tbuckley/cabot-search huggingface dataset:
Minocycline for reduction of patient-reported symptoms during radiation therapy for head and neck cancer: First results of a randomized trial.
Authors: Gary Brandon Gunn, Tito R. Mendoza, Adam S. Garden, Xin Shelley Wang, William H. Morrison, Steven J. Frank, Beth Michelle Beadle, Jack Phan, Clifton David Fuller, Mark Steven Chambers, Charles Lu, Ehab Y. Hanna, David Ira Rosenthal, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2014)

6040 Background: Local and systemic symptoms during radiation therapy (RT) may be exacerbated by dysregulated inflammation and its downstream toxic effects. Minocycline (mino) can suppress pro-inflammatory cytokine release. We conducted this study to investigate its potential to reduce patient (pt) reported symptom severity during RT for HNC. Methods: Eligible pts for this blinded, placebo-controlled trial were adults with oro- or nasopharyngeal carcinoma (T0-3, N-any, M0) dispositioned to intensity-modulated RT alone (no concurrent systemic therapy or prior resection). Participants were equally randomized to receive mino (100 mg twice daily) or placebo (P) during RT course. The primary endpoint was the area under the curve (AUC) of 5 pre-specified symptoms (pain, fatigue, sleep, appetite and swallowing) during RT course as assessed by the MDASI-HN (0-10 scale). As the overall goal of this study was to determine the potential signal/benefit of mino to inform future clinical trial design, we selected a modest power (70%) to detect a large standardized effect size (ES) of 0.70 (one-sided, 5% sig. level) on the primary endpoint, requiring 20 pts per arm. Results: From 8/10-7/13, 82 pts were approached and 47 were enrolled (safety analyses cohort); 7 withdrew and were replaced per protocol. 20 evaluable pts in each arm formed cohort used for symptom analyses. Pt characteristics and toxicity details will be presented. There were no grade 3+ potentially study medication-related AEs. There were 2 and 7 grade 1-2 AEs for P and mino arm respectively (p=0.53). All pts completed RT (66-70 Gy); there have been no recurrences to date. 5 pts in P arm required feeding tube during RT, versus 2 in mino arm (p<.21). The average daily AUC for the 5 preselected symptoms during RT were 3.7 (SD=1.7) and 3.1 (1.0) for the P and mino group (p<.16), respectively, and equivalent to an ES of 0.37. AUC ES comparisons for several individual symptoms and interference also favored mino but were not significant. Conclusions: Mino during RT for HNC is feasible and achieved a positive signal in terms of patient reported symptom severity and interference to justify and direct future trial design. Clinical trial information: NCT01173692.
Gene expression profiling for prediction of tissue of origin to direct site-specific therapy in patients with CUP: Treatment outcomes by assay predictive probability.
Authors: Mark S. Rubin, Frank A. Greco, Ralph V. Boccia, Michael A. Scola, David R. Spigel, Samuel Raby, Thabiso W. Chirwa, Raven Quinn, John D. Hainsworth
Journal: Journal of Clinical Oncology (2012)

e21023 Background: Tumor profiling as a diagnostic technique in CUP depends on the detection of similarities in gene expression between the cancer and the tissue of origin. Assay-directed site-specific therapy may be most effective in tumors with high-confidence molecular predictions, since a) the prediction may be more often correct due to greater similarity between the gene expression profile of the unknown tumor to the assay reference tumor database, and b) the tumor would more likely share biologic characteristics/treatment sensitivity with cancers of known origin. Methods: In a prospective trial performed by the Sarah Cannon Research Institute (SCRI), a 92-gene RT-PCR assay (CancerTYPE ID; bioTheranostics, Inc.) was performed on tumor biopsies from previously untreated CUP pts. Pts were then assigned standard site-specific treatment directed by the assay prediction. Treatment responses were evaluated based on the strength of the assay predictions; probabilities ≥80% were arbitrarily regarded as high confidence results. Results: Between 10/08 and 12/11, 224 pts (26 predicted tumor types) received treatment. Median overall survival (OS) was longer in 113 pts (50%) with high confidence predictions: 11.7 months (mos) vs 9.8 mos; p=.03. 120 pts (59%) had assay predictions of responsive tumor types, known to derive substantial benefit from standard site-specific therapy. Treatment responses, irrespective of predictive probability, were better in these pts vs those with less responsive tumor types (median OS 12.8 vs 7.4 mos; p=.027). Further stratification of high vs lower confidence assay predictions resulted in 4 groups with different OS (p=.03) (Table). Conclusions: Site-specific therapy for CUP pts directed by results of the 92-gene assay was more effective when the probability of the assay prediction was higher, particularly in pts with assay diagnoses of more responsive tumor types. [Table: see text]
Standardizing measurement of tobacco use in cancer clinical trials.
Authors: Stephanie R. Land, Benjamin Toll, Graham Walter Warren, Thomas H. Brandon, Sandra A. Mitchell, Carolyn M. Dresler, Ellen R. Gritz, Robert Schnoll, Linda Sarna, Carol Moinpour, Jamie S. Ostroff, Fadlo Raja Khuri, Jan C. Buckner, Kenneth Michael Cummings, Roy S. Herbst, Peter G. Shields, Sonia Duffy, Nancy Rigotti, Sheila Ann Prindiville, Jeffrey S. Abrams
Journal: Journal of Clinical Oncology (2014)

