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Journal of Cancer Research and Clinical Oncology

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Open Access 05-09-2023 | Research

Mesonephric-like adenocarcinoma of the female genital tract: possible role of KRAS-targeted treatment—detailed molecular analysis of a case series and review of the literature for targetable somatic KRAS-mutations

Authors: Christine E. Brambs, Lars-Christian Horn, Ruth Hiller, Irene Krücken, Christian Braun, Corina Christmann, Astrid Monecke, Anne Kathrin Höhn

Published in: Journal of Cancer Research and Clinical Oncology | Issue 17/2023

Abstract

Purpose

Mesonephric-like adenocarcinomas (MLA) of the female genital tract represent a rare and relatively recently described neoplasm exhibiting characteristic morphologic and immunohistochemical findings commonly associated with a KRAS-mutation. Most cases display an aggressive clinical behavior, but knowledge about treatment approaches is limited, especially for targeting KRAS.

Methods

We report a series of eight cases with a detailed molecular analysis for KRAS. These cases as well as the data of previously published cases with detailed information regarding KRAS-mutational events were reviewed for a potential targeted approach and its prognostic impact.

Results

Both the uterine and ovarian MLA harbor a somatic KRAS-mutation in about 85% of the reported cases, affecting the hotspot codons 12 and 13. 15.7% of the endometrial and 15.6% of ovarian MLA are wild type for KRAS. A p.G12A-alteration was seen in 5.6% (5/89) of the endometrial and in 6.2% (2/32) of the ovarian tumors, for p.G12C in 7.9% and 6.2%, for p.G12D in 32.6% and 34.5% and for p.G12V in 36% and 37.5%, respectively. Very limited data are available regarding the prognostic impact of different mutational sites within the KRAS-gene without significant prognostic impact.

Conclusion

Because of a specific p.G12C-KRAS somatic mutation, only the minority of MLA (7.9% with uterine and 6.2% with ovarian primary) are potentially targetable by sotarasib in that rare but aggressive subtype of adenocarcinoma of the female genital tract. Until now, the different location of a somatic KRAS-mutation is of no prognostic impact.

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Al Nabhani S, Doyle A, Kennedy S, McVey R, Crown J, Gibbons D (2022) Endometrial mesonephric-like adenocarcinoma presenting as an ocular lesion: a case report. Int J Gynecol Pathol 41(2):161–167PubMed

Chang CS, Carney ME, Killeen JL (2023) Two cases of mesonephric-like carcinoma arising from endometriosis: case report and review of the literature. Int J Gynecol Pathol 42(1):101–107PubMed

Chapel DB, Joseph NM, Krausz T, Lastra RR (2018) An ovarian adenocarcinoma with combined low-grade serous and mesonephric morphologies suggests a müllerian origin for some mesonephric carcinomas. Int J Gynecol Pathol 37(5):448–459PubMed

Chen Q, Shen Y, Xie C (2020) Mesonephric-like adenocarcinoma of the ovary: a case report and a review of the literature. Medicine (baltimore) 99(48):e23450PubMed

Cherri S, Melocchi L, Gandolfi L, Rossi G, Zaniboni A (2023) Integrated decision-making in the treatment of colon-rectal cancer: the case of KRAS-mutated tumors. Life (basel) 13(2):395PubMed

Chida K, Kotani D, Masuishi T, Kawakami T, Kawamoto Y, Kato K, Fushiki K, Sawada K, Kumanishi R, Shirasu H, Matsubara Y, Yuki S, Komatsu Y, Yamazaki K, Yoshino T (2021) The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: a multicenter retrospective observational study. Oncologist 26(10):845–853PubMedPubMedCentral

da Silva EM, Fix DJ, Sebastiao APM, Selenica P, Ferrando L, Kim SH, Stylianou A, Da Cruz PA, Pareja F, Smith ES, Zehir A, Konner JA, Cadoo K, Reis-Filho JS, Abu-Rustum NR, Mueller JJ, Weigelt B, Park KJ (2021) Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases. Mod Pathol 34(8):1570–1587PubMedPubMedCentral

