Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Studies

Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22)

British Journal of Cancer volume 127, pages 1479–1486 (2022)Cite this article

Subjects

Abstract

Background

Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published.

Methods

A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®).

Results

A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4–53.1) and OS was 105.4 months (95% CI: 82.7–not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found.

Conclusions

MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor’s characteristics.

Clinical trial registration

This study is registered under NCT02408536 on ClinicalTrials.gov.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Progression-Free Survival (PFS) of the overall population.
Fig. 2: Overall Survival (OS) of the overall population.

Data availability

The datasets used and analyzed during the current study are available from the corresponding authors on reasonable request.

References

  1. Slomovitz B, Gourley C, Carey MS, Malpica A, Shih IM, Huntsman D, et al. Low-grade serous ovarian cancer: state of the science. Gynecol Oncol. 2020;156:715–25.

    Article  Google Scholar 

  2. Gockley A, Melamed A, Bregar AJ, Clemmer JT, Birrer M, Schorge JO, et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstet Gynecol. 2017;129:439–47.

    Article  Google Scholar 

  3. Grabowski JP, Harter P, Heitz F, Pujade-Lauraine E, Reuss A, Kristensen G, et al. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol. 2016;140:457–62.

    Article  Google Scholar 

  4. Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114:48–52.

    Article  Google Scholar 

  5. Monk BJ, Grisham RN, Banerjee S, Kalbacher E, Mirza MR, Romero I, et al. MILO/ENGOT-ov11: binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. J Clin Oncol. 2020;38:3753–62.

    Article  CAS  Google Scholar 

  6. Singer G, Stöhr R, Cope L, Dehari R, Hartmann A, Cao DF, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol. 2005;29:218–24.

    Article  Google Scholar 

  7. Van Nieuwenhuysen E, Busschaert P, Laenen A, Moerman P, Han SN, Neven P, et al. Loss of 1p36.33 frequent in low-grade serous ovarian cancer. Neoplasia. 2019;21:582–90.

    Article  Google Scholar 

  8. Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew YE, Rowley SM, et al. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget. 2015;6:37663–77.

    Article  Google Scholar 

  9. Rambau PF, Vierkant RA, Intermaggio MP, Kelemen LE, Goodman MT, Herpel E, et al. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis Consortium study. J Pathol Clin Res. 2018;4:250–61.

    Article  CAS  Google Scholar 

  10. Singer G, Oldt R, Cohen Y, Wang BG, Sidransky D, Kurman RJ, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst. 2003;95:484–6.

    Article  CAS  Google Scholar 

  11. Wong KK, Tsang YTM, Deavers MT, Mok SC, Zu Z, Sun C, et al. BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol. 2010;177:1611–7.

    Article  CAS  Google Scholar 

  12. Emmanuel C, Chiew Y-E, George J, Etemadmoghadam D, Anglesio MS, Sharma R, et al. Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver. Clin Cancer Res. 2014;20:6618–30.

    Article  CAS  Google Scholar 

  13. Cheasley D, Nigam A, Zethoven M, Hunter S, Etemadmoghadam D, Semple T, et al. Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities. J Pathol. 2021;253:41–54.

    Article  CAS  Google Scholar 

  14. Gershenson DM, Miller A, Brady WE, Paul J, Carty K, Rodgers W, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(Feb):541–53.

    Article  CAS  Google Scholar 

  15. Monk BJ, Grisham RN, Banerjee S, Kalbacher E, Mirza MR, Romero I, et al. MILO/ENGOT-ov11: binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. J Clin Oncol. 2020;38(Nov):3753–62.

    Article  CAS  Google Scholar 

  16. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, 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;14:134–40.

    Article  CAS  Google Scholar 

  17. Escobar J, Klimowicz AC, Dean M, Chu P, Nation JG, Nelson GS, et al. Quantification of ER/PR expression in ovarian low-grade serous carcinoma. Gynecol Oncol. 2013;128:371–6.

    Article  CAS  Google Scholar 

  18. Buttarelli M, Mascilini F, Zannoni GF, Ciucci A, Martinelli E, Filippetti F, et al. Hormone receptor expression profile of low-grade serous ovarian cancers. Gynecol Oncol. 2017;145:352–60.

    Article  CAS  Google Scholar 

  19. Gershenson DM, Sun CC, Iyer RB, Malpica AL, Kavanagh JJ, Bodurka DC, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125:661–6.

