tbuckley/cabot-search huggingface dataset:
Associations with response to poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic breast cancer: Results of a meta-regression analysis.
Authors: Alexandra Desnoyers, Ramy Saleh, Michelle Nadler, Eitan Amir
Journal: Journal of Clinical Oncology (2019)

e12567 Background: PARP inhibitors (PARPi), when given as single agents, have modest antitumor activity in patients with advanced breast cancer and germline mutation in BRCA1 or BRCA2. It is unclear whether some subgroups derive greater benefit from treatment. Methods: Two electronic databases (MEDLINE, CENTRAL) and one registry (Clinicaltrials.gov) were searched from inception to November 2018 to identify trials of PARPi in patients with metastatic breast cancer. The response rates to PARPi were extracted and pooled. Analyses were performed for patients with a germline BRCA mutation. Meta-regression explored the influence of patient and tumor characteristics and previous chemotherapy on the objective response rate (ORR) as reported in individual studies. Analysis comprised of a linear regression weighted by individual study sample size using the weighted least squares (mixed effect) method. Quantitative significance was defined using methods described by Burnand et al. Results: Of 1855 citations, 11 studies comprising 813 patients were included in the analysis. 765 (94%) patients had a germline BRCA mutations; 48% of breast cancers were triple-negative. 76% of patients had received at least 1 previous line of chemotherapy in the metastatic setting and 30% were exposed to platinum-based chemotherapy. Pooled ORR was 47% in patients with a germline BRCA mutation. Meta-regression showed that previous chemotherapy in the metastatic setting ( = -0.94, p = 0.006), especially platinum-based chemotherapy ( = -0.89, p = 0.02) were associated with highly significant negative association with ORR. A highly quantitatively significant negative association was observed for age ( = -0.80, p = 0.10), but this did not meet statistical significance. Performance status ( = 0.44, p = 0.38) and hormone receptor status (hormone receptors positive: = 0.46, p = 0.30) were not associated with response. Conclusions: PARPi therapy is associated with lesser response in patient with prior chemotherapy exposure, especially platinum-based treatment. Younger patients may benefit more from PARPi. There was no association between ORR and hormone receptor status.
Longitudinal prostate cancer outcomes in a racially diverse cohort of military heath care beneficiaries: 1990-2017.
Authors: Jennifer Cullen, Nathan Oehrlein, Samantha Streicher, Huai-Ching Kuo, Yongmei Chen, Kevin R. Rice, Grace L. Lu-Yao, Inger L. Rosner
Journal: Journal of Clinical Oncology (2019)

e16581 Background: Prostate cancer (PCa) incidence and mortality disproportionately burden African American (AA) men compared to Caucasian American (CA) men. An interplay of biological, social, and health care factors is blamed for this disparity. However, a recent multi-center study of the Veterans Affairs population found no differences in cancer progression, disease specific survival, or overall survival for AA versus CA men. This study examines a large, racially diverse military health care beneficiary cohort, enrolled over 25+ years, to examine the roles of race and comorbidity on metastasis-free and overall survival. Methods: The Center for Prostate Disease Research (CPDR) multi-center national database was the source of study subjects. Eligible patients included all men who underwent radical prostatectomy (RP) as primary treatment for PCa between January 1, 1990 to December 31, 2017. Comprehensive demographic, clinical, treatment, and outcomes data were collected on all enrollees. Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis with adjustment for key clinical and pathologic factors were used to examine BCR-free, metastasis-free, and overall survival as a function of patient self-reported race (AA vs. CA). Results: There were 7,135 eligible men, among whom 22% self-reported as AA. Median age at RP and follow-up were 62 and 6.9 years, respectively. A total of 1521 BCR events, 210 metastasis events, and 879 deaths occurred. Compared to CA men, AA men were younger at diagnosis (59.4 vs. 62.7 years, p &lt; 0.05) with higher median PSA (5.8 vs. 5.5 ng/mL, p &lt; 0.05); however, NCCN risk strata, as well as clinical and pathologic stage and grade were distributed comparably across race. Despite slightly poorer BCR-free survival for AA men in both unadjusted and adjusted analysis, there were no statistically significant differences in 5-, 10-, and 15-year probabilities for metastasis-free or overall survival. Conclusions: In this racially diverse equal-access health care setting, this longitudinal cohort study revealed no differences in distant metastasis or overall survival between AA and CA men. Future work will examine molecular signatures of metastatic cancer.
Venous thromboembolism (VTE) in patients with ALK-rearranged non-small cell lung cancer (ALK-LC): A population-based cohort.
Authors: Alona Zer, Lilach Joseph, Erez Battat, Tzippy Shochat, Avi Leader, Daniel A. Goldstein, Ariel Hammerman
Journal: Journal of Clinical Oncology (2019)

