The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. The Natural History of EOC and Genetic Predisposition
3.2. Histologic Subtypes of Ovarian Cancer, Molecular Correlates, and Therapeutic Implications
3.3. BRCAness: Definition and Treatment Implications
3.4. Four Subtypes of Serous Papillary EOC: Diagnostic and Therapeutic Implications
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Jayson, G.C.; Kohn, E.C.; Kitchener, H.C.; Ledermann, J.A. Ovarian cancer. Lancet 2014, 384, 1376–1388. [Google Scholar] [CrossRef]
- Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin. 2011, 61, 69–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perren, T.J.; Swart, A.M.; Pfisterer, J.; Ledermann, J.A.; Pujade-Lauraine, E.; Kristensen, G.; Carey, M.S.; Beale, P.; Cervantes, A.; Kurzeder, C.; et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 2011, 365, 2484–2496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moore, K.; Colombo, N.; Scambia, G.; Kim, B.G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; Sonke, G.S.; et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2018, 379, 2495–2505. [Google Scholar] [CrossRef]
- Naumann, R.W.; Coleman, R.L. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs 2011, 71, 1397–1412. [Google Scholar] [CrossRef]
- Risch, H.A.; McLaughlin, J.R.; Cole, D.E.; Rosen, B.; Bradley, L.; Fan, I.; Tang, J.; Li, S.; Zhang, S.; Shaw, P.A.; et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada. J. Natl. Cancer Inst. 2006, 98, 1694–1706. [Google Scholar] [CrossRef]
- Chen, S.; Iversen, E.S.; Friebel, T.; Finkelstein, D.; Weber, B.L.; Eisen, A.; Peterson, L.E.; Schildkraut, J.M.; Isaacs, C.; Peshkin, B.N.; et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J. Clin. Oncol. 2006, 24, 863–871. [Google Scholar] [CrossRef] [Green Version]
- Hennessy, B.T.; Coleman, R.L.; Markman, M. Ovarian cancer. Lancet 2009, 374, 1371–1382. [Google Scholar] [CrossRef]
- Lynch, H.T.; Casey, M.J.; Snyder, C.L.; Bewtra, C.; Lynch, J.F.; Butts, M.; Godwin, A.K. Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and management. Mol. Oncol. 2009, 3, 97–137. [Google Scholar] [CrossRef]
- Lheureux, S.; Braunstein, M.; Oza, A.M. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J. Clin. 2019, 69, 280–304. [Google Scholar] [CrossRef] [Green Version]
- Norquist, B.M.; Harrell, M.I.; Brady, M.F.; Walsh, T.; Lee, M.K.; Gulsuner, S.; Bernards, S.S.; Casadei, S.; Yi, Q.; Burger, R.A.; et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016, 2, 482–490. [Google Scholar] [CrossRef] [PubMed]
- Bashashati, A.; Ha, G.; Tone, A.; Ding, J.; Prentice, L.M.; Roth, A.; Rosner, J.; Shumansky, K.; Kalloger, S.; Senz, J.; et al. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J. Pathol. 2013, 231, 21–34. [Google Scholar] [CrossRef] [PubMed]
- Kurman, R.J.; Shih Ie, M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Hum. Pathol. 2011, 42, 918–931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615. [Google Scholar] [CrossRef]
- Bowtell, D.D.; Bohm, S.; Ahmed, A.A.; Aspuria, P.J.; Bast, R.C., Jr.; Beral, V.; Berek, J.S.; Birrer, M.J.; Blagden, S.; Bookman, M.A.; et al. Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer. 2015, 15, 668–679. [Google Scholar] [CrossRef]
- Kroeger, P.T., Jr.; Drapkin, R. Pathogenesis and heterogeneity of ovarian cancer. Curr. Opin. Obstet. Gynecol. 2017, 29, 26–34. [Google Scholar] [CrossRef]
- Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011, 12, 852–861. [Google Scholar] [CrossRef]
- Kaldawy, A.; Segev, Y.; Lavie, O.; Auslender, R.; Sopik, V.; Narod, S.A. Low-grade serous ovarian cancer: A review. Gynecol. Oncol. 2016, 143, 433–438. [Google Scholar] [CrossRef]
