tbuckley/cabot-search huggingface dataset:
Variations of circulating KRAS amount as a biomarker to monitor chemotherapy response in pancreatic cancer.
Authors: Marzia Del Re, Caterina Vivaldi, Eleonora Rofi, Enrico Vasile, Mario Miccoli, Lorenzo Fornaro, Giuliana Restante, Stefania Crucitta, Chiara Caparello, Paolo Davide D'arienzo, Alfredo Falcone, Romano Danesi
Journal: Journal of Clinical Oncology (2017)

e15794 Background: Current treatment of pancreatic ductal adenocarcinoma (PDAC) is FOLFIRINOX or gemcitabine + nab-paclitaxel, and CA19-9 is the only approved biomarker to monitor tumor response. However, CA19-9 has several limitations (i.e. sensitivity and specificity), highlighting the need for new biomarkers. Being the majority of PDAC (75-95%) KRAS mutated (mutKRAS), the present study developed an analysis tool based on circulating tumor DNA (ctDNA) to monitor the variation of mutKRAS in PDAC undergoing first-line chemotherapy. Early variation of ctDNA mutKRAS after 15 days of treatment was correlated with response to therapy. Methods: Three ml of plasma were collected from patients with PDAC undergoing first-line FOLFIRINOX or gemcitabine + nab-paclitaxel. Patients underwent standard disease evaluation by imaging according to RECIST 1.1 criteria. Blood samples were drawn prior to cycle 1, after 14 days and at each radiological evaluation. ctDNA was extracted using a QIAmp Circulating nucleic acid Kit (Qiagen, Valencia, CA) and the KRAS codon 12 and p.G13D analysis was performed by digital droplet PCR (ddPCR, BioRad, Hercules, CA). Results: A total of 27 patients with locally advanced (15%) and metastatic (85%) PDAC were included in this study. mutKRAS in ctDNA was detected in 19 patients (70.3%) at baseline. There were no statistically significant differences in median PFS and OS in patients with baseline positive or negative ctDNA mutKRAS (p = 0.15). However, there was a statistically significant difference in PFS and OS between patients with increase vs. stability/reduction of ctDNA at the 14 day-evaluation (median PFS: 2.5 vs 7.5 months, p = 0.03; median OS: 9 vs 11.5 months p = 0.009). The imaging evaluation performed at 2 months after initiation of therapy demonstrated that all patients with an increase in ctDNA at 14 days had radiological progression of disease. Conclusions: The results of this pilot study support the use of ctDNA as a new marker for monitoring treatment outcome and disease progression in PDAC, suggesting that ctDNA mutKRAS is a non-invasive predictive factor of response in PDAC.
Prevalence of autoimmune conditions among patients with lung cancer: Implications for immunotherapy treatment options.
Authors: Saad A. Khan, Lei Xuan, Sandi Pruitt, David E. Gerber
Journal: Journal of Clinical Oncology (2016)

9039 Background: Immune checkpoint inhibitors have emerged as a highly promising treatment option for advanced lung cancer. Pre-existing autoimmune conditions, with some exceptions, are considered contraindications to these treatments. To estimate the potential effect of this exclusion policy, we determined the prevalence of autoimmune conditions among patients with lung cancer. Methods: Using linked Surveillance Epidemiology and End Results (SEER)-Medicare data 1991-2010, we identified lung cancer patients with ICD-9 codes for 7 systemic and 36 organ-specific autoimmune conditions. Autoimmune diagnoses generally considered acceptable for immunotherapy (eg, type 1 diabetes, vitiligo, hypothyroidism) were not included. Characteristics of patients with and without autoimmune diagnoses were compared using Chi-square test. Survival was compared using unadjusted Kaplan-Meier and multivariable adjusted Cox proportional hazard models. Results: Among 210,509 patients with lung cancer, 51,732 (24.6%) also had autoimmune diagnoses. The most common autoimmune conditions were rheumatoid arthritis (9%), psoriasis (4.4%), polymyalgia rheumatica (2.6%), Addison’s disease (1.9%), giant cell arteritis (1.4%) and ulcerative colitis (1.3%). Autoimmune diagnoses were more likely to occur in lung cancer patients who were older, female, and presented with earlier-stage disease (all P< 0.001). In multivariable Cox models, patients with autoimmune diagnoses had improved lung cancer-specific (HR 0.86; 95% CI, 0.85-0.87; P< 0.001) and all-cause (HR 0.88; 95% CI, 0.87-0.89, P< 0.001) survival. Conclusions: Autoimmune diagnoses occur among a substantial proportion of patients with lung cancer. Patients with autoimmune diagnoses (vs. those without) are more likely to be older, female, have earlier-stage disease, and have improved clinical outcomes. Given the promise of cancer immunotherapy and the prevalence of autoimmune diagnoses among lung cancer patients, additional research to determine whether these patients could be considered for such treatments is warranted.