6608 Background: Advanced NSCLC is associated with an increased risk for VTE, with a reported rate of 8-15%. Clinical observations suggest a higher rate of VTE in patients with ALK-rearranged NSCLC. Clalit Health Services (CHS) is both a healthcare payer and provider, covering over 50% of the population in Israel, with individual patient data recorded in a centralized electronic database. We aimed to determine the incidence of VTE in patients with ALK-LC using a population-based cohort. Methods: We identified all patients diagnosed with NSCLC between 01/2012-12/2017 within CHS. Clinical and demographic data (including VTE risk factors, i.e. components of the Khorana score) were extracted from the CHS registry for all patients. Patients with ALK-LC were identified according to crizotinib prescriptions (dispensed after an approved CHS' pre-authorization for an ALK-LC diagnosis). VTE was identified by ICD diagnosis codes 415.xx, 444.xx, 451.xx and 453.xx. VTE risk factors (Khorana score) were also extracted. Association between ALK-LC and VTE were analyzed using logistic regression, estimating univariate and multivariate Odds Ratios (OR). Results: Overall, 4327 patients with a diagnosis of NSCLC were identified. 149 (3%) had at least one prescription for crizotinib for advanced ALK-LC. The rate of VTE in these patients was 25% (38 of 149 patients), while in the non-ALK-LC the rate was 14% (596/4178), OR = 2.05, p = 0.0004. The association was significant also in a multivariate analysis adjusting for, age, smoking status, BMI, platelet count, hemoglobin and Charlson co-morbidity score (OR 1.66, p = 0.018). Conclusions: This pooled analysis of individual patient data confirms prior data from smaller retrospective studies, suggesting ALK-LC is associated with a high risk of VTE. Randomized trials with prophylactic anti-coagulation are unlikely to be performed in this rare subtype, thus increased awareness and consideration of VTE prophylaxis in high risk patients is warranted.
Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.
Authors: Rachael Hagen, Joanna Amy Kolodney, Jessica Patterson, Michael Kolodney
Journal: Journal of Clinical Oncology (2019)

e21063 Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G &gt; A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G &gt; A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.
Metabolomics Profiling before, during, and after the Beijing Olympics: A Panel Study of Within-Individual Differences during Periods of High and Low Air Pollution
Authors: Lina Mu, Zhongzheng Niu, Rachael Hageman Blair, Han Yu, Richard W. Browne, Matthew R. Bonner, Tiffany Fanter, Furong Deng, Mya Swanson
Journal: Environmental Health Perspectives (2019)

Background: The metabolome is a collection of exogenous chemicals and metabolites from cellular processes that may reflect the body's response to environmental exposures. Studies of air pollution and metabolomics are limited. Objectives: To explore changes in the human metabolome before, during, and after the 2008 Beijing Olympics Games, when air pollution was high, low, and high, respectively. Methods: Serum samples were collected before, during, and after the Olympics from 26 participants in an existing panel study. Gas and ultra-high performance liquid chromatography/mass spectrometry were used in metabolomics analysis. Repeated measures ANOVA, network analysis, and enrichment analysis methods were employed to identify metabolites and classes associated with air pollution changes. Results: A total of 886 molecules were measured in our metabolomics analysis. Network partitioning identified four modules with 65 known metabolites that significantly changed across the three time points. All known molecules in the first module (n=33) were lipids (e.g., eicosapentaenoic acid, stearic acid). The second module consisted primarily of dipeptides (n=24, e.g., isoleucylglycine) plus 8 metabolites from four other classes (e.g., hypoxanthine, 12-hydroxyeicosatetraenoic acid). Most of the metabolites in Modules 3 (19 of 23) and 4 (5 of 5) were unknown. Enrichment analysis of module-identified metabolites indicted significantly overrepresented pathways, including long- and medium-chain fatty acids, polyunsaturated fatty acids (n3 and n6), eicosanoids, lysolipid, dipeptides, fatty acid metabolism, and purine metabolism [(hypo) xanthine/inosine–containing pathways]. Conclusions: We identified two major metabolic signatures: one consisting of lipids, and a second that included dipeptides, polyunsaturated fatty acids, taurine, and xanthine. Metabolites in both groups decreased during the 2008 Beijing Olympics, when air pollution was low, and increased after the Olympics, when air pollution returned to normal (high) levels. https://doi.org/10.1289/EHP3705
Association between primary tumor site, perioperative CEA ratio, smoking status, and overall survival in patients with colorectal cancer.
Authors: Thomas A Odeny, Nicole Farha, Hannah Hildebrand, Jessica Allen, Wilfred Vazquez, Maximillian Martinez, Anwaar Saeed, Anup Kasi
Journal: Journal of Clinical Oncology (2019)

