadherence to ET, our findings did not support an association between opioid use at baseline and nonadherence. Our findings may be because of differences in our measurement of polypharmacy, which did not include assessment of frequency of opioid use at study baseline.

    Limitations and Strengths

    This study has several noteworthy limitations. First, the reason for early discontinuation of ET was not recorded in the trial. In addition, information on daily adherence to ET was not collected; therefore, we cannot draw conclusions on factors associated with missed daily medications. Finally, the PRO substudy of the TAILORx trial was limited in racial/ethnic heterogeneity, and findings from this study might not be generalizable to diverse breast cancer survivors. Time to initiation in the TAILORx trial varied by randomization to chemoendocrine therapy or ET, with women randomized to chemoendocrine therapy after completion of chemotherapy. The difference in time to initiation of ET was accounted for by adjusting for treatment type in our analyses.

    This study also has some strengths. A key strength is the rigorous longitudinal follow-up, which allowed us to include women who might discontinue ET later in the treatment trajectory, and the objective assessment of early discontinuation captured through a clinical trial. Another strength is the baseline administration of 4 domains of cancer-related HRQoL. By separating the domains of HRQoL, our findings provide valuable information on which HRQoL domains should be administered to screen for women at elevated risk for early discontinuation of ET and specific concerns for intervention.

    Conclusions

    Elucidating the factors that are associated with ET discontinuation is an important first step in improving adherence to ET. Previous interventions aimed at improving adherence to ET have focused on providing educational and management materials or reminders to take ET.36-39 These trials have had limited success in improving adherence outcomes, underscoring the need to better understand the specific factors associated with early discontinuation of ET. Findings from our study suggest that beyond age and treatment, modifiable factors such as poor social well-being, physical well-being, and comorbid depression are risk factors for early discontinuation of ET, and may be important targets for future interventions that seek to improve ET adherence. More specifically, our findings suggest that oncology clinicians should consider referral for psychosocial care or physical rehabilitation for patients at risk for early discontinuation of ET. Many cancer centers already integrate routine PRO screening into electronic health records, allowing clinicians to identify patients with depression and poor social and physical well-being, who may be at risk for early discontinuation.40 These findings underscore the importance of screening for PRO modifiable factors to identify patients at risk for early discontinuation prior to initiating ET.

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    Article Information

    Accepted for Publication: April 14, 2021.

    Published Online: June 17, 2021. doi:10.1001/jamaoncol.2021.1693

    Corresponding Author: Betina Yanez, PhD, Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, 625 N Michigan Ave, 21st Floor, Chicago, IL 60618 (betina.yanez@northwestern.edu).

    Author Contributions: Drs Gray and Sparano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Yanez, Gray, Sparano, Carlos, Sadigh, Garcia, Whelan, Sledge, Wagner.

    Acquisition, analysis, or interpretation of data: Yanez, Gray, Sparano, Carlos, Gareen, Cella, Wagner.

    Drafting of the manuscript: Yanez, Carlos, Whelan, Wagner.

    Critical revision of the manuscript for important intellectual content: Yanez, Gray, Sparano, Carlos, Sadigh, Garcia, Gareen, Sledge, Cella, Wagner.

    Statistical analysis: Yanez, Gray.

    Obtained funding: Cella, Wagner.

    Administrative, technical, or material support: Wagner.

    Supervision: Sparano, Cella, Wagner.

    Conflict of Interest Disclosures: Dr Yanez reported receiving grants from Northwestern University during the conduct of the study and consulting income from Blue Note Therapeutics outside the submitted work. Drs Gray, Sparano, and Gareen reported receiving grants from the National Cancer Institute during the conduct of the study. Dr Carlos reported receiving salary support as editor in chief of the Journal of the American College of Radiology; and travel support from the GE Radiology Research Academic Fellowship as board of review chair outside the submitted work. Dr Whelan reported receiving nonfinancial support from Genomic Health Inc outside the submitted work. Dr Sledge reported receiving grants from Eli Lilly during the conduct of the study; grants from Pfizer and Genentech; and personal fees from Verseau, Tessa Therapeutics, and Pionyr Inc outside the submitted work. Dr Cella reported receiving grants from the National Institutes of Health during the conduct of the study; and being president of FACIT.org. Dr Wagner reported receiving personal fees from Celgene Inc and Athenex Inc outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was conducted by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA189828, UG1CA189859, UG1CA233160, UG1CA233320, and UG1CA233247.

    Role of the Funder/Sponsor: The funding source 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.

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