Rushton Tullia, Krause Harris B, Samec Timothy, Elliott Andrew, Karnezis Anthony N, Toboni Michael D, Thaker Premal H, Braxton David R, Oberley Matthew, Gershenson David M, Armstrong Deborah K
Johns Hopkins University, Baltimore, MD, United States of America.
Caris Life Sciences, United States of America.
Gynecol Oncol. 2024 Dec;191:80-85. doi: 10.1016/j.ygyno.2024.09.021. Epub 2024 Oct 3.
Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart.
Using a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration.
Compared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed.
Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.
叶酸受体α（FOLR1）阳性的高级别浆液性卵巢癌（HGSOC）的靶向治疗现已成为铂耐药疾病的主要治疗手段。然而，低级别浆液性卵巢癌（LGSOC）中FOLR1阳性率的相关记录并不完善。LGSOC比HGSOC少见，对传统铂类化疗方案的反应往往较差，尤其是在复发时。因此，迫切需要确定分子靶点，以帮助找到更有效的LGSOC治疗方法。在本研究中，我们评估了FOLR1阳性/阴性LGSOC与其高级别对应物相比的基因组和转录组图谱。
利用一个大型精准肿瘤学数据库，对281例LGSOC和5086例HGSOC队列进行了二代测序和免疫组化检测。根据二代测序结果计算相关的MAPK激活情况，并按分子改变进行分层完成患者生存分析。
与LGSOC（24.6%）相比，HGSOC肿瘤中FOLR1+状态的患病率显著更高（43.5%），且PD-L1+状态显著更高。相反，LGSOC中KRAS和NRAS突变的患病率更高，与HGSOC相比，BRAF突变几乎是其特有的。FOLR1阴性的LGSOC和HGSOC中T细胞炎性肿瘤的患病率相似，不过FOLR1阳性的LGSOC中T细胞炎性肿瘤的患病率显著低于FOLR1阳性的HGSOC。通过MAPK激活评分（MPAS）量化的MAPK激活在低级别肿瘤中显著高于HGSOC，但FOLR1阳性与FOLR1阴性的LGSOC之间未观察到差异。
尽管低于高级别疾病，但仍有相当一部分低级别肿瘤为FOLR1阳性，这表明LGSOC中的FOLR1表达可能是这种罕见组织学类型的一个可行靶点，尤其是在复发情况下。
