tbuckley/cabot-search huggingface dataset:
PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma.
Authors: Fernando Rivera, Javier Gallego, Carmen Guillén Ponce, Manuel Benavides, Jose A. Lopez-Martin, Marc Küng
Journal: Journal of Clinical Oncology (2015)

e15269 Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer death, due to the local or distant progression at diagnosis. TTFields are alternating electric fields delivered to the region of the tumor by means of non-invasive transducer arrays surrounding the abdominal region. TTFields have shown an anti-mitotic effect by interfering with mitotic spindle formation, leading to apoptosis. TTFields have demonstrated to be an effective treatment in glioblastoma. In pancreatic cancer, TTFields decreased proliferation and clonogenic potential in vitro, and reduced tumor volume in vivo. The PANOVA trial was designed to test the safety of TTFields in the treatment of pancreatic cancer. Methods: Twenty advanced pancreatic adenocarcinoma patients were enrolled in a prospective, single arm study of TTFields at 150 kHz for at least 18 hours/day, concomitant with weekly gemcitabine. All patients had histologically-confirmed unresectable tumors, with an ECOG performance score of 0-1 and no prior chemotherapy or radiation therapy. The primary endpoint was the incidence and severity of treatment emergent adverse events. Results: Seven patients (35%) had locally advanced disease without metastasis and 3 (15%) had an ECOG score of 0 at baseline. The average TTFields treatment duration was 3.9 months and the median compliance was 74% of the planned duration in the protocol. Sixteen patients (80%) suffered from adverse events during their study period. Nine serious adverse events were reported, none were related to TTFields and the majority (78%) could be attributed to the underlying cancer. Only one SAE (Intestinal Perforation) was fatal. Dermatitis, a known TTFields-related adverse event, was reported in 9 patients (45%), 78% of whom had a mild-moderate skin toxicity. Eleven out of the 20 patients enrolled (55%) are still on TTFields. Conclusions: TTFields concomitant to gemcitabine are tolerable and safe for advanced pancreatic cancer patients. An extension of the current protocol is therefore planned to include 20 additional patients, who will be treated with gemcitabine, nab-paclitaxel and TTFields. Clinical trial information: NCT01971281.
Whole Brain Radiotherapy (WBRT) plus EGFR tyrosine kinase inhibitors (TKIs) versus WBRT alone for brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients: A meta-analysis.
Authors: Laiyu Liu, Mi Yang, Jian Guan, YaoWei Zhang, Qinyang Li, Y Zhang, Min Chen, Lu Li, Nanjie Xiao, Yongmei Dai, Chi Zhang, Longhua Chen
Journal: Journal of Clinical Oncology (2015)

e19060 Background: NSCLC accounts for 85%-90%of lung cancers, in which brain metastases (BMs) occur in 20–40%of all NSCLC cases. WBRT is the standard treatment for BMs in NSCLC, which leads to a unsatisfactory overall survival (OS) ranging from 3-6 month. It is reported that the use of EGFR-TKIs enhances therapeutic level and delays disease progression in the brain. This meta-analysis was performed to verify whether the addition of EGFR-TKIs would improve OS and Local progression-free survival (LPFS),when compared with WBRT alone in NSCLC patients with BMs. Methods: We comprehensively searched any relevant articles in PubMed, Embase, Cochrane Library, Web of Science, Science Direct and China National Knowledge Infrastructure (CNKI).The log-rank test was used to calculate pooled hazard ratios(HRs)for the endpoints as overall survival(OS),Local progression-free survival(LPFS)and Kaplan-Meier curves were read by Engauge-Digitizer. We performed this meta-analysis by RevMan 5.3 Software, using the fixed-or random-effects models. Results: 5 studies including a total of 439 cases were identified. There was no significant difference on median OS (HR = 0.76, 95%CI 0.50-1.16; P = 0.21) and median (LPFS) (HR = 0.56,95%CI 0.18-1.73;P = 0.32) between the EGFR mutation unselected patients treated with WBRT alone and WBRT plus EGFR-TKIs. Conclusions: The meta-analysis show no significant benefits from adding EGFR-TKIs to WBRT in OS and LPFS compared with WBRT alone, but the result did not indicate that EGFR-TKIs has no benefits in NSCLC patients with BMs. EGFR mutation status is a predictor of treatment effect, and the positive EGFR-mutant patients lead to favourable outcomes, but conversely the patients without mutations experienced a detrimental effect from EGFR-TKIs. The results need further validation as treatment efficacy estimated from unselected EGFR mutation patients enrolled in our studies. Therefore, we appeal that more prospective Phase III clinical trials are conducted in highly selective patients, to confirm whether EGFR-TKIs combined with WBRT would be better than WBRT alone.
Association between guideline-adherent imaging and overall survival following second-line targeted therapy for metastatic renal cell carcinoma.
Authors: Peggy L. Lin, Sumanta Kumar Pal, Eric Jonasch, James E. Signorovitch, Zhimei Liu, Kenneth W. Culver, Jeffrey A. Scott, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2013)

