tbuckley/cabot-search huggingface dataset:
Combination mTORC1/2 and BCL- X<sub>L</sub> inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.
Authors: Sarah Sammons, Grace Anderson, Suzanne Wardell, Donald P. McDonnell, Paul Kelly Marcom, Kris Wood
Journal: Journal of Clinical Oncology (2019)

e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-X L causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-X L /BCL-2 inhibitor). Results: Combination BCL-X L (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-X L inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-X L and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-X L.
Erlotinib monotherapy in the treatment of advanced non-small cell lung carcinoma: A single center experience with 187 patients from 2005-2018.
Authors: Felipe Matsunaga, David Pfau, Kai Laukamp, Elias Kikano, Nikhil H. Ramaiya, Afshin Dowlati
Journal: Journal of Clinical Oncology (2019)

e20718 Background: Inhibition of epidermal growth factor receptors (EGFR) bearing somatic mutations in the tyrosine kinase domain is an important molecular target in the treatment of advanced non-small cell lung carcinoma (NSCLC). As such, first generation tyrosine kinase inhibitors such as erlotinib have been adopted as standard of care in the treatment of EGFR mutation positive advanced NSCLC. Herein we describe our experience with erlotinib monotherapy since its approval for clinical use in the United States in late 2004. Methods: A retrospective analysis of 187 patients with a diagnosis of NSCLC who underwent erlotinib monotherapy from 2005-2018 was performed. Clinical variables including patient age, disease stage, EGFR genomic status, adverse events and survival were analyzed. Likelihood Ratio Chi-Square test was applied and statistical significance was set to p &lt; 0.05. Results: Among all patients who received erlotinib monotherapy (n = 187), treatment duration longer than 3 months was associated with EGFR mutant status (p &lt; 0.001), increased rates of repeat lung biopsies (p &lt; 0.002) as well as pulmonary (p = 0.008), gastrointestinal (p = 0.005) and cutaneous adverse events (p = 0.005). Subgroup analysis based on EGFR genomic status (n = 71) revealed that EGFR mutation positive patients remained on erlotinib for at least three months at a higher rate than wildtypes (p &lt; 0.001), but also sustained higher rates of lung re-biopsy (p = 0.0121) and concomitant gastrointestinal (diarrhea) and cutaneous (acneiform, maculopapular rashes) adverse events (grades 1-3) (p = 0.003). EGFR mutant status was associated with increased rates of survival of 12 months or greater since the initiation of erlotinib (p &lt; 0.001). Conclusions: Erlotinib monotherapy duration greater than 3 months and EGFR mutant status are associated with significantly higher rates of repeat lung biopsies and gastrointestinal and cutaneous adverse events. EGFR mutant status is further associated with survival of greater than 1 year.
A study of tobacco abuse as a risk factor for adrenal cortical carcinoma.
Authors: Joanna Amy Kolodney, Michael Kolodney, Jessica Patterson, Rachael Hagen, Matthew Smolkin, Gerald Hobbs, Thomas F. Hogan, Maria Hafez, Heidar Albandar
Journal: Journal of Clinical Oncology (2019)

e16119 Background: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but, due to the rarity of this tumor, this hypothesis has only been inferred from single study using a mixed population of adrenal tumors that included pheochromocytoma and neuroblastoma as well as ACC. Methods: De-identified IRB exempted records were analyzed for age, gender, and smoking history in adult patients diagnosed with ACC in both the West Virginia University database containing 2,699,193 patients and, in the larger TriNetX database of 21,426,477 patients from 2008-2018. In addition, the statewide ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the CDC. Results: Given the high rate of both tobacco use and ACC in the West Virginia Health System, we hypothesized that smoking contributed to increased prevalence of ACC in our state. We compared the rates of ACC and smoking in all 50 states using data from SEER. Among the 50 states, West Virginia had the highest smoking rate and the second highest rate of ACC. Utah had the lowest rate of smoking and the third lowest rate of ACC. The sample correlation between statewide smoking and ACC is .4177 indicating a significant association between the two (p = .0035). From 2008 to 2018, 20 patients with ICD10 code c74.0 (ACC) were abstracted from our EMR system. Examination of the individual charts determined 15 of the 20 patients had confirmed ACC diagnosis. This cohort was compared with matched age and gender matched controls. In the control group, there 13.3% were smokers while in the ACC group, 60% were smokers. The difference is significant (p = .0005) (OR) = 9.75 (95% CI; (2.54, 37.38). We next reviewed the larger TriNetX database and found that the prevalence of smoking in the ACC group to be 35.2% as compared to 9.0% in the TriNetX group(p-value &lt; .0001). Conclusions: Our retrospective review strongly supports smoking as a major risk factor ACC. To our knowledge, this is the first study to demonstrate a strong association of smoking in a cohort of biopsy proven ACCs.
Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.
Authors: Jorge Hernando-Cubero, Enrique Grande, Daniel E. Castellano, Toni Ibrahim, Nicola Fazio, Carlos Lopez, Alex Teule, Juan W. Valle, Rocio Garcia-Carbonero, Marc Diez, Daniel Acosta, Maria Roca, Jaume Capdevila
Journal: Journal of Clinical Oncology (2019)

