Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
Breast Cancer Res. 2021 Feb 12;23(1):21. doi: 10.1186/s13058-021-01398-8.
FGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear.
FGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied.
FGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models.
FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.
FGFR1 扩增而非过表达与激素阳性乳腺癌（HRPBC）的不良预后相关。FGFR1 过表达和扩增是否相关，它们在 luminal A 或 B HRPBC 中的分布如何，以及扩增和过表达是否存在潜在的不同预后作用，目前尚不清楚。FGFR1 抑制剂在 HRPBC 中的作用也不清楚。
在 N=251 例 HRPBC 患者队列和 METABRIC 队列中检测 FGFR1 扩增（FISH）和过表达（RNAscope）；并确定其对生存的影响和 FISH-RNAscope 一致性。我们构建了 ER+ MCF7 和 T47-D 和 ER+、FGFR1 扩增 HCC1428 细胞系的激素剥夺耐药（LTED-R）和 FGFR1 过表达细胞系变体。研究了 ER、CDK4/6 和/或 FGFR1 单独或联合阻断在 Rb 磷酸化、细胞周期和存活中的作用。
超过 20%的患者 FGFR1 过表达和扩增不一致，但两者与类似的复发风险相关（~2.5 倍；P<0.05）。FGFR1 扩增或过表达发生在无论 luminal 亚型如何，但在 luminal B（16.3%）肿瘤中比 A（6.6%）肿瘤更常见；P<0.05。过表达和扩增的 Kappa 指数为 0.69（P<0.001）。24%的患者 FGFR1 扩增和/或过表达，这与复发的危险比为 2.6（95%CI 1.44-4.62，P<0.001）相关。在体外，激素剥夺导致 FGFR1 过表达。原发性 FGFR1 扩增、工程化 mRNA 过表达或 LTED-R 获得的 FGFR1 过表达导致对单独激素治疗或与 CDK4/6 抑制剂 palbociclib 联合治疗的耐药。用激酶抑制剂 rogaratinib 阻断 FGFR1 导致 Rb 磷酸化抑制、细胞周期阻断和所有 FGFR1 模型的耐药性逆转。
FGFR1 扩增和过表达与激素阳性乳腺癌的不良预后相关。要捕获所有与 FGFR1 异常相关的不良预后患者，需要同时评估这两种特征。激素剥夺导致 FGFR1 过表达，FGFR1 过表达和/或扩增与激素单药治疗或与 palbociclib 联合治疗的耐药性相关。这两种耐药性都可以通过三重 ER、CDK4/6 和 FGFR1 阻断来逆转。
