bluuebunny/crossref_metadata_2025_split huggingface dataset:
Follow-up of patients with complete remission of locally advanced basal cell carcinoma treated with vismodegib after treatment discontinuation: A retrospective multicentric French study.
Authors: Herms Florian , Haudebourg Luc , Bagot Martine , Dutriaux Caroline , Grob Jean Jacques , Guillot Bernard , Jeudy Geraldine , Lambert Jérôme , Lebbe Celeste , Mateus Christine , Meyer Nicolas , Monestier Sandrine , Mortier Laurent , Poulalhon Nicolas , Prey Sorilla , Robert Caroline , Vabres Pierre , Mouri Mehdi , Basset-Seguin Nicole 
Published: September 2018

9535 Background: Vismodegib is a Hedgehog Pathway inhibitor (HPI) indicated for treatment of inoperable locally advanced basal-cell carcinoma (laBCC). Previous studies showed an objective response (OR) rate of 67%, including 34% of complete response (CR). Discontinuation of vismodegib is very frequent, mostly due to intolerable side-effects. Long-term response and predictive factors of relapse after suspension of vismodegib have not yet been evaluated, but should play a crucial role in the management of laBCC patients. Methods: We conducted an observational retrospective study in 9 onco-dermatological French units. Medical charts of laBCC patients treated with vismodegib from March 2012 until June 2016 were reviewed and patients with CR who stopped treatment were selected. Relapse was diagnosed clinically and/or histologically. A survival analysis was conducted, and predictive factors, characterization and management of relapse were studied. Results: 119 laBCC patients achieved CR and stopped treatment. 21 were lost to follow-up and 6 died before relapse. Event-free survival median was 18.4 months (12.1 – 24.1) and cumulative incidence of relapse at 36 months was 59.04% (48.05 - 70.04), implying that more than 40% of patients do not relapse. Multiple BCC and BCC not localized on the head and neck were associated with a higher risk of relapse, independently of the existence of Gorlin syndrome (HR = 3.3 (IC95 = 1.6 - 6.7) and 2.01 (IC95 = 1.05 - 3.87) respectively). Total duration of treatment was not associated with relapse. 50% (n = 27) of patients who relapsed during follow-up were retreated with vismodegib, with an OR of 85.2% (n = 23). 42% (n = 24) were eligible to surgery only and other patients received local treatments. Conclusions: Long term responders after vismodegib treatment discontinuation are frequent independently of the time exposure to the drug before and after CR. Most patients who relapse are still responder to vismodegib rechallenge. Patients with multiple or laBCC not localized on the head and neck are more at risk of relapse after discontinuation. This study emphasizes the interest of treatment of laBCC with HPI.
Association of concomitant use of acid reducing agents in full-dose vemurafenib users with risk of progression in BRAF V600 mutation-positive unresectable or metastatic melanoma patients: A retrospective cohort study.
Authors: Knapen Lotte Marieke , Koornstra Rutger H.T. , Driessen Johanna H.M. , Van Vlijmen Bas , Croes Sander , Schalkwijk Stein J. , Colbers Angela , Gerritsen Winald , Burger David , de Vries Frank , Van Erp Nielka P. 
Published: September 2018

9540 Background: Vemurafenib is used for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The approved fixed vemurafenib dose of 960 mg twice daily may result in overexposure. Concomitant use of acid reducing agents (ARAs) may result in underexposure. Both situations are likely to affect treatment outcome. Therefore, the aim of this study was to determine the association between the use of vemurafenib (full-dose versus reduced dose) and/or concomitant ARA use (yes versus no) and the risk of disease progression. Methods: A retrospective cohort study was conducted using data from the electronic health record software of the Radboudumc pharmacy and medical records of the Radboudumc (March 17th 2012 to March 17th 2016). Patients (N = 112) using vemurafenib as first line treatment for melanoma were included. Multivariable cox regression estimated adjusted hazard ratios (HRa) and 95% confidence intervals (CI) of progression in vemurafenib users (full-dose N = 67 versus reduced dose N = 45) and/or concomitant ARA users (N = 38). Adjustments were made for age and sex. Results: The mean follow-up time was 3.5 months and 41 patients (36.6%) developed progression on first line vemurafenib. Co-treatment of ARAs in patients using full-dose vemurafenib was associated with a 4.6-fold increased risk of progression (HRa 4.56; 95% CI 1.51-13.75) as compared to full-dose vemurafenib users not co-treated with ARAs. No increased risk was found for users of vemurafenib in a reduced dose, regardless of concomitant ARA use. Conclusions: Concomitant use of ARAs in full-dose vemurafenib users was associated with an increased risk of progression. Physicians should be cautious to prescribe ARAs to patients tolerating full-dose vemurafenib. The presence of considerable confounding by disease severity, the small number of events and the hypothesis generating character of this study emphasize the need to prospective validate these results.
Outcomes of patients with melanoma who discontinue immunotherapy.
Authors: Rosner Samuel , Bogatch Kita , Postow Michael Andrew 
Published: September 2018

