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Tolerability of Coronavirus Disease 2019 Vaccines, BNT162b2 and mRNA-1273, in Patients With Thymic Epithelial Tumors

Open AccessPublished:September 07, 2021DOI:https://doi.org/10.1016/j.jtocrr.2021.100229

      Abstract

      Introduction

      Defects in immunologic self-tolerance result in an increased risk for development of paraneoplastic autoimmune diseases (ADs) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of coronavirus disease 2019 (COVID-19) mRNA vaccines in patients with TETs, including individuals with preexisting AD.

      Methods

      After reviewing published data on adverse events associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at the following three time points: after each dose of vaccination and 1 month after the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data, and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines.

      Results

      From February 26 to June 1, 2021, we administered the survey to 54 participants (median age = 58 y, thymoma = 33, preexisting AD = 19). Common adverse events included injection site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three patients (16%) after the first dose and three patients (17%) after the second dose. Most AD flares were mild and self-limited. One patient (2%) was diagnosed with having a new AD after vaccination.

      Conclusions

      Tolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with preexisting AD did not experience disease flares, and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 owing to the documented benefits of vaccination and manageable risk profile.

      Keywords

      Introduction

      Thymomas and thymic carcinomas, collectively referred to as thymic epithelial tumors (TETs), are rare thoracic cancers with an incidence of 1.5 cases per million.
      • Conforti F.
      • Pala L.
      • Giaccone G.
      • De Pas T.
      Thymic epithelial tumors: from biology to treatment.
      ,
      • Zhao C.
      • Rajan A.
      Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?.
      TETs, particularly thymomas, are often associated with paraneoplastic autoimmune diseases (ADs) owing to impaired immunologic self-tolerance resulting from the persistence of autoreactive T cells.
      • Conforti F.
      • Pala L.
      • Giaccone G.
      • De Pas T.
      Thymic epithelial tumors: from biology to treatment.
      ,
      • Marx A.
      • Wilcox N.
      • Leite M.I.
      • et al.
      Thymoma and paraneoplastic myasthenia gravis.
      • Lippner E.A.
      • Lewis D.B.
      • Robinson W.H.
      • Katsumoto T.R.
      Paraneoplastic and therapy-related immune complications in thymic malignancies.
      • Evoli A.
      • Lancaster E.
      Paraneoplastic disorders in thymoma patients.
      • Marx A.
      • Yamada Y.
      • Simon-Keller K.
      • et al.
      Thymus and autoimmunity.
      Owing to these underlying defects in immunologic tolerance, patients with TETs display increased sensitivity to immune stimulation.
      • Zhao C.
      • Rajan A.
      Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?.
      Treatment with immune checkpoint inhibitors or cancer vaccines intended to stimulate the immune system can cause severe immune-related adverse events (AEs) in 3% to 57% of patients.
      • Zhao C.
      • Rajan A.
      Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?.
      ,
      • Oji Y.
      • Inoue M.
      • Takeda Y.
      • et al.
      WT1 peptide-based immunotherapy for advanced thymic epithelial malignancies.
      ,
      • Girard N.
      Immune checkpoints in thymic epithelial tumors: challenges and opportunities.
      This reactivity raises questions on the tolerability of other forms of immune stimulation, such as vaccination against coronavirus disease 2019 (COVID-19), in patients with TETs.
      At the time of study design, two mRNA vaccines had received emergency use authorization from the U.S. Food and Drug Administration for vaccination against COVID-19: BNT162b2 manufactured by Pfizer, Inc., and BioNTech and mRNA-1273 produced by ModernaTX, Inc. Phase 2 and phase 3 clinical trials have shown that both vaccines are safe and highly effective at preventing severe COVID-19 infection, hospitalization, and death.
      US Food and Drug Administration
      Emergency use authorization (EUA) for an unapproved product: review memorandum. Pfizer-BioNTech. COVID-19 vaccine/BNT162b2.
      ,
      US Food and Drug Administration
      Vaccines and related biological products advisory committee meeting: FDA briefing document: Moderna COVID-19 vaccine.
      Despite inclusion of a small number of participants with a history of AD in clinical trials evaluating the BNT162b2 vaccine, no specific safety concerns were observed after subgroup analysis by medical comorbidities.
      US Food and Drug Administration
      Emergency use authorization (EUA) for an unapproved product: review memorandum. Pfizer-BioNTech. COVID-19 vaccine/BNT162b2.
      Development of AD was not observed after vaccination with mRNA-1273 either, except for one case of rheumatoid arthritis after the second dose of the vaccine, which was considered not related to vaccination.
      US Food and Drug Administration
      Vaccines and related biological products advisory committee meeting: FDA briefing document: Moderna COVID-19 vaccine.
      Taken together, these data do not indicate an increased risk of developing new AD or a flare of a previously existing AD after vaccination with the BNT162b2 or mRNA-1273 vaccine.
      In view of the unique immune biology of TETs and absence of data regarding tolerability of COVID-19 vaccines in this population, we conducted this study to find the tolerability of vaccination in adults with TETs.

