For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) may provide a strategy to identify which patients who may safely de-escalate certain therapies. In this prospective, hybrid-decentralized trial (NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo upfront surgery in favor of primary endocrine therapy (pET). ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pre-treatment ctDNA positivity was associated with a significant risk of tumor progression (HR 30, 95% CI 4.4-209; p = 0.0005). No patients with pre-treatment ctDNA negativity experienced tumor progression. In correlative analysis examining tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation. These findings suggest that ctDNA may be a surveillance modality for older patients who receive pET, warranting future evaluation in a randomized setting.

TBD.

NCT05914792

This project was funded through the Hillman Cancer Center Developmental Pilot Program (to SO and AVL), the Shear Family Foundation (to SO and AVL), and the National Institutes of Health under awards 5T32CA82084-20 (to NC), 5F30CA264963-03 (to NC), P30CA047904 (to SO and AVL), and S10OD028483 (to AVL).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board at the University of Pittsburgh gave ethical approval for this work (STUDY 21100091).

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data needed to evaluate the conclusions in the paper are present in the paper and/or the supplemental information. Genomic data has been deposited to Gene Expression Omnibus (GEO) under embargo and will be released at time of publication. All code is available on GitHub under https://github.com/leeoesterreich/ctDNAManuscript.