9548 Background: The question of when to discontinue (d/c) anti-program death-1 (PD-1) monotherapy (mono) or nivolumab in combination with ipilimumab (combo) immunotherapy (IT) is unknown. Methods: After IRB approval, a single center (Memorial Sloan Kettering Cancer Center), retrospective study was performed of 162 pts with unresectable stage III or IV melanoma treated with either mono (n = 106) or combo (n = 56) IT. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were calculated for all pts from the 1stdose of IT. For pts (n = 40; mono and n = 40; combo) who d/c IT due to reasons (Table) other than progression or death, starting from the last date of IT, we then reported PFS, time to treatment failure (TTF) defined as any subsequent surgery/radiation/systemic therapy, and OS. Results: For pts that were alive at time of analysis, the median follow up was 28 mos. For all 162 pts (demographics in Table), ORR was 38.7% (mono) and 60.7% (combo); median PFS and OS were 12 months (mos) and 25 mos for mono; 34 mos and not reached (NR) for combo, respectively. From the last dose of IT, the PFS, TTF, and OS for 40 mono pts and 40 combo pts who d/c IT for reasons other than progression/death are shown in Table. Reasons included CR, toxicity, or other (most commonly protocol completion or prolonged PR). Conclusions: Outcomes in this cohort of pts with long follow-up treated with mono or combo IT are similar to results from other clinical trials. Pts who d/c IT for reasons other than progression/death were a highly selected group. Nonetheless, favorable PFS, TTF, and OS were seen after IT d/c, even in pts who did not obtain a CR. [Table: see text]
A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.
Authors: Boutros Celine , Mateus Christine , Lanoy Emilie , Routier Emilie , Chouaib Salem , Schwob Dominique , Vagner Stephan , Girault Isabelle , Caramella Caroline , Hibat Salima , Tao yun Gan , Cao Kim , Chaput Nathalie , Adam Julien , Soria Jean-Charles , Eggermont Alexander M. , Deutsch Eric , Robert Caroline 
Published: September 2018

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.
Analysis of mutational burden and adaptive immune response in desmoplastic melanomas treated with PD-1/L1 inhibitors.
Authors: Hu-Lieskovan Siwen , Eroglu Zeynep , Zaretsky Jesse Meir , Kim Dae Won , Algazi Alain Patrick , Johnson Douglas Buckner , Liniker Elizabeth , Kong Ben , Munhoz Rodrigo , Rapisuwon Suthee , Chmielowski Bartosz , Sosman Jeffrey Alan , Scolyer Richard A. , Joseph Richard Wayne , Postow Michael Andrew , Carlino Matteo S. , Hwu Wen-Jen , Long Georgina V. , Ribas Antoni 
Published: September 2018

9558 Background: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by a dense fibrous stroma, resistance to chemotherapy and no actionable driver mutation for targeted therapy. We investigated the efficacy of PD-1/L1 inhibitors and correlation with genetic landscape and tumor immune microenvironment in DM. Methods: Retrospective analysis of 1054 pts with melanoma treated with anti-PD-1/L1, resulting in 57 pts with unresectable or metastatic DM. Available baseline biopsies were analysed by digital quantitative immunohistochemistry (IHC) for CD8 and PD-L1 and by whole exome sequencing (WES), compared to available tissue from non-DM pts treated with anti-PD1/L1 at UCLA. Results: At a median follow up of 20 mo, 40 pts (70%, 95% CI 57-82) had an objective response by RECIST 1.1 criteria, including 18 (45%) CRs with no relapse observed to date. Responses were similar in DM subsets (23 pure, 29 mixed and 5 indeterminate). Kaplan-Meier estimated 1-year and 2-year overall survival were 85% (95% CI 78-98) and 74% (95% CI 64-89). WES revealed a median of 1282 (interquartile range 517-1692) non-synonymous somatic mutations per tumor in DM tumors (n = 17), significantly higher (p = 0.02) than the median of 462 (interquartile range 230-1150) in non-DM (n = 23). Mutations in NF-1 were the most common (13/17) followed by loss-of-function TP53 and ARID2, and > 82% of single nucleotide mutations were UV damage signatures. IHC analysis from 19 DM and 13 non-DM revealed a strikingly higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with CD8 density and PD-L1 expression in the tumor invasive margins, indicating an active adaptive immune response. No genetic mechanisms known to cause constitutive PD-L1 expression were detected in these samples. Conclusions: Patients with advanced DM derive significant clinical benefit from PD-1/L1 inhibitors, likely related to the high mutational burden and a highly active adaptive immune response as the main mechanism of immune escape prior to therapy. Our results challenge the general conception that dense fibrous stroma around the malignant cells interferes with immune cell infiltration and efficacy of immunotherapy.
Mutation burden as a potential prognostic marker of melanoma progression and survival.
Authors: Simpson Danny , Ferguson Robert , Martinez Carlos N. , Kazlow Esther , Moran Una , Heguy Adriana , Hanniford Douglas , Hernando Eva , Osman Iman , Kirchhoff Tomas 
Published: September 2018

