tbuckley/cabot-search huggingface dataset:
Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC): Cohort A of the phase 1b/2 KEYNOTE-365 study.
Authors: Evan Y. Yu, Christophe Massard, Margitta Retz, Ali Tafreshi, Joan Carles, Peter Hammerer, Peter C.C. Fong, Neal D. Shore, Anthony M. Joshua, Mark David Linch, Howard Gurney, Emanuela Romano, Marinela Augustin, Josep M. Piulats, Helen Wu, Charles Schloss, Christian Heinrich Poehlein, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

5027 Background: Individual activity with pembro or olaparib has been observed in mCRPC pts who progressed on second-generation hormone therapy (HT) and chemotherapy. Data from cohort A (pembro+olaparib) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts with mCRPC who progressed within 6 mo before screening, were docetaxel-pretreated (up to 1 other chemotherapy permitted) for mCRPC and had ≤2 second-generation HTs were eligible. Pts received pembro 200 mg IV Q3W+olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points: ORR per RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate, rPFS, and OS. Results: Median (95% CI) follow-up was 11 (6-15) mo. 41 pts initiated treatment (median age, 69 y; visceral disease, 42%; RECIST-measurable, 68%; homologous recombination deficient detected, 0%). Efficacy is outlined in the table. Treatment-related AEs occurred in 39 (95%) pts; most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs occurred in 21 (51%) pts. There were 2 deaths; 1 was treatment-related (cause unknown). Conclusions: Pembro+olaparib had activity in pts with mCRPC who were molecularly unselected and were previously treated with docetaxel and second-generation HT. The observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]
Food allergy endotype with high risk of severe anaphylaxis in children—Monosensitization to cashew 2S albumin Ana o 3
Authors: Lukasz Blazowski, Pawel Majak, Ryszard Kurzawa, Piotr Kuna, Joanna Jerzynska
Journal: Allergy (2019)

Abstract Background Food allergy in children can be life‐threatening. Component‐resolved diagnostics approach to food anaphylaxis is rarely assessed in children. The aim of the study was to identify the food allergen components as the triggers responsible for severe anaphylaxis, with regard to characteristics and associated risks, among children in a large, population‐based setting. Methods Two hundred and seventy‐one children who were hospitalized due to systemic allergic reaction (SAR) and food anaphylaxis were recruited. Medical history was assessed, and culprit allergen source and anaphylaxis severity grade were established. Specific IgE to 112 allergen components using multiplex ImmunoCAP ISAC immunoassay and specific IgE to hazelnut, Cor a 14, and cashew, Ana o 3, using singleplex ImmunoCAP immunoassay were determined. Results We analyzed data from 237 SAR/anaphylaxis in 237 children. Trigger at allergen component level was defined for every episode. The most common triggers of SAR/anaphylaxis were seeds (50.6%), among them, the storage proteins. Anaphylaxis triggered by Ana o 3, 2S albumin from cashews (aOR = 15.0; 95% CI: 3.27 to 73.47); Tri a 19 from wheat (aOR = 9.93; 95% CI: 1.73 to 56.97); and Cor a 9 from hazelnut (aOR = 6.53; 95% CI: 1.16 to 36.72) had the worst clinical presentation including cardiovascular and severe respiratory symptoms (grade IV‐V vs I‐III in Cox scale). Thirteen out of 237 (5.5%) SAR/anaphylaxis patients were triggered by Ana o 3. Almost 82% of patients with severe Ana o 3 anaphylaxis were sensitized only to this component and had no concomitant food sensitization. Conclusion Monosensitization to Ana o 3 is, irrespective of other parameters, connected with high risk of severe anaphylaxis.
Factors associated with twenty-year (y) risks of breast cancer-specific mortality (BCSM) in the Surveillance, Epidemiology, and End Results (SEER) Registry.
Authors: Jose Pablo Leone, Carlos Teodoro Vallejo, Michael J. Hassett, Julieta Leone, Rachel A. Freedman, Sara M. Tolaney, Bernardo Amadeo Leone, Nancy U. Lin, Eric P. Winer
Journal: Journal of Clinical Oncology (2019)