    Article  CAS  Google Scholar 

  20. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35:1103–11.

    Article  Google Scholar 

  21. Tang M, O’Connell RL, Amant F, Beale P, McNally O, Sjoquist KM, et al. PARAGON: a Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors. Gynecol Oncol. 2019;154:531–8.

    Article  CAS  Google Scholar 

  22. Zhang X, Devins K, Ko EM, Reyes MC, Simpkins F, Drapkin R, et al. Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary-Clinical significance of BRCA2 gene variants in genomically stable tumors. Gynecol Oncol. 2021;161:762–8.

    Article  CAS  Google Scholar 

  23. Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28:496–504.

    Article  Google Scholar 

  24. Prat J.FIGO Committee on Gynecologic Oncology Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124:1–5.

    Article  Google Scholar 

  25. Calzolari A, Napolitano M, Bravo E. Review of the Italian current legislation on research biobanking activities on the eve of the participation of national biobanks’ network in the legal consortium BBMRI-ERIC. Biopreserv Biobank. 2013;11:124–8.

    Article  Google Scholar 

  26. Gershenson DM, Sun CC, Wong KK. Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum. Br J Cancer. 2015;113:1254–8.

    Article  CAS  Google Scholar 

  27. Schmeler KM, Sun CC, Malpica A, Deavers MT, Bodurka DC, Gershenson DM. Low-grade serous primary peritoneal carcinoma. Gynecol Oncol. 2011;121:482–6.

    Article  Google Scholar 

  28. Schmeler KM, Sun CC, Bodurka DC, Deavers MT, Malpica A, Coleman RL, et al. Neoadjuvant chemotherapy for low-grade `or peritoneum. Gynecol Oncol. 2008;108:510–4.

    Article  CAS  Google Scholar 

  29. Dalton HJ, Fleming ND, Sun CC, Bhosale P, Schmeler KM, Gershenson DM. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol Oncol. 2017;145:37–40.

    Article  CAS  Google Scholar 

  30. Grisham RN, Iyer G, Sala E, Zhou Q, Iasonos A, DeLair D, et al. Bevacizumab shows activity in patients with low-grade serous ovarian and primary peritoneal cancer. Int J Gynecol Cancer. 2014;24:1010–4.

    Article  Google Scholar 

  31. Kaldawy A, Segev Y, Lavie O, Auslender R, Sopik V, Narod SA. Low-grade serous ovarian cancer: a review. Gynecol Oncol. 2016;143:433–8.

    Article  Google Scholar 

  32. Grisham RN, Vergote I, Banerjee SN, Drill EN, Fabbro M, Mirza MR, et al. Molecular results and potential biomarkers identified from MILO/ENGOT-ov11 phase 3 study of binimetinib versus physicians’ choice of chemotherapy (PCC) in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2021;39:5519–5519.

    Article  Google Scholar 

  33. Dong Y, Walsh MD, McGuckin MA, Gabrielli BG, Cummings MC, Wright RG, et al. Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavorable prognosis. Int J Cancer. 1997;74:57–63.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Gelsomina Iovane, Margherita Tambaro and Angela Maria Trujillo for data management.

Funding

A specific funding was received for this work. The research leading to these results has received funding from AIRC under IG 2016 – ID. 18921 and IG 2021 – ID. 25932 projects – P.I. SP and CO-2018–12367051 (Ministero della Salute) P.I SP; Ricerca Corrente grant M2/7 from Ministero della Salute to DC, Ricerca Corrente from Ministero della Salute to SP.

Author information

Authors and Affiliations

  1. Department of Women and Child Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Lucia Musacchio, Domenica Lorusso, Vanda Salutari, Viola Ghizzoni & Giovanni Scambia

  2. Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy

    Daniela Califano, Anna Spina & Daniela Russo

  3. Department of Medicine (DAME), University of Udine, Udine, Italy

    Michele Bartoletti

  4. Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy

    Michele Bartoletti & Simona Scalone

  5. Clinical Trial Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G.Pascale, Naples, Italy

    Laura Arenare & Francesco Perrone

  6. Department of Life Science and Public Health, Catholic University of Sacred Heart, Largo Agostino Gemelli, Rome, Italy