4109 Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]
A comparative analysis of RNA sequencing methods with ribosome RNA depletion for degraded and low-input total RNA from formalin-fixed and paraffin-embedded samples.
Authors: Xiaojing Lin, Lihong Qiu, Xue Song, Junyan Hou, Weizhi Chen, Jun Zhao
Journal: Journal of Clinical Oncology (2019)

e14654 Background: Formalin-fixed and paraffin-embedded (FFPE) blocks held in clinical laboratories are an invaluable resource for clinical research, especially in the era of personalized medicine. With the development of massive parallel sequencing, RNA expression profiles have become an important source of new biomarkers with potential values in cancer metastasis and disease prognosis. Standard practice in tissue fixing and paraffin-embedding has little impact on the expression analysis of RNA samples, which makes archived FFPE samples valuable and retrospective studies feasible. But it is still difficult for some FFPE samples which have low quality or low amount of RNA to be used in the RNA expression study. Methods: We compared four FFPE RNA library preparation kits (KAPA, TaKaRa, QIAGEN and Vazyme) based on two principles of rRNA depletion, with total RNA from FFPE samples and paired FF samples using two bioinformatics analysis methods. Furthermore, we tried to construct RNA libraries with the two kits allowing for degraded low-input RNA using clinical FFPE samples of different quality. HISAT was used to analyze the data of all the libraries. Results: Our results demonstrated that high concordance in transcript quantifications were shown between FF and FFPE samples using the same kit and more transcripts could be obtained by rRNA depletion after reverse transcript reaction. The gene expression profiling using the TaKaRa kit showed a difference with other kits, which may be due to the different principle of rRNA depletion or the amount of input total RNA. For seriously degraded RNA from FFPE samples, libraries could be constructed with as low as 50 ng of total RNA, although there was higher residual rRNA and lower unique mapping ratio in the libraries. Conclusions: These results indicated that most of clinical FFPE samples could be used in the RNA profiling study. The method of RNA library construction with rRNA depletion can be used for clinical FFPE samples. For degraded and low-input RNA samples, it is still possible to obtain repeatable RNA expression profiling but with a low unique mapping ratio and high residual rRNA.
Epidemiology and survival in patients with urethral clear cell carcinoma.
Authors: Mausam Patel, Jay Im, Austin Ivy, Sanjay Maraboyina, Thomas Kim
Journal: Journal of Clinical Oncology (2019)

