title: Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR-2 inhibitor in metastatic breast cancer.
abstract: OBJECTIVE
  Hypothyroidism is a common adverse event in patients treated with anti-VEGFR-2 targeting agents and may be a valuable predictive factor of efficacy. Famitinib is an inhibitor of multiple tyrosine kinases mainly targeting VEGFR-2. The objectives of this study were to assess the efficacy and safety of famitinib in patients with pretreated HER2-negative metastatic breast cancer (MBC) and to explore potential of famitinib-induced hypothyroidism and serum vascular endothelial growth factor (VEGF) level for efficacy prediction.
  
  
  METHODS
  The primary end point was objective response rate (ORR). Famitinib was administered 25 mg/d. Thyroid function assessments were done at baseline and then every 4 weeks. Plasma levels of VEGF were determined at baseline and 2 cycles after treatment.
  
  
  RESULTS
  A total of 28 patients were enrolled. ORR was 14.3%. The most common grade 3/4 AEs were hand-foot syndrome (25.0%), proteinuria (21.4%) and hypertension (17.9%). 64.0% patients were observed with elevated thyroid-stimulating hormone (TSH) (>4.94 mIU/L) at any time during the entire treatment period. Sixteen patients with an elevated TSH had a significantly longer PFS than nine patients with no TSH elevation (107 vs. 53 days, respectively, P = 0.002). TSH elevation was also an independent predictor of PFS in a Cox regression model. Plasma VEGF levels did not correlate significantly with clinical outcomes.
  
  
  CONCLUSIONS
  Famitinib did show substantial anti-tumor activities with a good safety profile in heavily pretreated patients with HER2-negative MBC. Famitinib-related TSH increase may be an early indicator of its efficacy. Serial monitoring of serum TSH may help define VEGFR-2-dependent or VEGFR-2-independent drug resistance.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Fudan University Cancer Hospital, Shanghai Medical School, No. 270, Dong'an Road, Shanghai, 200032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Wang
authors.forename: Biyun
authors.initials: B
authors.lastname: Wang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lv
authors.forename: Leiping
authors.initials: L
authors.lastname: Wang
authors.forename: Xichun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis* / Q000401:mortality; D007211:Indoles / Q000494:pharmacology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology*; D015996:Survival Rate; D013972:Thyrotropin / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; C584390:famitinib; D013972:Thyrotropin; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2