540 Background: Most reports describing the risk of late relapse in breast cancer have been based on selected patients (pts) enrolled into clinical trials. The aims of this study were to report on population-based long-term risks of BCSM, and the risks of BCSM conditional on having survived 5 y. Additionally, we aimed to identify factors associated with late deaths from breast cancer. Methods: Using SEER data, we identified women with breast cancer (T1-T2, N0-N2, M0) between 1990-2005, with one primary cancer in their lifetime, and known hormone receptor (HR) status. We used Kaplan-Meier analyses to determine the effect of baseline variables on cumulative risks of BCSM, we estimated annual rate of events per 100 person-years, and performed Cox regression stratified by HR status. Results: We included 202,080 pts (median follow-up = 12.25 y). Of all breast cancer deaths, the proportion after 5 y was 65% for HR+ vs 28% for HR- (p &lt; 0.001). The table shows risks of BCSM by HR and N status, and annual event rates. The cumulative risk of BCSM in y 5-20 ranged from 7.9% in HR-N0 to 38% in HR+N2. Among HR+ pts, adjusted risks of BCSM conditional on having survived 5 y were higher for T2 vs T1a (Hazard ratio [HzR] 3.3, p &lt; 0.001), N2 vs N0 (HzR 3.5, p &lt; 0.001), age at diagnosis (dx) &gt; 64 y vs &lt; 50 y (HzR 1.4, p &lt; 0.001), black race vs white (HzR 1.3, p &lt; 0.001) and grade III vs I (HzR 2.3, p &lt; 0.001). For HR- pts, adjusted risks of BCSM conditional on having survived 5 y were higher for T2 vs T1a (HzR 2.0, p &lt; 0.001), N2 vs N0 (HzR 2.8, p &lt; 0.001) and age at dx &gt; 64 y vs &lt; 50 y (HzR 1.6, p &lt; 0.001). Conclusions: For HR+ breast cancer, risks of BCSM remain high beyond 5 y from dx and depend on T-N status, age, race and grade. In HR- breast cancer, the risk of BCSM is highest within 5 y from dx; however, risks beyond 5 y are still considerable and depend on T-N status and age. Our results underscore the need for better adjuvant therapies in both HR+ and HR- breast cancer. [Table: see text]
CALGB 90203 (Alliance): Radical prostatectomy (RP) with or without neoadjuvant chemohormonal therapy (CHT) in men with clinically localized, high-risk prostate cancer (CLHRPC).
Authors: James Andrew Eastham, Glenn Heller, Susan Halabi, Paul Monk, Steven K. Clinton, Russell Zelig Szmulewitz, Jonathan Coleman, Martin Gleave, Christopher P. Evans, David W. Hillman, Himisha Beltran, Mary-Ellen Taplin, Olwen Mary Hahn, J Kellogg Parsons, Eric Jay Small, James Mohler, Michael J. Morris
Journal: Journal of Clinical Oncology (2019)

5079 Background: Neoadjuvant CHT followed by RP did not increase 3-year biochemical progression free-survival (bPFS) compared to RP alone in men with CLHRPC. However, there is evidence that bPFS and overall survival over time was improved. In the current analysis we assessed whether CHT followed by RP improved pathological specimen features compared to RP alone. Methods: CALGB 90203 (Alliance) is a Phase III study which randomly assigned, in a 1:1 fashion, men with CLHRPC [biopsy Gleason Grade Group (GGG) 4 or 5 or Kattan pre-op nomogram bPFS &lt; 60%] to RP alone or RP plus neoadjuvant CHT [androgen deprivation plus docetaxel (75 mg/m 2 every 3 weeks for 6 cycles)]. We conducted an exploratory analysis comparing histologic findings, determined at the treating center, in the RP specimens of men receiving CHT plus RP and men treated with RP alone. We used the Chi-square test, with P-values adjusted by the Holm method for multiple comparisons. Results: A total of 788 men (median age, 62; range: 32-83 years) were randomized, with 738 ultimately undergoing RP. There was no difference in pathologic GGG (Table). Men treated with neoadjuvant CHT had a lower pathologic T-stage and lower likelihood of having seminal vesicle invasion (SVI), positive pelvic lymph nodes, or positive surgical margins (SM) (Table). Conclusions: Most pathologic features in the RP specimen were improved in men receiving neoadjuvant CHT compared to RP alone. The relationship between pathologic changes and the development of metastasis and survival require further analysis. RP pathologic outcomes. Summary statistics are calculated for the number of patients with non-missing data for each characteristic. Clinical trial information: NCT00430183. [Table: see text]
First-line stereotactic radiosurgery combined with systemic targeted and immune checkpoint inhibitor therapy in melanoma patients with newly diagnosed brain metastases.
Authors: Thatcher Ross Heumann, Peter Wu, Rebecca Ye, Alexandra Sansosti, Akram Habibi, Marc Kryger, Cameron Beaudreault, Kenneth Bernstein, Joshua Seth Silverman, Jeffrey S. Weber, Anna C. Pavlick, Douglas Kondziolka
Journal: Journal of Clinical Oncology (2019)

e13577 Background: Of solid tumors, melanoma has the highest propensity for central nervous system spread with historic median survivals of 5-8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. Results: Among 123 newly diagnosed MBM patients:65% were male, 24%were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis . Locally, 73% received SRS as first-line treatment.Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With median follow up of 11 months (mo), totalcohort median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS) when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS) when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither systemic therapy. SRS and BRAF targeted therapy were associated with improved OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant prognosticators for OS.At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. Conclusions: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line brain radiosurgery combined with BRAF targeted therapies and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM.
Correlation between <i>NDRG1</i> gene polymorphism and neuropathy (N) in metastatic breast cancer (MBC) patients (pts) enrolled in the PAINTER study (Polymorphism And INcidence of Toxicity in ERibulin treatment).
Authors: Nicla Maria La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Giulio Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro Stefano Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Barbara Bocci, Gabriella Farina
Journal: Journal of Clinical Oncology (2019)