1550 Background: Clear cell carcinoma (CCC) of the urethra is a very rare histologic variant of urethral adenocarcinoma. The majority of studies have been case reports and case series with no large population based studies. A retrospective analysis was performed with the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) database to establish the epidemiology of urethral CCC and determine the clinical factors associated with survival. Methods: All cases of clear cell carcinoma of the urethra diagnosed from January 1, 1973 to December 31, 2014 were extracted from SEER. Age at diagnosis, sex, marital status, race, grade, stage, surgery, radiation, chemotherapy, overall survival (OS), disease specific survival (DSS), and survival months were extracted for analysis. Descriptive statistics were calculated for all variables. Univariable analysis to assess for differences in survival with respect to covariates was performed using the log rank test. Multivariable analysis was performed with Cox proportional hazards regression models to determine the predictive performance of covariates with respect to OS and DSS, reported as hazard ratio [HR] with 95% CIs. Comparisons were considered statistically significant at P &lt; 0.05. Results: Sixty one cases were extracted for analysis. The mean ± SD was 63.0 ± 13.9 years. Fifty eight (95.1%) patients were female with 53 (86.8%) locoregional cases at presentation. There were 50 (82%), 18 (29.5%), and 12 (23.0%) patients who underwent surgery, radiation, and chemotherapy, respectively. On univariable analysis, the following covariates were associated with both OS and DSS: age, stage, and surgery (all p &lt; 0.001; log rank test). On multivariable analysis, surgery was a predictor for improved OS and DSS (HR, 0.178; 95% CI [0.068; 0.464]) and HR, 0.166; 95% CI [0.196; 2.132], respectively). Additionally, both increasing age and distant disease were associated with worse OS and DSS. Neither radiation nor chemotherapy were significantly associated with OS or DSS. Conclusions: Surgery improves OS and DSS in patients with urethral CCC. While neither radiation nor chemo were significantly associated with survival, additional studies are necessary to determine how these therapeutic interventions may impact prognosis.
Diagnostic and treatment delays in young women with breast cancer.
Authors: Philip D Poorvu, Yue Zheng, Tal Sella, Shoshana M. Rosenberg, Kathryn Jean Ruddy, Shari I. Gelber, Rulla M Tamimi, Jeffrey M. Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Ellen Warner, Ann H. Partridge
Journal: Journal of Clinical Oncology (2019)

6575 Background: Delays in diagnosis (dx) and treatment (tx) affect breast cancer (BC) outcomes. We sought to identify factors associated with delays among young women, who do not undergo routine screening and often have pregnancy or breastfeeding-related breast changes that may mask a BC. Methods: The Young Women’s Breast Cancer Study is a multicenter, prospective cohort that enrolled 1302 women with newly dx BC age ≤40 between 2006-2016. Women reported the method and timing of cancer detection on the baseline survey. 231 were ineligible or excluded due to missing information. Among those reporting self-detected cancers, using multivariable regression we evaluated factors associated with delays ≥90 days (d) from symptom to presentation (self delay) and presentation to dx (care delay); in stage 0-III BC we evaluated delays ≥60d from dx to tx (tx delay). Results: 1071 eligible women had median age at dx of 37 yrs (17-40) and 74% reported self-detected cancers. Self delay or care delay ≥90d was reported in 17% and 13%, respectively. Factors inversely associated with self delay included pregnancy at dx (vs nulliparous, OR 0.10, CI 0.01-0.78) and perceived financial comfort (vs not, OR 0.62, CI 0.41-0.93). Women dx ≤1 year post-partum who breastfed (vs nulliparous, OR 2.60, CI 1.14-5.93) and those with a family history of breast/ovarian cancer (vs none, OR 1.79, CI 1.00-3.19) were more likely to have a care delay. Age was inversely associated with care delays (OR 0.94, CI 0.89-0.99). Tx delay was reported by 10% (105/1015), and associated with being single (vs partnered, OR 1.61, CI 1.02-2.56 ), non-white (vs white, OR 1.85, CI 1.09-3.13) and having Stage 0 BC (vs stage 1, OR: 3.08, CI 1.65-5.77); women with stage 3 BC (vs stage 1, OR 0.13, CI 0.03-0.56) were less likely to have a tx delay. Conclusions: In this cohort, most young women with BC underwent timely dx and tx initiation. Women dx ≤1 year post-partum who breastfed were more likely to experience a care delay, likely because lactational changes may mask BC signs and symptoms. The associations of perceived financial status with self delay and non-white race with tx delay underscore the need for additional support to ensure timely care for underserved populations with the goal of eliminating disparities in outcomes.
Randomized phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small cell lung cancer.
Authors: James William Welsh, Hari Menon, Chad Tang, Vivek Verma, Mehmet Altan, Kenneth R. Hess, Patricia de Groot, Quynh Nguyen, George R. Simon, Ferdinandos Skoulidis, Joe Y. Chang, Vassiliki Papadimitrakopoulou, John Heymach
Journal: Journal of Clinical Oncology (2019)

9104 Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.
Evaluation of transdermal permeation and plasma protein binding of CZ48, lactone-stabilized camptothecin-C20-propionate, in vitro using microdialysis technique
Authors: Diana Chow, Yousif Rojeab, Beppino Giovanella
Journal: Cancer Research (2005)