e17658 Background: The 2014 Surgeon General’s Report highlights the known hazards of cigarette smoking for cancer patients and the need to assess tobacco use as a critical behavioral factor in cancer research. Smoking increases mortality, toxicity, recurrence, and risk of second primary cancers. However, further research is needed regarding smoking and other tobacco products, and assessments are not routinely incorporated into clinical trials designs. There are no national recommendations for reliable, valid, and clinically meaningful tobacco use measurement. Methods: In 2013, an expert task force was charged with conducting literature review and evaluation of existing measurement tools to develop clinically efficient evidence-based assessments that could be translated across clinical trial systems. The task force was also asked to specify the timing of assessments, define the research agenda regarding tobacco use by cancer patients, and engage in scientific dissemination. Results: Two tiers of tobacco use measurement items were developed with a protocol for the timing and conduct of the assessment in cancer clinical trials. Tier 1 is a minimum set of baseline and follow-up items recommended for clinical trials in any cancer patient or survivor study. Tier 2 is a longer menu of curated items for use when more comprehensive assessment is feasible. Domains include tobacco use history, status, and intensity. The task force detailed areas in need of research including associations between tobacco use or cessation with clinical outcomes, effects of tobacco on cancer biology, and comparative effectiveness of cessation methods during and after cancer treatment. Conclusions: A standardized tobacco use assessment implemented in cancer research protocols across a range of organ sites and treatment modalities will permit data pooling across trials and comparisons between populations. Recommendations for core item sets and the accompanying research agenda facilitate tobacco use assessment in clinical trials and will enable researchers to identify novel clinical interactions, better understand the effects of tobacco use on cancer treatment efficacy and toxicity, and improve clinical outcomes.
Concordance of driver mutations in primary and matched metastasis from patients with non-small cell lung cancer (NSCLC) using next-generation sequencing (NGS).
Authors: Stéphane Vignot, Garrett Frampton, Roman Yelensky, Christian Brambilla, Anne-Claire Toffart, Vincent A. Miller, Gary A. Palmer, Maureen T. Cronin, Vladimir Lazar, Jean-Charles Soria, Philip Stephens, Elisabeth Brambilla
Journal: Journal of Clinical Oncology (2012)

7529 Background: Progress in treating NSCLC continues to be limited by high recurrence rates after definitive treatment of localized disease and frequent presentation with metastatic disease. In these pts, diagnostic samples are often limited in size and may be inadequate for genotyping necessary in this disease. In applying genomic profiling to aid treatment planning for patients with metastatic NSCLC, it is critical to determine whether archived primary tumor adequately reflects the genomic spectrum of the patient’s metastatic disease or whether biopsy of a metastatic site is required. We undertook this study using NGS technology to characterize paired primary-metastatic biopsy genomic profiles. Methods: Primary and matched metastatic tumor pairs plus adjacent normal tissue from 15 pts with NSCLC (adenocarcinoma 9/squamous 4/large cell 2) and heavy smoking history were analyzed using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 778X with 99% of bases covered &gt;100X. Results: Among the 30 tumors, 373 somatic alterations were identified; 96 were known NSCLC drivers including: TP53 (14 pts), KRAS (4 pts), SOX2 (4 pts), STK11 (2 pts), CDKN2A (2 pts) and SMARCA4 (2 pts) in full agreement with their respective histological type. In all cases (15/15), primary and metastatic tumors from the same patient demonstrated 90% driver mutation concordance (74/82, 95 % CI, 82-95%). For other mutations, the majority of which are likely passengers, the 69% (201/291) concordance rate was significantly lower (p&lt; .001).The total number of alterations between primaries (190) and metastases (183) was remarkably similar. Conclusions: These results suggest that genomic profiles of primary tumor can identify the key somatic alterations present in matched NSCLC metastases and therefore is a suitable specimen for clinical decision making in the majority of cases. Our data does not support the routine need for a new biopsy upon recurrence since variability in mutational status is low.
18F-fluorodeoxyglucose PET/CT imaging for predicting treatment response in patients with advanced melanoma treated with anti-PD1 immunotherapy.
Authors: Miguel Hernandez Pampaloni, Michelle T. Ashworth, Alain Patrick Algazi, Adil Daud
Journal: Journal of Clinical Oncology (2014)

