Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Real-World Palbociclib Use in HR+/HER2− Advanced Breast Cancer in Canada: The IRIS Study

Background: Palbociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). Palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2− ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study ({"type":"clinical-trial","attrs":{"text":"NCT03159195","term_id":"NCT03159195"}}NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. Methods: This retrospective chart review included women with HR+/HER2− ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan–Meier analysis. Results: Thirty-three physicians examined medical records for 247 patients (P+L, n = 214; P+F, n = 33). Median follow-up was 8.8 months for P+L and 7.0 months for P+F. Most patients were initiated on palbociclib 125 mg/d (P+L, 90.2%; P+F, 84.8%). Doses were reduced in 16.6% of P+L and 14.3% of P+F patients initiating palbociclib at 125 mg/d. The PFR for P+L was 90.3% at 12 months and 78.2% at 18 months; corresponding SRs were 95.6% and 93.0%. For P+F, 6-month PFR was 91.0%; 12-month SR was 100.0%. Conclusions: Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.     

Babesiosis as a cause of acute respiratory distress syndrome: a series of eight cases

Objectives: The characteristics of patients with Acute Respiratory Distress Syndrome (ARDS) as a complication of Babesia microti infection have not been systematically described.

Methods: Adult patients admitted to the medical intensive care unit (MICU) of a tertiary care hospital in the Lower Hudson Valley of New York from 1/1/2008 to 8/1/2016 were evaluated for ARDS complicating babesiosis.

Results: Of 22 patients with babesiosis in the MICU, eight (36.4%; 95% CI: 19.7–57.0%) had ARDS. Six patients (75%) developed ARDS following initiation of anti-babesia drug therapy; however, the mean duration of symptoms in these patients exceeded that of patients who developed ARDS prior to initiation of treatment (7.50 ± 3.83d vs. 4.50 ± 0.71d, p = 0.34). Three patients (37.5%; 95% CI: 13.7–69.4%) expired without recovery from ARDS. In comparison, the mortality rate for the 14 MICU babesiosis patients without ARDS was 14.3% (p = 0.31). There was a trend toward younger age in survivors relative to non-survivors (mean age 54.6 ± 13.8y vs. 74.0 ± 6.24y, p = 0.07). Three of the five survivors did not require mechanical ventilation. The mean sequential organ failure assessment score of non-survivors was significantly higher than that of survivors (12.3 ± 1.15 vs. 6.0 ± 1.4, p = 0.0006).

Conclusion: Among 22 critically ill adult patients with B. microti infection, ARDS developed in eight (35.4%), and three (37.5%) expired without resolution of the ARDS. ARDS often followed the initiation of anti-babesia drug therapy, raising the question of whether the death of the parasite per se contributed to its development. However, this observation was confounded by the longer duration of symptoms preceding initiation of drug therapy.