    Domenica Lorusso & Giovanni Scambia

  7. Surgical Pathology Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy

    Nunzia Simona Losito & Michele Del Sesto

  8. Gynecologic Oncology Istituto Tumori Giovanni Paolo II – IRCCS, Bari, Italy

    Gennaro Cormio

  9. Interdisciplinary Department of Medicine, University of Bari, Bari, Italy

    Gennaro Cormio, Vera Loizzi & Vittoria Del Vecchio

  10. Gynecologic Oncology Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy

    Stefano Greggi

  11. Gynecologic Oncology Unit, Istituto Nazionale Tumori, IRCCS, Milan, Italy

    Francesco Raspagliesi & Monika Ducceschi

  12. Department of Oncology, University of Torino at Ordine Mauriziano Hospital, Turin, Italy

    Giorgio Valabrega & Valentina Tuninetti

  13. Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy

    Carmela Pisano & Sandro Pignata

  14. Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, National Cancer Institute, Aviano, Italy

    Vincenzo Canzonieri

  15. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

    Vincenzo Canzonieri

  16. Medical Oncology Department, San Vincenzo Hospital, Taormina, Messina, Italy

    Francesco Ferraù & Domenico Priolo

  17. Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Gian Franco Zannoni

  18. Pathological Anatomy Institute, Catholic University of Sacred Hearth, Rome, Italy

    Gian Franco Zannoni

  19. Oncology Department, Santa Maria delle Croci Hospital, Ravenna, Italy

    Claudia Casanova

Authors
  1. Lucia Musacchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Califano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michele Bartoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Arenare
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Domenica Lorusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nunzia Simona Losito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gennaro Cormio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stefano Greggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francesco Raspagliesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giorgio Valabrega
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vanda Salutari
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Carmela Pisano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Anna Spina
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Daniela Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michele Del Sesto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Vincenzo Canzonieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Francesco Ferraù
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Gian Franco Zannoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Vera Loizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Viola Ghizzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Claudia Casanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Valentina Tuninetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Monika Ducceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Vittoria Del Vecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Simona Scalone
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Domenico Priolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Francesco Perrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Giovanni Scambia
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Sandro Pignata
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SP conceived the study; LM, DC and SP contributed to methodology; All authors collected the data; DC, GFZ, NSL were responsible for the assessment of the primary FFPE tumor tissue, including the estimation of tumor cellularity; LM and LA interpreted and analyzed the data; LM wrote the manuscript; LA, LM, DC and SP played a key role in interpreting the results and revised the article critically for important intellectual content; SP supervised the project and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Sandro Pignata.

Ethics declarations

Competing interests

DL reports research funding from Clovis, GSK and MSD, personal interests with AstraZeneca, Clovis Oncology, GSK, Pharmamar, MSD and financial interests with Clovis, Genmab, GSK, MSD. Board of Directors, GCIG (Gynecologic Cancer Inter Group). FR reports honoraria from GSK, Pharmamar, Clovis, MSD and Roche. VS reports honoraria from GSK, PharmaMar, Roche, MSD, EISAI, Clovis, Oncology, AstraZeneca. FP reports honoraria for educational and advisory activity from Incyte, GSK, Eli Lilly, Ipsen, Astellas, AstraZeneca, Roche, BMS, Bayer, Clovis, Pierre Fabre and grants for clinical trials to his institution from Roche, Astra Zeneca, Pfizer, MSD, Bayer, Incyte Taiho, Janssen, Exelixis, Ailenor, Daiichi Sankyo. GS reports research support from MSD and honoraria from Clovis Oncology. Consultant for Tesaro and Johnson & Johnson. SP reports honoraria from AstraZeneca, MSD, Roche, Pfizer, Clovis, GSK, Pharmamar and research funding from MSD, Roche, Astrazeneca and Pfizer. LM, DC, MB, LA, NSL, GC, SG, GV, CP, AS, DR, MDS, VC, FF, GFZ, VL, VG, CC, VT, MD, VDV, SS and DP have nothing to disclose.

Ethics approval and consent to participate

This study was approved by the ethics committee of the National Cancer Institute of Naples (22/14 OSS) and the ethics committees of the participating centers, and it was conducted in accordance with the Declaration of Helsinki. The study participants gave written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Musacchio, L., Califano, D., Bartoletti, M. et al. Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22). Br J Cancer 127, 1479–1486 (2022). https://doi.org/10.1038/s41416-022-01897-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01897-1

Search

Advanced search

Quick links