tbuckley/cabot-search huggingface dataset:
Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): Long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.
Authors: Elena Palassini, Stefano Ferrari, Javier Martin Broto, Paolo Verderio, Antonio Lopez-Pousa, Angela Buonadonna, Rosalba Miceli, Silvia Stacchiotti, Angelo Paolo Dei Tos, Antonino De Paoli, Davide Maria Donati, Andres Poveda, Vittorio Quagliuolo, Alessandro Comandone, Stefano Bottelli, Piero Picci, Paolo Giovanni Casali, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2016)

11045 Background: From 2002 to 2007, we carried out a multicentric Italian/Spanish Phase 3 trial comparing 3 vs 5 cycles of adjuvant CT with full-dose epirubicin + ifosfamide in high-risk STS. A previous Italian randomized study had demonstrated a survival benefit with 5 cycles of the same CT vs nil (JCO 2001;19:1238). The results of this trial were reported (JCO 2012;30:850), with no difference between the two arms in terms of OS and RFS, at a median follow-up (FU) of 5 years. We herein update these results with a longer FU. Methods: Patients were randomized to receive 3 preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same 3 preoperative cycles plus 2 postoperative cycles (Arm B). Radiotherapy (RT) could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary endpoint, OS, was assessed by the confidence interval (CI) of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. Results: Between January 2002 and April 2007, 160 pts were assigned to arm A and 161 to arm B. 158 patients received preoperative RT (77 in Arm A and 81 in Arm B). At a median FU of 116 months (IQ range 102-130 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that 3 cycles were not inferior to 5 cycles (one-sided 95% upper confidence limit was 1.24). A per-protocol analysis confirmed these results. Distant metastases (DM) were observed in 114 patients, 57 in Arm A and 57 in Arm B. The 10-year crude cumulative incidence of DM from surgery was 34.5%, 34.1% in Arm A and 34.8% in Arm B. Conclusions: The updated results of this trial at a longer FU confirm the non inferiority of 3 cycles of a full-dose conventional CT in comparison to 5, with about 60% patients alive and disease-free in both arms at 10 years. This regimen is currently tested prospectively within an ongoing international trial against 3 cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176). Clinical trial information: EudraCT 2004-003979-36.
Cost-effectiveness of nivolumab in advanced renal cell carcinoma.
Authors: Michal Sarfaty, Moshe Leshno, Noa Gordon, Assaf Moore, Victoria Neiman, Eli Rosenbaum, Daniel A. Goldstein
Journal: Journal of Clinical Oncology (2017)

e18338 Background: In recent years, new drugs have been introduced to the second line setting of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting based on the Checkmate 025 study. However, due to nivolumab's high cost there is a need to define its value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab for the second-line treatment of advanced RCC from the US payer perspective. Methods: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus or placebo in the second-line treatment of advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2016. Model robustness was addressed in univariable and probabilistic sensitivity analyses. We addressed the controversial issue of the extensive duration of immunotherapy treatment amongst long term survivors, which may or may not be approved by payers. Results: The total mean cost per-patient of nivolumab versus everolimus was $101,070 and $50,935, respectfully. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) over everolimus and 0.89 LYs (0.96 QALYs) over placebo. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146,532/QALY versus everolimus and $105,232/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to two years lowered the ICER to $121,788/QALY versus everolimus and $96,418/QALY versus placebo. Conclusions: Our analysis established an ICER of $146,532/QALY for nivolumab versus everolimus in second-line advanced RCC treatment.
Whole-exome sequencing to identify HOMEZ mutation as a prognostic marker in esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.
Authors: Hong Lei Luo, Zhao Jing, Rui Fei Xie, Hong Jin Wu, Xiao Yan Zhang, Hong Fang Zhang, Wen Xin Li, Yu Hui Hua, Shi Xiu Wu
Journal: Journal of Clinical Oncology (2017)

