Phase II trial of chemopreventive effects of levonorgestrel on ovarian and fallopian tube epithelium in women at high risk for ovarian cancer

An NRG oncology group/GOG study

Gustavo C. Rodriguez, James Kauderer, Jessica Hunn, Larry G. Thaete, William G. Watkin, Samantha Russell, Michael Yozwiak, Jack Basil, Jean Hurteau, Shashikant Lele, Susan C. Modesitt, Oliver Zivanovic, Hao Helen Zhang, Peter H. Bartels, David S Alberts

Research output: Contribution to journalArticle

Abstract

A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO. The ovarian and fallopian tube epithelia (FTE) were compared immunohistochemically for effects of levonorgestrel on apoptosis (primary endpoint). Secondary endpoints included TGFb isoform expression, proliferation, and karyometric features of nuclear abnormality. In both the ovary and fallopian tube, levonorgestrel did not confer significant changes in apoptosis or expression of the TGFb1, 2, or 3 isoforms. In the ovarian epithelium, treatment with levonorgestrel significantly decreased the proliferation index. The mean ovarian Ki-67 value in the placebo arm was 2.027 per 100 cells versus 0.775 per 100 cells in the levonorgestrel arm (two-sided P value via Mann-Whitney U test = 0.0114). The karyometric signature of nuclei in both the ovarian and FTE deviated significantly from normal controls (women at average risk of ovarian cancer), but was significantly less abnormal in women treated with levonorgestrel. These karyometric data further support the idea that progestins may clear genetically abnormal cells and act as chemopreventive agents against ovarian and fallopian tube cancer.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalCancer Prevention Research
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2019

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Levonorgestrel
Fallopian Tubes
Ovarian Neoplasms
Progestins
Epithelium
Ovariectomy
Protein Isoforms
Fallopian Tube Neoplasms
Biomarkers
Placebos
Apoptosis
Nonparametric Statistics
Ovary
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase II trial of chemopreventive effects of levonorgestrel on ovarian and fallopian tube epithelium in women at high risk for ovarian cancer : An NRG oncology group/GOG study. / Rodriguez, Gustavo C.; Kauderer, James; Hunn, Jessica; Thaete, Larry G.; Watkin, William G.; Russell, Samantha; Yozwiak, Michael; Basil, Jack; Hurteau, Jean; Lele, Shashikant; Modesitt, Susan C.; Zivanovic, Oliver; Zhang, Hao Helen; Bartels, Peter H.; Alberts, David S.

In: Cancer Prevention Research, Vol. 12, No. 6, 01.06.2019, p. 401-412.

Research output: Contribution to journalArticle

Rodriguez, GC, Kauderer, J, Hunn, J, Thaete, LG, Watkin, WG, Russell, S, Yozwiak, M, Basil, J, Hurteau, J, Lele, S, Modesitt, SC, Zivanovic, O, Zhang, HH, Bartels, PH & Alberts, DS 2019, 'Phase II trial of chemopreventive effects of levonorgestrel on ovarian and fallopian tube epithelium in women at high risk for ovarian cancer: An NRG oncology group/GOG study', Cancer Prevention Research, vol. 12, no. 6, pp. 401-412. https://doi.org/10.1158/1940-6207.CAPR-18-0383
Rodriguez, Gustavo C. ; Kauderer, James ; Hunn, Jessica ; Thaete, Larry G. ; Watkin, William G. ; Russell, Samantha ; Yozwiak, Michael ; Basil, Jack ; Hurteau, Jean ; Lele, Shashikant ; Modesitt, Susan C. ; Zivanovic, Oliver ; Zhang, Hao Helen ; Bartels, Peter H. ; Alberts, David S. / Phase II trial of chemopreventive effects of levonorgestrel on ovarian and fallopian tube epithelium in women at high risk for ovarian cancer : An NRG oncology group/GOG study. In: Cancer Prevention Research. 2019 ; Vol. 12, No. 6. pp. 401-412.
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abstract = "A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO. The ovarian and fallopian tube epithelia (FTE) were compared immunohistochemically for effects of levonorgestrel on apoptosis (primary endpoint). Secondary endpoints included TGFb isoform expression, proliferation, and karyometric features of nuclear abnormality. In both the ovary and fallopian tube, levonorgestrel did not confer significant changes in apoptosis or expression of the TGFb1, 2, or 3 isoforms. In the ovarian epithelium, treatment with levonorgestrel significantly decreased the proliferation index. The mean ovarian Ki-67 value in the placebo arm was 2.027 per 100 cells versus 0.775 per 100 cells in the levonorgestrel arm (two-sided P value via Mann-Whitney U test = 0.0114). The karyometric signature of nuclei in both the ovarian and FTE deviated significantly from normal controls (women at average risk of ovarian cancer), but was significantly less abnormal in women treated with levonorgestrel. These karyometric data further support the idea that progestins may clear genetically abnormal cells and act as chemopreventive agents against ovarian and fallopian tube cancer.",
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AU - Basil, Jack

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AU - Modesitt, Susan C.

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AU - Alberts, David S

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