e15538 Background: NCCN guidelines recommend imaging at 2-6 months after initiation of targeted therapy for metastatic renal cell carcinoma (mRCC). This study assessed the association between guideline-adherent imaging and overall survival in mRCC. Methods: Thirty-six community-based medical oncologists/hematologists reviewed charts for ≤ 15 mRCC patients each. Included patients were aged ≥ 18 years and initiated 2nd targeted therapy in 2010 or later. Patients alive up to month 6 were categorized into 3 groups based on time of first imaging test: early (0-60 days), guideline-adherent (61-180 days), and delayed(&gt; 180 days). Overall survival (OS) was compared using multivariable Cox proportional hazards models adjusted for age, gender, duration of mRCC, prior treatments, comorbidities, metastatic sites, 1st targeted therapy, ECOG and MSKCC status, 2nd targeted therapy, and progression status (based on symptoms or imaging) in the first 6 months on 2nd line therapy. Reasons for imaging were also assessed. Results: Among the 192 patients included in the analysis, 25 received early imaging, 136 received guideline-adherent imaging, and 31 received delayed imaging. First imaging tests were more likely due to worsening symptoms or changes in a palpable mass, as opposed to routine monitoring, among patients with delayed vs. guideline adherent imaging (20.0% vs. 7.1%, P = 0.005). After adjusting for baseline characteristics, guideline-adherent imaging was associated with a 64% lower hazard of death compared to delayed imaging (hazard ratio (HR) = 0.36, 95% confidence interval (CI) 0.14 to 0.93, P = 0.035). Adjusted 1-year survival was 82% in the guideline-adherent compared to 67% in the delayed imaging group. The hazard of death did not differ between those with early vs. guideline-adherent imaging (HR = 1.05, 95% CI 0.35-3.12, P = 0.927). Conclusions: Among patients surviving 6 months after the initiation of 2nd targeted therapy for mRCC, timely first imaging within 2-6 months, consistent with guidelines, was associated with significantly prolonged overall survival compared to delayed imaging. Further investigation is warranted with larger samples.
Identification of novel and potentially targetable receptor tyrosine kinase alterations in colorectal carcinoma using a 341 gene hybrid capture-based next-generation sequencing assay.
Authors: Jaclyn Frances Hechtman, Maria E. Arcila, Donavan T. Cheng, David B. Solit, Rona D. Yaeger, David Michael Hyman, Michael F. Berger, Jinru Shia, Efsevia Vakiani, Ahmet Zehir, Marc Ladanyi
Journal: Journal of Clinical Oncology (2015)