Oncological outcomes in a cohort of patients with biliary tract carcinoma in a Mexican reference center.
Authors: Mónica Isabel Meneses Medina, Fidel David Huitzil Melendez
Journal: Journal of Clinical Oncology (2017)

e15618 Background: In Mexico there is scarce information about oncological outcomes of biliary tract carcinomas (BTC). Methods: we retrospectively reviewed medical records from 150 patients with histologically confirmed BTC (excluding gallbladder cancer) treated in our institution from January 2005 to December 2015.Clinical and pathological information was recorded. Survival was estimated by Kaplan Meir method and compared by Log rank test. Results: we found 63.3% women and 36.7% men, with a median age of 62 years (23 - 88). Tumor localization was intrahepatic in 34.7%, hilar in 43.3% and distal in 22%. Clinical stage was advanced in 71%, regional in 13% and local in 16%. Diagnostic delay was 3.7 months (0.37 - 32.9). For patients with localized disease (which included local and regional disease, n=43), a potentially curative surgery was attempted in 64% (n=27), achieving a R0 resection in 59% (n=16) of cases. There was a 3.9 months (0.83-29.63) treatment initiation delay. There were 7 surgical deaths. For advanced disease (n=107), treatment initiation delay was 4.2 months (0.5 - 34.5), 59% (n=63) of patients did not received oncological active treatment, and 26% (n=28) of patients received a systemic palliative chemotherapy, more frequently gemcitabine (n=20). At progression just eleven patients received a second chemotherapy line. In localized disease resected patients by univariate analysis high levels of CA 19.9 (p=0.04) and CEA (0.03) were associated with decreased survival. For patients with advanced disease prognostic factors included poorly differentiated histology (p=0.04), high bilirrubin level (p=0.04), low albumin level (p=0.001), abscense of chemotherapy (p=0.000) and high CEA levels (p=0.03). Conclusions: Survival is poor in this Mexican cohort of patients with BTC possibly related to diagnostic and therapeutic delay and advanced disease at presentation. [Table: see text]
Phase 1 study to evaluate the safety and tolerability of the CD40 agonistic monoclonal antibody APX005M in subjects with solid tumors.
