tbuckley/cabot-search huggingface dataset:
Early reduction in circulating tumor DNA (ctDNA) and survival in gastric cancer patients (pts) treated with durvalumab (D), tremelimumab (T), or durvalumab in combination with tremelimumab (D+T).
Authors: Philip Z. Brohawn, Brandon W. Higgs, Michael Kuziora, Judson Englert, Koustubh Ranade
Journal: Journal of Clinical Oncology (2018)

e15027 Background: Mutation variant allele frequencies (VAFs) in ctDNA indicate the frequency of cancer clones harboring the specific variant in the primary lesion and metastases, providing a surrogate for tumor burden. We previously reported that early reduction in ctDNA VAF was associated with improved survival on durvalumab in NSCLC and UC pts from a phase 1/2 study of D monotherapy. Here we performed similar analyses in gastric cancer pts treated with D, T, or D+T. Methods: This is a multicenter, open-label, phase 1b/2 study evaluating safety and clinical activity of D, T, and D+T in metastatic or recurrent gastric or gastro-esophageal junction adenocarcinoma in second- and third-line settings. 89 pts were enrolled. A 73-gene panel measured DNA variants using the Guardant360 cancer panel in plasma ctDNA from 72 gastric pts pre-treatment and 31 pts pre and 9 weeks on-treatment. Treatment arms were combined to demonstrate associations of changes in VAF with clinical response. Mean VAF and total mutation count of pt single nucleotide variants (SNVs) and insertion/deletions were correlated with clinical outcomes. ORR was calculated according to RECIST v1.1. Cox proportional hazards ratios (HR) were calculated while adjusting for age, sex, ECOG, line of therapy, and treatment arm. Results: Partial responders (PRs) showed a decrease (Δ = -10.05%, p = 0.26) in VAF post-treatment compared to a significant increase in mean VAF in progressive disease (PD) pts (Δ = +8.14%, p = 0.03). This correlation was also observed in total mutation count in PR (Δ = -6.7, p = 0.17) compared to PD pts (Δ = +2.2, p = 0.06). Pts with a decrease in VAF at week 9 had longer median PFS (5.4 mo [95% CI: 3.7, NR]) and OS (median 13.8 mo [95% CI: 7.0, NR]) compared to those with an increase in VAF (median PFS 1.9 mo [95% CI: 1.8, NR]; HR = 0.33 [95% CI: 0.09, 1.21] and median OS 8.2 mo [95% CI: 6.2, NR]; HR = 0.07 [95% CI: 0.01, 0.66]). Conclusions: CtDNA VAFs were consistently reduced in responders but not non-responders after 9 weeks of therapy. A decrease in VAF following 9 weeks of treatment correlated with longer PFS and OS, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT02340975.
Building an oncology EMR database for outcomes research.
Authors: Joel D. Kallich
Journal: Journal of Clinical Oncology (2017)

e18157 Background: Electronic medical records (EMR) are a resource affording many advantages. As structured data fields grow, unstructured data decreases, the potential number of research questions which can be addressed exponentially increases. Over many years working with oncology practices, we licensed HIPAA compliant EMRs into a common data format, resulting in a data base (DB) of over 1 million patients. Methods: We provide a historical perspective, information, and analysis of successes and challenges encountered working with this data, with suggestions for similar projects. Results: See table below. Conclusions: EMR DBs will be the big data sources for the analysis of cancer treatment in the US, including safety surveillance, quality improvement efforts and cost effectiveness research. Careful attention to previous efforts should facilitate adoption of new health information technology to the practice of medicine in oncology. [Table: see text]
Primary sarcomas of the urinary bladder: A comprehensive genomic profiling (CGP) study.
Authors: Robert John Corona, Jeffrey S. Ross, Laurie M. Gay, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, Sugganth Daniel, Jonathan Keith Killian, Eric Allan Severson, Jon Chung, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2018)

e16530 Background: Primary sarcomas of the urinary bladder (Bsarc) represent a rare but highly aggressive genitourinary malignancy. We searched for potential biomarkers for targeted and immunotherapies in Bsarc using comprehensive genomic profiling. Methods: DNA was extracted from 40 microns of FFPE specimen for 14 cases of clinically advanced Bsarc and 1,576 urothelial bladder carcinomas (UCB). CGP was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay to a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) determined by principal components analysis of optimal homopolymer loci. Results: All 14 (100%) Bsarc cases were confirmed on routine histology and featured positive IHC staining for mesenchymal differentiation and negative staining for epithelial differentiation (cytokeratin negative); 2 (14%) Bsarc were malignant GISTs. The 14 Bsarc patients had a median age of 63 years (range 32-77 years) and 7 (50%) were male. All (100%) of the Bsarc cases were high grade tumors. At the time of CGP, all (100%) Bsarc were stage IV. The primary Bsarc was used for sequencing in 9 (64%) cases and a metastasis sample in 5 (36%). The 14 Bsarc featured 3.71 GA/case. The genomics of Bsarc differed significantly from UCB, with higher frequencies of GA in TP53, ATRX, PTEN and KIT for Bsarc tumors. UCB featured higher GA frequencies in FGFR3, and ERBB2 (Table). High TMB was much more common in UCB tumors (9% with TMB > 20 mut/Mb and 31% with TMB > 10 mut/Mb) than Bsarc (7% and 0%, respectively). None (0%) of the Bsarc were MSI-high. Conclusions: The GA seen in Bsarc differ significantly from those seen in UCB. When bladder GIST cases are excluded, targeted therapies opportunities for Bsarc appear limited, in contrast with UCB, and the relatively low TMB and absence of MSI-High status predicts that Bsarc may be resistant to immunotherapies. GA UCB (1,576 cases) Bsarc (14 Cases) Significance TP53 56% 71% NS ATRX 1% 50% P < 0.0001 PTEN 5% 29% P = 0.0046 RB1 20% 21% NS KIT 1% 14% P = 0.01 FGFR3 19% 0% NS ERBB2 16% 7% NS TMB > 10 mut/Mb; > 20 mut/Mb 31%; 9% 7%; 0% NS
Impact of a fully integrated specialty pharmacy on patients’ out-of-pocket cost for oral therapies in a hematology clinic.
Authors: Jeremiah Moore, Kendra Delibert
Journal: Journal of Clinical Oncology (2018)

e18928 Background: Oral therapies have revolutionized the treatment of cancer, providing alternatives to infusion therapies while increasing convenience and outcomes. However, patient financial burden for oral therapies is being recognized as a toxicity of cancer therapy. High cost may limit access to therapies and delay starting treatment. UR Medicine has an on-site specialty pharmacy with fully integrated pharmacists. The pharmacists provide medication education and follow up for adherence, drug-interactions, reasons for missed doses, and adverse events. Additionally, the pharmacy helps to secure financial support for patients through drug manufacturer voucher cards, grants from independent foundations, and internal social work funding. Methods: We conducted retrospective review of oral prescriptions filled at UR Specialty pharmacy for lymphoma, leukemia, or multiple myeloma from January 1st to June 30th 2017. Drug name, dosage, indication, insurance type, and copayment before and after financial assistance were collected. Results: The cohort included 235 patients and over 1000 prescriptions. Medicare patients accounted for 64.7% versus 35.3% which were commercially insured. A total of $331,638.54 in financial assistance was obtained: $35,725.25 from manufacturer voucher cards, $241,586.33 in grants from independent foundations, and $54,326.96 from internal social work funding. Average initial and subsequent copayments were $1,133.52 and $3.18 for Medicare patients and $178.53 and $118.64 for commercially insured patients. After financial assistance, the reduction in cost for medicare patients was 80.4% for the initial and 80.8% for subsequent co-pays and for commercially insured, 89% for initial and 86.6% on subsequent co-pays. Financial assistance was needed in 65.5% of Medicare patients and 34.5% of those with commercial coverage. Conclusions: Out-of-pocket costs for oral therapy can be extremely high with some patients requiring additional support from independent foundations, drug manufacturers, and internal social work funding. An integrated specialty pharmacy can assist patients in obtaining funding to help patients afford their medications.
Phase 1, open-label, adaptive biomarker trial that informs the evolution of combination immuno-oncology (IO) therapies (ADVISE), a precision IO approach to personalized medicine.
Authors: Jason J. Luke, Nilofer Saba Azad, Robin Edwards, Shih-Min A. Huang, Adriana Comprelli, Manish Monga, Timothy P. Reilly, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2018)

