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

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 wildtype 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.