9567 Background: Recently, tumor mutation burden (TMB) has been shown to increase the presentation of neoantigens that stimulate immune tumor recognition, resulting in improved immunotherapy (IT) outcomes in melanoma and other cancers. As melanoma is highly immunogenic, here we tested whether TMB associates with immune recognition during tumor progression, hence impacting melanoma overall survival (OS), independently of IT treatment. Methods: We have generated somatic mutation data from 314 IT-naive metastatic melanomas from The Cancer Genome Atlas (TCGA). In the TCGA cohort, TMB has been calculated for 210 genes (200GS) previously established from TMB studies of anti-CTLA4 and anti-PD1/PD-L1 IT. For validation, we have sequenced exonic regions of 20 genes (20GS) with the highest TMB among 200GS in 89 IT-naive metastatic melanomas ascertained at New York University Langone Medical Center. The TMB was defined using total number of somatic, non-synonymous mutations in either 200GS (TCGA discovery) or 20GS (validation), respectively. For discovery and validation cohorts, OS from primary diagnosis of samples with high TMB was compared against low TMB, using thresholds established in previous studies. Results: We found that total TMB predicts better OS (p = 0.03, HR = 2.64) in TCGA melanomas. Restricting the analysis only to the established 200GS, this association became more significant in all patients (p = 0.01, HR = 2.67) as well as in patients without IT (p = 0.01, HR = 2.67). In the validation stage of 89 melanomas without prior IT treatment, a high TMB in a subset of 20GS accurately determined favorable OS (p = 0.02, HR = 2.69) and confirmed TCGA observations from the 200GS. Conclusions: Here we show, for the first time, that in addition to IT, high TMB predicts more favorable OS in patients that never received IT, potentially serving as a novel marker of prognosis of melanoma and likely other immunogenic tumors at early stages. In addition, our study suggests that TMB test can be robust when applied to only a small subset of genes that trigger significantly higher immunogenicity. This may also eventually assist with accurate sub-selection of early stage patients likely to respond to IT regimens.
Investigation of the immune infiltrate of melanoma metastases under immune checkpoint inhibition.
Authors: Hassel Jessica Cecile , Flossdorf Michael , Hänzelmann Sonja , Winkler Julia , Roth Jasmin , Lauenstein Claudia , Appel Lena , Streit Enrico , Halama Niels , Faryna Marta , Enk Alexander , Offringa Rienk , Sahin Ugur , Poschke Isabel 
Published: September 2018

9570 Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the number of CD8+ TILs in pretreatment samples of responders and non-responders. Instead, the number of CD4 + TILs including regulatory T cells (Treg) and the number of PD-1 + cells was higher in responders especially when receiving pembrolizumab. Samples taken at least 6 weeks after start of the immune checkpoint blocker showed a significant higher number of immune cells in responders through all T cell subsets (CD3,4,8,FoxP3, PD-1), B cells (CD20) as well as macrophages (CD68, CD163). TCR repertoire profiling by deep TCR sequencing demonstrated that responders develop a more diverse repertoire under treatment (p = 0.05). Pretreatment samples as well as the size of the top 10 TCR clones posttreatment did not differ significantly in responders and non-responders. By RNA sequencing no differential expression profiles between responders and non-responders was found pretreatment. Posttreatment samples expressed different genes compared to pretreatment samples in responders including MHC molecules, CDK2/4, Myc, TNF family members and different apoptosis-inducing genes. There was no differential gene expression in non-responders pre- and posttreatment. Conclusions: Pretreatment metastases from responders and non-responders do not differ much. With treatment responding patients have significant higher numbers of immune cells including T- and B- cells as well as macrophages and develop a more diverse TCR repertoire. RNA sequencing revealed a differential expression pre- versus posttreatment only in responding patients.
Molecular and immune predictors of response and toxicity to combined CTLA-4 and PD-1 blockade in metastatic melanoma (MM) patients (pts).
Authors: Chen Wei-Shen , Andrews Miles Cameron , Spencer Christine , Tawbi Hussein Abdul-Hassan , Lazar Alexander , Tetzlaff Michael T. , Patel Sapna Pradyuman , Hwu Patrick , Hwu Wen-Jen , Diab Adi , Glitza Isabella Claudia , Amaria Rodabe Navroze , Burton Elizabeth M. , Woodman Scott Eric , Davies Michael A. , Gershenwald Jeffrey E. , Sharma Padmanee , Allison James Patrick , Futreal Andrew , Wargo Jennifer Ann 
Published: September 2018

