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Abstract：
OBJECTIVE: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features.
METHODS: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined.
RESULTS: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008).
CONCLUSIONS: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.
METHODS: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined.
RESULTS: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008).
CONCLUSIONS: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.
摘要：
目的：Mirvetuximabsoravantine可能是卵巢低级别浆液性癌（LGSC）的潜在有效治疗选择，但叶酸受体α(FRα)过度表达在这种肿瘤类型中的患病率尚不清楚.我们试图表征LGSC中FRα的表达及其与临床和分子特征的关联。
方法：在由89个LGSCs和42个卵巢浆液性交界性肿瘤（SBT）组成的组织微阵列上进行FRα免疫组织化学。对78个LGSC进行基于临床肿瘤-正常组的测序。检查了FRα高状态与临床病理特征和生存结果之间的关联。
结果：在89个LGSC中，36（40％）为高FRα（≥75％的活肿瘤细胞表现出中至强膜表达）。在9名LGSC患者和来自不同时间点的样本中，4人(44%)的结果不一致，在3例(33%)中从FRα阴性转化为FRα高。FRα高状态与年龄之间没有关联，种族,或无进展/总生存期。MAPK通路遗传改变，最常见的是KRAS(n=23)，存在于45（58％）LGSC中。与MAPK改变的LGSCs相比，缺乏MAPK通路改变的人更可能是FRα高（61％vs20％，p<0.001)。在SBT中，与没有恶性复发的常规SBT相比，FRα高表达与高风险（微乳头状）组织学和/或随后的LGSC复发相关（53％vs9％，p=0.008)。
结论：有必要对LGSC患者进行FRα定向治疗的未来研究。复发时FRα状态不一致提示复检的潜在益处。建议采用生物标志物驱动的方法来指导LGSC中的治疗选择。由于高FRα表达在缺乏MAPK通路遗传改变的肿瘤中更常见，FRa测试以确定米维妥昔单抗soravantine治疗的资格特别推荐用于此亚组。
方法：在由89个LGSCs和42个卵巢浆液性交界性肿瘤（SBT）组成的组织微阵列上进行FRα免疫组织化学。对78个LGSC进行基于临床肿瘤-正常组的测序。检查了FRα高状态与临床病理特征和生存结果之间的关联。
结果：在89个LGSC中，36（40％）为高FRα（≥75％的活肿瘤细胞表现出中至强膜表达）。在9名LGSC患者和来自不同时间点的样本中，4人(44%)的结果不一致，在3例(33%)中从FRα阴性转化为FRα高。FRα高状态与年龄之间没有关联，种族,或无进展/总生存期。MAPK通路遗传改变，最常见的是KRAS(n=23)，存在于45（58％）LGSC中。与MAPK改变的LGSCs相比，缺乏MAPK通路改变的人更可能是FRα高（61％vs20％，p<0.001)。在SBT中，与没有恶性复发的常规SBT相比，FRα高表达与高风险（微乳头状）组织学和/或随后的LGSC复发相关（53％vs9％，p=0.008)。
结论：有必要对LGSC患者进行FRα定向治疗的未来研究。复发时FRα状态不一致提示复检的潜在益处。建议采用生物标志物驱动的方法来指导LGSC中的治疗选择。由于高FRα表达在缺乏MAPK通路遗传改变的肿瘤中更常见，FRa测试以确定米维妥昔单抗soravantine治疗的资格特别推荐用于此亚组。