      Materials and Methods

      Individuals 18 years or older with active or previously treated thymoma or thymic carcinoma with or without paraneoplastic AD who had received vaccination against COVID-19 were invited to participate in this survey. The participants had either received care at the National Institutes of Health (NIH) Clinical Center or were in the process of screening for ongoing NIH institutional review board–approved clinical trials. Consenting patients were interviewed in person during scheduled clinic visits or by means of a phone call.
      The study questionnaire was designed on the basis of solicited local and systemic AEs reported within seven days of BNT162b2 and mRNA-1273 vaccination in participants aged 18 years and older (details in Supplementary Appendix). All efforts were made to conduct interviews within 1 week after each dose of the vaccine and within 1 month after the second dose to correspond to the BNT162b2 and mRNA-1273 data collection time points. Information was collected on TET histology, patient age, presence or absence of thymoma-related AD, and use of concomitant medications, including immunosuppressive drugs. Data were deidentified and secured per institutional guidelines. The study was reviewed by the NIH institutional review board and determined to meet the criteria for category 2 of exempt human subject research.

      Statistical Analysis

      Statistical analysis was conducted using descriptive statistics. A two-sided Fisher’s exact test was used for appropriate paired comparison to evaluate differences in tolerability of BNT162b2 and mRNA-1273 vaccines in patients with TETs and individuals without TETs as reported from published vaccine clinical trial results. The frequency and relative risk of developing AEs were calculated for each group. Because this is an initial effort to evaluate the tolerability of COVID-19 mRNA vaccines in patients with TETs, power calculations were not performed for a study of this nature. Nevertheless, with a minimum of 50 participants, the study was expected to provide indications on differences in tolerability of vaccination among individuals with and without TETs.

