Accounting for sex differences variability in the design of sex-adapted cancer treatments

The significant sex differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. We hypothesized that one barrier to translation is that sex differences in cancer phenotypes resemble sex differences in height: highly overlapping, but distinct, male and female population distributions that vary continuously between female- and male- biased extremes. A consequence of this variance is that sex-specific treatments are rendered unrealistic, and our translational goal should be adaptation of treatment to the unique mix of sex-biased mechanisms that are present in each patient. To develop a tool that could advance this goal, we applied a Bayesian Nearest Neighbor (BNN) analysis to 8370 cancer transcriptomes from 26 different adult and 4 different pediatric cancer types to establish patient-specific Transcriptomic Sex Indices (TSI). TSI precisely partitions an individual patients whole transcriptome into female- and male- biased components such that cancer type, patient sex, and transcriptomics, provide a novel and patient-specific mechanistic identifier that can be used for sex-adapted, precision cancer treatment planning. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Work on sex differences in the Rubin lab is supported by the National Cancer Institute R01 CA174737-06, P01CA245705, Joshuas Great Things, Siteman Investment Program, Barnard Research Fund, St. Louis Childrens Hospital Foundation, Taylor Roziers Hope for a Cure Foundation, Prayers from Maria Foundation, and the Haubrich and Griffiths family foundations ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The results analyzed and published here are based upon datasets generated by the TCGA Research Network https://www.cancer.gov/tcga, accessed from https://pancanatlas.xenahubs.net, by Gabriella Miller Kids First Pediatric Research Program projects (phs001436.v1.p1), accessed from dbGaP (www.ncbi.nlm.nih.gov/gap), and by the Childhood Brain Tumor Tissue Consortium, accessed from https://cbtn.org. The use of publicly accessible human datasets for research has been approved by the Washington University Institutional Review Board (IRB# 201102299). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript