tbuckley/cabot-search huggingface dataset:
BRAFv600e mutated gliomas: From biology to radiology and treatments.
Authors: Benoit Lhermitte, Eric Guerin, Agathe Chammas, Izzie Jacques Namer, Guillaume Gauchotte, Stephane Kremer, Gaelle Roques, Marie Pierre Chenard, Monique Dontenwill, Natacha Entz-Werle
Journal: Journal of Clinical Oncology (2019)

e13552 Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. Methods: We studied retrospectively a monocentric cohort of 12 LGGs and 9 HGG with BRAFv600e positivity. The patients were aged from 1 to 47 years. Most of the LGG were under 25 years and only 3 patients with HGGs had less than 18 years old. We focused on extended biology assessment by Next generation sequencing of the tumors and their relapses, tumor metabolomics analyses, radiology comprising MRI, PET-scanning and spectroscopy and correlate them to tumor’s evolution and its treatment. Results: Among the LGGs, we had 9 GG and 3 pilocytic astrocytomas and only one had a CDKN2A deletion and one a gain on chromosome 5. 6 had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapeutic treatment after partial surgery and underwent relapses. All HGGs had a surgical resection followed by chemotherapy (mainly Stupp protocol) and radiotherapy. 5 relapsed rapidly, benefit from targeted therapy with vemurafenib and are still in long term remission. In this HGG group, we had two subgroups: 4 patients with “de novo” tumors and 5 patients with a past history of LGG tumors in the same brain region. Both were responding well to targeted treatments and all had an additional CDKN2A deletion. Specific radiological and spectroscopic signs were linked to those two groups and seem to be associated to a specific metabolomic profile in each group. Currently, we are going further in the correlation between MAPK signaling pathway and metabolomic profile to be able to predict in LGG their potential evolution. Conclusions: BRAF mutated gliomas seem to have specific radiological and metabolomic correlations associated to their biology
Postoperative radiotherapy in resected sinonasal mucosal melanoma.
Authors: Li Zhou, Chuanliang Cui, Bin Lian, Xuan Wang, Zhihong Chi, Lu Si, Xinan Sheng, Yan Kong, Lili Mao, Xieqiao Yan, Bixia Tang, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e21059 Background: Mucosal melanoma is rare but highly aggressive. Sinonasal melanoma comprised approximately 26% of the whole mucosal melanoma. Complete surgery plus postoperative radiotherapy is often recommended for early-stage sinonasal melanoma patients. However, the role of postoperative radiotherapy is still disputable. Methods: Mucosal melanoma patients with stage I-III sinonasal primaries which were completely resected were enrolled as part of the multicenter, randomized, controlled, phase 3 trial for the comparison of adjuvant chemotherapy (TMZ plus DDP 6 cycles) with high-dose interferon (HDI, 1 year) (NCT03435302). Postoperative radiotherapy was recommended in the trial for their own choice, prescribed as GTV 60-70Gy/CTV 60Gy/30f. Patients were divided into two groups, those who completed adjuvant radiotherapy after surgery (group S+R, n = 41) and those who received surgery alone (group S, n = 32). Results: Seventy three patients were enrolled from Feb 2014 to Jun 2016. Two groups were balanced regarding to age, gender, and adjuvant therapy of either HDI or chemotherapy. There are more locally advanced patients in Group S, namely T3-4 or N positive ( P= 0.001). At a median follow-up of 31.2 months (range: 5.3-60.0m), the median RFS was not reached in the S+R group, as compared with 17.1 months (95% CI: 2.3-31.9m, P= 0.008) in the S group. The median DMFS was 27.2 months (95% CI: 19.3-35.1m) in the S+R group, as compared with 24.8 months (95% CI: 13.9-35.7m, P= 0.475) in the S group. Patients in the S group had an increased probability of locoregional recurrence as a first event (46.7% vs. 14.6%), while patients in the S+R group are more likely to have metastases first (41.5% vs. 12.5%). Estimated OS was 46.8 months in the S+R group and 37.3 months (95% CI: 20.8-53.8m, P= 0.097) in the S group. T&amp;N staging also had an influence on RFS, DMFS, and OS. In COX multivariate analysis, T&amp;N staging was the only significant prognostic factor. Common toxicities included mucositis, dermatitis, nausea, and leukopenia. Conclusions: This study suggested that postoperative radiotherapy improved local-regional control rate and might had no effect on DMFS. OS was better in radiotherapy group but still mostly depends on T&amp;N staging. More prospective data are needed for this subtype of melanoma. Clinical trial information: NCT03435302.
