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Will patients with cancer treated with antineoplastic compounds associated with lower angiotensin-converting enzyme 2 (ACE2) expression exhibit lower SARS-CoV-2 infection rates?
In an in silico analysis of the Library of Integrated Network-Based Cellular Signatures database, 91 compounds were associated with gene downregulation of the ACE2 entry receptor for SARS-CoV-2, including mTOR/PI3K inhibitors and antimetabolites. Patients who received a potential ACE2-lowering antineoplastic exhibited a statistically significantly reduced SARS-CoV-2 positivity rate of 7.0% compared with 12.9% in patients who received other antineoplastic therapies.
Potential ACE2-lowering antineoplastics, including mTOR/PI3K inhibitors and antimetabolites, may exhibit clinical anti–SARS-CoV-2 activity.
Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity.
To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates.
Design, Setting, and Participants
We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020.
Main Outcome and Measure
The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test.
In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87).
Conclusions and Relevance
In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti–SARS-CoV-2 properties of identified antineoplastic compounds is warranted.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: June 17, 2021.
Published Online: August 19, 2021. doi:10.1001/jamaoncol.2021.3585
Corresponding Author: Luis A. Diaz Jr, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (firstname.lastname@example.org).
Author Contributions: Dr Diaz Jr 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. Drs Foote and White contributed equally to this work.
Concept and design: Foote, White, Diaz Jr.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Foote, White, Wan, Diaz Jr.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Foote, White, Wan, Rousseau.
Administrative, technical, or material support: Foote, White, Jee, Pessin.
Supervision: Foote, Diaz Jr.
Conflict of Interest Disclosures: Dr White reported personal fees from Memorial Sloan Kettering Cancer Center during the conduct of the study and is the founder and owner of Resphera Biosciences LLC. Dr Jee holds a patent licensed by MDSeq Inc. Dr Argilés has received honoraria for advisory roles from Hoffmann-La Roche, Bayer, Amgen, Merck, Sanofi, and Servier; honoraria for speaking engagements from Hoffmann-La Roche, Bristol Myers Squibb, Bayer, and Servier; travel grants from Hoffmann-La Roche, Bayer, Servier, Amgen, and Merck; and research funds from Bayer. Dr Argilés also serves as an uncompensated advisor for Menarini and Treos Bio Inc. Dr Wan is an inventor of patents for methods for circulating tumor DNA detection. Dr Rousseau reported personal fees from Bayer and Roche, as well as nonfinancial support from Servier outside the submitted work. Dr Diaz Jr is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics; a paid consultant to PGDx, 4Paws Dx, Innovatus Capital Partners, Se’er, Kinnate Biopharma, and NeoPhore; an uncompensated consultant for Merck but has received research support for clinical trials from Merck; an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University, therefore some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins University and Dr Diaz Jr; and an equity holder in PGDx, Delfi Diagnostics, Jounce Therapeutics, Thrive Earlier Detection, and Neophore. No other disclosures were reported.
Funding/Support: This work is supported by a Stand Up to Cancer Colorectal Cancer Dream Team Translation Research Grant (SU2C-AACR-DT22-17). Dr Foote is partially supported by a Memorial Sloan Kettering Cancer Center/National Institutes of Health grant (T32-CA009512-32) and an American Society of Clinical Oncology Young Investigator Award. Dr Jee is partially supported by a Memorial Sloan Kettering Cancer Center training grant (T32-CA009207).
Role of the Funder/Sponsor: The funders 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.
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