TPS3101 Background: Immune checkpoint inhibitor therapies have revolutionized treatment paradigms for numerous tumor types. However, improved understanding of the tumor microenvironment (TME) and tumor immune biology is needed to enhance and extend benefits to more patients. Personalized pairing of IO agents to the immune biomarkers in the TME of individual patients using pretreatment biopsies could transform cancer care, but the feasibility of using biomarkers to study IO combinations in specific patient populations has not been established. The ADaptiVe biomarker trial that InformS Evolution of therapy (ADVISE; NCT03335540) was designed to assess the clinical feasibility and utility of real-time biomarker data to allow specific IO agents in combination with nivolumab to be selected for individual patients across various tumor-specific cohorts. Methods: Approximately 50 patients with selected solid tumors will initially be enrolled. Patients must be ≥ 18 years of age, have an ECOG PS ≤ 1, and have had ≥ 1 prior therapy. Prior IO therapy is permitted; however, patients will not be assigned to receive an IO regimen containing an agent directed against the same target (aside from PD-[L]1). Treatment selection will be driven by biomarker analyses in pretreatment biopsies. Patients will receive nivolumab in combination with a second IO agent that is implicated in tumor immune escape (lirilumab [anti-KIR], relatlimab [anti–LAG-3], cabiralizumab [anti–CSF-1R], ipilimumab [anti–CTLA-4], BMS-986205 [IDO-1 inhibitor], or BMS-986156 [anti-GITR]) or nivolumab with stereotactic body radiation therapy (for noninflamed tumors). The primary endpoint is the ratio of patients with qualified tumor biopsy specimens at baseline providing sufficient biomarker data and analysis time to guide treatment decisions. Other endpoints include safety, preliminary clinical activity, and biomarker analyses. Clinical trial information: NCT03335540.
Clinicopathological characteristics compared between primary effusion lymphoma and human herpesvirus 8 (HHV8)-unrelated primary effusion lymphoma-like lymphoma.
Authors: Junghoon Shin, Youngil Koh
Journal: Journal of Clinical Oncology (2017)

e19024 Background: Primary effusion lymphoma (PEL) and human herpesvirus 8 (HHV8)-unrelated primary effusion lymphoma-like lymphoma (PEL-LL) are among the most rare subtypes of non-Hodgkin B-cell lymphoma. Although a few number of case reports and small case series have suggested a better outcome of PEL-LL compared to PEL, systematic comparison of prognosis between PEL and PEL-LL has never been conducted owing to their rare incidence. Methods: We consecutively collected PEL and PEL-LL patients diagnosed between 2000 and 2016 in 10 institutions in South Korea. All patients were cytogically confirmed and received systemic evaluation to exclude detectable tumor formation. Clinicopathological characteristics and prognosis were compared. Results: A total of 12 PEL and 4 PEL-LL cases were analyzed. Median age at diagnosis was 68.5 (range, 40-88) and 68.5 (range, 59-77) for PEL and PEL-LL, respectively. Male-to-female ratio was 7:5 and 3:1 in each group. Pleural effusion was the most common presentation in both groups. One patient in PEL-LL group presented with vitreous fluid containing lymphoma cells. Seven and two PEL patients were treated with CHOP and CVP-based chemotherapy, respectively and 3 did not receive chemotherapy due to poor performance. Three PEL-LL patients were treated with R-CHOP and the remaining 1 patient with malignant vitreous fluid received high dose methotrexate. One PEL patient received autologous hematopoietic stem cell transplantation after second remission and lived over 14 years thereafter. With estimated median follow-up duration of 99.6 and 20.7 months for PEL and PEL-LL respectively, 3 and 1 death occurred during the entire period in each group. Median overall survival was 119.6 and 66.5 months in PEL and PEL-LL group respectively without statistically significant difference. Conclusions: In our study, long-term prognosis of PEL and PEL-LL showed no difference. This result might be attributed to 2 remarkably long-lived patients in PEL group (longer than 174 and 123 months, respectively) and low statistical power owing to the small sample size.
Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling
Authors: Antoine Forget, Loredana Martignetti, Stéphanie Puget, Laurence Calzone, Sebastian Brabetz, Daniel Picard, Arnau Montagud, Stéphane Liva, Alexandre Sta, Florent Dingli, Guillaume Arras, Jaime Rivera, Damarys Loew, Aurore Besnard, Joëlle Lacombe, Mélanie Pagès, Pascale Varlet, Christelle Dufour, Hua Yu, Audrey L. Mercier, Emilie Indersie, Anaïs Chivet, Sophie Leboucher, Laura Sieber, Kevin Beccaria, Michael Gombert, Frauke D. Meyer, Nan Qin, Jasmin Bartl, Lukas Chavez, Konstantin Okonechnikov, Tanvi Sharma, Venu Thatikonda, Franck Bourdeaut, Celio Pouponnot, Vijay Ramaswamy, Andrey Korshunov, Arndt Borkhardt, Guido Reifenberger, Patrick Poullet, Michael D. Taylor, Marcel Kool, Stefan M. Pfister, Daisuke Kawauchi, Emmanuel Barillot, Marc Remke, Olivier Ayrault
Journal: Cancer Cell (2018)
BRAF-mutant non-small cell lung cancer (NSCLC): Patient (pt) characteristics and outcomes by class of mutation.
Authors: Ibiayi Dagogo-Jack, Pablo Martinez, Beow Y Yeap, Chiara Ambrogio, Christine A. Lydon, Tom Nguyen, A. John Iafrate, Jochen K Lennerz, Bruce E. Johnson, Alice Tsang Shaw, Mark M. Awad
Journal: Journal of Clinical Oncology (2018)