Authors: Johanna C. Bendell, Marwan Fakih, Jeffrey R. Infante, David Lawrence Bajor, Mihaela C. Cristea, Thomas Tremblay, Ovidiu C. Trifan, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2016)

TPS3110 Background: Immunotherapy is an effective approach for the treatment of solid tumors. In addition to reversing tumor-induced immune suppression, immune activating antibodies are being explored as the next generation of immuno-oncology therapeutics. CD40 is primarily expressed on antigen presenting cells such as dendritic and B cells, and initiates and regulates both innate and adaptive immunity and is essential for the activation of tumor-specific T cells. APX005M is a humanized IgG1 CD40 agonistic antibody developed using Apexigen’s APXiMAB discovery platform. APX005M binds with high affinity to human CD40 (Kd = 0.12nM), recognizes a unique epitope that overlaps with the CD40 ligand binding sites and induces its potent agonistic activity through crosslinking by Fc-gamma receptors. Methods: This is an ongoing, phase I, multicenter, open-label, first-in-human, dose-escalation study evaluating APX005M in patients with advanced solid tumors. Eligible subjects ( ≥ 18 years) will have an Eastern Cooperative Oncology Group performance status of 0 or 1, histologically documented solid tumor with no standard treatment options available, measurable disease by RECIST 1.1, adequate bone marrow, liver, and kidney function, and no toxicities related to prior treatments. The primary objectives of the study are to assess safety and tolerability and to define the maximum tolerated dose of APX005M. Secondary objectives include an evaluation of the pharmacokinetic, immune pharmacodynamic and antitumor effects of APX005M. Recruitment is ongoing, with a target enrollment of approximately 32 subjects across 3 centers in the United States. Clinical trial information: NCT02482168.
Efficacy and safety of nivolumab (Nivo) in patients (pts) with advanced or recurrent uterine cervical or corpus cancers.
Authors: Kosei Hasegawa, Kenji Tamura, Noriyuki Katsumata, Koji Matsumoto, Shunji Takahashi, Hirofumi Mukai, Hiroyuki Nomura, Hironobu Minami
Journal: Journal of Clinical Oncology (2018)

5594 Background: Recent advances in immuno-oncology provide evidence for the efficacy of PD-1/PD-L1 blockade therapy for a variety of cancers. However, the clinical activity of Nivo, an anti-PD-1 monoclonal antibody, in the treatment of advanced/recurrent uterine cervical (CVC) and corpus cancers (CC) is not yet clear. Methods: Phase 2, multicenter, multicohort, open-label study evaluating the efficacy and safety of Nivo in pts with advanced/recurrent CVC or CC (JapicCTI-163212). Patients received Nivo 240 mg every 2 weeks until progression or unacceptable toxicity. Primary end point was overall response rate (ORR; complete or partial response [PR]); an ORR ≥19.2% was considered efficacious. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. PD-L1 immunohistochemical staining, microsatellite instability (MSI) testing, and HPV typing (CVC only) were evaluated for biomarker analysis. Results: A total of 20 CVC (14 squamous, 5 adenocarcinoma [AC], 1 adenosquamous) and 23 CC (15 endometroid AC, 6 other endometrial cancer, 2 carcinosarcoma) pts were enrolled. Most pts had ≥2 prior chemotherapy regimens (CVC 13/20; CC 14/23). ORR was 25% (5/20) and 23% (5/22 evaluable), median PFS was 5.6 and 3.4 months, 6-month OS was 84% and 73%, and 12-month OS (preliminary) was 73% and 49% in CVC and CC, respectively. One pt with CVC AC had PR. Most of the pts who responded had a durable response (4/5 CVC, 5/5 CC) at data cut-off (Aug 18, 2017). Drug-related adverse events were seen in 63% (Grade 3-4, 19%) of pts. There were no drug-related deaths. In CVC, ORR was higher in pts with PD-L1+ tumors (33%; 5/15) than in pts with PD-L1− tumors (0%; 0/5) based on a PD-L1 expression level of ≥1%; HPV status did not affect ORR (33% in both HPV+ [3/9] and HPV− [1/3]). In CC, ORRs were similar, regardless of PD-L1 status (PD-L1+, 25% [2/8] vs PD-L1−, 21% [3/14]). All CC pts with MSI-High (n = 2) had PRs that were durable; no pts with CVC had MSI-High. Conclusions: This study demonstrates that Nivo has acceptable toxicity with evidence of clinical activity (primary end point met) in pts with CVC and CC. PD-L1 expression in CVC and MSI-High in CC may predict the clinical activity of Nivo. Clinical trial information: JapicCTI-163212.