      Results

      Between February 26, 2021, and June 1, 2021, responses were collected from 54 individuals. As of data cutoff on June 1, 2021, a total of 50 individuals had completed all three questionnaires, 52 had completed two questionnaires, and 54 had completed one questionnaire. Baseline characteristics are included in Table 1. Of the 54 patients, 33 (61.1%) had thymoma and 20 (37.0%) had thymic carcinoma. Furthermore, 19 (35.2%) had preexisting AD, and 12 patients (22.2%) were using immunosuppressive drugs. All patients were vaccinated against COVID-19 with either the BNT162b2 or mRNA-1273 vaccine.
      Table 1Patient Characteristics
      Characteristicsn
      Includes individuals who received at least one dose of the vaccine and completed the questionnaire at the first time point.
      (%)
      Age, median (range, y)58 (32–81)
      Sex
       Female26 (48.1)
       Male28 (51.9)
      Histology (WHO subtype)
       B1 thymoma2 (3.7)
       B2 thymoma21 (38.9)
       B2/3 thymoma3 (5.6)
       B3 thymoma7 (13.0)
       Thymic carcinoma20 (37.0)
       Unknown1 (1.9)
      Vaccine
       BNT162b225 (46.3)
       mRNA-127329 (53.7)
      Paraneoplastic autoimmune disease
      Paraneoplastic autoimmune diseases include eight participants with myasthenia gravis, five with inflammatory arthritis, two with myositis, two with Sjogren’s syndrome, two with systemic lupus erythematosus, and one each with Isaac syndrome, Hashimoto disease, lichen planus, minimal change nephrotic syndrome, pure red cell aplasia, and ulcerative colitis.
      19 (35.2)
      Immunosuppressant use
      Two patients were taking immunosuppressive agents at the time of dose 1, but not when they received dose 2. In one case, a patient was on a taper of prednisone and mycophenolate, which stopped around the time of dose 1. In the second case, a patient received dexamethasone on the day of vaccination as premedication for chemotherapy; this did not occur again during dose 2.
      12 (22.2)
      Corticosteroids2 (3.7)
      Noncorticosteroids
      Nonsteroidal immunosuppressant drugs include intravenous immunoglobulin, rituximab, mycophenolate mofetil, methotrexate, and azathioprine.
      4 (7.4)
      Both types7 (13.0)
      NSAID/acetaminophen routine use11 (20.4)
      NSAID/acetaminophen prophylactic use
      Two of three patients who took an NSAID or acetaminophen prophylactically did so only before dose 1.
      3 (5.6)
      NSAID, nonsteroidal anti-inflammatory drug.
      a Includes individuals who received at least one dose of the vaccine and completed the questionnaire at the first time point.
      b Paraneoplastic autoimmune diseases include eight participants with myasthenia gravis, five with inflammatory arthritis, two with myositis, two with Sjogren’s syndrome, two with systemic lupus erythematosus, and one each with Isaac syndrome, Hashimoto disease, lichen planus, minimal change nephrotic syndrome, pure red cell aplasia, and ulcerative colitis.
      c Two patients were taking immunosuppressive agents at the time of dose 1, but not when they received dose 2. In one case, a patient was on a taper of prednisone and mycophenolate, which stopped around the time of dose 1. In the second case, a patient received dexamethasone on the day of vaccination as premedication for chemotherapy; this did not occur again during dose 2.
      d Nonsteroidal immunosuppressant drugs include intravenous immunoglobulin, rituximab, mycophenolate mofetil, methotrexate, and azathioprine.
      e Two of three patients who took an NSAID or acetaminophen prophylactically did so only before dose 1.
      AEs experienced by patients with TETs and reported in the participants of the BNT162b2 and mRNA-1273 clinical trials stratified by dose number and vaccine type are illustrated in Table 2 and Figure 1. AEs experienced by greater than 10% of patients with TETs are described in the Supplementary Appendix. Patients with TETs were significantly more likely to experience local redness (20.7%; p = 0.03) after the second dose of the mRNA-1273 vaccine, whereas the incidence of myalgia was significantly less after the second dose of the BNT162b2 (8.7%; p = 0.01) and mRNA-1273 vaccines (24.1%; p = 0.0005) (Table 2 and Fig. 1).
      Table 2Adverse Events After Vaccination in Patients With TETs and Published Results From Phase 2 and Phase 3 Clinical Trials Evaluating the BNT162b2 and mRNA-1273 Vaccines
      BNT162b2Dose 1Dose 2
      SymptomsTET AE, n (%)Trial AE, n (%)Relative Risk (95% CI)p ValueTET AE, n (%)Trial AE, n (%)Relative Riskp Value