9045 Background: BRAF mutations (muts) occur in 2-4% of NSCLC. Recent work suggests that BRAF muts may be grouped into 3 classes: 1) V600 muts that signal as monomers, 2) activating non-V600 muts that function as dimers, and 3) kinase-impaired non-V600 muts that require RAS input. Whether mut class is associated with specific clinicopathologic features or clinical outcome is unknown. Methods: We performed a retrospective analysis of NSCLC pts with BRAF muts treated at Massachusetts General Hospital and Dana-Farber Cancer Institute between 2006 and 2017 to determine clinicopathologic characteristics and estimate overall survival (OS). Results: We identified 237 pts with Stage I-IV BRAF-mutant NSCLC (107 (45%) class 1, 76 (32%) class 2, and 54 (23%) class 3). Most pts were white (85%) smokers (88%) with adenocarcinoma (90%). Smoking status was similar for pts with class 2 and 3 muts (3% vs 6% never-smokers, p = 0.649), but pts with class 1 muts were more likely to be never-smokers (22%; p < 0.001 vs class 2, p = 0.011 vs class 3). The frequency of concurrent RAS (KRAS or NRAS) co-alterations in class 1 was 1%, which was significantly lower than the frequency in class 2 (12%, p = 0.002) and class 3 (24%, p < 0.001). Nine (47%) of 19 kinase-dead tumors had RAS co-alterations. Among 140 pts with metastatic NSCLC, median OS was 40.1 months (mos, n = 69, 95% CI:17.5-56.1) for class 1, 13.9 mos (n = 39, 95% CI:7.4-18.7) for class 2, and 15.6 mos (n = 32, 95% CI 8.9-37.4) for class 3 pts. OS was not different for class 2 and 3 pts (p = 0.591), but presence of a class 1 mut was associated with improved OS (median 40.1 vs 15.6 mos when class 2 and 3 pts were pooled, HR = 0.5,95% CI 0.3-0.8, p = 0.002). When 40 pts who received therapies targeting the mitogen-activated protein kinase pathway were excluded, there was still a trend toward improved OS for class 1 muts (median 39.1 vs 13.9 mos for class 2 and 3 pts; HR = 0.6, 95% CI 0.3-1.0, p = 0.059). Conclusions: Pts with class 2 and 3 BRAF-mutant NSCLC share clinicopathologic features and outcomes that may be distinct from pts with class 1 muts. Our findings highlight the need for therapies that effectively target class 2 and 3 BRAF muts.
Abstract 19607: Impact of Gender on Clinical Outcomes Associated With Subcutaneous Implantable Cardioverter Defibrillators
Authors: Andrea M Russo, Raul Weiss, Stefan Kääb, Sharad Agarwal, Paul Roberts, Martin Burke, Jens Brock Johansen, Bradley P Knight, Angel R Leon, Elizabeth Duffy, Radhika R Tunstall, Pier D Lambiase
Journal: Circulation (2016)