Prognosis and chemosensitivity of non-V600E BRAF mutations in metastatic colorectal carcinoma (mCRC): An AGEO French multicenter retrospective cohort.
Authors: Aline Derosiere, Vincent Nicolai, David Malka, Astrid Pozet, Julien Lazartigues, Anthony Turpin, David Tougeron, Thomas Walter, Pascal Artru, Jean-Baptiste Bachet, Jean Marc Phelip, Come Lepage, Astrid Lievre, Morgane Caulet, Emmanuelle Norguet, Nelson Lourenco, Romain Coriat, David Sefrioui, Julie Dremaux, Vincent Hautefeuille
Journal: Journal of Clinical Oncology (2019)

3575 Background: BRAF mutations are present in 5-15% of mCRC. V600E BRAF mutations account for ~80% of cases and are mostly found in right-sided tumors. Non-V600E BRAF mutations are rare (~2% of mCRC), mostly left-sided. Although BRAF V600E mutations are associated with a dismal prognosis, some studies suggest that non-V600E BRAF mutations may be associated with a favorable outcome. The chemosensitivity of non-V600E BRAF-mutated mCRC has never been studied. Methods: From 2017 to 2018, all consecutive patients (pts) with non-V600E BRAF-mutated mCRC (next generation sequencing) treated in the participating centers were included. Survival analyses were performed using Kaplan-Meier method and LogRank test. Results: A total of 108 pts in 34 centers in France were included between October 2017 and August 2018 (median age, 66 years [range, 58-77]; ECOG performance status 0-1, 86%). The primary was mostly left-sided (66%). Main metastatic sites were the liver (73%), lungs (33%), lymph nodes (39%) and peritoneum (26%). D594 (34%), G469 (15%), K601 (11%), N581 (7%) and L597 (7%) were the most frequent mutations. A concomitant RAS mutation was found in 22% of pts. Microsatellite instability (MSI) was found in 3/67 pts (4.5%). First-line chemotherapy (CTx) (n = 69) efficacy was (overall response rate/disease control rate) 49%/77% (anti-EGFR-containing CTx [n = 20], 75%/85%; antiangiogenic-containing CTx [n = 22], 55%/73%). Median overall survival (mOS) was 25.6 months (95% CI : 17.1-43.8) overall; it was 8.0 months with best supportive care alone (n = 10), 16.0 months with palliative CTx alone (n = 63), and attained 105.1 months with curative-intent management of metastases (n = 35). mOS did not differ according to sidedness (p = 0.22), type of mutation (p = 0.52), or its functional impact on BRAF (p = 0.19). Conclusions: Non-V600E BRAF-mutated mCRC retain sensitivity to CTx + biologics and harbor a good prognosis (especially when amenable to curative-intent surgery), regardless of the type of mutation and its impact on BRAF kinase function. Contrarily to BRAF V600E mutations, non-V600E mutations may occur along with RAS mutations, but uncommonly with MSI.
Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.
Authors: Sean Matthew McBride, Michael J. Zelefsky, Daniel Eidelberg Spratt, Channing Judith Paller, Marisa Kollmeier, Susan F. Slovin, Jahan Aghalar, Jason W.D. Hearn, Robert Benjamin Den, Curtiland Deville, Han Xiao, Wassim Abida, Howard I. Scher, Dana E. Rathkopf
Journal: Journal of Clinical Oncology (2019)

e16563 Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or &gt; 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( &lt; 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.
