TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties.

BACKGROUND/PURPOSE: TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. EXPERIMENTAL DESIGN/METHODS: To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. RESULTS: TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. CONCLUSIONS: Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.

The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies.

PURPOSE: Estrogen receptor-alpha (ER) is a therapeutic target of ER-positive (ER+) breast cancers. Although ER signaling is complex, many mediators of this pathway have been identified. Specifically, phosphorylation of ER at serine 118 affects responses to estrogen and therapeutic ligands and has been correlated with clinical outcomes in ER+ breast cancer patients. We hypothesized that a newly described germline variant (S118P) at this residue would drive cellular changes consistent with breast cancer development and/or hormone resistance. METHODS: Isogenic human breast epithelial cell line models harboring ER S118P were developed via genome editing and characterized to determine the functional effects of this variant. We also examined the frequency of ER S118P in a case-control study (N = 536) of women with and without breast cancer with a familial risk. RESULTS: In heterozygous knock-in models, the S118P variant demonstrated no significant change in proliferation, migration, MAP Kinase pathway signaling, or response to the endocrine therapies tamoxifen and fulvestrant. Further, there was no difference in the prevalence of S118P between women with and without cancer relative to population registry databases. CONCLUSIONS: This study suggests that the ER S118P variant does not affect risk for breast cancer or hormone therapy resistance. Germline screening and modification of treatments for patients harboring this variant are likely not warranted.

Standardising practice in cardiology: reducing clinical variation and cost at Ochsner Health System.

Objective: Low quality and unwarranted clinical variation harm patients and increase unnecessary costs. Effective approaches to improve clinical and economic value have been difficult. The Ochsner Health System looked to improve clinical care quality and reduce unnecessary costs in cardiology using active measurement and customised feedback. Methods: We serially measured care decisions using online, simulated cases to capture clinical details of cardiology practice and provide individual feedback. Fifty cardiologists cared for two simulated patients in each of six assessment rounds occurring 4 months apart. Simulated patients presented with heart failure (HF), coronary artery disease (CAD), supraventricular tachyarrhythmia (SVT) or valvular heart disease. Using Ochsner's patient-level data, we performed real-world pre-post analyses of physician practice changes, patient outcomes and costs. Results: Between baseline and final rounds, overall simulated quality-of-care scores improved 14.1% (p<0.001). In the same period, we found cost-of-care variation decreased in patient-level data, with larger decreases for more severely ill patients. The total per-patient direct costs decreased $493 in SVT, $305 in HF and $55 in CAD (p<0.05 for SVT and HF). Readmission rates fell significantly for HF (from 20.0% to 11.9%) and SVT (from 14.5% to 7.8%) (both p<0.001) and non-significantly for CAD (from 13.7% to 11.3%, p=0.112). The cost avoidance/revenue generation opportunity from reduced readmissions and direct costs amounted to annual savings of $4.34 million, with no significant changes to in-hospital mortality rates (p>0.05). Conclusions: Using simulated patients to serially measure and provide individual feedback on clinical practice significantly raises quality and reduces practice variation and costs without negatively impacting outcomes.