- Jones, S.; Wang, T.L.; Kurman, R.J.; Nakayama, K.; Velculescu, V.E.; Vogelstein, B.; Kinzler, K.W.; Papadopoulos, N.; Shih Ie, M. Low-grade serous carcinomas of the ovary contain very few point mutations. J. Pathol. 2012, 226, 413–420. [Google Scholar] [CrossRef]
- Hsu, C.Y.; Bristow, R.; Cha, M.S.; Wang, B.G.; Ho, C.L.; Kurman, R.J.; Wang, T.L.; Shih Ie, M. Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas. Clin. Cancer. Res. 2004, 10, 6432–6436. [Google Scholar] [CrossRef] [Green Version]
- Banerjee, S.; Kaye, S.B. New strategies in the treatment of ovarian cancer: Current clinical perspectives and future potential. Clin. Cancer. Res. 2013, 19, 961–968. [Google Scholar] [CrossRef] [Green Version]
- Farley, J.; Brady, W.E.; Vathipadiekal, V.; Lankes, H.A.; Coleman, R.; Morgan, M.A.; Mannel, R.; Yamada, S.D.; Mutch, D.; Rodgers, W.H.; et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: An open-label, single-arm, Phase 2 study. Lancet Oncol. 2013, 14, 134–140. [Google Scholar] [CrossRef] [Green Version]
- Pauly, N.; Ehmann, S.; Ricciardi, E.; Ataseven, B.; Bommert, M.; Heitz, F.; Prader, S.; Schneider, S.; Du Bois, A.; Harter, P.; et al. Low-grade serous tumors: Are we making progress? Curr. Oncol. Rep. 2020, 22, 8. [Google Scholar] [CrossRef] [PubMed]
- Marks, E.I.; Brown, V.S.; Dizon, D.S. Genomic and Molecular Abnormalities in Gynecologic Clear Cell Carcinoma. Am. J. Clin. Oncol. 2020, 43, 139–145. [Google Scholar] [CrossRef] [PubMed]
- Fukumoto, T.; Magno, E.; Zhang, R. SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications. Mol. Cancer. Res. 2018, 16, 1819–1825. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Itamochi, H.; Oishi, T.; Oumi, N.; Takeuchi, S.; Yoshihara, K.; Mikami, M.; Yaegashi, N.; Terao, Y.; Takehara, K.; Ushijima, K.; et al. Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. Br. J. Cancer 2017, 117, 717–724. [Google Scholar] [CrossRef]
- Shibuya, Y.; Tokunaga, H.; Saito, S.; Shimokawa, K.; Katsuoka, F.; Bin, L.; Kojima, K.; Nagasaki, M.; Yamamoto, M.; Yaegashi, N.; et al. Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing. Genes Chromosomes Cancer 2018, 57, 51–60. [Google Scholar] [CrossRef]
- Hashiguchi, Y.; Tsuda, H.; Inoue, T.; Berkowitz, R.S.; Mok, S.C. PTEN expression in clear cell adenocarcinoma of the ovary. Gynecol. Oncol. 2006, 101, 71–75. [Google Scholar] [CrossRef]
- Lheureux, S.; Tinker, A.; Clarke, B.; Ghatage, P.; Welch, S.; Weberpals, J.I.; Dhani, N.C.; Butler, M.O.; Tonkin, K.; Tan, Q.; et al. A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium. Clin. Cancer. Res. 2018, 24, 6168–6174. [Google Scholar] [CrossRef] [Green Version]
- Berns, K.; Caumanns, J.J.; Hijmans, E.M.; Gennissen, A.M.C.; Severson, T.M.; Evers, B.; Wisman, G.B.A.; Jan Meersma, G.; Lieftink, C.; Beijersbergen, R.L.; et al. ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors. Oncogene 2018, 37, 4611–4625. [Google Scholar] [CrossRef]
- Vierkoetter, K.R.; Ayabe, A.R.; VanDrunen, M.; Ahn, H.J.; Shimizu, D.M.; Terada, K.Y. Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary. Gynecol. Oncol. 2014, 135, 81–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McConechy, M.K.; Ding, J.; Senz, J.; Yang, W.; Melnyk, N.; Tone, A.A.; Prentice, L.M.; Wiegand, K.C.; McAlpine, J.N.; Shah, S.P.; et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod. Pathol. 2014, 27, 128–134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cybulska, P.; Paula, A.D.C.; Tseng, J.; Leitao, M.M., Jr.; Bashashati, A.; Huntsman, D.G.; Nazeran, T.M.; Aghajanian, C.; Abu-Rustum, N.R.; DeLair, D.F.; et al. Molecular profiling and molecular classification of endometrioid ovarian carcinomas. Gynecol. Oncol. 2019, 154, 516–523. [Google Scholar] [CrossRef] [PubMed]