de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, Wolf J, Schuler M, Lena H, Skoulidis F, Yoneshima Y, Kim SW, Linardou H, Novello S, van der Wekken AJ, Chen Y, Peters S, Felip E, Solomon BJ, Ramalingam SS, Dooms C, Lindsay CR, Ferreira CG, Blais N, Obiozor CC, Wang Y, Mehta B, Varrieur T, Ngarmchamnanrith G, Stollenwerk B, Waterhouse D, Paz-Ares L, CodeBreaK 200 Investigators (2023) Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS^G12C mutation: a randomized, open-label, phase 3 trial. Lancet 401(10378):733–746PubMed

Deolet E, Van Dorpe J, Van de Vijver K (2021) Mesonephric-like adenocarcinoma of the endometrium: diagnostic advances to spot this wolf in Sheep’s clothing. A review of the literature. J Clin Med 10(4):698PubMedPubMedCentral

Deolet E, Arora I, Van Dorpe J, Van der Meulen J, Desai S, Van Roy N, Kaur B, Van de Vijver K, McCluggage WG (2022) Extrauterine mesonephric-like neoplasms: expanding the morphologic spectrum. Am J Surg Pathol 46(1):124–133PubMed

Dundr P, Gregová M, Němejcová K, Bártů M, Hájková N, Hojný J, Stružinská I, Fischerová D (2020) Ovarian mesonephric-like adenocarcinoma arising in serous borderline tumor: a case report with complex morphological and molecular analysis. Diagn Pathol 15(1):91PubMedPubMedCentral

Erlanson DA, Webster KR (2021) Targeting mutant KRAS. Curr Opin Chem Biol 62:101–108PubMed

Euscher ED, Bassett R, Duose DY, Lan C, Wistuba I, Ramondetta L, Ramalingam P, Malpica A (2020) Mesonephric-like carcinoma of the endometrium: a subset of endometrial carcinoma with an aggressive behavior. Am J Surg Pathol 44(4):429–443PubMed

Fakih MG, Kopetz S, Kuboki Y, Kim TW, Munster PN, Krauss JC, Falchook GS, Han SW, Heinemann V, Muro K, Strickler JH, Hong DS, Denlinger CS, Girotto G, Lee MA, Henary H, Tran Q, Park JK, Ngarmchamnanrith G, Prenen H, Price TJ (2022) Sotorasib for previously treated colorectal cancers with KRAS^G12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 23(1):115–124PubMed

Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 39(Database issue):D945–D950PubMed

Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT (2020) KRAS^G12C Inhibition with sotorasib in advanced solid tumors. N Engl J Med 383(13):1207–1217PubMedPubMedCentral

Horn LC, Höhn AK, Krücken I, Stiller M, Obeck U, Brambs CE (2020) Mesonephric-like adenocarcinomas of the uterine corpus: report of a case series and review of the literature indicating poor prognosis for this subtype of endometrial adenocarcinoma. J Cancer Res Clin Oncol 146(4):971–983PubMed

Howitt BE, Nucci MR (2018) Mesonephric proliferations of the female genital tract. Pathology 50(2):141–150PubMed

Kessler D, Gerlach D, Kraut N, McConnell DB (2021) Targeting son of sevenless 1: the pacemaker of KRAS. Curr Opin Chem Biol 62:109–118PubMed

Kim H, Na K, Bae GE, Kim HS (2021) Mesonephric-like adenocarcinoma of the uterine corpus: comprehensive immunohistochemical analyses using markers for mesonephric, endometrioid and serous tumors. Diagnostics (basel) 11(11):2042PubMed

Kim HG, Kim H, Yeo MK, Won KY, Kim YS, Han GH, Kim HS, Na K (2022) Mesonephric-like adenocarcinoma of the uterine corpus: comprehensive analyses of clinicopathological, molecular, and prognostic characteristics with retrospective review of 237 endometrial carcinoma cases. Cancer Genom Proteom 19(4):526–539