Development of an immunohistochemistry assay for PD-L1 for using the 22C3 antibody in melanoma.
Authors: Charlotte Roach, Jeanette Musser, Gary Ponto, Grant Toland, Malinka Jansson, Kenneth Emancipator, Marisa Dolled-Filhart, Dave Stanforth, Karina Kulangara
Journal: Journal of Clinical Oncology (2016)

e14503 Background: The expression of PD-L1 has been reported in a number of human malignancies. Studies showed the correlation of PD-L1 expression in tumor or inflammatory cells, with clinical outcomes, which indicate that PD-L1 may be a predictive biomarker. PD-L1 expression on tumors contributes to tumor escape from immune surveillance. Here we describe the development of a highly reproducible and robust immunohistochemistry (IHC) assay for melanoma. Methods: IHC staining procedure was performed using the Dako Autostainer Link 48 platform (Dako AS480) and an automated staining protocol validated for the PD-L1 IHC 22C3 pharmDx assay. Deparaffinization, rehydration and target retrieval was performed in the PT Link (Dako PT100) using a 3-in-1 procedure. The enzymatic conversion of the subsequently added 3,3’-diaminobenzidine tetrahydrochloride (DAB) chromogen followed by DAB enhancer resulted in precipitation of a visible reaction product at the site of antigen. The specimens were then counterstained with Hematoxylin and coverslipped. Results were interpreted using a light microscope. Results: The in-house analytical validation consisted of inter-instrument, -operator, -day, and –lot, and intra-day and -run variations. Robustness studies included differences in target retrieval time, temperature and pH. Negative, positive and overall agreements met the acceptance criteria for all these studies. Interpretation included PD-L1 expression on tumor and immune cells. Conclusions: Our studies demonstrate that the Dako PD-L1 IHC 22C3 assay is a sensitive, specific, precise, and robust assay, which can reliably identify patients who express PD-L1 as a biomarker across multiple tumor types. Clinical trial information: NCT01295827.
Impact of margin status on survival after radical nephrectomy for renal cell carcinoma (RCC).
Authors: Lindsay Kaye Morris, Alaa Altahan, John Mays, Upama Giri, Eric Wiedower, Daniel A. Vaena, Martin D. Fleming, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

e16084 Background: Data is limited regarding outcomes in patients with RCC with positive surgical margins. We sought to evaluate the impact of margin status after radical nephrectomy (RN) on relapse free survival (RFS) and overall survival (OS). Methods: A retrospective study was conducted evaluating patients with RCC having undergone RN at Methodist University Hospital in Memphis, Tennessee, between January 2009 and December 2013. Patients were identified from the tumor registry at this institution, and IRB approval obtained. Patient and tumor characteristics and survival were analyzed by GraphPad Prism, Microsoft Excel and IBM SPSS. Results: 156 patients that underwent RN for RCC were identified; 12 patients (7.7%) had positive margins and 144 had negative margins. Mediation duration of follow-up was 3.4 years. 5 of 12 patients with positive margins relapsed, versus 20 of 144 with negative margins (41.7% v. 13.9%, p = 0.022) with a RR of 3.10 (95% CI 1.417-6.799). Among those who relapsed, there was a statistically significant difference in time to relapse between patients with positive and negative margins (mean number of days to relapse 275 versus 621, respectively, with p = 0.038). On multivariate analysis of age, gender, ethnicity, laterality, tumor histology, margin status, and tumor size, margin status was not a statistically significant determinant of OS at 1, 3, and 5 years (p = 0.051, 0.124 and 0.185 respectively) or RFS at 1, 3, and 5 years (p = 0.372, 0.271 and 0.242 respectively). Pearson correlation analysis showed significant correlation between tumor size and margin status, R = 0.478, p &lt; 0.001. Conclusions: Positive margins were associated with earlier time to relapse among patients following RN. However, in multivariate analysis, margin status was not a statistically significant determinant of OS or RFS. In the current era of multiple available agents in RCC capable of cytoreduction, the risk factors that are predictive of a positive surgical margin at RN should be considered in the design of neoadjuvant systemic therapy trials, with the goal of improving long-term outcomes.