- Nakayama, K.; Rahman, M.T.; Rahman, M.; Nakamura, K.; Ishikawa, M.; Katagiri, H.; Sato, E.; Ishibashi, T.; Iida, K.; Ishikawa, N.; et al. CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas. Int. J. Oncol. 2016, 48, 506–516. [Google Scholar] [CrossRef] [Green Version]
- Gorringe, K.L.; Cheasley, D.; Wakefield, M.J.; Ryland, G.L.; Allan, P.E.; Alsop, K.; Amarasinghe, K.C.; Ananda, S.; Bowtel, D.D.L.; Christie, M.; et al. Therapeutic Options for mucinous ovarian carcinoma. Gynecol. Oncol. 2020, 156, 552–560. [Google Scholar] [CrossRef] [Green Version]
- Yang, D.; Khan, S.; Sun, Y.; Hess, K.; Shmulevich, I.; Sood, A.K.; Zhang, W. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011, 306, 1557–1565. [Google Scholar] [CrossRef] [Green Version]
- Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014, 15, 852–861. [Google Scholar] [CrossRef]
- Patch, A.M.; Christie, E.L.; Etemadmoghadam, D.; Garsed, D.W.; George, J.; Fereday, S.; Nones, K.; Cowin, P.; Alsop, K.; Bailey, P.J.; et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015, 521, 489–494. [Google Scholar] [CrossRef]
- Mendes-Pereira, A.M.; Martin, S.A.; Brough, R.; McCarthy, A.; Taylor, J.R.; Kim, J.S.; Waldman, T.; Lord, C.J.; Ashworth, A. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 2009, 1, 315–322. [Google Scholar] [CrossRef]
- Konecny, G.E.; Wang, C.; Hamidi, H.; Winterhoff, B.; Kalli, K.R.; Dering, J.; Ginther, C.; Chen, H.W.; Dowdy, S.; Cliby, W.; et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J. Natl. Cancer Inst. 2014, 106. [Google Scholar] [CrossRef]
- Wang, Z.C.; Birkbak, N.J.; Culhane, A.C.; Drapkin, R.; Fatima, A.; Tian, R.; Schwede, M.; Alsop, K.; Daniels, K.E.; Piao, H.; et al. Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome. Clin. Cancer. Res. 2012, 18, 5806–5815. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pennington, K.P.; Walsh, T.; Harrell, M.I.; Lee, M.K.; Pennil, C.C.; Rendi, M.H.; Thornton, A.; Norquist, B.M.; Casadei, S.; Nord, A.S.; et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer. Res. 2014, 20, 764–775. [Google Scholar] [CrossRef] [Green Version]
- Manie, E.; Popova, T.; Battistella, A.; Tarabeux, J.; Caux-Moncoutier, V.; Golmard, L.; Smith, N.K.; Mueller, C.R.; Mariani, O.; Sigal-Zafrani, B.; et al. Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas. Int. J. Cancer 2016, 138, 891–900. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Popova, T.; Manie, E.; Rieunier, G.; Caux-Moncoutier, V.; Tirapo, C.; Dubois, T.; Delattre, O.; Sigal-Zafrani, B.; Bollet, M.; Longy, M.; et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012, 72, 5454–5462. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.F.; Barry, W.T.; Birrer, M.; Lee, J.M.; Buckanovich, R.J.; Fleming, G.F.; Rimel, B.; Buss, M.K.; Nattam, S.; Hurteau, J.; et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol. 2014, 15, 1207–1214. [Google Scholar] [CrossRef] [Green Version]
- Ray-Coquard, I.; Pautier, P.; Pignata, S.; Perol, D.; Gonzalez-Martin, A.; Berger, R.; Fujiwara, K.; Vergote, I.; Colombo, N.; Maenpaa, J.; et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2416–2428. [Google Scholar] [CrossRef]
- Verhaak, R.G.; Tamayo, P.; Yang, J.Y.; Hubbard, D.; Zhang, H.; Creighton, C.J.; Fereday, S.; Lawrence, M.; Carter, S.L.; Mermel, C.H.; et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J. Clin. Investig. 2013, 123, 517–525. [Google Scholar] [CrossRef]
- Kommoss, S.; Winterhoff, B.; Oberg, A.L.; Konecny, G.E.; Wang, C.; Riska, S.M.; Fan, J.B.; Maurer, M.J.; April, C.; Shridhar, V.; et al. Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes. Clin. Cancer. Res. 2017, 23, 3794–3801. [Google Scholar] [CrossRef] [Green Version]
- Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer. 2016, 16, 275–287. [Google Scholar] [CrossRef]
- Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2015, 33, 4015–4022. [Google Scholar] [CrossRef]