Koh HH, Park E, Kim HS (2022) Mesonephric-like adenocarcinoma of the ovary: clinicopathological and molecular characteristics. Diagnostics (basel) 12(2):326PubMed

Kolin DL, Costigan DC, Dong F, Nucci MR, Howitt BE (2019) A combined morphologic and molecular approach to retrospectively identify kras-mutated mesonephric-like adenocarcinomas of the endometrium. Am J Surg Pathol 43(3):389–398PubMed

Li S, Balmain A, Counter CM (2018) A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer 18(12):767–777PubMed

Ma T, Chai M, Shou H, Ru G, Zhao M (2022) Mesonephric-like adenocarcinoma of uterine corpus: a clinicopathological and targeted genomic profiling study in a single institution. Front Oncol 5(12):911695

Malapelle U, Passiglia F, Cremolini C, Reale ML, Pepe F, Pisapia P, Avallone A, Cortinovis D, De Stefano A, Fassan M, Fontanini G, Galetta D, Lauricella C, Listì A, Loupakis F, Pagni F, Pietrantonio F, Pilotto S, Righi L, Bianchi AS, Parra HS, Tiseo M, Verzè M, Troncone G, Novello S (2021) RAS as a positive predictive biomarker: focus on lung and colorectal cancer patients. Eur J Cancer 146:74–83PubMed

Mao W, Wei S, Yang H, Yu Q, Xu M, Guo J, Gao L (2020) Clinicopathological study of organ metastasis in endometrial cancer. Future Oncol 16(10):525–540PubMed

McCluggage WG (2022) Mesonephric-like adenocarcinoma of the female genital tract: from morphologic observations to a well-characterized carcinoma with aggressive clinical behavior. Adv Anat Pathol 29(4):208–216PubMed

McCluggage WG, Vosmikova H, Laco J (2020) Ovarian combined low-grade serous and mesonephric-like adenocarcinoma: further evidence for a mullerian origin of mesonephric-like adenocarcinoma. Int J Gynecol Pathol 39(1):84–92PubMed

McFarland M, Quick CM, McCluggage WG (2016) Hormone receptor-negative, thyroid transcription factor 1-positive uterine and ovarian adenocarcinomas: report of a series of mesonephric-like adenocarcinomas. Histopathology 68(7):1013–1020PubMed

Mills AM, Jenkins TM, Howitt BE, Fan J, Ring KL, Cook I (2022) Mesonephric-like endometrial carcinoma: results from immunohistochemical screening of 300 endometrial carcinomas and carcinosarcomas for this often overlooked and potentially aggressive entity. Am J Surg Pathol 46(7):921–932PubMed

Mirkovic J, McFarland M, Garcia E, Sholl LM, Lindeman N, MacConaill L, Dong F, Hirsch M, Nucci MR, Quick CM, Crum CP, McCluggage WG, Howitt BE (2018) Targeted genomic profiling reveals recurrent KRAS mutations in mesonephric-like adenocarcinomas of the female genital tract. Am J Surg Pathol 42(2):227–233PubMed

Na K, Kim HS (2019) Clinicopathologic and molecular characteristics of mesonephric adenocarcinoma arising from the uterine body. Am J Surg Pathol 43(1):12–25PubMed

Nilforoushan N, Liu L, Finkelman BS, Andersen J, Liu Y, James J, Hung CF, Wu TC, Vang R, Xing D (2023) Ovarian combined serous borderline tumor/low-grade serous carcinoma and mesonephric-like lesion: report of 2 cases with new observations. Int J Gynecol Pathol 42(2):182–191PubMed

Park S, Park E, Kim HS (2022) Mesonephric-like carcinosarcoma of the uterine corpus: clinicopathological, molecular and prognostic characteristics in comparison with uterine mesonephric-like adenocarcinoma and conventional endometrial carcinosarcoma. Cancer Genom Proteom 19(6):747–760