A comparison of adjuvant therapy approaches for patients with early-stage uterine serous carcinoma.
Authors: Katherine Kurnit, Silvana Pedra Nobre, Bryan M. Fellman, David A Iglesias, Kristina Lindemann, Ane Gerda Zahl Eriksson, Beyhan Atasevan, Gretchen Elizabeth Glaser, Jennifer Jean Mueller, Pamela T. Soliman
Journal: Journal of Clinical Oncology (2019)

5517 Background: Uterine serous carcinoma is a less common subtype of endometrial cancer that is associated with poorer survival. The optimal post-operative adjuvant treatment strategy for these patients remains uncertain. Methods: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher’s exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free survival (RFS) and overall survival (OS). Results: 634 patients were included. 77% of patients had Stage IA disease, 42% showed no myometrial invasion. The majority had pure serous histology (72%) and LVSI (76%). Adjuvant treatment varied: 12% received no adjuvant therapy, 7% had chemotherapy alone, 51% had cuff brachytherapy, 12% had cuff brachytherapy with chemotherapy (cuff/chemo), and 19% underwent pelvic radiation (EBRT). Complete RFS and OS data were available for 607 and 609 patients, respectively, and the median follow-up time was 58 months. As compared with patients who received no adjuvant therapy, patients who received cuff or cuff/chemo had improved RFS (cuff: HR 0.70, p = 0.02; cuff/chemo HR 0.53, p = 0.01) and OS (cuff HR 0.56, p = 0.001; cuff/chemo HR 0.48, p = 0.01). In a direct comparison, patients with cuff/chemo had better RFS and OS than those with chemotherapy alone (RFS HR 0.52, p = 0.03; OS HR 0.50, p = 0.05). There were no differences in RFS or OS for women who received chemotherapy alone or EBRT. Improved survival with cuff and cuff/chemo persisted on multivariable analyses (included age, stage, LVSI, adjuvant therapy type); additionally, EBRT was also associated with improved OS. In analyses limited to patients without myometrial invasion, patients with cuff or cuff/chemo had improved RFS and OS compared with observation alone. Conclusions: The use of adjuvant cuff brachytherapy with and without chemotherapy was associated with improved RFS and OS in patients with early stage uterine serous carcinoma.
THU0257 DIAGNOSTIC PERFORMANCE OF 2002AECG, 2012ACR AND 2016ACR/EULAR CLASSIFICATION CRITERIA FOR SJÖGREN’S SYNDROME IN A HISPANIC POPULATION
Authors: Nicolás Alfaro, Janett Carmen Riegatorres, Cesar Vidal Solis, David Vega Morales, Dionicio Ángel Galarza-Delgado, Jesús Mohamed Noriega, Karim Mohamed Noriega
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Primary Sjögren's syndrome (pSS) has several classification criteria, whose diagnostic performances vary depending on the studied population<sup>1</sup>. Concordance and differences among these criterias should be evaluated for independent populations to determine the diagnostic performance. <h3>Objectives:</h3> To compare the performance among 3 classification criteria for pSS and determine the level of concordance among them. <h3>Methods:</h3> Descriptive, retrospective, and cross-sectional study including 172 patients from the Rheumatology Service of the Hospital Universitario "Dr. José Eleuterio González", who were studied for dry syndrome. The clinical criterion of the attending physician was considered as the gold standard for diagnosis. Different parameters were collected: presence of xerostomia, xerophthalmia, Schirmer's test, sialometry, ocular staining, ANA, anti-Ro/SSA and anti-La/SSB antibodies, RF isotypes (IgA, IgM, IgG), and focal lymphocytic infiltrate in minor salivary gland biopsy. The criteria proposed by the American European Consensus Group (AECG), ACR and, ACR/EULAR were used to evaluate the classification. Compliance was determined for each set of criteria. <h3>Results:</h3> Sociodemographic characteristics and clinical manifestations are shown in Table 1. For the AECG, ACR, and ACR/EULAR criteria, the sensitivity was 89.1%, 98.9% and 88% and the specificity was 93.8%, 71.3%, and 96.3%, respectively (Table 2). The ACR/EULAR criteria have an adequate level of agreement (k=0.663, <i>P</i>&lt;0.001) with those of the AECG and with respect to the ACR criteria a moderate level of agreement (k=0.561, <i>P</i>&lt;0.001). AECG: American European Consensus Group criteria; <h3>Conclusion:</h3> In our population, the ACR criteria showed the highest sensitivity, while the ACR/EULAR criteria showed the highest specificity, showing a moderate level of agreement. Despite the validation of these criteria, its application in real life tests its performance according to the population studied. <h3>References:</h3> [1] Tsuboi, H., et al. (2017). Comparison of performance of the 2016 ACR-EULAR classification criteria for primary Sjögren's syndrome with other sets of criteria in Japanese patients. Annals of the Rheumatic Diseases, 76(12), 1980?1985. https://doi.org/10.1136/annrheumdis-2016-210758. <h3>Disclosure of Interests:</h3> None declared
Influence of post-resection time to chemotherapy in pancreatic adenocarcinoma on overall survival.