P05.66 Metastatic atypical teratoid rhabdoid tumor (ATRT) of the central nervous system in the adult: A case report
Authors: T Ros, N Boc, B Zakotnik
Journal: Neuro-Oncology (2018)

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant tumor of the central nervous system, ussually diagnosed in children less than 5 years of age. ATRT is rarely found in adults with average survival of these patients less than two years. Treatment regimens are often extrapolated from the pediatric experience and modified according to adults characteristics. Here we present a case of a 35-year-old right-handed woman with metastatic ATRT of the brain first seen at our institution in march 2016. She complained on three months lasting loose of hearing and face paresis of the left side, with slight equilibrium disturbances. MRI of the head revealed four lesions intracranially, with homogeneous enhancement after contrast aplication. These lesions were located in both pontocerebellar angles, one in the roof of the forth ventricle and one deeply in the hypothalamic and campal region of the left brain. She was operated the largest tumor, supposed to be nevrinoma of the left acustic nerve. Histological examination confirmed ATRT. Before starting with pooperative radiation therapy (RT), she revealed spastic paraparesis with the subsequent MRI finding of spinal cord compression caused by an intradural, extramedullar tumor at C7 level. There were also found many homogeneously enhanced deposits along the spine, namely meningeal carcinomatoses. Following successful surgical resection of the metastases at C7 level, she started with craniospinal RT. Later on the disease progressed intracranially with signs of epileptic seazures and right hemiparesis. She was treated with additional RT of the head. From January 2017 till august 2017 she was treated with chemotherapy, exchanging VACA/ICE sheme, achieving a partial remission. In february 2018 disease progressed in the posterior fossa, she received palliative irradiation. Presented case report is our first and the only adult patient of rare ATRT of the CNS. Although the prognosis is dismal in pediatric population, long term survival is possible in adult ATRT cases after combination of surgery, RT and chemotherapy. As the disease of our patient was metastatic at the time of diagnoses more two years ago, the patient is still alive with a relatively good quality of life for the most part of the time.
Predicting disease progression in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): An analysis from the phase 3 SPARTAN trial.
Authors: Eric Jay Small, Fred Saad, Dana E. Rathkopf, Boris A. Hadaschik, Simon Chowdhury, Margaret K. Yu, Angela Lopez-Gitlitz, Oliver Brendan Rooney, Youyi Shu, Mohamed Darif, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2018)

5034 Background: Men with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mo are at high risk for metastatic disease and associated death. Apalutamide (APA), a next-generation androgen receptor inhibitor, extended metastasis-free survival (MFS) by median > 2 years in men with nmCRPC (HR [95% CI] 0.28 [0.23-0.35]; p < 0.0001) in SPARTAN. A multivariate analysis (MVA) was undertaken to identify independent predictors of MFS in this pt population. Methods: A nonstratified proportional hazards model assessed predictors of clinical end points and examined the following covariates: treatment, PSADT, use of bone-sparing agents, N0 vs N1 at study entry, Eastern Cooperative Oncology Group performance status (ECOG PS), prior therapies, Gleason score, age, and baseline PSA. Results: 1207 pts were randomized (806, APA; 401, PBO), and the overall population was evaluated. The following covariates emerged as independent predictors of longer MFS for the combined arms: APA treatment, PSADT > 6 mo, N0 disease, Gleason score at diagnosis ≤ 7, and baseline PSA ≤ 7.8 ng/mL (Table). A relationship