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By Charles Bankhead, Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerEndometrial cancers have been broadly classified into two groups: Type I endometrioid tumors with favorable prognosis and type II, primarily serous, tumors that have a worse outcome and different treatment approaches.This study proposes a reclassification of endometrial carcinoma which may affect therapy.A comprehensive molecular analysis separated endometrial cancers into four distinct subtypes that have the potential to influence decision making about adjuvant therapy, investigators reported.
The analysis allowed scientists to categorize the cancers as microsatellite instability hypermutated, copy-number low, copy-number high, and a previously unrecognized subset of high-grade endometrioid tumors -- POLE ultramutated -- that have a molecular phenotype similar to that of uterine serous carcinomas.
Given that early serous-type uterine cancers are usually treated by chemotherapy and early endometrioid cancers by radiotherapy, the reclassification resulting from the analysis suggests a need to rethink treatment and clinical trial strategies, the researchers wrote online in Nature.
"The compelling similarities between this subset of endometrioid tumors and uterine serous carcinomas suggest that genomic-based classification may lead to improved management of these patients," Douglas A. Levine, MD, of Memorial Sloan-Kettering Cancer Center in New York City, and co-authors concluded.
"Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in prospective clinical trials. Furthermore, the marked molecular differences between endometrioid and serous-like tumors suggest that the tumors warrant separate clinical trials to develop the independent treatment paradigms that have improved outcomes in other tumor types, such as breast cancer."
Historically, endometrial cancer has been divided into two classifications: type I endometrioid and type II serous. The former is associated with estrogen excess, obesity, hormone-receptor positivity, and more favorable prognosis. Type II cancers occur more often in older, non-obese women and are associated with worse prognosis.
Recent studies have identified new characteristics that might further distinguish type I and type II tumors, the authors noted in their introduction. Most of the observations have come from studies of type I cancers and include early occurrence of PTEN mutations, co-occurrence with other mutations in the PI3K/AKT pathway, and microsatellite instability in about one third of the tumors.
Studies of type II tumors have show that microsatellite instability is an infrequent occurrence and that mutations in TP53, PIK3CA, and PPP2R1A occur frequently.
Previous studies have been limited to DNA sequencing of heterogeneous samples. Levine and colleagues in the Cancer Genome Atlas Research Network performed a more comprehensive, multiplatform analysis of low- and high-grade endometrioid tumors and serous uterine carcinoma designed to provide more insight into molecular basis of uterine cancer.
The analysis involved specimens and germline DNA from 373 patients: 307 with endometrioid tumors, 53 with serous tumors, and 13 with mixed histology.
The investigators performed multiples tests on varying fractions of the specimens/DNA, including somatic copy number alterations; exome sequence analysis; subtype classification via expression of messenger RNA, protein, and microRNA, and DNA methylation; somatic chromosomal (structural) aberrations; and pathway alterations. They also compared clinical/pathologic features of uterine serous carcinoma to those of serous ovarian and basal-like breast cancers.
Broadly speaking, the analysis showed that serous tumors and about one fourth of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen/progesterone receptor levels, and frequent TP53 mutations.
Most of the remaining endometrioid tumors had few copy number alterations or TP53 mutations, but frequently harbored mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS. Investigators also found novel mutations in the SWI/SNF chromatin remodeling-gene ARID5B.
A subset of endometrioid tumors frequently harbored transversion mutations and newly identified hotspot mutations in POLE, which were associated with worse prognosis.
Levine and colleagues found that uterine serous carcinoma shared many molecular features with high-grade serous ovarian carcinoma and basal-like breast carcinoma, despite having more mutations. The observation suggests opportunities for overlapping treatment strategies, they said.
The results make a compelling argument in favor of broadening the classification system for uterine cancer to improve diagnostic precision and to guide selection of treatment for uterine cancer, according to Thanh Dellinger, MD, of City of Hope in Duarte, Calif.
“We have been treating uterine cancers based essentially on histopathologic criteria. This model is really outdated. This kind of two-tier classification really has not helped us out,” she said. “We need to predict who should receive radiation and who should receive chemotherapy. We really need a new, more personalized approach of molecular assays to identify genetic aberrations to predict who will do well, who will live longer, what type of therapy they should receive.”
The findings derived from the Cancer Genome Atlas Research Network are an important first step “in the right direction,” Dellinger added.
UPDATE: This article, originally published May 2, 2013 at 8:07 a.m. was updated with new material at 1:01 p.m.
The Cancer Genome Atlas Research Network is supported by the National Institutes of Health.
The authors reported no competing interests.
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
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