Authors: Stephen Abel, Richard White, Suzanne Schiffman, Kenneth Williams, Shyam Thakkar, Dulabh K. Monga, Gene Grant Finley, Mohammed Islam, Alexander V. Kirichenko, Rodney E Wegner
Journal: Journal of Clinical Oncology (2019)

e15791 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity for distant spread. To date, surgery remains the only potentially curative treatment option; which has traditionally been followed by adjuvant chemotherapy. Past research from the pancreatic literature as well as other disease sites has shown conflicting outcomes as it relates to timely delivery of adjuvant chemotherapy. We thus used the National Cancer Database (NCDB) to evaluate time to initiation of chemotherapy following pancreatic resection and if there was any correlate with outcome. Methods: We identified patients diagnosed with stage 1-3 pancreatic adenocarcinoma in the NCDB, excluding those with stage IV disease, those treated nonoperatively, with adjuvant or neoadjuvant chemotherapy or radiotherapy and those with unknown or inadequate ( &lt; 3 months) follow-up. Receiver operator curve analysis identified an interval of 66 days as associated with outcome. Multivariable logistic regression analysis identified variables associated with increased time to chemotherapy postoperatively ( &gt; 66 days). Propensity matching was done to account for indication bias. Overall survival (OS) was compared between both propensity-matched groups receiving earlier and postponed chemotherapy post-resection, with an additional breakdown by stage. Results: In total, 6,873 and 3,348 patients received chemotherapy before and after the 66 day cutoff, respectively. Predictors of expedited chemotherapy included lower comorbidity, treatment outside a community program in an urban location, having insurance, Caucasian race and treatment after 2009. Median overall survival was 21.8 months for all patients and of these, 6462 were stage 1. 5-year OS was 20% in patients receiving chemotherapy within 66 days and 18% in those not (p = 0.0266). In stage 1 patients, 5-year OS was 23% versus 21% (p = 0.0116) in favor of expedited chemotherapy. In stage 2 patients, 5-year OS was 16% in both arms (p = 0.7231). Higher stage and comorbidity score, treatment at a community cancer program, lower salary, increased time from surgical resection to chemotherapy, higher grade, positive margins, and more distant year of treatment were associated with worse prognosis. Conclusions: The present propensity-matched analysis showed a significant benefit to earlier delivery of chemotherapy in the adjuvant setting, with the largest benefit seen in stage 1 patients.
DUTRENEO Trial: A phase II randomized trial of DUrvalumab and TREmelimumab as NEOadjuvant approach in muscle-invasive urothelial bladder cancer (MIBC) patients prospectively selected by immune signature scores.