9579 Background: Combined treatment with ipilimumab and nivolumab (Ipi/Nivo) achieves clinical responses in > 50% of mm pts. However, responses are not universal and toxicity may be limiting, thus biomarkers of response and toxicity are needed to optimize and personalize this therapy. Methods: Tumor biopsies were collected before (n = 29) and on treatment (n = 7) from mm pts (n = 40) treated with Ipi/Nivo. Whole exome sequencing (WES), gene expression profiling, TCR sequencing, and immunohistochemistry (IHC) were performed to define molecular and immune features of the tumors. Radiographic responses in patients were assessed via RECIST 1.1criteria, and patients were classified as responders (R) deriving clinical benefit (with SD, PR, CR) and non-responders (NR) not deriving clinical benefit (PD). Toxicity was also scored, with patients dichotomized into low toxicity ( < grade 2) versus high toxicity ( > grade 3) re: immune-related (IR) toxicities. Results: In this cohort, the response rate was 80%, with 53% of patients experiencing > grade 3 toxicity. There was no significant difference in baseline mutational load in responders (R) vs non-responders (NR) to Ipi/Nivo, but NR had a higher burden of copy number alterations (CNA; p = 0.013), with frequent alterations detected in PTEN, JAK2, and B2M. There were no significant differences in baseline CD8+ T cell density, expression of immune-related genes, or T cell clonality for R vs NR pts. Ipi/Nivo treatment increased intratumoral T cell clonality, but this did not correlate with response. A more diverse peripheral T cell repertoire at baseline was detected in pts who developed IR toxicity (p < 0.05). Conclusions: This data suggests that responses to Ipi/Nivo in mm may occur in the absence of high mutational load or brisk immune infiltrate at baseline. Putative mechanisms of resistance to Ipi/Nivo include high burden of CNA and alterations in PTEN, JAK2, and B2M. Together these studies identify candidate biomarkers of resistance and toxicity for Ipi/Nivo, though they need to be tested in larger cohorts and across cancer types.
Patient/oncologist decisions about adjuvant chemotherapy in ER+ve, HER2-ve early breast cancer following endopredict testing.
Authors: Bloomfield David J , Arbon Amy , Cox Jane , Hack Berkin , Hall Julia , Harper-Wynne Catherine , Hinde Sebastian , Jenkins Val , Mackay James , Matthews Lucy A , May Shirley F , Moss Adrian , Patel Gargi Surendra , Simcock Richard , Thanopoulou Eirini , Westwell Sarah , Wlaszly Dominika , Fallowfield Lesley 
Published: September 2018

e12002 Background: Endopredict is a multigene test including tumor size and nodal status; it predicts low or high risk of distant recurrence in patients (pts) with ER+ve, HER2–ve breast cancer treated with adjuvant endocrine therapy alone. We compared adj chemotherapy decisions pre and post Endopredict test results, pts’ anxiety, decisional conflict and oncologists’ (oncs) confidence about decisions made. Methods: 14 oncs in 8 UK hospitals saw 149 pts judged by clinical teams to have equivocal indications for chemotherapy. Pts and oncs discussed provisional treatment decisions based on conventional prognostic factors. Initial decisions were reconsidered when Endopredict results were available. Pre and post-test pts completed Spielberger’s State/Trait Anxiety inventory (STAI) and a decision conflict scale (DCS). Oncs answered questionnaires probing:- basic demographic,/clinical details, agreement with, and confidence about treatment decisions (endocrine (E) therapy +/- chemotherapy(C)) Results: 66.7% pts with an initial E alone decision and a high risk result upgraded to E+C. 9.4% pts with initial E+C decisions and high risk results down-graded to E. None of 46 pts initially favouring E alone who were low risk changed decisions. 82.8% who initially wanted E+C and had low risk scores downgraded to E alone. Endopredict results increased oncs’ confidence (8% ‘strongly agreed’ pre-test, 50% post-test). Oncs neither agreeing nor disagreeing with decisions fell (24% to 5%). Anxiety was stable in pts with unchanged decisions. Pts whose therapy was downgraded had significantly lower anxiety scores (p<0.01); those whose treatment was upgraded had increased scores (p<0.001). Likewise overall uncertainty on DCS fell post-test (p<0.023) Conclusions: Endopredict results increased oncs’ and pts’ decision-making confidence, improved matching of risk with therapy decisions and thus a potential for improved outcomes. Clinical trial information: ISRCTN69220108. [Table: see text]