11071 Background: The current mainstay of clinical molecular testing for advanced colorectal carcinoma (CRC) is mutation analysis for KRAS, NRAS, and BRAF to determine anti-EGFR therapy eligibility. However, the growing number and potential of targeted therapies has led to the need for broader molecular panels to triage patients. Here, we report our experience with a next-generation sequencing (NGS) assay that enables the detection as well as molecular characterization of CRC with rare and potentially targetable receptor tyrosine kinase (RTK) alterations. Methods: We use a hybrid capture-based NGS assay encompassing all exons of 341 cancer genes (MSK-IMPACT) to sequence tumor against matched normal to detect potentially actionable somatic alterations including point and indel mutations, copy number alterations, and selected structural rearrangements. CRC with hotspot mutations in KRAS/ NRAS exons 2-4 and BRAF exons 11 and 15 were excluded from further analysis as these downstream mutations often lead to primary resistance. Results: Seventy four of 164 CRC had wild type RAS/RAF. Twelve cases (16%) of this subgroup harbored RTK alterations previously reported to be activating and potentially targetable. Hotspot mutations commonly seen in other tumor types were also identified, including one each of EGFR p. L858R in a patient also harboring an ERBB2 p. S310F, EGFR p. L861R, and ERBB2 p. V842I a patient with ERBB2 amplification. One each of in-frame fusions of RTKs were also detected: ERBB2-GRB7 in a patient with ERBB2 amplification, RET-NCOA4, and ETV6-NTRK3. Additional RTK amplifications were also observed in the absence of other oncogene alterations, including FGFR1 (n = 3), ERBB2 (n = 2), MET (n = 1) . No ALK or ROS1fusions were detected in any of the 164 CRC. Of these 12 patients with potentially targetable RTK alterations, 3 have already enrolled in ‘matched’ targeted therapies. Conclusions: Using a broad molecular assay to interrogate potentially actionable mutations, approximately 16% of RAS/ RAF wild type CRC harbor RTK alterations that are known to be activating and potentially responsive to inhibition.
A Comprehensive Genetic Analysis of MDS Patients From Peripheral Blood Combining FISH- and SNP-Array-Analysis
Authors: Christina Ganster, Katayoon Shirneshan, Gabriela Salinas-Riester, Friederike Braulke, Julie Schanz, Katharina S. Götze, Gesine Bug, Peter Majunke, Aristoteles Giagounidis, Catharina Müller-Thomas, Andrea Kündgen, Ulrich Germing, Lorenz Trümper, Uwe Platzbecker, Detlef Haase
Journal: Blood (2012)
Adjuvant denosumab for breast cancer: What efficacy in the D-CARE trial will translate into cost effectiveness?
Authors: Nathan William Dana Lamond, Chris Skedgel, Daniel Rayson, Tallal Younis
Journal: Journal of Clinical Oncology (2014)

551 Background: Bone targeted agents are important therapies in the treatment of metastatic breast cancer and have a potential role in the adjuvant setting. Several trials and metaanalyses have suggested that adjuvant bisphosphonates may reduce breast cancer recurrence rates by 15% or more in postmenopausal women. Adjuvant denosumab is currently being investigated in D-CARE, an ongoing phase III trial. The aim of the current study was to estimate the absolute disease-free survival (DFS) advantage that would have to be observed in D-CARE for adjuvant denosumab to be considered cost-effective in the Canadian healthcare system. Methods: A Markov model was developed to calculate cumulative lifetime costs and quality-adjusted life year (QALY) gains for adjuvant therapy with and without denosumab in a hypothetical cohort of women with early-stage breast cancer. Costs, utilities and probabilities were derived from the literature. A one-way sensitivity analysis (SA) was performed to explore the relationship between a range of DFS hazard ratios (HR) and incremental cost-effectiveness ratios (ICER) with all other parameters held constant. Further one-way and probabilistic sensitivity analyses were performed to explore the effects of changes to other model parameters including menopausal status. The model took a direct payer perspective with all costs and benefits discounted at 3%. Results: The one-way SA showed that the ICER for adjuvant denosumab was directly related to the HR for DFS. At an ICER threshold of $100,000/QALY, the corresponding DFS HRs were 0.94 and 0.89 for pre and postmenopausal breast cancer patients, respectively. The ICER also varied with changes to other model parameters, but was stable over reasonable ranges of uncertainty. Conclusions: This model suggests that adjuvant denosumab will be considered cost-effective by current North American standards, should it reduce breast cancer recurrence rates by more than approximately 10%. In the event of positive results from D-CARE of at least this magnitude, the current anticipatory analysis may help inform treatment choices, influence drug funding decisions, and provide patients with timely access to disease-modifying therapy.
Randomized trials of adjuvant tamoxifen versus tamoxifen and octreotide LAR in early-stage breast cancer: NCIC CTG MA.14 and NSABP B-29.
Authors: Judy-Anne W. Chapman, Joseph P. Costantino, Bin Dong, Richard G. Margolese, Kathleen I. Pritchard, Lois E. Shepherd, Karen A. Gelmon, Norman Wolmark, Michael N. Pollak
Journal: Journal of Clinical Oncology (2012)