3084 Background: Immune checkpoint inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Anti-PD1 therapy has been reported to produce durable tumor regression in phase 1 trials. Development of biomarkers to evaluate treatment response are pivotal for optimizing individual therapy. We aim to evaluate whether pretreatment 18F-fluorodeoxyglucose (FDG) PET/CT imaging can be a predictor of tumor response or disease progression in patients on anti-PD1 therapy as a marker of tumoral increased glucose utilization rate. Methods: Twenty-three patients (15 males) with BRAF wild type mutation advanced melanoma who failed prior treatment with antineoplastic regimens and started therapy with MK-3475 alone were included in the study. Standard of care whole-body FDG PET/CT imaging was performed at baseline before the anti-PD1 therapy was initiated (10 ± 5 days interval time between FDG PET/CT imaging and therapy start date). FDG uptake was semi-quantitatively measured by maximum standardized uptake value (SUV). Treatment response was evaluated with computed tomography imaging by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: Sixteen patients showed significant and stable tumor regression to date while seven patients demonstrated tumor progression by conventional imaging wtihin 6 months of the therapy starting date. All patients with treatment response remain currently on MK-3475 monotherapy. Of the seven patients who showed disease progression, all had at least 2 or more abnormal hypermetabolic foci by FDG PET/CT imaging (SUV max 9.44). Interestingly, of the 16 patients with maintained tumor regression, 8 patients did not showed any hypermetabolic finding, while the remaining 8 patients showed hypermetabolic lesions. (SUV max 6.0). Conclusions: Absence of abnormally increased FDG uptake by PET/CT imaging may be a useful tool to predict durable anti-PD1 immunotherapy response, while pre-therapy, single time point increased glucose utilization rate could represent a necessary but insufficient step for the assessment of disease progression.
Metastatic pattern of breast cancer according to immunohistochemical defined subtypes in the transitional phase of adjuvant trastuzumab treatment.
Authors: Florian Heitz, Fatemeh Lorenz-Salehi, Sherko Kümmel, Alexander Traut, Wolfgang Weikel, Johannes Holtschmidt, Philipp Harter, Annette Fisseler-Eckhoff, Georg Arnold, Ondra du Bois, Alexander Queck, Andreas Du Bois
Journal: Journal of Clinical Oncology (2014)

