tbuckley/cabot-search huggingface dataset:
Variation in mechanisms of acquired resistance (AR) among EGFR-mutant NSCLC patients with more than one post-resistant biopsy.
Authors: Zofia Piotrowska, Matthew J. Niederst, Mari Mino-Kenudson, Vicente Morales-Oyarvide, Linnea Fulton, Elizabeth L. Lockerman, Emily Howe, Justin F. Gainor, Panos Fidias, Subba Digumarthy, Rebecca Suk Heist, Alice Tsang Shaw, Jeffrey A. Engelman, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2014)

8053 Background: AR typically develops after 9-12 mos of EGFR TKI therapy among EGFR-mutant patients (pts). Here we report a unique series of 42 EGFR mutants who had >1 post-resistant biopsy (bx) that illustrates the heterogeneity of AR within individual pts. Methods: We analyzed prospective data from 126 EGFR mutants with advanced NSCLC who had ≥1 bx after AR developed on EGFR TKI therapy. All biopsies underwent multiplexed CLIA-certified SNaPshot genotyping. Some pts consented to provide tissue for patient-derived cell-line (PDCL) establishment. 42 pts had >1 post-AR bx. We collected data on EGFR TKI therapy, mechanisms of AR observed over multiple biopsies, bx safety and correlations between clinical and PDCL data. Results: Among 42 pts with multiple post-AR biopsies, median age= 57 (range 39-88), 73% were female, 62% had EGFR exon 19 deletion and 31% had L858R. The median number of post-AR biopsies was 2 (range 2-5). While the original EGFR mutation was uniformly maintained, we observed variation in AR mechanisms among 20/42 pts, with changes in T790M status over time in 10 pts. Notably, both gain and loss of T790M were observed on serial biopsies, without a clear correlation to the timing of EGFR TKI therapy or bx site. Changes in histology (8), development of EMT (1) and EGFR amp (1) were also seen. 22/42 pts had no variations in detected mechanisms of AR on serial biopsies, including T790M (n=11), MET amp (2), EGFR amp (1), both MET and EGFR amp (1), SCLC transformation (1), BRAF mutation (1), and no AR mechanism identified (5). Repeat biopsies were safe, with 2.4% bx-related complications and no serious complications. Conclusions: We observed frequent and unexpected changes in the mechanism of AR, particularly T790M status, in pts undergoing serial biopsies, suggesting heterogeneity of resistant clones in these pts. Among pts with T790M, 48% gained or lost the mutation over time. Relationship of AR mechanisms to therapy at the time of bx, bx location and correlations with PDCL data to understand their biologic implications will be presented. Our data suggest serial biopsies in EGFR pts are informative and safe, and may become increasingly important as T790M-specific TKIs become available.
CA184-161: A phase I/II trial of vemurafenib and ipilimumab in patients with BRAF V600 mutation-positive metastatic melanoma.
Authors: Antoni Ribas, F. Stephen Hodi, John F. Kurland, Vafa Shahabi, Stephen Francis, Cyril Konto, Andrew K. Joe, Ioannis Lainas, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2012)

TPS8603 Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipi significantly improved overall survival (OS) in two separate phase III trials of metastatic melanoma (MM): (1) at 3 mg/kg as monotherapy in previously treated patients and (2) at 10 mg/kg combined with dacarbazine in previously untreated patients. The most common drug-related adverse events with ipi were immune-related, and were generally reversible using treatment guidelines. Vemurafenib (vem) is a potent inhibitor of BRAF V600E-mutated kinase, which occurs in ~50% of MM. In clinical studies, vem produced objective response rates of ~50% with a significant improvement in the rate of OS in patients with previously untreated BRAF V600-positive MM. The purpose of this phase I/II study is to determine the safety and feasibility of ipi plus vem in patients with BRAF V600-positive MM, and to evaluate the efficacy of the combination in comparison to historical results observed with each agent alone. Methods: In phase I, an escalating dose design is used to assess safety/tolerability and to determine the maximum tolerated dose (MTD) of each agent. Vem will initially be given alone for 28 days at 960 mg p.o. BID, followed by vem in combination with ipi i.v. at 3 mg/kg [induction (q3w x 4) and maintenance (q12w)]. The next cohort will receive vem at 960 mg plus ipi increased to a dose of 10 mg/kg. Phase I will enroll an estimated 20 patients who have not previously received a CTLA-4 antagonist or BRAF inhibitor. If new or heightened frequency or severity of toxicities is not observed, a phase II single-arm extension at the MTD of each agent will be conducted in patients with previously untreated MM. The primary objectives of phase II (estimated enrollment of 30 patients) are to obtain preliminary evidence of efficacy (OS, 1- and 2-year survival rates) and to evaluate safety of the combination. Major inclusion criteria are ≥ 18 years of age, BRAF V600-positive MM, measurable tumor, no active brain metastasis, and an ECOG PS of 0-1. The first patient was enrolled in November 2011 and enrollment is ongoing (ClinicalTrials.gov identifier: NCT01400451).
Up-titration of sorafenib for hepatocellular carcinoma: Impact on duration of exposure and cost.
Authors: David Edward Kaplan, Shun Yu, Tamar H. Taddei, Kim Anna Reiss, Rajni Mehta, Kathryn D'Addeo, Ayse Aytaman, Kristel Hunt, Rena Fox, Michelle Baytarian, Adriana Valdarrama
Journal: Journal of Clinical Oncology (2017)