      Local pain16 (64.00)3186 (77.84)0.82 (0.61–1.10)0.1413 (56.52)2730 (72.65)0.78 (0.54–1.11)0.10
      Local redness1 (4.00)189 (4.62)0.87 (0.13–5.94)1.001 (4.35)243 (6.47)0.67 (0.10–4.59)1.00
      Local swelling2 (8.00)250 (6.11)1.31 (0.34–4.98)0.663 (13.04)256 (6.81)1.91 (0.66–5.54)0.21
      Fatigue7 (28.00)1700 (41.53)0.67 (0.36–1.27)0.2215 (65.22)2086 (55.51)1.17 (0.87–1.59)0.40
      Headache4 (16.00)1413 (34.52)0.46 (0.19–1.14)0.066 (26.09)1732 (46.09)0.57 (0.28–1.13)0.06
      Myalgia1 (4.00)738 (18.03)0.22 (0.03–1.52)0.072 (8.70)1260 (33.53)0.26 (0.07–0.98)0.01
      Arthralgia2 (8.00)406 (9.92)0.81 (0.21–3.06)1.002 (8.70)772 (20.54)0.42 (0.11–1.59)0.20
      Chills2 (8.00)434 (10.60)0.75 (0.20–2.86)1.003 (13.04)1114 (29.64)0.44 (0.15–1.27)0.11
      Fever1 (4.00)111 (2.71)1.48 (0.21–10.2)0.504 (17.39)512 (13.62)1.28 (0.52–3.12)0.54
      Vomiting037 (0.90)1.00051 (1.36)1.00
      Diarrhea0402 (9.82)0.171 (4.35)356 (9.47)0.46 (0.07–3.13)0.72
      mRNA-1273Dose 1Dose 2
      SymptomsTET AE, n (%)Trial AE, n (%)Relative Risk (95% CI)p ValueTET AE, n (%)Trial AE, n (%)Relative Risk (95% CI)p Value
      Local pain26 (89.66)12,690 (83.69)1.07 (0.95–1.21)0.6125 (86.21)12,325 (88.39)0.98 (0.84–1.13)0.77
      Local redness1 (3.45)431 (2.84)1.21 (0.18–8.34)0.576 (20.69)1193 (8.56)2.42 (1.18–4.94)0.03
      Local swelling3 (10.34)934 (6.16)1.68 (0.57–4.91)0.425 (17.24)1695 (12.16)1.42 (0.64–3.15)0.39
      Axillary swelling01553 (10.24)0.071 (3.45)1956 (14.03)0.24 (0.04–1.69)0.11
      Fatigue6 (20.69)5635 (37.17)0.56 (0.27–1.14)0.0817 (58.62)9096 (65.23)0.90 (0.66–1.22)0.44
      Headache6 (20.69)4952 (32.66)0.63 (0.31–1.29)0.235 (17.24)8165 (58.56)0.29 (0.13–0.65)<0.0001
      Myalgia3 (10.34)3441 (22.70)0.46 (0.16–1.33)0.127 (24.14)8036 (57.63)0.42 (0.22–0.80)0.0005
      Arthralgia2 (6.90)2510 (16.55)0.42 (0.11–1.59)0.215 (17.24)5937 (42.58)0.40 (0.18–0.90)0.0073
      Chills2 (6.90)1253 (8.26)0.83 (0.22–3.18)1.007 (24.14)6100 (43.75)0.55 (0.29–1.05)0.04
      Fever0115 (0.76)1.004 (13.79)2172 (15.58)0.89 (0.36–2.20)1.00
      Nausea/vomiting01263 (8.33)0.176 (20.69)2634 (18.89)1.10 (0.54–2.24)0.81
      AE, adverse event; CI, confidence interval; TET, thymic epithelial tumor; TET AE, AEs observed in patients with TETs; Trial AE, AEs reported in clinical trials evaluating the BNT162b2 and mRNA-1273 vaccines.
      Figure thumbnail gr1
      Figure 1AEs after administration of BNT162b2 and mRNA-1273 vaccines in patients with TETs. The frequency of selected AEs observed in patients with TETs is compared with the frequency of solicited AEs reported from phase 2 and phase 3 trials evaluating the BNT162b2
      US Food and Drug Administration
      Emergency use authorization (EUA) for an unapproved product: review memorandum. Pfizer-BioNTech. COVID-19 vaccine/BNT162b2.
      and mRNA-1273
      US Food and Drug Administration
      Vaccines and related biological products advisory committee meeting: FDA briefing document: Moderna COVID-19 vaccine.
      vaccines after (A) dose 1 and (B) dose 2. AE, adverse event; TET, thymic epithelial tumor.
      Of the 19 patients with a previously diagnosed AD, all completed the first questionnaire and 18 completed the second. Of these patients, three experienced symptomatic flares after dose 1 and three experienced flares after dose 2 (Supplementary Table 1). Patients who experienced an autoimmune flare after the first dose had been diagnosed with having myasthenia gravis (MG), MG and polymyositis, and Isaac syndrome, MG, systemic lupus erythematosus, and arthritis, respectively. These autoimmune flares were mild and self-limited, with the exception of the last patient, who experienced intermittent burning of hands and feet, difficulty in swallowing, fasciculations, and a rash that was treated with a topical steroid. This patient experienced similar symptoms after receiving the second dose of vaccination. Other patients who experienced mild and self-limited flares after the second dose included an individual with MG and another with inflammatory arthritis.
      Two patients were diagnosed with having new AD after receiving the first dose of the mRNA-1273 vaccine: one patient with autoimmune alopecia who had been symptomatic for several months but had sought medical attention after vaccination and another patient with chronic idiopathic urticaria presenting as a full-body rash that responded temporarily to oral corticosteroids but recurred after discontinuation of steroids and has not resolved at the time of data cutoff.