- Fujiwara, K.; McAlpine, J.N.; Lheureux, S.; Matsumura, N.; Oza, A.M. Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer. Am. Soc. Clin. Oncol. Educ. Book 2016, 35, e247–e257. [Google Scholar] [CrossRef] [PubMed]
- Howitt, B.E.; Strickland, K.C.; Sholl, L.M.; Rodig, S.; Ritterhouse, L.L.; Chowdhury, D.; D’Andrea, A.D.; Matulonis, U.A.; Konstantinopoulos, P.A. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology 2017, 6, e1277308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Type I EOC | Type II EOC | |
---|---|---|
Frequency | 25% of EOCs | 75% of EOCs |
Mortality | 10% | 90% |
Diagnosis | Usually Early stage | Usually Advanced stage (carcinomatosis) |
Progression | Slow | Fast |
Histologic subtypes | Low-grade serous Low-grade endometrioid Clear-cell Mucinous | High-grade serous High-grade endometrioid Undifferentiated carcinoma Carcinosarcoma |
Mutations | KRAS, BRAF (serous) CTTNNB1, PTEN, PI3KCA (endometrioid) KRAS, BRAF, HER2, P53 (mucinous) (P53 for 25% of mucinous EOC) PI3KCA, HER2 (clear-cell) ARID1A, PPP2R1A | P53 (96% of high-grade serous EOCs) BRCA (21% of cases) |
Genomic stability | Stability | Instability |
Precursors | Benigh cyst » borderline » malignant | Precursors: de novo, STIC |
Histologic Subtype | High-Grade Serous | Low-Grade Serous | Mucinous | Endometrioid | Clear-Cell |
---|---|---|---|---|---|
% of all EOCs diagnosed | 71% | 4% | 3% | 8% | 9% |
% of early stage EOCs diagnosed | Nearly 0% | 17% | 12% | 33% | 38% |
% of advanced stage EOCs diagnosed | 88% | 3% | 2% | 3% | 4% |
Progression speed | High | low | low (50%) high (50%) | Low (90%) High (10%) | low |
Mutations | P53 BRCA1 or BRCA2 | KRAS BRAS HER2 | P53 KRAS | PTEN PI3KCA | PI3KCA |
Intracellular signaling pathway targeted | P53, which controls mitosis and apoptosis | MEK/BRAF/KRAS pathway | PI3K/AKT/mTor | ||
Function of signaling pathway | BRCA involved in double-strand DNA repair | Cell proliferation | Regulates cell proliferation, motility, and survival | ||
Drugs targeting signaling pathway | PARP inhibitor (olaparib) for tumors with a BRCAness profile | Selumetinib, trametinib, dabrafenib | mTor inhibitor (e.g., temsirolimus, everolimus) |
Subtypes of High-Grade Serous Ovarian Cancer | High Expression | Low Expression | Five-Year Survival | Potential Targeted Therapy |
---|---|---|---|---|
Mesenchymal | Genes in stromal component (fibroblasts, vascular pericytes, etc.) | 18% | Bevacizumab (anti-VEGF) | |
Proliferative | Transcription factors and proliferation markers | Differentiation markers (MUC16 and MUC1) | 22% | Bevacizumab (anti-VEGF) |
Differentiated | Differentiation markers (MUC16 and MUC1) | 42% | ||
Immunoreactive | T-cell chemokines MHC class I and II PD-L1 | 45% | Nivolumab (Anti PD1/PD-L1 monoclonal antibody) |
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Dion, L.; Carton, I.; Jaillard, S.; Nyangoh Timoh, K.; Henno, S.; Sardain, H.; Foucher, F.; Levêque, J.; de la Motte Rouge, T.; Brousse, S.; et al. The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer. J. Clin. Med. 2020, 9, 2239. https://doi.org/10.3390/jcm9072239
Dion L, Carton I, Jaillard S, Nyangoh Timoh K, Henno S, Sardain H, Foucher F, Levêque J, de la Motte Rouge T, Brousse S, et al. The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer. Journal of Clinical Medicine. 2020; 9(7):2239. https://doi.org/10.3390/jcm9072239
Chicago/Turabian StyleDion, Ludivine, Isis Carton, Sylvie Jaillard, Krystel Nyangoh Timoh, Sébastien Henno, Hugo Sardain, Fabrice Foucher, Jean Levêque, Thibault de la Motte Rouge, Susie Brousse, and et al. 2020. "The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer" Journal of Clinical Medicine 9, no. 7: 2239. https://doi.org/10.3390/jcm9072239