e15156 Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, CEA ratio, smoking status and overall survival (OS) among patients with CRC. Methods: We analysed 323 patients who underwent resection for CRC at KUMC. After excluding those without pre- or post-operative CEA data, 162 patients were classified as either high ( &gt; = 0.5) or low ( &lt; 0.5) ratio. Primary outcomes were: 1) OS stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether the association between CEA ratio and OS differed by tumor location, after adjusting for stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 63 years (inter-quartile range 53-72), 61% male, 43% smokers, 73% left-sided tumors, median pre-operative CEA was 3.0 (IQR 1.5-7), and 64% had CEA ratio &gt; = 0.5. The OS rates were 85.7% and 91.9% in patients with left-sided vs right-sided tumors respectively (log-rank p-value = 0.9). The OS rates were 83.5% and 91.5% in patients with high vs low CEA ratios respectively (log-rank p-value = 0.3). The effect of CEA ratio on OS was significantly different when stratified by tumor location (p-value for interaction &lt; 0.001). However, in the stratified analysis, the n was too small to permit further inferential analysis. In multivariate analysis, both tumor location (HR 0.6; p = 0.5) and CEA ratio (HR 1.5; p = 0.5) were not significantly associated with OS after adjusting for smoking status and tumor stage. Smoking was significantly associated with higher rates of death (HR 3.9; p = 0.04) when adjusted for tumor location, CEA ratio, and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left vs right warrants validation in a larger cohort as our sample size was limited. Smoking increases mortality irrespective of right vs left sided CRC.
Real-world evidence of male breast cancer (BC) patients treated with palbociclib (PAL) in combination with endocrine therapy (ET).
Authors: Cynthia Huang Bartlett, Jack Mardekian, Michelle Yu-Kite, Matthew James Cotter, Sindy Kim, Jaclyn Decembrino, Tamara Snow, Kenneth R. Carson, Jillian Motyl Rockland, Albert L. Kraus, Keith D. Wilner, Norihiko Oharu, Patrick Schnell, Dongrui (Ray) Lu, Jennifer Tursi
Journal: Journal of Clinical Oncology (2019)

1055 Background: The rarity of BC in men limits the feasibility of randomized clinical studies in this population. Treatment guidelines recommend that men with BC be treated similarly to postmenopausal women. PAL, a cyclin-dependent kinase 4/6 inhibitor, is used in men with metastatic BC (mBC) in real-world clinical practice, presenting an opportunity to utilize real-world evidence to enable healthcare providers to assess novel agents in this space. Methods: Two parallel approaches were taken. In the first approach, pharmacy and medical claims data from IQVIA Inc were retrospectively analyzed to describe the treatment patterns and duration of PAL + ET (aromatase inhibitor or fulvestrant) compared to ET in men with mBC. The second approach was a retrospective analysis of data derived from electronic health records in the Flatiron Health database to understand real-world clinical response to PAL + ET vs ET alone. Median duration of treatment (mDOT) was estimated by the Kaplan-Meier method. Results: Between Feb 2015 and Apr 2017, 12.9% (147/1139 [IQVIA dataset]) of men receiving treatment for mBC were prescribed PAL + ET for any line of therapy. The mDOT in the first-line setting was numerically longer in the PAL cohort (n=37) compared with the non-PAL cohort (n=214; 8.5 vs 4.3 mo, respectively). In particular, mDOT in the first-line setting was longer with PAL + letrozole (LET; n=26) than with LET alone (n=63; 9.4 vs 3.0 mo, respectively). In the Flatiron Health dataset between Feb 2015 and July 2017, the real-world maximum response rate in the PAL + ET cohort across all lines of therapy in the mBC setting (n=12) was 33.3% (2 complete responses [CR], 2 partial responses [PR]) vs 12.5% (0 CR, 1 PR) for the ET alone cohort (n=8). Conclusions: The real-world data sources used in this study support that men with mBC derive clinical benefit from the addition of PAL to ET. Given the challenges of conducting randomized clinical trials in men with mBC, noninterventional, real-world evidence data appear to be useful to delineate the benefit of such therapies in this setting. Funding: Pfizer.
Clinical benefit and prices of cancer drugs in the United States and Europe.
Authors: Kerstin Noëlle Vokinger, Thomas J Hwang, Ariadna Tibau Martorell, Thomas J Rosemann, Aaron S Kesselheim
Journal: Journal of Clinical Oncology (2019)