Patel V, Kipp B, Schoolmeester JK (2019) Corded and hyalinized mesonephric-like adenocarcinoma of the uterine corpus: report of a case mimicking endometrioid carcinoma. Hum Pathol 86:243–248PubMed

Pors J, Cheng A, Leo JM, Kinloch MA, Gilks B, Hoang L (2018) A comparison of GATA3, TTF1, CD10, and calretinin in identifying mesonephric and mesonephric-like carcinomas of the gynecologic tract. Am J Surg Pathol 42(12):1596–1606PubMed

Pors J, Segura S, Chiu DS, Almadani N, Ren H, Fix DJ, Howitt BE, Kolin D, McCluggage WG, Mirkovic J, Gilks B, Park KJ, Hoang L (2021) Clinicopathologic characteristics of mesonephric adenocarcinomas and mesonephric-like adenocarcinomas in the gynecologic tract: a multi-institutional study. Am J Surg Pathol 45(4):498–506PubMedPubMedCentral

Sakamoto K, Masutani T, Hirokawa T (2020) Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo. Sci Rep 10(1):21671PubMedPubMedCentral

Schirripa M, Nappo F, Cremolini C, Salvatore L, Rossini D, Bensi M, Businello G, Pietrantonio F, Randon G, Fucà G, Boccaccino A, Bergamo F, Lonardi S, Dei Tos AP, Fassan M, Loupakis F (2020) KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population. Clin Colorectal Cancer 19(3):219–225PubMed

Seay K, Akanbi T, Bustamante B, Chaudhary S, Goldberg GL (2020) Mesonephric-like adenocarcinoma of the ovary with co-existent endometriosis: a case report and review of the literature. Gynecol Oncol Rep 4(34):100657

Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R (2021) Sotorasib for lung cancers with KRAS p.G12C Mutation. N Engl J Med 384(25):2371–2381PubMedPubMedCentral

Soslow RA, Tornos C, Park KJ, Malpica A, Matias-Guiu X, Oliva E, Parkash V, Carlson J, McCluggage WG, Gilks CB (2019) Endometrial carcinoma diagnosis: use of FIGO grading and genomic subcategories in clinical practice: recommendations of the International Society of Gynecological Pathologists. Int J Gynecol Pathol 38(Iss 1 Suppl 1):S64–S74PubMed

Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, Schuler M, Burns TF, Coveler AL, Falchook GS, Vincent M, Sunakawa Y, Dahan L, Bajor D, Rha SY, Lemech C, Juric D, Rehn M, Ngarmchamnanrith G, Jafarinasabian P, Tran Q, Hong DS (2023) Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer. N Engl J Med 388(1):33–43PubMed

Xie C, Chen Q, Shen Y (2021) Mesonephric adenocarcinomas in female genital tract: a case series. Medicine (baltimore) 100(35):e27174PubMed

Yang Y, Zhang H, Huang S, Chu Q (2023) KRAS mutations in solid tumors: characteristics, current therapeutic strategy, and potential treatment exploration. J Clin Med 12(2):709PubMedPubMedCentral

Yano M, Shintani D, Katoh T, Hamada M, Ito K, Kozawa E, Hasegawa K, Yasuda M (2019) Coexistence of endometrial mesonephric-like adenocarcinoma and endometrioid carcinoma suggests a Müllerian duct lineage: a case report. Diagn Pathol 14(1):54PubMedPubMedCentral

Title: Mesonephric-like adenocarcinoma of the female genital tract: possible role of KRAS-targeted treatment—detailed molecular analysis of a case series and review of the literature for targetable somatic KRAS-mutations
Authors: Christine E. Brambs
Lars-Christian Horn
Ruth Hiller
Irene Krücken
Christian Braun
Corina Christmann
Astrid Monecke
Anne Kathrin Höhn
Publication date: 05-09-2023
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 17/2023
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-05306-9

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