538 Background: MA.14 and B-29 examined whether the addition of Octreotide (SMS 201-995 pa LAR; OCT) to 5 years adjuvant tamoxifen (TAM) prolonged disease-free survival (DFS). Excessive gallbladder (GB) toxicity in B-29 led to DMC recommended stopping of OCT and MA.14 shortening of OCT to 2 years. Data for the 2 trials were pooled. Methods: Median follow-up of the 667 MA.14 patients was 9.8 years, and of the 893 B-29 patients, 6.8 years for ITT analysis. The primary endpoint was DFS, defined as time from randomization to time of (local, regional or distant) breast cancer recurrence; any second primary cancer other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death. The primary test statistic was a pooled stratified log-rank test, with stratification within each trial by applicant stratification factors. Multivariate assessment was with Cox regression. Results: MA.14 patients were all postmenopausal with 97% ≥50 years of age while 62% of B-29 women were ≥50. 53% of MA.14 patients were lymph node negative (LN-), while all of B-29 patients were LN-. 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while 53% of B-29 received concurrent chemotherapy. 90% of MA.14 patients were hormone receptor positive while 100% of B-29 were positive. MA.14 patients experienced a 5 year DFS rate of 80% on TAM and 76% on TAM+OCT, while B-29 patients had a 5 year rate of 88% for both arms. The pooled 5 year rates were 85% and 83%. Pooled univariate stratified Cox HR of TAM+OCT to TAM was 0.99 (95% CI 0.81-1.20; p-value= 0.69). The HR for MA.14 was 0.93 (0.72-1.19; p= 0.50) and for B-29 was 1.09 (0.80-1.50; p=0.59). Multivariate pooled HR of TAM+OCT to TAM was 0.98 (0.81-1.20; p=0.84). Patients who were older (p=0.0006), and had higher T stage (p&lt;0.0001) with LN+ (p=0.0008) had shorter DFS. Conclusions: OCT did not significantly improve DFS for women who were a broad spectrum of patients: pre- or post-menopausal, LN- or LN+, and received sequential, concurrent or no adjuvant chemotherapy. Neither study had the intended duration of OCT due to GB toxicity; thus, the results do not negate targeting the insulin - IGF-I receptor family.
Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production
Authors: Aurora Merovci, Carolina Solis-Herrera, Giuseppe Daniele, Roy Eldor, Teresa Vanessa Fiorentino, Devjit Tripathy, Juan Xiong, Zandra Perez, Luke Norton, Muhammad A. Abdul-Ghani, Ralph A. DeFronzo
Journal: Journal of Clinical Investigation (2014)
Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study.
Authors: Gilles A. Salles, Stephen J Schuster, Sven De Vos, Nina D. Wagner-Johnston, Andreas Viardot, Christopher Flowers, Matthias Will, Madlaina Breuleux, Wayne Russell Godfrey, Bess Sorensen, Ajay Gopal
Journal: Journal of Clinical Oncology (2015)