e11581 Background: Prognosis of early breast cancer (BC) differs significantly upon subtypes (ST). Treatment with adjuvant trastuzumab improves outcome of HER2 overexpressing BC, however, less in known about its impact on metastatic pattern. Methods: Early BC pts consecutively treated in two specialized BC units were included. Estrogen- (ER), progesterone- (PR), tumor grade (G) and later on HER2 receptor status (HER2) were prospectively analyzed and were used to define breast cancer subtypes. Missing HER2 status in early cases were assessed retrospectively. Distant-recurrence free survival (DRFS) was calculated using cumulative incidence rates (CIR; Grays´ test and death as competing risk). P<.05 was considered statistically significant. Results: Between 1999 and 2013 4,172 pts were treated. Of them, 60.5% were classified as LA, 14.3% as LB, 12.3 as TN, 8.9% as HER2/HR+ and 4.1% as HER2/HR-, respectively. 55.3% of the 371 HER2/HR+ and 53.2% of the 171 HER2/HR- pts were treated with adjuvant trastuzumab. After a median follow-up of 67.2 months the CIR of DRFS events at 5 years (5-DRFS) was 7.0% for LA, 18.0% for LB (p<.05 LA vs LB) and 18.0% for TN BC (LA vs TN p<.05, LB vs TN p=.93). CIR of 5-DRFS was significantly reduced in HER/HR+ (10% vs 24%; P<.05) and HER/HR- (15% vs 30%; p<.05) treated with or w/o adjuvant trastuzumab, respectively. The most frequent metastatic lesions (5 year CIR) in HER2/HR+ BC treated w/o and with trastuzumab were bone/liver (both 11.5%), brain (7.0%), lung (6.3%) and bones (4.6%), brain (4.2%), liver (4.0%), lung (1.4%), respectively. The most frequent metastatic lesions in HER2/HR- BC treated w/o and with trastuzumab were liver (12.9%), lung (11.0%), bone (10.2%), brain (8.1%) and brain (6.6%), bone (5.3%), liver (5.1%) and lung (4.1%), respectively. Conclusions: BC ST assessed by routinely conducted immunohistochemistry harbors significant prognostic impact. We observed a difference in metastatic pattern in pts treated w/o and with adjuvant trastuzumab.
68Ga-PSMA PET/CT Uptake in Intramuscular Myxoma Imitates Prostate Cancer Metastasis
Authors: Helle D. Zacho, Julie B. Nielsen, Katja Dettmann, Sonja H. Hjulskov, Lars J. Petersen
Journal: Clinical Nuclear Medicine (2017)

Ga-PSMA PET/CT is becoming the most promising imaging modality for detecting recurrent prostate cancer. The modality has the advantage of being able to detect recurrent disease, even at very low prostate-specific antigen levels. However, several studies report Ga-PSMA uptake in tissue unrelated to prostate cancer. We present a 74-year-old man who underwent Ga-PSMA PET/CT for recurrent prostate cancer 5 years after radical prostatectomy. The Ga-PSMA PET/CT showed an intramuscular lesion with increased PSMA uptake in the left vastus medialis muscle. The lesion was surgically removed, and histopathology found it to be an intramuscular myxoma that showed immunohistochemical PSMA expression.
Catumaxomab with and without prednisolone in patients with malignant ascites due to epithelial cancer: Results from the phase IIIb CASIMAS study.
Authors: Jalid Sehouli, Pauline Wimberger, Ignace B. Vergote, Per Rosenberg, Andreas Schneeweiss, Carsten Bokemeyer, Christoph Salat, Giovanni Scambia, Dominique Berton-Rigaud, Salvatore Siena, Armando Santoro, Andres Cervantes-Ruiperez, Jean Paul Guastalla, Christophe Tournigand, Nicoletta Colombo, Alexander Serg Dudnitchenko, Vladimir Bondar, A.M. Westermann, Florian Lordick
Journal: Journal of Clinical Oncology (2012)

e13097^ Background: The primary objective of this study was to compare catumaxomab with prednisolone (CP) to catumaxomab without prednisolone (C) as 3-hour intraperitoneal (i.p.) infusion by demonstrating superiority for safety and non-inferiority for efficacy of the CP arm. Methods: 219 patients were randomized to catumaxomab plus premedication of 25 mg prednisolone (111 pts) or to catumaxomab alone (108 pts). The primary endpoint was the composite safety score (CSS) summarizing the worst CTCAE grades for the main TEAEs (pyrexia, nausea, vomiting, and abdominal pain). A potential impact of prednisolone on efficacy was assessed by the co-primary endpoint puncture-free survival (PuFS). Further parameters included overall survival (OS) and time to next therapeutic puncture (TTPu). Results: The superiority of CP for safety was not proven as the mean CSS was comparable in the two groups (CP: 4.1; C: 3.8 for; p= 0.383). The median PuFS was slightly lower in CP (30 days) compared to C (37 days). However the hazard ratio (HR) for PuFS (HR: 1.130, p=0.402) as well as the 75% quartiles (CP: 155 days, C: 92 days) were in favour of CP compared to C. The median TTPu was similar in both groups (CP: 78 days; C: 102 days, p= 0.599). The majority of patients (123 pts) had no therapeutic paracentesis prior to death (CP: 54.8%; C; 61.7%, p=0.297). Median OS was longer for CP (CP: 124 days; C: 86 days, p= 0.186) without statistical significance. Conclusions: The CASIMAS results are in concordance with the data of the pivotal study and thus confirm the robustness of the treatment effect of catumaxomab in malignant ascites. The administration of 25mg prednisolone as premedication prior to catumaxomab infusion did not change the safety profile and did not negatively impact the efficacy of catumaxomab. The composite safety score after 3-hour infusion time was comparable to that seen in the pivotal study using 6 hours.
Prognostic value of <i>BRAF</i> and <i>KRAS</i> mutations in colorectal cancer patients.
Authors: Paola Murata, Agostina Stradella, David Páez, Maria Tobeña, Ana Sebio, Laia Paré, Alan González, Iñigo Espinosa, Eduardo Targarona, Ignasi Gich, Agust Barnadas, Montserrat Baiget, Marta Martin-Richard
Journal: Journal of Clinical Oncology (2012)

