tbuckley/cabot-search huggingface dataset:
Efficacy of trastuzumab re-therapy in routine treatment of HER2-positive breast cancer patients who relapsed after completed (neo-)adjuvant anti-HER2 therapy.
Authors: Lars Christian Hanker, Thomas Hitschold, Tobias Hesse, Andrea Grafe, Frank Gerhard Foerster, Jan Klaus Schroeder, Jan Janssen, Dietmar Arno Reichert, Carsten Hielscher, Jasmin Greinemann, David Julian Borquez, Marcus Schmidt
Journal: Journal of Clinical Oncology (2013)

602 Background: Addition of trastuzumab (Roche; T) to chemotherapy (CT) has improved outcomes in patients (pts) with HER2+ breast cancer at all stages, including locally advanced and metastatic disease. Anti-HER2 re-treatment with T is an increasingly used therapy option for the treatment of recurrent/metastatic breast cancer (MBC). However, limited data on T re-treatment is currently available. Methods: Patients with locally recurrent and/or MBC who received T re-therapy were included in this non-interventional study. Among 232 pts enrolled at 121 sites in Germany, 174 pts (33 locally recurrent disease, 141 MBC) were already sufficiently documented to be analyzed for efficacy of T re-therapy in this ongoing study. Progression-free survival (PFS) was assessed by the investigator. Results: The median disease-free interval (calculated from the time of resection of the primary tumor to diagnosis of local recurrence/MBC) was 3.1 years. Median duration of re-therapy with T was 9.3 months. The median PFS of all patients was 10.1 months (95% confidence interval (CI), 8.5 to 13.1). PFS for pts with only locally recurrent disease (n= 33) was 23.6 months. PFS for MBC pts (n=141) was 8.9 months (95% CI, 7.4 to 10.6). For pts with visceral metastases (n=96) a PFS of 8.0 months compared to 10.1 months in patients with only non-visceral (n=45) was recorded. 104 pts were re-treated with T + CT (&gt;70% paclitaxel, vinorelbine, capecitabine or docetaxel alone; PFS= 9.3 months), 26 pts with T + hormonal therapy (HT) (mostly anastrozole, fulvestrant, exemestane, letrozole or tamoxifen; PFS=10.1 months), 24 pts with T+CT+HT (PFS= 19.9 months) and 20 pts with T monotherapy (PFS= 9.4 months). Conclusions: This study provides clinical evidence that re-application of T in combination with either CT, HT or alone is effective in the routine treatment of patients with MBC and/or locally recurrent disease. The benefit observed for pts receiving first-line treatment with T in combination with taxane in pivotal trials as well as recently published data seems comparable to the presented results of pts receiving T re-therapy.
Translational research (TR) results from pointbreak: A randomized, open-label, phase III study of pemetrexed (Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by maintenance pem+bev (Pem Arm) versus paclitaxel (Pac)+cb+bev followed by maintenance bev (Pac Arm) in patients (pts) with stage IIIB or IV nonsquamous non-small cell lung cancer (ns-NSCLC).
Authors: Edward B. Garon, Jyoti D. Patel, Scott Myrand, Tuan Nguyen, Craig H. Reynolds, David R. Spigel, Robert C. Hermann, Jingyi Liu, Susan C. Guba, Ramaswamy Govindan, Mark A. Socinski, Philip Bonomi
Journal: Journal of Clinical Oncology (2013)

