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  • br ACCEPTED MANUSCRIPT br There are numerous


    339 There are numerous reasons why our investigation did not identify previously published
    340 biomarkers in endometrial cancer. First, we conducted an exploratory global proteomic analysis
    341 of prediagnostic serum whereas previous investigations performed targeted analyses for specific
    342 biomarkers using immunoassay approaches on serum drawn from patients at the time of
    343 diagnosis (17-24). Additionally, protein abundance, serum depletion, and the dynamic range in
    344 serum also likely played a role. Depending on the protein, there can be several factors that also
    345 might not make them amenable to LC-MS. Also, the abundance of these 162758-94-3 within the
    346 individual samples that comprise each plex may impact how well they are represented in the pool
    347 and therefore may not be selected during the MS/MS process. In short, the levels measured from
    348 an enzyme-linked immunosorbent assay or other assay may not necessarily reflect detectability
    349 by a global proteomics approach.
    350 Clinical Implications
    351 There is currently no available screening test for asymptomatic women at average risk for
    352 endometrial cancer. CA125 and CA 15-3 have been evaluated as potential screening biomarkers
    356 to inflammatory conditions not related to endometrial cancer. Identifying biomarkers which can
    357 be used for early detection of endometrial cancer may lead to improvements in practice and
    359 Research Implications
    360 Our exploratory proteomic investigation of prediagnostic serum from the PLCO Cancer 361 Screening Trial revealed a biomarker panel of 6 proteins able to differentiate cases from controls.
    362 Our next step is to confirm these findings in a separate cohort. Validation of these findings with
    363 an independent prediagnostic serum set would provide justification to evaluate this panel in a
    364 clinical setting.
    365 Strengths and Limitations
    366 Strengths of this study include that the PLCO Cancer Screening Trial prospectively
    367 collected serum samples prior to endometrial cancer diagnosis with uniform collection and
    368 storage protocols. Reported cases in the PLCO Cancer Screening Trial were confirmed by review
    369 of medical records and pathology reports. The population of the PLCO Cancer Screening Trial is
    370 geographically diverse with follow up data spanning two decades.
    371 Limitations of this study include that 94.6% of the study population was white, limiting
    372 generalizability to other racial groups. Additionally, 86.6% of cases consisted of endometrioid
    373 histology. We only had stage data for 21.4% of cases and had minimal information on depth of
    374 myometrial invasion and lymphovascular space invasion, preventing us from evaluating
    375 intermediate-risk cases. Lastly, this was an exploratory analysis of prediagnostic serum, and
    376 requires further validation before definitive conclusions may be drawn.
    377 Conclusions
    378 This prospective analysis of prediagnostic serum from participants of the PLCO Cancer
    379 Screening Trial introduces a new biomarker panel which can differentiate endometrial cancer
    380 cases from controls ≤ 2 years from diagnosis. There is also a trend in the change in concentration
    381 of these proteins beginning at > 5 years prior of diagnosis, warranting further investigation to
    382 determine the possible utility as an early screening test for endometrial cancer. The results of this
    383 exploratory study are preliminary and require validation in an independent prediagnostic serum
    384 set to determine whether this biomarker panel may be investigated in a clinical setting.
    385 Acknowledgment: The authors thank the National Cancer Institute and all patients who
    386 contributed to the PLCO Cancer Screening Trial.
    387 References
    390 endometrial cancer projections to 2030: should we be concerned? Future Oncol.
    392 3.American Cancer Society. Endometrial Cancer Survival Rates, by Stage.
    395 4.Liu JR, Conaway M, Rodriguez GC, Soper JT, Clarke-Pearson DL, Berchuck A.
    396 Relationship between race and interval to treatment in endometrial cancer. Obstet Gynecol.
    398 5.Matteson KA, Robison K, Jacoby VL. Opportunities for Early Detection of Endometrial
    401 Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year