e14104 Background: KRAS mutation has been established as a predictive marker of resistance to antiEGFR therapy in patients (pts) with colorectal cancer (CRC) but the role of BRAF is not yet clear. Both gene mutations have also been studied as prognostic factors but results are contradictory. AntiEGFR therapies impair evaluation of KRAS and BRAF as prognostic factors when overall survival is an endpoint. We hypothesized that if KRAS or BRAF were prognostic factors, they would influence time to relapse (TTR) after complete tumor resection. Methods: Patients who underwent surgery between 2007 and 2011 for stage II and III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and V600E BRAF mutation were analyzed. Clinical characteristics and mutation status were correlated with TTR. Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were located in the right colon in 27% of pts, in the transverse colon in 3%, in the left colon in 41%, and in the rectum in 29%. Most (55.3%) were stage III; 59% received adjuvant chemotherapy. KRAS and BRAF mutations were present in 66 (38.8%) and 5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71 weeks (w) (95% CI 63-79). V600E BRAF mutation was the only factor associated with TTR. TTR was 42 w in tumors with the BRAF mutation and 74 w in wild-type tumors (p=0.041). Among KRAS mutations, KRAS G12V conferred a significantly longer TTR (100w) than the other subtype mutations (69 w; p=0.05). Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic factor in CRC, conferring a shorter time to relapse. Additionally, the KRAS G12V determines a different behavior among KRAS mutation tumors.
Early changes in angiogenesis and hypoxia following bevacizumab therapy in primary breast cancer.
Authors: Shaveta Mehta, Nicholas Peter Hughes, Adrian M. Jubb, Helen Turley, Chen Han, Sonia Patricia Li, N Jane Taylor, Anwar R. Padhani, Rosemary Frances Adams, Andreas Makris, Adrian L. Harris
Journal: Journal of Clinical Oncology (2012)

1066 Background: Bevacizumab (BV), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), is an approved anti-angiogenic agent, but despite its widespread use, little is known about how tumours develop resistance to BV. We have conducted a window-of-opportunity study in which BV is administered as a short-term first-line treatment for primary breast cancer (PBC) patients, and assessed histological markers of tumour angiogenesis and hypoxia before and after therapy. Methods: 47 patients with locally advanced breast cancer were prospectively enrolled. Informed consent was obtained from all patients. A single infusion of BV (15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and core biopsies for immunohistochemistry (IHC) analysis were performed immediately prior to and 2 weeks after BV. 36 patients with invasive ductal carcinoma and good quality MRI scans and core biopsies were included in this analysis. Wilcoxon rank test and Spearman’s correlation test were used for statistical analysis. Results: IHC revealed a significant upregulation of carbonic anhydrase 9 (P = 0.04) and hypoxia inducible factor-1a (P = 0.001) following BV therapy along with a significant reduction in plasmalemma vesicle associated protein (PLVAP) (p=0.01) and Ki67 (p= 0.006). DCE-MRI analysis revealed a significant reduction in vessel permeability and blood flow following BV, as measured by a decrease in the forward transfer constant K trans (P &lt; 0.0001) and the reverse rate constant k ep (P &lt; 0.0001). In addition, we found a significant negative correlation between CA9 levels and median K trans at baseline (Spearman’s rho = -0.46; P = 0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found that PBC patients treated with single-agent BV showed a decrease in markers of tumour angiogenesis, together with a corresponding increase in tumour hypoxia. Our results suggest that tumour hypoxia may be a key mechanism governing the early onset of resistance to BV therapy, and argue for the use of suitable combination therapies to overcome the resistance and ultimately improve patient survival.