between shorter PSADT and faster time to metastasis or death was observed. Conclusions: APA treatment, PSADT, nodal disease, Gleason score, and baseline PSA were independent predictors of MFS in pts with nmCRPC from SPARTAN. The treatment effect of APA remained highly significant after adjusting for covariates, with a similar magnitude of risk reduction for MFS in the MVA to that of the original primary analysis. Furthermore, there is a continuous relationship between PSADT and time to metastasis or death. Clinical trial information: NCT01946204.Covariate HR (95% CI) p Value Treatment, APA vs PBO 0.26 (0.21-0.32) < 0.0001 Baseline PSA, ≤ 7.8 ng/mL vs > 7.8 ng/mL 0.59 (0.47-0.73) < 0.0001 PSADT, > 6 mo vs ≤ 6 mo 0.65 (0.51-0.84) 0.0007 Loco-regional disease, N0 vs N1 0.68 (0.52-0.89) 0.0055 Gleason score at diagnosis, ≤ 7 vs ≥ 8 0.75 (0.61-0.92) 0.0063 Age per 10 years 0.88 (0.77-1.01) 0.0784 ECOG PS at baseline, 0 vs 1 0.84 (0.66-1.07) 0.154 Use of bone-sparing agent, yes vs no 0.78 (0.55-1.12) 0.174 Prior hormonal therapies; n, ≥ 2 vs 1 0.90 (0.69-1.16) 0.406
P05.36 Skull base meningiomas: prognostic factors analysis for recurrence with multimodality treatment
Authors: F Pessina, P Navarria, E Clerici, G Carta, M Scorsetti, L Bello
Journal: Neuro-Oncology (2018)

Meningioma is the most common primary intracranial tumor, accounting for approximately 15–30% of primary brain tumors. Skull base meningiomas, represent a subgroup of tumors in which a complete surgical removal is rarely achieved and the amount of surgical resection represents a crucial factor influencing the risk of recurrence. The role of adjuvant radiotherapy (RT) is still unclear and evidence is lacking. The aim of the present study was to evaluate prognostic factors influencing the local recurrence rate in a large series of grade I-II skull base meningiomas treated with surgery followed by RT in selected cases. Local toxicity, patients symptoms relief and local control rate were evaluated as well. Newly diagnosed skull base meningiomas underwent surgery, were included. The extent of surgical resection (EOR) was defined according to Simpson criteria, and were dichotomized as gross total resection (GTR) and subtotal resection (STR). Adjuvant RT was considered in case of STR. Clinical outcome was evaluated by neurological examination and brain MRI performed every 6 months for the first year and yearly thereafter. The 30-days postoperative morbidity and mortality were recorded. From January 2000 to December 2015, 142 patients were analyzed. The majority were female (69.1%), with a KPS ≥80 (95.8%), grade I meningioma(86.6%), and symptoms at diagnosis (92.3%). STR was performed in 69.7%, followed by adjuvant RT in 15%. Improvement or stability of neurological status was obtained in 78.9% of patients. The median follow-up time was 71 months (range 24–214 months). Local recurrence occurred in 43 (30.3%) patients at a median time of 32 months (range 6–199 months). No patients who underwent surgery plus adjuvant RT had local relapse. The median PFS was 172 months (95%CI 144–193 months), and the 2,5,10-year PFS were 87.9%(±2.8%), 78.2%(±3.8%) and 65.1%(±5.6%), respectively. The 2, 5, 10-year OS were (median not reached) 98.6% (±0.9%),96.7% (±1.6%), and 94.4% (±2.7%), respectively. On univariate analysis factors identified as significantly impacting PFS were the EOR (p value<0.01), the combined treatment, surgery plus RT (p value<<0.01), and the meningioma grade (p value <0.01). The combined treatments was confirmed on multivariate too (p value <<0.01). Overall, our findings suggest that recurrence rates are influenced by WHO meningiomas grade, the extent of surgical resection, and the employ of adjuvant RT in not completely resected meningioma, regardless of tumor grade. Local control and durability of results suggest for a routine application of this approach in properly selected cases.