      Discussion

      To our knowledge, this survey represents the first attempt to systematically evaluate the tolerability of COVID-19 vaccines in patients with TETs. Our results indicate that most patients with TETs tolerate the mRNA vaccines, BNT162b2 and mRNA-1273, without complications. Common AEs such as local pain and swelling, fatigue, and headaches are self-limited and manageable. The use of immunosuppressive drugs to treat AD or nonsteroidal anti-inflammatory drugs and acetaminophen to manage pain could abrogate constitutional symptoms, such as headaches, myalgia, and arthralgia. Nevertheless, the use of these concomitant medications was comparable between patients with TET who did and did not experience these AEs. Of note, patients with TETs were significantly less likely to experience myalgia after the second dose of both BNT162b2 (p = 0.01) and mRNA-1273 (p = 0.0005) vaccines. This observation is of particular interest because patients with TETs, especially thymoma, are at increased risk of muscle inflammation when exposed to immune stimulation, such as with immune checkpoint inhibitors.
      • Rajan A.
      • Heery C.R.
      • Thomas A.
      • et al.
      Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.
      ,
      • Cho J.
      • Kim H.S.
      • Ku B.M.
      • et al.
      Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial.
      Notwithstanding the decreased incidence of myalgia, it is advisable to initiate workup for myositis if patients with TETs experience persistent or severe myalgia after receiving the BNT162b2 and mRNA-1273 vaccines.
      Despite underlying defects in immune tolerance and a predisposition to paraneoplastic autoimmunity, very few patients with TETs developed new AD after vaccination and most of those with preexisting AD did not experience a disease flare, even though a large fraction of patients (61%) had WHO subtype B thymomas, the histologic subtype most associated with paraneoplastic AD and immune-mediated toxicity on immune stimulation.
      • Lippner E.A.
      • Lewis D.B.
      • Robinson W.H.
      • Katsumoto T.R.
      Paraneoplastic and therapy-related immune complications in thymic malignancies.
      ,
      • Rajan A.
      • Heery C.R.
      • Thomas A.
      • et al.
      Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.
      ,
      • Cho J.
      • Kim H.S.
      • Ku B.M.
      • et al.
      Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial.
      The episodes that did occur were generally self-limited and did not require medical intervention. Nevertheless, given the potential risk for AD flare or development, patient education and close monitoring are highly recommended after vaccination in this population.
      Limitations of this study include a small sample size owing to the rarity of TETs and self-reporting by participants, which can potentially add an element of subjectivity in assessment. Despite these limitations, we feel that the results of this study are clinically meaningful and provide guidance to patients with TETs considering vaccination against COVID-19.
      Physician awareness of the tolerability of vaccination against COVID-19 among patients with TET and the relatively low frequency of autoimmune flares, most of which are mild and self-limited, are keys to promoting vaccination within this population. Two surveys conducted among individuals with AD regarding vaccination against COVID-19 found that the percentage of those willing to get vaccinated ranged from 54% to 61%.
      • Boekel L.
      • Hooijberg F.
      • van Kempen Z.L.E.
      • et al.
      Perspective of patients with autoimmune diseases on COVID-19 vaccination.
      ,
      • Felten R.
      • Dubois M.
      • Ugarte-Gil M.F.
      • et al.
      Vaccination against COVID-19: expectations and concerns of patients with autoimmune and rheumatic diseases.
      Key concerns among these patients regarding vaccination were the potential for inducing an autoimmune flare or experiencing other AEs. Notably, both surveys found that recommendations from their physicians regarding vaccination increased the percentage of patients willing to get vaccinated. This observation is particularly relevant to physicians treating patients with TETs to allay patient concerns.