e15523 Background: The outcomes of inoperable esophageal squamous carcinoma (ESCC) patients treated with concurrent chemoradiotherapy remain poor. The discovery of novel biomarkers for predicting prognosis could allow for more accurate risk stratification and identification of high-risk patients. Although previous studies have elucidated some genomic alterations could be predictors of survival in these patients, none has focused on comprehensive genetic analysis using high-throughput platforms. Methods: Whole-exome sequencing was done in 96 inoperable ESCC patients treated with concurrent chemoradiotherapy from our phase Ⅲ clinical trial (NCT00686114). The prognostic marker was developed using a Random Survival Forest supervised classification methods based on log-rank splitting rules. The independence of the marker in survival prediction was evaluated by multivariable Cox regression analysis. The marker was further validated for the prognostic utility in an independent cohort (n = 150). The biological function of the genomic alteration was predicted by GO annotations. Results: A HOMEZ mutation (chr14:23744800_ACATCAT/ACAT) was detected in 54.1% of patients with ESCC received concurrent chemoradiotherapy. We identified the mutation was significantly associated with overall survival (hazard ratio [HR] 1.842; 95% confidence interval [CI] 1.080-3.142; P = 0.025) and loco-regional free survival (HR 3.008; 95% CI 1.302-6.947; P = 0.010). Multivariable Cox regression analysis showed that the mutation was also an independent prognostic factors for patients with ESCC (mutation type vs. wild type, overall survival: HR 2.161; 95% CI 1.241-3.764; p = 0·007; loco-regional free survival: HR 3.576; 95% CI 1.509-8.473; p = 0.004). GO annotations showed that HOMEZ tended to be frequently related to transcription factor activity, sequence-specific DNA binding and transcription corepressor activity. Conclusions: HOMEZ mutation is a novel independent prognostic factor for inoperable ESCC patients treated with concurrent chemoradiotherapy, and may be a potential therapeutic target.
Merkel cell carcinoma in Turkey: A multicentric study.
Authors: Fatih Yildiz, Mahmut Büyüksimsek, Teoman Sakalar, Ovgu Aydin, Hande Turna, Nalan Akgul Babacan, Birol Yildiz, Cagatay Arslan, Nuriye Özdemir, Yuksel Urun, Mukremin Uysal, Ozge Gumusay, Gulnihal Tufan, Ferit Aslan, Semra Paydas, Umut Demirci
Journal: Journal of Clinical Oncology (2018)

e21591 Background: Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin. Although it is rare, it can be aggressive. In this study, we aimed to investigate the clinico-pathologic features and survival data of MCC. Methods: Between July 2005 and December 2017, 47 MCC patients in 10 different centers from Turkey were included to the study. Patients data were analyzed retrospectively by the electronic registration system and patient files. Results: Twenty five (53.2%) patients were female and the median age at the diagnosis of MCC was 67 years (range 34–87). Primary tumors were located in extremities (n = 24, 51.1%), head and neck (n = 13, 27.7%), and trunk (n = 9, 19.1%). Immunohistochemically, CK20 positivity was present in 32 patients (68.1%), while CK20 status in seven patients was unknown. Only one patient had malignant lymphoma and was receiving chemotherapy for this disease. Eleven patients (23.4%) were diagnosed with metastatic disease. In the early stage of diagnosis (n = 36), six patients were locoregional and three patients had distant metastases. Surgery was performed for all patients in the early stage and adjuvant radiotherapy was applied in 12 patients. In the metastatic stage, 13 patients received first-line and seven patients received second-line chemotherapy. In the first-line, platinum / etoposide combination was used in all patients whereas in the second-line, the combination of cyclophosphomide / doxorubicin / vincristine (CAV) was the most preferred combination. None of the patients received immunotherapy for metastatic MCC. Median follow-up was 20.2 months (1.7-150.4) and 18 patients (37.5%) were died. In the early stage, nine patients (20.8%) had recurrence and 5 year disease free survival was 66.1% (std err 10.1%). The 5-year overall survival (OS) in all patients was 50.3% (std err 8.9%). Median progression free survival of the patients at the metastatic stage was 7 months (5,1-8,9) and median OS was 16.7 months (%95 Cl:9-24,39). Conclusions: In our study, female gender and extremity involvement were observed more frequently than the literature in patients with MCC. However, recurrence rates and OS were similar to the literature.
PS1 Phase 3 KEYNOTE-042 Study: Pembrolizumab vs Platinum-Based Chemotherapy as 1l Therapy for Advanced NSCLC with a PD-L1 TPS ≥1%
Authors: G. Lopes, Y. Wu, I. Kudaba, D. Kowalski, B. Cho, H. Turna, G. De Castro, V. Srimuninnimit, K. Laktionov, I. Bondarenko, K. Kubota, G. Lubiniecki, J. Zhang, D. Kush, T. Mok
Journal: Journal of Thoracic Oncology (2018)
Clinical presentation of immune-related colitis associated with PD-1 inhibitor monotherapy (MONO) and combination PD-1/CTLA-4 inhibitors (COMBO) in melanoma.
Authors: Daniel Ying Wang, Dae Won Kim, Neil J. Shah, Robert Martin Conry, Rutika Jitesh Mehta, Ann W. Silk, Alice Zhou, Amber L Voorhees, Svetlana B McKee, Jacqueline Norrell, Janice M. Mehnert, Igor Puzanov, Geoffrey Thomas Gibney, Suthee Rapisuwon, Zeynep Eroglu, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2017)