8086 Background: Results of PointBreak were previously reported. Correlative tissue TR results are presented. Methods: Of 939 pts in the intent-to-treat population (ITT), 211 (22.5%) signed TR consent forms and had evaluable samples. Specimens were analyzed for: Epidermal Growth Factor Receptor (EGFR) mutations by polymerase chain reaction (n=132); thyroid transcription factor-1 (TTF-1) (n=205), thymidylate synthase (TS) (n=189), and folate receptor-alpha (FR-α) (n=180) by immunohistochemistry (IHC) (H-scores range, 0-300). H scores were dichotomized based on positive (&gt;0)/negative (=0) cutpoint. Adjusted Cox/logistic regression determined correlations between overall survival (OS), progression-free survival (PFS), response rate (RR), and dichotomous IHC markers. A 2-sided test with α = 0.05 and 0.1 evaluated treatment and interaction effects, respectively. Results: Median (m) OS and mPFS were similar in the ITT and TR populations for both arms. 11/132 (8.3%) pts had activating EGFR mutations. For TS or FR-α, no significant between-arm differences in OS, PFS and RR were seen. 139/205 (67.8%) pts had positive TTF-1 (TTF-1+). TTF-1+ pts, compared with TTF-1-, independent of treatment, had significantly longer mOS (14.9 vs 8.7 mos, HR 0.48, p&lt;0.001), mPFS (6.9 vs 4.5 mos, HR 0.62, p=0.006), and higher RR (38.9% vs 19.7%, OR 2.68, p=0.008). For TTF-1+ pts, compared with Pac arm, Pem arm had longer mOS (17.6 vs 12.8 mos, HR=0.7, p=0.08; interaction p=0.12) and mPFS (7.3 vs 5.8 mos, HR=0.78, p=0.20; interaction p=0.261); although not statistically significant. Conclusions: The number of pts with EGFR mutations was too small to draw conclusions. No significant between-arm differences for TS and FR-α were seen. Longer survival in TTF-1+ pts suggests TTF-1 expression is prognostic. Additional studies will be needed to better understand trends favoring pem for survival among TTF-1+ pts and other prognostic and/or predictive relationships of these markers. Clinical trial information: NCT00762034.
Expression of p16, ERCC1, and EGFR amplification as predictors of responsiveness of locally advanced squamous cell carcinomas of head and neck (SCCHN) to cisplatin, radiotherapy, and erlotinib: A phase II randomized trial.
Authors: Melissa Austin, Rodney Schmidt, Upendra Parvathaneni, Julie E. Bauman, David N. Hayes, Michael A. Papagikos, Keith D. Eaton, Jay Justin Liao, Eduardo Mendez, Brenda F Kurland, Shawn Xiaoyu, Sarah G. Wallace, Renato Martins
Journal: Journal of Clinical Oncology (2012)

5515 Background: This study evaluated the expression of p16 and ERCC1 and EGFR amplification as predictive and prognostic factors in a recently completed phase II randomized trial comparing cisplatin (100 mg/m 2 on d 1, 22, 43) with radiotherapy (70Gy) +/- erlotinib (150 mg/d during radiotherapy) in locally advanced SCCHN. p16 (HPV surrogate) is a known prognostic factor in oropharyngeal SCCHN, and high ERCC1 expression has been correlated with resistance to cisplatin. EGFR gene copy number may be prognostic in SCCHN and alter response to erlotinib. Methods: Pretreatment formalin-fixed, paraffin-embedded tumor tissue was available for 84/204 patients. EGFR copy number was assessed using Vysis LSI DNA probes, and immunohistochemistry was performed on Leica Bond III machines using Lab Vision ERCC-1 (8F1) and CINtec p16 antibodies. All assays were performed in accordance with manufacturer instructions; all studies were reviewed by a single Pathologist (MA) who was blinded to patient outcome. Logistic regression and Cox regression models fit a treatment arm by marker interaction and tested selected linear contrasts. Results: Efficacy analysis showed no difference in complete response rate (CRR) and progression-free survival (PFS) between treatment arms. However, PFS in both arms was better than historical comparisons, with only 46 events over a median follow-up of 23 months. Positivity in p16 was associated with greater CRR (OR 3.5, p=0.03) and longer PFS (HR=0.38; p= 0.07). The CRR effect was greater for the erlotinib arm (OR 8.1, p=0.01) than for Arm A (OR 1.5, p=0.56). The ERCC1 (+) rate was 46% (39/84).ERCC1 expression above the median was not associated with worse CRR (OR 0.69; p=0.46) or PFS (HR 0.99; p=0.98). Only 4 tumors showed EGFR amplification precluding further analysis. Conclusions: p16(+) tumors had a better outcome, similar to other recent trials, and erlotinib seemed to increase the CRR among p16(+) tumors. ERCC1 expression did not predict chemoradioresistance in this study. EGFR amplification was too rare in the tested population to assess predictive or prognostic value.
The role of stromal cancer-associated fibroblasts in pancreatic cancer
Authors: Dagny von Ahrens, Tushar D. Bhagat, Deepak Nagrath, Anirban Maitra, Amit Verma
Journal: Journal of Hematology & Oncology (2017)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6. The role of downstream signaling pathways including JAK/STAT, mTOR, sonic hedge hog (SHH), and NFkB have also been shown to play an important function in PDAC-CAF cross talk. The role of autophagy and other metabolic effects on each cell type within the tumor have also been proposed to play roles in facilitating CAF secretory function and enhancing tumor growth in a low-glucose microenvironment. Targeting the stroma has gained interest with multiple preclinical and clinical trials targeting SHH, JAK2, and methods of either exploiting the secretory capability of CAFs to enhance drug delivery or inhibiting it to prevent its influence on cancer cell chemoresistance. This review summarizes the most recent progress made in understanding stromal formation; its contribution to tumor proliferation, invasion, and metastasis; its role in chemoresistance; and potential therapeutic strategies on the horizon.
Translating genomics into risk prediction
Authors: Emily S Wan, Dawn L DeMeo
Journal: Thorax (2017)