3116 Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m 2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]
Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.
Authors: Matthew Dyer, Matthew Green, simon jones, Rachel Hodge
Journal: Journal of Clinical Oncology (2019)

e20560 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.
Detection of brain metastasis by metabolomics methods in metastatic breast cancer patients.
Authors: Özge Özer, Emirhan Nemutlu, Cemil Can Eylem, Sedef Kır, Tuba Reçber, Burak Yasin Aktas, Ayse Kars, Sercan Aksoy
Journal: Journal of Clinical Oncology (2019)

e12572 Background: The aim of this study was to identify markers for the early diagnosis of brain metastasis by metabolomic methods in breast cancer patients. Methods: A total of 88 breast cancer patients with distant metastases were included the study. The patients were divided into two groups according to their metastasis status as patients with brain metastases and patients with distant metastases without any brain metastases. For metabolomic analyses, liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) and gas chromatography mass spectrometry (GC-MS) analysis methods were used. Results: 88 patients were included the study. 33 of the 88 patients had brain metastasis group and 55 patients had distant metastases without brain metastasis. A total of 79 metabolites were identified by the GC-MS analysis. Of these, 11 of them (alanine, sphingosine, fructose, fumaric acid, glycine, lactic acid, phenylalanine, pyroglutamic acid, serine, threonine, and valine) were found at statistically significantly higher levels in the patient group with brain metastases (p &lt; 0.05). In LC-qTOF-MS analysis 47 metabolites were identified with statistically significant results between the two groups. Predictive accuriecies for idendification of the brain metastasis with 5 and 10 metobolites models were 94.6% and 95.2%, respectively.Amino acyl tRNA biosynthesis, arginine and proline metabolism, nitrogen metabolism, cyanaminoacid metabolism, nicontic and nicotinicamide metabolism, glycine, serine and threonine metabolism pathways have been involved more significantly in patients with brain metastasis (p &lt; 0.05). Conclusions: Although these results need to be confirmatory prospective studies, these data promising for early detection of the brain metastasis by markers in sera.
The rate of tumor growth, g, as a biomarker for overall survival (OS) in prostate cancer (PC) in clinical trials as well as in real-world data from the Veterans Administration Medical Centers (VAMCs).
Authors: Harshraj Leuva, Mengxi Zhou, Julia Wilkerson, Keith Sigel, Ta-Chueh Hsu, David Henry Aggen, Erik Langhoff, Yeun-Hee Anna Park, Susan Elaine Bates, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2019)

5074 Background: Novel assessments of efficacy are needed to improve determination of treatment outcomes in clinical trials and in real-world settings. Methods: Cancer treatments usually lead to concurrent regression and growth of the drug-sensitive and drug-resistant fractions of a tumor, respectively. We have exploited novel methods of analysis that assess these two simultaneous processes and have estimated rates of tumor growth ( g) and regression ( d) in over 30,000 patients (pts) with diverse tumors. Results: In prostate cancer (PC) we have analyzed both clinical trial and real-world data from Veterans. Using clinical trial data from 6819 pts enrolled in 15 treatment arms we have established separately and by combining all the data that g correlates highly (p&lt;0.0001) with overall survival (OS) – slower g associated with better OS. In PC, abiraterone (ABI) and docetaxel (DOC) are superior to placebo, prednisone and mitoxantrone. ABI (median g =0.0017) is superior to DOC ( g=0.0021) in first line (p=0.0013); and ABI in 2 nd line ( g=0.0034) is inferior to ABI in 1 st line ( g=0.0017; p&lt;0.0001). Finally, using combined clinical trial data as a benchmark we could assess the efficacy of novel therapies in as few as 30-40 patients. Amongst 7457 Veterans, the median g on a taxane ( g=0.0022) was similar to that from clinical trials ( g=0.0012). Although only 258 Veterans received cabazitaxel (CAB), g values for CAB ( g=0.0018) and DOC ( g=0.0023) were indistinguishable (p=0.3) consistent with their identical mechanism of action. Finally, outcomes with DOC in African American (AA) ( g=0.00212) and Caucasian ( g=0.00205) Veterans were indistinguishable (p=0.9) and comparable across all VAMCs. Conclusions: The rate of tumor growth, g, is an excellent biomarker for OS both in clinical trials and in real-world settings. g allows comparisons between trials and for large trial data sets to be used as benchmarks of efficacy. Real-world outcomes in the VAMCs are similar to those in clinical trials. In the egalitarian VAMCs DOC efficacy in PC is comparable in AA and Caucasian Veterans -- indicating inferior outcomes reported in AAs are likely due to differential health care access, not differences in biology.
Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.
Authors: Ian M. Silverman, Karthikeyan Murugesan, Christine F. Lihou, Luis Féliz, Garrett M. Frampton, Robert C Newton, Hiroomi Tada, Lee A. Albacker, Timothy C. Burn
Journal: Journal of Clinical Oncology (2019)

4080 Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/ FRS2 (5.8%), and BRAF (4.7%). FGFR2: BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10 -13 , Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.