9566 Background: Ipilimumab-related colitis has been well described, but the clinical presentation of colitis related to MONO or COMBO therapy has not. We aimed to characterize clinical features that define this serious adverse event. Methods: This retrospective study included melanoma pts with colitis screened from 6 academic centers treated with either MONO or COMBO therapy. Clinically relevant colitis was defined as diarrhea/colitis symptoms requiring systemic steroids. The onset, management, and outcomes related to colitis were summarized. Results: We screened 866 pts and identified 72 with clinically relevant colitis. For the MONO cohort, the incidence was 3.5% (23/657) and 23.4% (49/209) in the COMBO cohort. MONO-colitis occurred at a median 33 weeks (wks) into therapy, while median onset was 8 wks with COMBO therapy. One pt had grade 5 colitis from COMBO therapy. Despite the use of systemic steroids, COMBO-colitis needed more infliximab therapy (38.8% vs 26.1%). The median prednisone equivalent dose was higher for COMBO therapy (1.5 vs 1 mg/kg), and the median taper was shorter for MONO-colitis (4 vs 6 wks). Steroid dose-escalation for worsening symptoms during taper was more common with COMBO-colitis (42.9% vs 17.3%). Relapse was similar between cohorts (MONO: 26.1%, COMBO: 20.4%). Relapses occurred more frequently in COMBO therapy with tapers shorter than the median (38.1% vs 25.0%), and more frequently in MONO therapy with steroid doses lower than the median (60% vs 21.7%). MONO-colitis pts (17.4%) were less likely than COMBO-colitis pts (46.9%) to be restarted on PD-1 therapy. When restarted, only 13% with COMBO therapy relapsed as compared to 50% with MONO therapy. Objective response rates for MONO and COMBO cohorts were 72.7% and 56.1%, respectively. Conclusions: Colitis occurred with a much higher incidence in COMBO therapy. MONO-colitis was associated with a milder course with later onset, shorter duration and lower dose of steroids, fewer dose-escalations, and need for infliximab as compared to COMBO therapy. Relapse of colitis was generally associated with shorter steroid tapers for COMBO therapy and lower steroid doses for MONO therapy.
Endoglin (CD105) expression in non-seminomatous germ cell tumors.
Authors: Swati Sikaria, Shefali Chopra, Shigang Xiong, Dongyun Yang, Charles P. Theuer, James Hu
Journal: Journal of Clinical Oncology (2017)