Cigarette smoking is a leading risk factor in the development of cardiovascular, pulmonary and malignant diseases worldwide.1 Yet, it remains one of the most challenging environmental exposures to quantify. Rudimentary categorisations of ‘never’, ‘former’ and ‘current’ smoker capture only a fraction of the complexity associated with the exposure. Attempts to quantify cumulative cigarette smoke exposure, for example by calculating ‘pack-years’, are notoriously imprecise, partially because of a failure to account for variations in behaviour such as (1) depth of inhalations, retention time before exhalation and timing between puffs, (2) intermittent periods of abstinence or relapse, and (3) a reliance on self-reported recall of smoking habits over extended periods of time (often years to decades). Additionally, biological differences related to age, gender, body size, and variations in absorption and metabolism among smokers further complicate our attempts to quantify the ‘effective exposure’ to cigarette smoke for any given individual.

Given these complexities, the use of biomarkers, both qualitative and quantitative, as an objective measurement of ‘effective exposure’ is conceptually appealing. To date, the most widely used smoking biomarkers are cotinine and carbon monoxide (CO). Measurement of CO, either in exhaled breath or in blood as carboxyhaemoglobin, has been shown to correlate with smoking intensity, however the relatively short half-life of CO (t1/2 1–6 hours) limits its utility to assessments of recent smoking behaviours.2 Cotinine, a direct metabolite of nicotine which is measurable in the blood, urine and tissues is another well validated biomarker of cigarette smoke exposure. The slightly longer half-life (t1/2 16–20 hours), as well as the assessment of cotinine in slower growing tissues such as hair and nail clippings, extends the potential period of monitoring for this assay to the order of weeks to months. …
Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness
Authors: Soah Lee, Vahid Serpooshan, Xinming Tong, Sneha Venkatraman, Meelim Lee, Jaecheol Lee, Orlando Chirikian, Joseph C. Wu, Sean M. Wu, Fan Yang
Journal: Biomaterials (2017)
Willingness of patients to provide biologic samples for pharmacogenomic testing.
Authors: Tenneille T. Loo, Sinead Cuffe, Henrique Hon, Petra Martin, M Catherine Brown, Shabbir M.H. Alibhai, Natasha B. Leighl, Celine Mascaux, Ming-Sound Tsao, Frances A. Shepherd, Xin Qiu, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2013)

