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.
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.
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