Introduction: Previous studies demonstrate that women experience worse outcomes following transvenous ICD implantation. This analysis compares outcomes of women vs. men undergoing Subcutaneous Implantable Cardioverter Defibrillator (S-ICD) implantation in the two largest S-ICD studies. Methods: The IDE study included 321 patients (enrolled Jan 2010 -May 2011) & EFFORTLESS Registry included 985 patients (enrolled Aug 2009-Dec 2014). Outcomes at 360 days were all major complications, freedom from inappropriate shocks (IAS) & efficacy. Multivariate analysis was performed to identify predictors of complications. Results (see table attached): Women consisted of 26% in IDE and 28% in EFFORTLESS. Women had a higher EF (41 ± 17 vs. 34 ± 15%, p =0.002 and 48 ± 17 vs. 42 ± 18%, p<0.001) and were younger than men (48 ± 16 vs. 53 ± 15y, p =0.008, and 45 ± 16 vs. 50 ± 17y, p <0.001,) in IDE & EFFORTLESS respectively. The 1y KM (Kaplan-Meier) rate of freedom from IAS was 82.5% (F); 89.1% (M), p =0.12 for IDE and 93.3% ...
Genetics of periodontitis: Discovery, biology, and clinical impact
Authors: Arne S Schaefer
Journal: Periodontology 2000 (2018)

This review provides an update on genome-wide association studies in periodontitis. Studies in populations with European ancestry have dominated the landscape of periodontitis genetics studies but, increasingly, studies in Asian populations are being reported. The review also summarizes evidence for suggested associated genetic variations. The loci associated with genome-wide association studies consist of noncoding variations, many of which are predicted to modulate levels of gene expression. In this article, the biological functions of the genes that are nearest to the associations and their implications for disease etiology are also examined. A major challenge in the genetics of periodontitis is identification of the causal variant(s) underlying associations with periodontitis, elucidation of the molecular mechanisms that are potentially affected by the associated variants, and understanding how they contribute to disease phenotypes and traits. This will allow emerging medical initiatives to make clinical use of genetic discoveries. Large collaborative studies, across research centers and across subspecialties and disciplines, will be required to realize the promise of genetic discovery in periodontitis.
Phase ib trial of dose-escalating AZD1775 in combination with concurrent radiation and cisplatin for intermediate and high risk head and neck squamous cell carcinoma.
Authors: Bhishamjit S. Chera, Gaorav P. Gupta, Jared Weiss, Juneko E. Grilley-Olson, Dominic T. Moore, Jose Zevallos, Trevor Hackman, Samip Patel, Adam M Zanation, Mark Christian Weissler, David N. Hayes
Journal: Journal of Clinical Oncology (2016)

TPS6106 Background: Patients with significant tobacco histories (intermediate risk) and those who are HPV negative (high risk) have modest to poor outcomes and have been shown to have more disruptive p53 mutations. AZD1775 is a highly selective oral tyrosine kinase inhibitor of Wee1. Wee 1 inhibits cyclin-dependent kinases (CDK) 1 and 2. When DNA is damaged (e.g. radiation, chemotherapy), Wee1 inhibition is expected to abrogate the G2-M checkpoint leading to premature mitotic entry and consequently cell death. P53-deficient tumors rely more heavily on the G2-M checkpoint and thus may be particularly sensitive to Wee1 inhibition. We hypothesize that AZD1775 in combination with chemoradiotherapy will improve clinical outcomes for patients with intermediate/high risk HNSCC. We are conducting an open label, single arm Phase 1b study (using a traditional 3+3 design) to identify the maximum tolerated dose (MTD) and recommended phase 2 dose of AZD1775 when added to standard of care chemoradiotherapy for the treatment of intermediate/high risk squamous cell cancer of the head and neck. Methods: Eligible patients will have T1-T4, N0-N3, M0 intermediate and high risk HNSCC defined as: primary tumors located in the oral cavity, larynx, or hypopharynx; HPV/p16 negative oropharynx; and HPV/p16 positive with > 10 pack-years smoking history. All patients will receive Intensity Modulated Radiotherapy Treatments as per standard of care. The total dose will be 70 Gy at 2Gy/fx, 35 fractions, Mon to Fri, for 7 weeks. Cisplatin at a dose of 40 mg/m2 IV will be infused day 1 of each week of radiation. AZD1775 will be taken orally twice daily Mon to Wed during the 7 week course of chemoradiotherapy. The starting dose level for AZD1775 is 50mg and escalates in increments of 50 mg for three additional levels (100 mg, 150 mg, and 200 mg). With a maximum of 6 patients enrolled at each dose level, a maximum of 24 patients will be enrolled. The MTD will be determined by the development of dose limiting toxicities 7 weeks of therapy. We will perform correlative studies on archival tissue (p53 mutational status) and mid-treatment biopsies (phosphor-CDK1(Tyr-15) and γH2AX levels). Clinical trial information: NCT02585973.