e16036 Background: Nonseminomatous germ cell tumors are known for hematogenous spread and new therapeutics are needed. Endoglin (CD105) is a cell-surface protein that is overexpressed on endothelial cells and a potential target for anti-angiogenic therapy. Preclinical studies demonstrate overexpression of CD105 in tumor vasculature and targeting CD105 in murine models have resulted in tumor regression. We examine CD105 expression in tumor cells and tumor vasculature of patients with non-seminomatous germ cell tumor. Methods: Slides of NSGCT were incubated with rabbit anti-human CD105 followed by horseradish peroxidase-labeled anti-rabbit IgG and then with substrate chromogen followed by hematoxylin counterstaining. Human kidney served as positive internal control. Endoglin positivity was assessed in tumor cells and vasculature and graded (0-3+). Results: 37 total samples were obtained, 4 were excluded (3 seminoma, 1 pure teratoma) All 37 specimens had positive endoglin staining in tumor vasculature. Of 33 specimens, 79% (26/33) had positive staining for endgolin, whereas 21% did not (7/33). (Table 1)Of patients with relapsed or refractory disease, 83% (5/6) stained positively for CD105. While this is a small sample size, 3+ staining was seen in 50% of patients (n=6) with relapsed or refractory disease, but vs 18.5% of patients (n=27) in 1 st remission (Fisher’s exact test p =0.14). Conclusions: Endoglin was highly expressed in tumor and tumor vasculature of NSGCT. This small pilot study suggests high (&gt;50%) expression correlating with relapsed or refractory disease. Further samples from patients with relapsed or refractory disease are being collected and analyzed. Endoglin is a potential target for study in non-seminomatous germ cell tumors. [Table: see text]
Prognostic factors for overall survival of patients with head and neck soft tissue sarcoma based on 25 years data from the Netherlands Cancer registry.
Authors: Lotte Ten Thije, Eline Boon, Ingrid Desar, Uta E Flucke, Winette TA van der Graaf, Vincent K.Y. Ho, Carla M.L. Van Herpen
Journal: Journal of Clinical Oncology (2016)

6050 Background: Head and neck soft tissue sarcomas (HNSTS) account for 2% of head and neck cancers. The aim of this research is to establish prognostic factors for overall survival (OS) in patients (pts) with HNSTS in general and dermatofibrosarcoma protuberans (DFSP) in particular. Methods: We retrieved data from the Netherlands Cancer Registry (NCR) on pts diagnosed with HNSTS (WHO classification) from 1989 to 2013, including pts’ vital status. OS was analyzed using univariable and multivariable-adjusted Cox proportional hazards models, for the total group as well as for the subset of surgically treated patients. In the Cox analysis, we used multiple imputations for missing data on tumor grade, size, depth, and resection status. Results: The most common subtypes in the total of 1573 pts were high-grade sarcoma not otherwise specified, leiomyosarcoma and DFSP. Median age of pts was 66 years, the majority was male (64%). The 5-year and 10-year OS were 57% and 43%, respectively. OS did not change over time. The 5- and 10-year OS were 73 and 69% in pts < 18 years (n = 178), 78% and 71 % in pts 18-34 years (n = 152), 72% and 64% in pts 35-64 years (n = 439), and 40% and 20% in elderly ( ≥ 65 years, n = 804), respectively. OS was better for surgically treated pts (5-year: 62% versus 33%, 10-year: 47% versus 24%). Among pts who had surgery (n = 1285, 82%), multivariable analysis on the imputed dataset identified old age ( ≥ 65 years), high tumour grade, presence of metastases at time of diagnosis, and residual disease (R1-2) as independent unfavorable prognostic factors affecting OS. Pts with DFSP of the head and neck (n = 212) had significantly worse OS compared with DFSP in the rest of the body (n = 1458) (p < 0.001) with 10 year OS of 70% versus 92%, respectively. Conclusions: We analyzed the largest population of pts suffering from HNSTS so far. Survival did not improve in 25 years despite improvements in diagnostics and treatments. While prognosis was better for pts who were surgically treated, old age, tumors exhibiting aggressive behavior and incomplete surgery negatively impacted survival in this group. OS of head and neck DFSP was significantly worse compared with the rest of the body.
Predicting tumor evolution through subclonal classification using variant allele frequency clustering in breast cancer.
Authors: Parth Shah, Kamil Rechache, Siddharth Srivastav, Khushbu Patel, Corrine Zarwan
Journal: Journal of Clinical Oncology (2018)

