Early detection of endometrial cancer.

The incidence of and morality from endometrial cancer (EC) has been increasing globally, in part due to rising obesity rates, changes in reproductive patterns, and an increase in high-risk histologies [1National Cancer Institute SEER Program. Cancer Stat Facts: Uterine Cancer.2023Google Scholar, 2Clarke M.A. Devesa S.S. Hammer A. Wentzensen N. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype.JAMA Oncol. 2022; 8: 895-903Crossref PubMed Scopus (23) Google Scholar, 3Lu K.H. Broaddus R.R. Endometrial cancer.N. Engl. J. Med. 2020; 383: 2053-2064Crossref PubMed Scopus (275) Google Scholar]. Although surgery alone is often curative for stage IA EC, this requires detecting the cancer early. Additionally, while approximately 75% of women diagnosed with EC have early-stage disease and overall favorable survival rates, clinical outcomes for women with high-risk histologies, advanced-stage at diagnosis, or disease recurrence remain suboptimal [[3]Lu K.H. Broaddus R.R. Endometrial cancer.N. Engl. J. Med. 2020; 383: 2053-2064Crossref PubMed Scopus (275) Google Scholar]. Despite this, clinical research funding, discovery, and subsequent treatment success has lagged that of other women's cancers [[4]Wethington S.L. Fader A.N. ProMisE on the horizon: molecular classification of endometrial cancer in young women.Gynecol. Oncol. 2019; 153: 465-466Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. The most common symptom associated with EC is painless vaginal bleeding. However, fewer than 10% of women undergoing evaluation for abnormal uterine bleeding (AUB) or postmenopausal uterine bleeding (PMB) are ultimately diagnosed with EC [[5]National Comprehensive Cancer Network Uterine Neoplasms (Version 1.2022).2023Google Scholar,[6]Clarke M.A. Long B.J. Del Mar Morillo A. Arbyn M. Bakkum-Gamez J.N. Wentzensen N. Association of endometrial cancer risk with postmenopausal bleeding in women: a systematic review and meta-analysis.JAMA Intern. Med. 2018; 178: 1210-1222Crossref PubMed Scopus (184) Google Scholar]. The current diagnostic process often involves invasive procedures, resulting in substantial costs to the healthcare system and discomfort for patients [[7]Jacobs I. Gentry-Maharaj A. Burnell M. Manchanda R. Singh N. Sharma A. et al.Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort.Lancet Oncol. 2011; 12: 38-48Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Therefore, there is an unmet clinical need for less invasive diagnostic testing that can reliably distinguish between benign AUB/PMB and bleeding associated with EC or its precursors. Recent studies have shed light on the potential of molecular testing of vaginal or Pap test fluid to facilitate minimally invasive triage of AUB and PMB [8Wang Y. Li L. Douville C. Cohen J.D. Yen T.T. Kinde I. et al.Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers.Sci. Transl. Med. 2018; : 10Google Scholar, 9Kinde I. Bettegowda C. Wang Y. Wu J. Agrawal N. Shih Ie M. et al.Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.Sci. Transl. Med. 2013; 5 (167ra4)Crossref PubMed Scopus (238) Google Scholar, 10Maritschnegg E. Wang Y. Pecha N. Horvat R. Van Nieuwenhuysen E. Vergote I. et al.Lavage of the uterine cavity for molecular detection of mullerian duct carcinomas: a proof-of-concept study.J. Clin. Oncol. 2015; 33: 4293-4300Crossref PubMed Scopus (61) Google Scholar]. These studies have demonstrated that diver gene mutations from Pap test or uterine lavage fluid could signal the presence of EC or EC precursor lesions. This provides a rationale for thinking that vaginal fluid molecular testing could serve as a promising approach in the noninvasive detection of EC. In line with this research direction, the paper by Bakkum-Gamez et al. featured in this edition of Gynecologic Oncology makes an important contribution to the field. The authors focus on employing reduced representation bisulfite sequencing to identify differentially methylated regions (DMRs) in frozen EC, benign endometrium, and benign cervicovaginal tissues. Thirty-three candidate DMRs were selected based on their ability to discriminate between cancers and controls. Validation of methylated DNA markers using quantitative Methylation-Specific PCR (qMSP) was also conducted on independent EC and BE FFPE tissue sets. A tampon-based pilot study was conducted and included women over 45 years of age with AUB or PMB, as well as women of any age with biopsy-proven EC. The vaginal fluid DNA was assayed by qMSP for EC-associated methylated DNA markers (MDMs), and random forest modeling analysis was performed to generate the predictive probability of underlying disease. The tampon-based pilot study demonstrated the highly discriminative potential of a 28-MDM panel, exhibiting strong specificity (96%) and sensitivity (76%) in distinguishing EC from benign endometrium. A strength of the study is the use of qMSP, a much less expensive technique compared to sequencing-based assays [[8]Wang Y. Li L. Douville C. Cohen J.D. Yen T.T. Kinde I. et al.Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers.Sci. Transl. Med. 2018; : 10Google Scholar]. Since roughly ten patients with abnormal postmenopausal bleeding need to be tested to detect one cancer, this approach has the potential to make the widespread implementation of endometrial cancer screening more cost-effective and accessible, which may help reduce well-documented disparities in endometrial cancer outcomes [[2]Clarke M.A. Devesa S.S. Hammer A. Wentzensen N. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype.JAMA Oncol. 2022; 8: 895-903Crossref PubMed Scopus (23) Google Scholar,[11]Whetstone S. Burke W. Sheth S.S. Brooks R. Cavens A. Huber-Keener K. et al.Health disparities in uterine cancer: report from the uterine cancer evidence review conference.Obstet. Gynecol. 2022; 139: 645-659Crossref PubMed Scopus (12) Google Scholar]. Likewise, due to increased convenience and privacy, the tampon-based collection method tested in the study could increase uptake of the test compared to in-office collection methods. Despite these strengths, some questions remain about the approach. Differentially methylated regions were selected based on a frequency of <2% in controls. However, as demonstrated in prior sequencing studies, the fraction of endometrial tumor cells in Pap fluid samples is often below 2% [[8]Wang Y. Li L. Douville C. Cohen J.D. Yen T.T. Kinde I. et al.Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers.Sci. Transl. Med. 2018; : 10Google Scholar]. The background frequency used to exclude DMRs may therefore need to be lowered to maintain high specificity in larger cohorts. Additionally, although the 28-MDM panel detected nearly 80% of serous carcinomas, this sensitivity may not be high enough to adopt a watchful waiting approach in patients who test negative. The test therefore may not obviate the need for invasive work-up for many patients. Addition of further biomarkers and/or incorporation with clinical risk prediction models may help address this limitation. In conclusion, Bakkum-Gamez et al. highlight the potential of DNA methylation analysis in detecting endometrial cancer through vaginal fluid, with promising initial results. Follow-up prospective studies with larger cohorts will be needed to validate their findings. However, these data are an important step forward in realizing the promise of less invasive early detection of EC and its precursors, a malignancy that is rising worldwide at an alarming rate and warrants increased attention and research efforts. Detection of endometrial cancer using tampon-based collection and methylated DNA markersGynecologic OncologyVol. 174PreviewAlterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. Full-Text PDF