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. 2022 Jun 1;40(16):1721-1731.
doi: 10.1200/JCO.21.02209. Epub 2022 Mar 24.

Defining Clinical Utility of Germline Indicators of Toxicity Risk: A Perspective

Daniel L Hertz  1 , Lisa M McShane  2 , Daniel F Hayes  3
Affiliations

Defining Clinical Utility of Germline Indicators of Toxicity Risk: A Perspective

Daniel L Hertz et al. J Clin Oncol. .
No abstract available

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Conflict of interest statement

Daniel L. HertzResearch Funding: Disarm TherapeuticsOther Relationship: Advocates for Universal DPD/DPYD Testing (AUDT)Uncompensated Relationships: PEPID, Saladax Biomedical Lisa M. McShaneThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Daniel F. HayesStock and Other Ownership Interests: InBiomotionHonoraria: TempusConsulting or Advisory Role: Cepheid, Freenome, Epic Sciences, Cellworks, BioVica, Oncocyte, Turnstone Bio, Predictus Biosciences, Guardant Health, L-Nutra, MacroGenics, TempusResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Merrimack (Inst), Menarini Silicon Biosystems (Inst)Patents, Royalties, Other Intellectual Property: Royalties from licensed technology, Diagnosis and Treatment of Breast Cancer. Patent No. US 8,790,878 B2. Date of Patent: July 29, 2014. Applicant Proprietor: University of Michigan. Dr Daniel F. Hayes is designated as an inventor/coinventor, Circulating Tumor Cell Capturing Techniques and Devices. Patent No.: US 8,951,484 B2. Date of Patent: February 10, 2015. Applicant Proprietor: University of Michigan. Dr Daniel F. Hayes is designated as an inventor/coinventor, Title: A method for predicting progression-free and overall survival at each follow-up timepoint during therapy of metastatic breast cancer patients using circulating tumor cells. Patent No. 05725638.0-1223-US2005008602Travel, Accommodations, Expenses: Menarini Silicon BiosystemsOther Relationship: Menarini, UpToDateUncompensated Relationships: UpToDateNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Dose reduction prevents toxicity via different mechanisms in GITR-PK and GITR-PD. (A) GITR-PK increase systemic drug exposure. (B) Decreasing dosing normalizes drug exposure, decreasing toxicity while maintaining efficacy. (C) GITR-PD increase the patient's toxicity sensitivity, meaning that they experience more severe toxicity at a given exposure. (D) Decreasing dosing normalizes their toxicity severity but reduces exposure and may reduce efficacy. See the text for details. GITR-PD, germline indicators of toxicity risk-pharmacodynamic; GITR-PK, germline indicators of toxicity risk-pharmacokinetic.
FIG 2.
FIG 2.
Modeled clinical utility of GITR determined by benefits and risks. The clinical utility of GITR is determined by the net benefit, from toxicity avoidance, and net risk, primarily from the loss of treatment effect, from switching the standard of care to alternative treatment. See the text for details. Green, yellow, and red regions indicate high, moderate, and low clinical utility, respectively. Black indicators: examples of (A and C) high, (B or D) moderate, or (E) low clinical utility. GITR, germline indicators of toxicity risk.
FIG 3.
FIG 3.
Prospective clinical trial designs to test clinical utility of GITR: (A) biomarker strategy design, (B) biomarker-enrichment design, (C) biomarker-stratified design, and (D) nonrandomized biomarker-guided design. See the text and Table 3 for description and limitations of each study design. Black box (R) indicates randomization. GITR, germline indicators of toxicity risk; SOC, standard-of-care.
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