e13084 Background: The treatment of breast cancer is based on assessment of ER, PR and HER2. Previous large studies were limited in subclone identification because of sequencing depth thus masking true tumor complexity and limiting possible modeling of clonal evolution. Methods: 46 breast cancer samples were sequenced via semiconductor sequencing to a mean depth of 1400x using a 52 gene panel analyzing SNVs, multi nucleotide variations and amplifications. Samples were obtained at initial diagnosis from the primary site. Average tumor cellularity was > 50%. All samples were molecularly barcoded prior to amplification to avoid biases. Results: Samples were classified as Her2 negative (Her2-Neg), Her2 equivocal (Her2-Eq) and Her2 enriched (Her2-E). Clonal populations were determined using variant allele frequency clustering. Each sample was noted to have at least 3 different clones. A minimum of 15 mutations per sample were required to make this assessment with a minimum of 3 mutations per clone. Prior data shows a high clonal burden mainly in recurrent or metastatic disease. Interestingly, FGFR mutations were detected in every sample. HER2-E tumors showed a greater mutational burden, but HER2-neg samples had a larger quantity of subclones with putative driver mutations. HER2-Neg driver mutations were mainly seen in PIK3CA, CCND1, and AR. Her2-Neg tumors showed a PIK3CA mutational frequency of 83.3%, Her2-Eq showed a frequency of 60% with Her2-E showing 25%. These are significantly higher percentages than previously documented data and are largely due to the low frequency allele detection. Mutational profiles of FISH classified HER2 Eq and borderline HER2-E( ratio < 3) appear to be largely similar to HER2-neg samples. Conclusions: The detection of likely clonal distributions is possible through algorithmic clustering of mutational frequencies. This may help identify putative driver mutations and subclones in the neoplasm at time of initial biopsy which may allow tracking of mutations through targeted liquid biopsies and formation of multifaceted treatment plans over the course of the disease.
Molecular profiling of tumour and ctDNA in a gastrointestinal cancer cohort at an academic cancer centre
Authors: S. Rack, G. Brady, A. Wallace, M. Galvin, K. Frese, M. Krebs, C. Dive, D. Rothwell, M. Ayub, N. Cook
Journal: Annals of Oncology (2018)

Background: Circulating tumour DNA (ctDNA) can provide a minimally invasive liquid biopsy that may better capture tumour heterogeneity than archival biopsies. We report results of ctDNA and tumour molecular profiling from a gastrointestinal subset of patients recruited to the Tumour characterisation to Guide Experimental Targeted Therapy Trial (TARGET). Methods: 68 patients (pts) with metastatic small bowel cancer (SBC) or colorectal cancer (CRC) were recruited to TARGET between May 2015 and May 2018. Archival biopsies were analysed using a 24 gene NGS panel (Qiagen GeneRead DNAseq Targeted Panel V2) and in some cases a 322 gene NGS panel (Foundation Medicine). Upon recruitment pts underwent further testing with a plasma-based ctDNA NGS assay examining 653 genes. Patients were consented (optional) for pre-clinical model development from fresh blood (circulating tumour cells (CTCs)) and tumour biopsy samples. Results: The median age of pts was 56 (range 32-75). 48% (33/68) were colon tumours, 34% (23/68) rectal, 9% (6/68) rectosigmoid and 7% (5/68) small bowel. Pts had failed an average of 3 lines (range 1-5) of treatment prior to recruitment. 74% (50/68) of patients had both sufficient tumour DNA in their plasma, and archival biopsies for analysis. Sequencing of ctDNA detected all mutations reported in tumour in 76% (38/50) of pts. ctDNA analysis picked up additional mutations in 30% (15/50) of pts. The interval between collection of archival biopsies and blood tests (p = 0.300) did not affect detection of new mutations. 31% (6/19) of pts treated with anti-EGFR therapy developed recognised resistance mutations (KRAS and EGFR) in ctDNA on serial analysis. The most commonly detected mutations were TP53 (60%), KRAS (51%), PIK3CA (15%) and PTEN (3%). Other mutated genes included CTNNB1, BRAF, FGFR3 and ERRB2. Pre-clinical models (organoids and patient-derived xenografts (PDX)) were attempted from blood (CTCs) and/or tumour tissue in 29% (20/68) of pts. CTC organoid cultures were optimised and successful in 1/17 pts. Conclusions: ctDNA may be used for routine molecular characterisation of metastatic SBC/CRC and results can be analysed to track the development of resistance. Legal entity responsible for the study: Manchester Cancer Research Centre. Funding: The Christie NHS Foundation Trust Manchester Cancer Research Institute. Disclosure: All authors have declared no conflicts of interest.