Authors: Enrique Grande, Félix Guerrero, Javier Puente, Isabel Galante, Ignacio Duran, Javier Fuentes, Teresa Alonso-Gordoa, Javier Burgos, Albert Font Pous, Oscar Buisan, Alvaro Pinto, Mario Alvarez-Maestro, Oscar Reig Torras, Pablo Maroto, Xavier Garcia del Muro, Patricia Galvan, Nuria Malats, Aleix Prat, Francisco X. Real, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2019)

TPS4588 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by cystectomy improves overall survival in patients (pts) with MIBC. Immune checkpoint inhibitors as single agents are approved in pts with advanced UC. Combination of both programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoints might be synergistic. Durvalumab (DU) is a selective, engineered, human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (TRE) is an anti-CTLA-4 mAb of the lgG2 isotype. Pembrolizumab and atezolizumab, have shown a promising activity (including significant pathologic complete responses (pT0)) in MIBC pts candidate to cistectomy, with better results in those pts with PD-L1 overexpression. It is expected that the dual targeting of the immune system with an anti-PDL1 + antiCTLA4 such as DU and TRE in the neoadjuvant setting may improve these outcomes. In addition, the most precise selection of pts according to a molecular INF-gamma signature is intended to increase the efficacy. Methods: This is a prospective and randomized phase II, open-label study conducted in urothelial MIBC pts diagnosed of T2-T4 and/or N+ candidates to cystectomy, ECOG 0-1 and adequate organ function. Pts will be treated according to the score of a pro-inflammatory signature (PIS) determined with Nanostring technology. Pts with a low PIS will receive standard cisplatin-based neoadjuvant therapy (22 pt). Pts with a high PIS will be randomized 1:1 to receive cisplatin-based neoadjuvant therapy (22 pt) or DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles (22 pt). If more than 8 responses (pT0) are observed in first 22 pts included in DU+TRE arm, 24 additional pts will be recruited in this arm. Primary objective is to assess the antitumor activity of DU+TRE measured as pT0 rate in pts with a positive PIS. Disease free survival and safety profile will be also evaluated. Tissue, plasma and urine samples will be collected for translational studies. Clinical trial information: NCT03472274.
Preclinical study of PD-0332991 on EBV-positive NPC cell lines and xenografts.
Authors: Zhichao Xue
Journal: Journal of Clinical Oncology (2019)

e17506 Background: Originated from nasopharynx, nasopharyngeal carcinoma is a subtype of head and neck cancer, which is consistently associated with EBV infection. It is prevalent exclusively in south of China, Malaysia and southeast Asia. Previously, there was only one EBV positive cell line, c666-1, for NPC study, the new EBV positive cell lines and xenografts established by our lab recently represent better models for preclinical drug test. The objective of this preclinical study is to evaluate the therapeutic effect of specific CDK4/6 inhibitor PD-0332991 in our new established EBV positive NPC cell lines and Xenografts. Methods: Cell lines were cultured in both 2D and 3D condition, cytotoxic test was conduct by Resazurin in 2D and by cell titer-glo in 3D. Cell cycle was analyzed by Western blot and flow cytometry. In the animal study, PD-0332991 was first used as single drug administrated to xenograft mice daily by oral gavage. Secondly, SAHA as a HDAC inhibitor was used to combine with PD-0332991 in this study, which was i.p. injected into animal every other day. Tumor size, body weight well as micro-pets scan data was recorded. The data from each experiment was analyzed by ANOVA and unpaired t-test for significant drug responses. Results: PD-0332991 was first identified to be effective during in vitro study. Beside single drug effect, when combination with SAHA, a synergistic effect was observed both in vitro and in vivo. In single drug study, PD-0332991 can significantly inhibit tumor growth in 3 of our xenografts (XENO76: P &lt; 0.0001, XENO32: P &lt; 0.0001, XENO23: P = 0.0019). In combination study, through tumor size and micro-pets scan, combination treatment induced significant decrease in tumor size and tumor metabolism states in animal models compare to vehicle, PD-0332991 and SAHA treatment. Conclusions: PD-0332991 is identified to be effective in our preclinical test by using our new established EBV positive cell lines and xenografts, this could be a promising treatment for NPC patients after clinical trial.