8529 Background: There is an unmet need for new treatment options in FL, particularly for heavily pretreated, high-risk patients refractory to anti-CD20 and chemotherapy. Idelalisib, a PI3Kδ inhibitor, showed antitumor activity and acceptable tolerability as monotherapy in a pivotal phase 2, open-label study in indolent non-Hodgkin lymphoma (iNHL) refractory to rituximab (R) and an alkylating agent (NCT01282424). This post hoc analysis evaluated efficacy and safety in the FL patient subset. Methods: Double refractory patients with histologically confirmed iNHL received oral idelalisib 150 mg BID until disease progression (PD) or unacceptable tolerability; patients with FL (grade 1, 2, or 3a; n = 72) were included in this analysis. Responses were evaluated by an independent review committee using standardized criteria. The primary endpoint was the overall response rate (ORR). Results: At study entry, patients’ median age was 62 y, 54% had a high-risk FLIPI score, 22% had bulky disease, and 17% had FL grade 3a. Median (range) number of prior treatments was 4 (2–12); 86% were refractory to their last therapy (32/50 to bendamustine). At data cutoff, median (range) treatment duration was 6.5 (0.6–31.0) mo, with 65 (90%) patients off treatment (PD, 38; adverse events [AEs], 15; investigator decision, 7; death, 5). Lymph node size decreased during treatment by ≥ 50% SPD in 57%. The ORR (95% CI) was 56% (43–67; P< 0.001), including 10 complete responses (CR) and 30 partial responses. Kaplan-Meier (KM)—estimated median (range) time to response was 2.6 (1.6–11.0) mo, median response duration was 11 mo (27 mo in patients with CR), and progression-free survival was 11 mo, substantially longer vs the last regimen. Median overall survival (OS) was not reached; KM-estimated OS at 1, 1.5, and 2 y was 87%, 74%, and 68%.The most common AEs (any/grade ≥ 3, %) were diarrhea (51/14), cough (32/0), pyrexia (29/4), fatigue (28/0), and nausea (28/3). Rates of grade ≥ 3 transaminase elevation, pneumonitis, neutropenia, anemia, and thrombocytopenia were 14%, 4%, 22%, 3%, and 6%. Conclusions: Idelalisib demonstrated rapid, durable responses and acceptable safety in highly refractory, relapsed FL patients with limited treatment options. Clinical trial information: NCT01282424.
Oncologic outcomes of radiation therapy following active surveillance for low- and intermediate-risk localized prostate cancer.
Authors: Ardalan Ahmad, Melvin Chua, Jure Murgic, Hamid Reza Raziee, Ali Hosni, Fabio Ynoe De Moraes, Narhari Timilshina, Robert G. Bristow, Alejandro Berlin, Antonio Finelli
Journal: Journal of Clinical Oncology (2017)

42 Background: To evaluate the oncologic outcomes and potential impact of delayed radical treatment in the form of radiotherapy (RT), in men with localized prostate cancer progressing after active surveillance (AS). Methods: We identified patients on AS subsequently treated with state-of-the-art RT (either dose-escalated image-guided intensity modulated radiotherapy [IG-IMRT] or low-dose-rate brachytherapy [LDR-BT]). Based on the clinical characteristics at time of AS progression, we compared the oncologic outcomes to matched patients treated with upfront RT after diagnose. One to two matching patients per AS case were identified from existing RT databases based on: age (+/- 3 years), clinical prognostic factors (NCCN risk group; PSA +/- 2ng/mL; cT category; primary and secondary Gleason score; percentage of diagnostic cores involved dichotomized at &lt; or &gt; 50%), and treatment modality (IG-IMRT or LDR-BT). We aimed to determine whether patients on AS have potentially compromised outcomes. Results: We identified 215 patients (out of 1070 AS cohort) undergoing RT after a median of 26 months (IQR 16-52.5) on AS. Median follow-up post RT was 4.8 years (IQR 2.9-7.2). No patient died of prostate cancer. At 5-years, the biochemical relapse free-, metastases free- and overall-survival rate were respectively 98.6%, 99.1%, 98.6% in the AS cohort. Matched cohort comprised 400 patients treated with IG-IMRT (71%) or LDR-BT (29%). Adequate matching was confirmed. The median follow-up post RT was 8.2 years (IQR 4.7-10). At 5-years, biochemical relapse free-, metastases free- and overall-survival rates of 98.5%, 98.7%, 93.7% respectively, which were not statistically different compared to those patients treated upon AS progression. Conclusions: Curative-intent radiotherapy (i.e. dose-escalated IG-IMRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Moreover, the delay of therapy after a period of AS does not appear to result in inferior oncologic outcomes compared to patients with similar risk characteristics undergoing upfront radical radiotherapy.
Analysis of <i>KRAS/NRAS</i> and <i>BRAF</i> mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC).
Authors: Kelly S. Oliner, Jean-Yves Douillard, Salvatore Siena, Josep Tabernero, Ronald L. Burkes, Mario Edmundo Barugel, Yves Humblet, Gyorgy Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocáková, Paul Ruff, Maria Blasinska-Morawiec, Martin Smakal, Richard Thomas Williams, Alan Rong, Jeffrey S. Wiezorek, Roger Sidhu, Scott D. Patterson
Journal: Journal of Clinical Oncology (2013)

3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = &lt; 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]