1403   Objective. The lactone moiety of camptothecin (CPT) is unstable in vivo, but essential for anti-tumor efficacy. CZ48, CPT-C20-propionate, was synthesized to improve the lactone stability, and exerts anti-neoplastic activity after its hydrolysis to CPT. This study was to implement the technique of microdialysis to monitor the trasdermal permeation flux of CZ48 (and CPT if possible) and evaluate its plasma protein binding in Sprague-Dawley rats, in vitro, as a pre-requesite for further in vivo investigation. A microemulsion formulation of CZ48 that has already demonstrated promising in vitro permeation profiles was applied as the source of CZ48. Methods. Surgically excised full-thickness rat skin barrier was mounted onto Franz diffusion cells. Microdialysis probe (Bioanalytical Systems Inc.) was implanted intra-dermally with the aid of 27.5 gauge needle. Temperature was maintained at 32 °C. 200 μl of Microemulsion formulation containing CZ48 (0.21 mg/ml) was applied to the donor compartment and covered with paraffin film. Perfusate solution was composed of 20%w/v Hydroxypropyl β cyclodextrin, at a flow rate of 3.0 μl/min. Samples were collected at pre-determined time points up to 72 hr. For the protein binding experiment, microdialysis probe was perfused through well-stirred CZ48 solution (1.0 μg/ml) in either PBS or rat plasma. Samples from both experiments were analyzed by HPLC for CZ48 concentration with reversed phase C8 column and fluorescent detection. The assay was validated with 1.98 and 2.62% within-day (n=3) and between-day (n=6) variability for CZ48, respectively. Results. Relative in vitro recovery of CZ48 was significantly improved over PBS with the addition of 20%w/v hydroxypropyl β cyclodextrin, 1.5 to 3.4%. Microdialysis technique was able to quantify CZ48 concentrations intra-dermally at levels as low as 2 ng/ml. The rat plasma protein binding of CZ48 was found to be 62%, a value which was very consistent with that obtained from the conventional method of dialysis bag, 59%. Conclusions. Microdilysis technique can be employed to detect CZ48 concentrations after topical drug administration in vitro. Microdialysis is a successful tool for quantifying CZ48 plasma protein binding in rat. Evaluation of relative in vivo recovery is required to proceed with further in vivo work.
PD-1 versus PD-L1 inhibitors for previously treated advanced non-small cell lung cancer (NSCLC): Bayesian network meta-analysis (NMA).
Authors: Abdulaali Almutairi, Ali McBride, Linda L. Garland, Ivo Abraham
Journal: Journal of Clinical Oncology (2019)

e20511 Background: PD-1 (pembrolizumab, nivolumab; PD-1i) and PD-L1(atezolizumab, avelumab; PD-L1i) inhibitors have been evaluated in patients with advanced NSCLC who failed first line therapy. We performed a Bayesian NMA to compare PD-1i and PD-L1i as groups as to efficacy and safety. Methods: Medline and Embase were searched for phase 2/3 randomized controlled trials (RCT) of PD-1i/PD-L1i in pretreated NSCLC setting. Bayesian NMA with fixed effect model was used to compare efficacy (overall survival (OS), progression-free survival (PFS), objective response rate (ORR)) and safety (grade 3-5 adverse events (AE), pneumonitis, and discontinuation rate due to AEs ). Outcomes were expressed as hazard (HR) or odds ratio (OR) with 95% credible interval (Crl). Results: 6 RCTs (3 PD-1i, 3 PD-L1i) involved comparison to docetaxel and were included. Table summarizes the results. PD-1i were ranked as the first therapy for the efficacy measures (OS (96.5%), PFS (98%), and ORR (99.92%)), and for the rate of grade3-5 AEs (60.17%). PD-L1 ranked first for the discontinuation rate due to AEs (56,51%) and docetaxel ranked first for pneumonitis (99.98%). Conclusions: PD-1i had better PFS/ORR benefits and similar OS benefit and safety profile compared to PD-L1i. Compared to docetaxel, PD-1i showed better PFS/ORR benefits and both PD-1i/PD-L1i had better OS benefit, lower grade 3-5 AEs and AE related discontinuation rate, and higher risk of pneumonitis. [Table: see text]