6543 Background: Additional biopsies and/or blood sampling (i.e.: germline and plasma markers, circulating DNA or tumour cells) may be necessary to complete pharmacogenomic testing (PGT) in some patients. Cancer patients’ perspectives on providing additional biospecimens are important in addressing potential knowledge translation barriers. Methods: 790 clinic patients from the Princess Margaret Cancer Centre (Toronto, Canada) were interviewed with a standardized questionnaire, representing a wide distribution of adult solid and hematological disease sites. Study endpoints included patient preferences and willingness to provide biological samples (new blood, new biopsy, or pre-existing tumor samples) on a 5-point Likert scale. Univariate and multivariate models were created using SAS 9.3. Results: Patients were 49% female; 77% Caucasian/12% Asian; median age 58 years; and 67% had completed high school. Median household income was evenly trichotomized at $50K and $100K. Despite 33% of the patients being uncomfortable with the level of their knowledge about PGT, 75% agreed that additional tests would be beneficial to their health. Patient willingness to provide new samples was 88% for blood and 53% for biopsy, and 27% preferred existing tumor samples to be used in lieu of additional sampling. Caucasians and those with the highest incomes were more agreeable to providing blood and/or biopsy samples, whereas non-Caucasians and low-income earners preferred utilization of existing tumor samples over additional blood sampling (p&lt;0.05). Conclusions: Patients were more willing to provide a new blood sample than a biopsy sample for PGT. Despite the vast majority agreeing to the potential benefit of additional sampling, only half were willing to provide a new biopsy sample. Level of willingness was related to sociocultural and economic factors. Improved patient education and increased efforts to design blood-based markers may improve uptake of PGT.
Lenalidomide in relapsed/refractory mantle cell lymphoma post-bortezomib: Subgroup analysis of the MCL-001 study.
Authors: Michael E. Williams, Andre Goy, Rajni Sinha, Sevgi Kalayoglu Besisik, Johannes W. Drach, Rod Ramchandren, Lei Zhang, Sherri Cicero, Tommy Fu, Thomas E Witzig
Journal: Journal of Clinical Oncology (2013)

8534 Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Single-agent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N=134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio=0.193; p=0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. [Table: see text]
Comparison of anal HPV natural history among men by country of residence: Brazil, Mexico, and the United States
Authors: Staci L. Sudenga, Alan G. Nyitray, B. Nelson Torres, Roberto Silva, Luisa Villa, Eduardo Lazcano-Ponce, Martha Abrahamsen, Maria Luiza Baggio, Jorge Salmeron, Manuel Quiterio, Anna R. Giuliano
Journal: Journal of Infection (2017)
ARIEL 2/3: An integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response.
Authors: Elizabeth M. Swisher, Iain A. McNeish, Robert L. Coleman, James Brenton, Scott H. Kaufmann, Andrew R. Allen, Mitch Raponi, Heidi Giordano, Lara Maloney, Jeff Isaacson, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2014)

TPS5619 Background: PARP inhibitors (PARPi) are active in patients (pts) with mutations in BRCA, a critical component of homologous recombination repair (HRR). PARPi activity extends beyond BRCA, most likely in tumors with other mutations leading to homologous recombination deficiency (HRD), although the best molecular predictors of PARPi response are unknown. Platinum sensitivity, often used as a surrogate predictive indicator for PARPi response, does not adequately identify all pts likely to respond. Next generation sequencing (NGS) analysis of tumor tissue can identify somatic BRCA mutations as well as other gene alterations in the DNA repair pathway and thus may be a superior method for selection of pts for PARPi therapy. Rucaparib, an oral PARPi, is being developed for treatment of high grade ovarian cancer (HGOC). A novel, integrated, translational-clinical program (ARIEL) is ongoing to identify pts who may benefit from rucaparib treatment. Methods: ARIEL2 (NCT01891344) is a Phase 2 trial of rucaparib that aims to identify a molecular HRD signature that predicts response. The signature will be applied prospectively to the analysis of ARIEL 3 (NCT01968213), a Phase 3 study in a similar population. ARIEL2 is ongoing. Eligible pts (n=180) have relapsed, platinum-sensitive HGOC and measurable disease. All pts have a pre-dose biopsy and provide archival tumor tissue. Tumor tissue HRR status assessment uses Foundation Medicine’s NGS platform and Univ. of Washington’s BROCA-HR panel, with the initial HRD algorithm developed using in vitro/in vivo and TCGA (and similar) bioinformatic data. Key efficacy analyses to be correlated with tumor HRR status are PFS and response (RECIST v1.1, GCIG CA-125). The number of gBRCA pts is limited to maximize analysis of non-gBRCA response predictors. The optimized algorithm will then be tested prospectively in ARIEL3 (n=540), an ongoing, randomized (2:1), placebo-controlled maintenance trial in platinum-sensitive HGOC in remission after platinum-based therapy. The primary endpoint of ARIEL3 is PFS in HRD subgroups determined by NGS analysis of archival tumor tissue using the ARIEL2 optimized algorithm. Clinical trial information: NCT01891344 and NCT01968213.
Clinical trials versus clinical practice in colorectal cancer: Equivalent populations?
Authors: Alejandra Magdaleno Cremades, María del Carmen Ors Castaño, María Ballester Espinosa, Marta Llopis Cuquerella, María del Rocío Ramirez Belloch, Vicente Boix Aracil, Lucía Gómez González, Roberto Morales Giménez, Elena Asensio Martinez, Javier Gallego Plazas
Journal: Journal of Clinical Oncology (2017)

