Jacques Bonneterre1, Emilie Hutt2, Jacques Bosq3, J Dinny Graham4, Matthew A Powell5, Eric Leblanc2, Keiichi Fujiwara6, Thomas J Herzog7, Robert L Coleman8, Christine L Clarke4, Erard M Gilles9, Alexander A Zukiwski10, Bradley J Monk11. 1. Centre Oscar-Lambret, 3 Rue Frédéric Combemale, 59000 Lille, France. Electronic address: j-bonneterre@o-lambret.fr. 2. Centre Oscar-Lambret, 3 Rue Frédéric Combemale, 59000 Lille, France. 3. Institut Gustave Roussy, 114 Rue Édouard Vaillant, 94805 Villejuif, France. 4. Centre for Cancer Research, Westmead Millennium Institute Sydney Medical School - Westmead, University of Sydney, New South Wales, Australia. 5. Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. 6. Saitama Medical University International Medical Center, Hidaka Campus, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan. 7. University of Cincinnati Cancer Institute, 3255 Eden Ave. Suite 250, Cincinnati, OH 45267, USA. 8. The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. 9. Invivis Pharmaceuticals, 547 Meadow Road, Bridgewater, NJ 08807, USA; Arno Therapeutics, 200 Route 31 Flemington, NJ 08822, USA. 10. Arno Therapeutics, 200 Route 31 Flemington, NJ 08822, USA. 11. University of Arizona Cancer Center-Phoenix, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA.
Abstract
OBJECTIVE: Hormonal therapy is generally reserved for patients with endometrial cancers that fail cytotoxic chemotherapy, but there is a lack of sufficiently sensitive diagnostics to identify potential responders. We sought to develop a diagnostic technique to detect activated progesterone receptors (APR) in endometrial cancers using routine immunohistochemistry (IHC) and to correlate the presence of APR with other histopathological features and clinical disease stage. METHODS: Seventy-two tumor block specimens from patients with endometrial cancer were processed with conventional IHC methods for estrogen receptor-α (ERα), progesterone receptor (PR) and Ki67, a marker of proliferation. Tumor specimens were analyzed for the PR nuclear distribution patterns in individual tumor cells: APR positive (APR(pos)) tumors were prospectively defined as any tumor with >5% countable malignant cells with an aggregated nuclear pattern. Tumor APR status was analyzed against other biomarkers including ERα expression, Ki67 and tumor grade. RESULTS: Fifty-six of 72 samples were endometrioid. Twenty-six of 49 PR-positive endometrioid tumors (53%; 95% CI 39-67%) were APR(pos). Percent of ER(pos) cells correlated with % PR(pos) malignant cells (p=0.001, rho=0.44). APR positivity did not correlate with % PR(pos) cells in a given tumor, nor did it correlate with % Ki67 positivity; APR positivity was independent of disease stage and tumor grade (p=NS). CONCLUSIONS: In this study, approximately half of endometrioid tumors were APR(pos). APR is independent of histopathological and other known risk factors. Refining conventional PR detection has the potential to prospectively identify patients with endometrial cancer who may benefit from anti-progestin therapy.
OBJECTIVE: Hormonal therapy is generally reserved for patients with endometrial cancers that fail cytotoxic chemotherapy, but there is a lack of sufficiently sensitive diagnostics to identify potential responders. We sought to develop a diagnostic technique to detect activated progesterone receptors (APR) in endometrial cancers using routine immunohistochemistry (IHC) and to correlate the presence of APR with other histopathological features and clinical disease stage. METHODS: Seventy-two tumor block specimens from patients with endometrial cancer were processed with conventional IHC methods for estrogen receptor-α (ERα), progesterone receptor (PR) and Ki67, a marker of proliferation. Tumor specimens were analyzed for the PR nuclear distribution patterns in individual tumor cells: APR positive (APR(pos)) tumors were prospectively defined as any tumor with >5% countable malignant cells with an aggregated nuclear pattern. Tumor APR status was analyzed against other biomarkers including ERα expression, Ki67 and tumor grade. RESULTS: Fifty-six of 72 samples were endometrioid. Twenty-six of 49 PR-positive endometrioid tumors (53%; 95% CI 39-67%) were APR(pos). Percent of ER(pos) cells correlated with % PR(pos) malignant cells (p=0.001, rho=0.44). APR positivity did not correlate with % PR(pos) cells in a given tumor, nor did it correlate with % Ki67 positivity; APR positivity was independent of disease stage and tumor grade (p=NS). CONCLUSIONS: In this study, approximately half of endometrioid tumors were APR(pos). APR is independent of histopathological and other known risk factors. Refining conventional PR detection has the potential to prospectively identify patients with endometrial cancer who may benefit from anti-progestin therapy.
Authors: Yan Huang; Wei Hu; Jie Huang; Fangrong Shen; Yunjie Sun; Cristina Ivan; Sunila Pradeep; Robert Dood; Monika Haemmerle; Dahai Jiang; Lingegowda S Mangala; Kyunghee Noh; Jean M Hansen; Heather J Dalton; Rebecca A Previs; Archana S Nagaraja; Michael McGuire; Nicholas B Jennings; Russell Broaddus; Robert L Coleman; Anil K Sood Journal: Mol Cancer Ther Date: 2017-12-13 Impact factor: 6.261
Authors: Laura J Mauro; Megan I Seibel; Caroline H Diep; Angela Spartz; Carlos Perez Kerkvliet; Hari Singhal; Elizabeth M Swisher; Lauren E Schwartz; Ronny Drapkin; Siddharth Saini; Fatmata Sesay; Larisa Litovchick; Carol A Lange Journal: J Clin Endocrinol Metab Date: 2021-06-16 Impact factor: 5.958
Authors: Paul H Cottu; Jacques Bonneterre; Andrea Varga; Mario Campone; Alexandra Leary; Anne Floquet; Dominique Berton-Rigaud; Marie-Paule Sablin; Anne Lesoin; Keyvan Rezai; François M Lokiec; Catherine Lhomme; Jacques Bosq; Alice S Bexon; Erard M Gilles; Stefan Proniuk; Veronique Dieras; David M Jackson; Alexander Zukiwski; Antoine Italiano Journal: PLoS One Date: 2018-10-10 Impact factor: 3.240