6638 Background: Given rising cancer drug costs, Medicare recently proposed to tie some US drug prices to average prices paid by comparable countries. To understand the potential scope of this policy, we assessed differences in cancer drug prices in the US and selected European countries. We also evaluated the correlation between drug prices and their clinical benefit, as measured by two value frameworks: the American Society of Clinical Oncology Value Framework v2 (ASCO VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale v1.1 (ESMO-MCBS). Methods: We identified all new drugs for adult solid and hematologic cancers, approved by the FDA from 2009-2017 and that have also been approved by the EMA by December 31, 2018. US average sales prices (and if not available, wholesale acquisition costs) were extracted as of February 1, 2019, and compared to comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland. ASCO VF and ESMO-MCBS scores were assessed for pivotal trials supporting solid tumor drugs; in case of multiple trials, we focused on the highest score. Consistent with the developers of the rating scales, “high benefit” was defined as scores of A-B (neo/adjuvant setting) and 4-5 (palliative setting) on the ESMO-MCBS scale and scores≥45 on the ASCO VF. Linear regression models and non-parametric Kruskal-Wallis test and were used to assess the association between drug prices and benefit scores. Results: The study cohort included 63 drugs approved by the FDA and the EMA during the study period. 46 (73%) were approved for solid tumors, and 17 (27%) were approved for hematologic malignancies. Overall, median cancer drug prices in included European countries were 52% (interquartile range: 37-72%) lower than US prices. There was no statistically significant association between monthly treatment cost and ASCO-VF or ESMO-MCBS scores in any country. There was also no association between price differential between US and median European drug prices and either ASCO-VF (P = 0.599) or ESMO-MBCS (P = 0.321) scores. Conclusions: Cancer drug prices in the US were significantly higher than in the compared European countries. Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries.
Prediction of lesion shrinkage using CT imaging with radiomic and deep learning approaches.
Authors: Junshui Ma, Rongjie Liu, Gregory V. Goldmacher, Richard Baumgartner
Journal: Journal of Clinical Oncology (2019)

e14592 Background: Radiomic features derived from CT scans have shown promise in predicting treatment response (Sun et al 2018, and others). We carried out a proof-of-concept study to investigate the use of CT images to predict lesion-level response. Methods: CT images from Merck studies KEYNOTE-010 (NCT01905657) and KEYNOTE-024 (NCT02142738), were used. Data from each study were evaluated separately and split for training (80%) and validation (20%) in each study. A lesion was classified as “shrinking” if ≥30% size reduction from baseline was seen on any future scan. There were 2004 (613 shrinking vs. 1391 non-shrinking) and 588 (311 vs. 277) lesions in KN10 and KN24, respectively. 130 radiomic features were extracted, followed by random forest to predict lesion response. In addition, end-to-end deep learning was used, which predicts the response directly from ROIs of CT images. Models were trained in two ways: (1) using pre-treatment baseline (BL) only or (2) using both BL and the first post-treatment image (V1) as predictors. Finally, to evaluate the predictive power without relying on initial lesion size, size information was omitted from CT images. Results: Results from the KN10 and KN24 are summarized in Table. Conclusions: The results suggest that the BL CT images alone have little power to predict lesion response, while BL and the first post-baseline image exhibit high predictive power. Although a substantial part of the predictive power can be attributed to change in ROI size, the predictive power does exist in other aspects of CT images. Overall, the radiomic signature followed by random forest produced predictions similar to, if not better than, the deep learning approach. [Table: see text]
Triple-negative (TNBC) metastatic breast cancer (MBC) patients (pts): Is chemotherapy (CHT) choice influenced by adjuvant (adj) treatments? Results from the GIM-13 AMBRA study.
Authors: Giorgio Mustacchi, Paolo Pronzato, Grazia Arpino, Alessia D'Alonzo, Michela Piezzo, Clara Natoli, Andrea Milani, Alessandra Bologna, Livio Blasi, Sabino De Placido, Lucrezia Diodati, Alessandra Beano, Emanuela Romagnoli, Marina Elena Cazzaniga
Journal: Journal of Clinical Oncology (2019)

e12549 Background: TNBC shows a very bad prognosis: median time to relapse is 18 months and median overall survival (OS) is less than 24 months. Methods: AMBRA is a longitudinal cohort study, describing the choice of 1st- and subsequent treatments in HER2-ve MBC pts in the years 2012-2015. The present analysis is focused on TNBC pts (127 out of 879 evaluable; 14.4%) and CHT strategies, overall and according to adj treatment. Kaplan Meyer probability of survival from primary (DFS), 1st (PFS 1 ) and 2nd (PFS 2 ) progression and Time from last CHT and death were calculated for the whole population and according the main adj regimens. Results: Median age at primary diagnosis was 53 years. The most used regimens in the adj setting were anthra/taxane(tax) 50.7%, anthra 22.1% or others (CMF included) 20.6%). Median time to events was: DFS 23.2, PFS 1 6.5 and PFS 2 4.3 months, respectively. CHT choices in the metastatic setting according to adj treatment were: Conclusions: Our results show that taxanes play a crucial role in MBC even if used in 50% of Adj. CAPE/VRL, Platinum regimens and Eribuline are also widely used. Time from last CHT administration and Death is very short in 30% of cases[Table: see text]