Citations

Abstract Dysregulation of estrogen receptor gene (ESR1) is an established mechanism of inducing endocrine therapy resistance. We previously discovered a chromosomal translocation event generating an estrogen receptor gene fused in-frame to C-terminal sequences of YAP1 (ESR1-YAP1) that contributed to endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer models. This current study compares functional and pharmacological properties of additional ESR1 gene fusion events of both early stage (ESR1-NOP2) and advanced endocrine therapy resistant (ESR1-YAP1 and ESR1-PCDH11x) breast cancers. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth in T47D, an ER+ breast cancer cell line in vitro and in vivo, in contrast to the NOP2 fusion which was sensitive to hormone deprivation. Immunohistochemical (IHC) staining of mouse lungs revealed significantly higher numbers of micrometastatic ER+ cells from the T47D tumors expressing the YAP1 and PCDH11x fusions than YFP control and NOP2 fusion. Estrogen response element (ERE) reporter and pull down assays revealed that although all ESR1 fusions studied bound EREs, only the YAP1 and PCDH11x caused ERE activation. Cell lines containing these “canonical” ESR1 fusions upregulated expression of ER responsive genes such as TFF1 and GREB1 in hormone deprived conditions. In contrast, the NOP2 fusion neither induced ERE activity nor upregulated TFF1 and GREB1 gene expression. The proliferative ability of canonical fusion-containing T47D cells was inhibited by palbociclib, a CDK4/6 inhibitor, in a dose-dependent manner. In vivo growth of patient-derived xenograft tumors naturally harboring the ESR1-YAP1 fusion (WHIM18) was significantly reduced in mice fed palbociclib-containing chow. Mice transplanted with WHIM18 also formed lung micrometastases, with an ER IHC staining pattern similar to lungs from YAP1 and PCDH11x fusion expressing T47D xenografts. In conclusion, in-frame ERE activating canonical fusions occur in end-stage, drug resistant, advanced breast cancer and can be added to ESR1 point mutations as a class of somatic mutation that may cause acquired resistance. Endocrine therapy resistant growth induced by these fusions can be treated with CDK4/6 inhibition, using an FDA approved drug, palbociclib, which could potentially improve outcomes in patients with ESR1 translocated tumors. Citation Format: Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Ryoichi Matsunuma, Xiaping He, Purba Singh, Yoshimasa Kosaka, Robert Crowder, Svasti Haricharan, Shyam Kavuri, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Romalho, Wei-Chu Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan Parikh, Sherri Davies, Cynthia Ma, Vera Suman, Kelly Hunt, Mark Watson, Katherine A. Hoadley, Aubrey Thompson, Charles Perou, Chad J. Creighton, Chris Maher, Matthew J. Ellis. Estrogen receptor gene fusions drive endocrine therapy resistance in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1033. doi:10.1158/1538-7445.AM2017-1033

Abstract Photon-counting computed tomography (PCCT) uses a photon counting detector to count individual photons and allocate them to specific energy bins by comparing photon energy to preset thresholds. This enables simultaneous multi-energy CT with a single source and detector. Phantom studies were performed to assess the spectral performance of a research PCCT scanner by assessing the accuracy of derived images sets. Specifically, we assessed the accuracy of iodine quantification in iodine map images and of CT number accuracy in virtual monoenergetic images (VMI). Vials containing iodine with five known concentrations were scanned on the PCCT scanner after being placed in phantoms representing the attenuation of different size patients. For comparison, the same vials and phantoms were also scanned on 2nd and 3rd generation dual-source, dual-energy scanners. After material decomposition, iodine maps were generated, from which iodine concentration was measured for each vial and phantom size and compared with the known concentration. Additionally, VMIs were generated and CT number accuracy was compared to the reference standard, which was calculated based on known iodine concentration and attenuation coefficients at each keV obtained from the U.S. National Institute of Standards and Technology (NIST). Results showed accurate iodine quantification (root mean square error of 0.5 mgI/cc) and accurate CT number of VMIs (percentage error of 8.9%) using the PCCT scanner. The overall performance of the PCCT scanner, in terms of iodine quantification and VMI CT number accuracy, was comparable to that of EID-based dual-source, dual-energy scanners.

Background Donor safety and the impact on quality of life continue to concern transplant centers as living liver transplantation increases. Methods Living liver donors participated in a focus group to discuss their perceptions of the donation process. Results The decision to donate was a personal choice made before the request by the recipient or transplant service. Spouses verified their support, but indicated that they were not included in the process. No donors felt coerced. The explanation of the procedure was thorough but excessive. Hospital care was good; however, donors admitted being unprepared for the pain and side effects of pain medications. Ongoing incisional discomfort continued beyond 6 weeks and prevented donors from feeling normal. Donors felt conflicted about competing with the “true” patient for healthcare. Conclusions Donors were positive about the need and willingness to donate. Sensitivity to the order of the disclosure process is identified.

ObjectiveTo investigate the use of glucocorticoids (GCs) and related adverse events (AEs) in a long‐term, geographically defined cohort of patients with polymyalgia rheumatica (PMR).MethodsUsing a population‐based inception cohort, details of GC therapy were abstracted from medical records of all patients diagnosed with PMR in 2000–2014. Age‐ and sex‐matched comparators without PMR were identified from the same underlying population. Cumulative and daily dosage of GC, rate of disease relapse, occurrence of GC‐related AEs, and rate of GC discontinuation were analyzed.ResultsThe study included 359 patients with PMR and 359 comparators. The median time to taper below 5 mg/day for 6 months was 1.44 years (95% confidence interval [95% CI] 1.36–1.62), while the median time to permanent discontinuation was 5.95 years (95% CI 3.37–8.88). The mean ± SD cumulative dose of GC at 2 and 5 years was 4.0 ± 3.5 grams and 6.3 ± 9.8 grams, respectively. The mean ± SD daily dose of GC at 2 and 5 years was 6.1 ± 7.6 mg/day and 7.2 ± 9.5 mg/day, respectively. There were no differences in rates of AEs between patients with PMR and comparators for diabetes mellitus, hypertension, hyperlipidemia, or hip, vertebral, or Colles fractures (P > 0.2 for all). Cataracts were more common in patients with PMR than comparators (hazard ratio 1.72 [95% CI 1.23–2.41]).ConclusionRelapse rates in PMR are highest in the early stages of therapy. Despite often protracted therapy, with the exception of cataracts, the rates of studied morbidities linked to GC are not more common in PMR than comparators.

Abstract Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.