Probes for INS

CONTEXT:

FSH receptor (FSHR), besides being expressed in gonads, is also expressed in some extragonadal tissues at low levels.

OBJECTIVE:

We examined the functional expression of FSHR in different types of endometriotic lesions.

DESIGN:

Extensive studies were carried out to detect functional FSHR expression and FSH-stimulated estrogen production in ovarian endometriomas and recto-vaginal endometriotic nodules (RVEN). Normal endometrium, ovary, and myometrium tissues from nonpregnant cycling women served as controls.

SETTINGS:

This laboratory-based study was carried out on tissue specimens from patients with endometriosis and healthy donors.

RESULTS:

Endometriotic lesions and normal secretory-phase endometrium showed FSHR expression at both mRNA and protein level. RVEN and ovarian endometrioma demonstrated up-regulated CYP19A1, dependent on the activation of CYP19A1 proximal promoter II. Estrogen receptor-β (ESR2) expression was significantly increased in RVEN vs normal endometrium. Recombinant human FSH stimulation of RVEN explants significantly increased estradiol production and CYP19A1 and ESR2 expression. FSHR was up-regulated in recombinant human FSH-stimulated endometrial and decidualized stromal cells with increased CYP19A1 expression.

CONCLUSIONS:

We described a novel functional FSHR expression, where FSH-stimulated CYP19A1 expression and estrogen production in RVEN are demonstrated. This locally FSH-induced estrogen production may contribute to the pathology, development, progression, and severity of RVEN.

Introduction

Pre-clinically, high FGFR1 mRNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to FGFR inhibitors in NSCLC and SCLC cell lines. KRAS mutations did not preclude sensitivity.

Patients and Methods

Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Positive cases were offered ponatinib, a multi-kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed using log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed using Fisher’s exact test and Kruskal-Wallis rank sum test.

Results

171 cases were prescreened: 9/123 (7.3%) SISH+; 53/126 (42.1%) ISH+; 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (p=0.03) than SISH- cases, and ISH+ cases had worse OS (p=0.020) than ISH- cases. Data distributions suggested a distinct higher positivity cutpoint for FGFR1 ISH (≥20%), occurring in 23% [29/126] cases, was associated with SCLC histology (p=0.022), soft tissue metastases (p=0.050) and shorter OS (p=0.031). Four patients received ponatinib on study: All ISH+ by the initial cutpoint, 2/4 by higher cutpoint, 1/4 SISH+. Tolerability was poor. The best response for the two higher ISH cases was SD and PD for the two lower ISH cases.

Conclusions

Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib’s poor tolerance suggests further FGFR exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

BACKGROUND:

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung.

METHODS:

Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off. The primary endpoint was overall response. Secondary endpoints were progression-free survival, overall survival, and toxicity.

RESULTS:

All 26 patients were men with a median age of 68 years (range, 52-80 years). The majority of patients were ever-smokers. The median duration of dovitinib administration (28 days per cycle) was 2.5 months (range, 0.7-8.6 months). The overall response rate was 11.5% (95% confidence interval [95% CI], 0.8%-23.8%) and the disease control rate was 50% (95% CI, 30.8%-69.2%), with 3 patients achieving partial responses. Response durations for the patients with partial responses were ≥4.5 months, ≥ 5.1 months, and 6.1 months, respectively. After a median follow-up of 15.7 months (range, 1.2-25.6 months), the median overall survival was 5.0 months (95% CI, 3.6-6.4 months) and the median progression-free survival was 2.9 months (95% CI, 1.5-4.3 months). The most common grade 3 or higher adverse events were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) (event severity was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]).