      The need for an additional (booster) dose of COVID-19 vaccines to maintain immunogenicity is under review. The U.S. Centers for Disease Control and Prevention has recently recommended an additional dose of an mRNA COVID-19 vaccine for individuals with moderately to severely compromised immune systems, including patients on active or recent treatment for solid tumor and hematological malignancies, at least 28 days after a second dose of the BNT162b2 or mRNA-1273 vaccine.
      Centers for Disease Control and Prevention
      COVID-19 vaccines for moderately to severely immunocompromised people.
      Previous observations of high rates of mortality among patients with cancer hospitalized with COVID-19 and lower antibody titers in patients with cancer after two doses of BNT162b2 vaccination support the recommendation for a booster dose to achieve adequate protection.
      • Desai A.
      • Gupta R.
      • Advani S.
      • et al.
      Mortality in hospitalized patients with cancer and coronavirus disease 2019: a systematic review and meta-analysis of cohort studies.
      ,
      • Massarweh A.
      • Eliakim-Raz N.
      • Stemmer A.
      • et al.
      Evaluation of seropositivity following BNT162b2 messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer.
      Studies of a booster dose of the BNT162b2 or mRNA-1273 vaccine in solid-organ transplant recipients have revealed them to be safe and result in substantially improved immunogenicity.
      • Kamar N.
      • Abravanel F.
      • Marion O.
      • Couat C.
      • Izopet J.
      • Del Bello A.
      Three doses of an mRNA COVID-19 vaccine in solid-organ transplant recipients.
      ,
      • Hall V.G.
      • Ferreira V.H.
      • Ku T.
      • et al.
      Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients [e-pub ahead of print]. N Engl J Med.
      In view of these data, and the ability of most patients with TETs to tolerate two doses of COVID-19 mRNA vaccines without complications, a booster dose should be considered to improve immunogenicity, especially in individuals receiving myelosuppressive chemotherapy or other immunosuppressive medicines.
      In conclusion, patients with TETs seem to tolerate vaccination against COVID-19 with the mRNA vaccines, BNT162b2 and mRNA-1273, and those without TETs. AEs, including flares of preexisting AD, are usually mild and self-limited, and the likelihood of inducing paraneoplastic autoimmunity is low. Given the risks associated with severe COVID-19 infection and the tolerability of vaccination, the overall benefit seems to outweigh risks, and patients with TETs should be encouraged to undergo vaccination after discussion with their physicians. Close monitoring for new or worsening AD is essential. Further research in patients with TETs experiencing autoimmune flares can potentially yield insights into the immune changes induced by vaccination in these individuals.

      CRediT Authorship Contribution Statement

      Madison Ballman: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing - original draft, Writing - review & editing.
      Shannon Swift, Cristina Mullenix, Yvonne Mallory: Methodology, Investigation, Data curation, Writing - review & editing.
      Chen Zhao: Conceptualization, Methodology, Visualization, Formal analysis, Writing - review & editing.
      Eva Szabo: Conceptualization, Methodology, Visualization, Writing - review & editing.
      Meenakshi Shelat: Methodology, Writing - review & editing.
      Susan Sansone, Meredith J. McAdams: Writing - review & editing.
      Seth M. Steinberg: Methodology, Formal analysis, Software, Resources, Writing - review & editing.
      Arun Rajan: Conceptualization, Methodology, Visualization, Formal analysis, Project administration, Resources, Supervision, Writing - review & editing.

      Acknowledgments

      This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

      Disclaimer

      The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

      Supplementary Data

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