802 Background: Clinical trials are criticized due to inclusion of selected populations. The aim of this analysis is to compare populations included in clinical trials which justify treatment recommendations in stage III and IV colorectal cancer (CRC) to patient populations in our area. Methods: Data related to age, sex, primary tumor and stage of CRC patients consecutively diagnosed in Vega Baja Hospital and Elche University General Hospital were collected. Also data regarding the same variables were collected from the publications of clinical trials which justify adjuvant treatment in stage III colon cancer and combination treatment with chemotherapy and targeted therapies in stage IV CRC. Results: We analyzed 249 patients with stage III colon cancer and 237 patients with stage IV CRC from our area. In our experience, 56.6% of stage III colon cancer were males, and median age was 66.2 years (23 - 91), with 41.8% ≥ 70 years. In clinical trials supporting adjuvant treatment 54 - 56.1% of patients were males, and median age was 59 - 61 years (19-83), with 14 - 21.7% ≥ 70 years. In our experience 64.4% of stage IV CRC patients were males, and median age was 67.2 years (38-89), 76.4% primary tumor in colon. In clinical trials supporting combination treatment with chemotherapy and targeted therapies 60-67% of patients were males, and median age was 59.2 – 62 years, primary tumor in colon 57.9 – 81% (Table). Conclusions: Patient populations included in clinical trials which support standard treatment in CRC are younger to those in our area. This fact, added to the restrictions based on inclusion and exclusion criteria of clinical trials, justify the qualification of “selected” to these populations not being representative of our clinical practice. [Table: see text]
Pharmacodynamic evaluation of pCDC2 as the target engagement biomarker to assess activity of MK-1775 a Wee1 tyrosine kinase inhibitor.
Authors: Shelonitda Rose, Jonathan D. Cheng, Johnny Viscusi, Robert Iannone, Jan HM Schellens, Suzanne Leijen, Geoffrey Shapiro, Anna C. Pavlick, Amit M. Oza, Lee S. Rosen, Alessandra Tosolini, Raymond Lam, Tim Demuth
Journal: Journal of Clinical Oncology (2012)

e13598 Background: Wee1 kinase regulates the G2 checkpoint through phosphorylation of CDC2. MK-1775 is a first-in-class inhibitor of Wee1, and thereby reduces pCDC2 levels relative to CDC2. pCDC2therefore can be used as a target engagement (TE) biomarker to assess activity of MK-1775. This was investigated in a phase I first-in-man clinical trial of MK-1775. Methods: This is a multicenter, open-label, non-randomized phase I dose escalation study in patients with locally advanced or metastatic solid tumors. MK-1775 was administered orally in escalating doses as monotherapy, and either single dose or multi-dose in combination with chemotherapy including cisplatin, carboplatin and gemcitabine. Serial skin biopsies were performed at baseline and either 8, 24 or 48 hours following MK-1775 administration and analyzed by IHC for CDC2 and pCDC2. Based on preclinical efficacy experiments, TE was defined as a decrease of pCDC2 of at least 50% (or fold change &gt; 0.50) from pre- to post-dose MK-1775. Results: To date a total of 176 patients have received at least one dose of MK-1775 either as monotherapy or in combination (single or multi-dose MK-1775) with chemotherapy at doses ranging from 25 mg to 1300 mg to define maximum tolerated dose. Dose dependent decreases in pCDC2 were observed in skin biopsies between pre-dose and post-dose treatment in all treatment groups. TE with monotherapy was achieved at 325 mg. TE with multi-dose MK-1775 in combination with cisplatin and carboplatin were achieved at 125 mg BID and 225 mg BID. Gemcitabinecombination treatment is on-going. In contrast, chemotherapy alone resulted in an increase of pCDC2. Conclusions: Based on preclinical data, in this first-in-man clinical trial of MK-1775, we were able to demonstrate TE required for maximal efficacy at tolerable doses of MK-1775 either as a single agent or in combination with chemotherapy. [Table: see text]