385 Background: Few data exist how sorafenib starting dose impacts duration of exposure and cost of sorafenib therapy for patients with HCC. Methods: HCC patients exposed to sorafenib, initial doses, number of sorafenib fills, and medication exposure days were identified from the VA CDW using ICD9 codes and pharmacy records. ICD9 codes, CPT codes, AUDIT-C surveys and laboratory tests were utilized to characterize underlying liver disease, calculate Child-Turcotte-Pugh (CTP) and MELD scores. Two abstractors achieved 100% chart verification of tumor number, size, MVI/EHS on imaging proximate to sorafenib to quantify Barcelona Clinic Liver Cancer (BCLC) stage and to determine the provider specialty initiating sorafenib. Results: 2292 patients with BCLC B-C HCC, CTP A cirrhosis with ECOG PS ≤ 2 prescribed sorafenib for HCC between 2007 and 2015 were included in this interim analysis. Median age was 62; 98.8% were male, 61.8% white/26.0% black; Pre-sorafenib BCLC B-43%/C-57%. Prescription at full-dose became less common over 2007-2015, dropping from 80% to 48%. First-dose up-titration was more commonly done by hepatologists (21% vs. 4.5%, p &lt; 0.0001), but oncologists were more likely to up-titrate at the second prescription (8.9% vs. 3.8%, p &lt; 0.001). Overall, 38% of first sorafenib prescriptions were initiated at doses below 800mg/day; 43% were up-titrated whereas 57% never up-titrated. Patients starting at &lt; 800 mg/d received fewer total pills (median 284 vs. 360, p = 0.008) but a greater number of prescription fills (median 4 vs. 3, p &lt; 0.0001) and longer exposure duration (median 120 vs 90 days, p = 0.0012) at lower total cost (median $8,143 vs $9,685, p &lt; 0.0001). Median overall survival for those starting &lt; 800mg/d was not significantly different from full dose initiators (median 284 vs. 292 days, p = 0.33). Conclusions: Initiation of sorafenib &lt; 800mg/d was associated with lower pill utilization, but longer exposure duration and equivalent survival at lower cost. Starting at a lower dose with uptitration may select patients with a higher likelihood of sustained benefit and improve cost-effective utilization of resources. This approach should be tested prospectively.
Phase I clinical and pharmacokinetic study of the farnesyl transferase inhibitor BMS-214662 administered intravenously for five consecutive days in patients with advanced malignancies
Authors: R. S. McDermott, N. J. Meropol, L. M. Weiner, G. Yeslow, G. R. Hudes
Journal: Journal of Clinical Oncology (2004)

2033 Background: BMS-214662 is a potent inhibitor of farnesyltransferase (FTase), an enzyme that modifies the carboxy-terminal of many cell-signaling proteins enabling membrane association and activation. We conducted a Phase I trial to determine the maximum tolerated dose (MTD), pharmacokinetic (PK), and pharmacodynamic (PD) properties of BMS-214662 given as a one hour infusion for five days q21 days in patients with refractory solid tumors. Methods: Nineteen patients (13 males, 6 females, median age 65, PS 0–2) received BMS-214662 at doses ranging from 24 to 181 mg/m2 daily. Dose was escalated in successive single patients by increments of 50% until the first CTC grade II toxicity, when a modified Fibonacci scheme with at least 3 patients per cohort was utilized. PK/PD analysis was carried out on days 1 and 5 of cycle one. Results: Total clearance and VSS were dose-independent and ranged from 268 to 540mL/min/m2 and 17.4 to 39.6L/m2 respectively. BMS-214662 Cmax increased from 625 (± 82) to 9675 (± 5080)ng/ml and AUC from 728 (± 43) to 12,372 (± 4964)ng-hr/ml, over the dose range studied. AUC values were similar on days 1 and 5. No significant decreases from baseline in peripheral-blood mononuclear cell FTase activity using a H-ras peptide as substrate were seen at doses <81mg/m2, 1 hour post treatment, while a >80% reduction in activity was seen following 16/22 doses assessed in 13 patients receiving ≥81mg/m2. This inhibition was maintained at 6 hours in only 2 patients, both treated at 81mg/m2. Diarrhea and neutropenia were principal Gr 3–4 toxicities, with Gr 3 vomiting (1 patient), and Gr 3 thrombocytopenia (1 patient) also seen. Toxicity was dose-limiting in 4 of 8 patients receiving ≥121 mg/m2 vs. 0 of 11 patients treated at <121 mg/m2. The MTD is 81 mg/m2day. Conclusions: We conclude that the daily times five, q21 day schedule of BMS-214662 is safe at doses up to 81 mg/m2/day, but results in only transient inhibition of tissue FTase. Alternative schedules that maintain plasma concentrations sufficient to inhibit FTase may be required to achieve clinical activity Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
A phase II study of alternative sunitinib scheduling in patients with metastatic renal cell carcinoma.
Authors: Eric Jonasch, Rebecca Slack, Daniel M. Geynisman, Matthew I. Milowsky, Kimryn Rathmell, Summer Stovall, Donna Juarez, Elizabeth R. Plimack, Nizar M. Tannir, Brian I. Rini
Journal: Journal of Clinical Oncology (2017)

533 Background: Sunitinib is an oral antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3 rd and 4 th weeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with all patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade &gt; 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade &gt; 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure that the upper bound of a 95% confidence would fall below the standard schedule rate of 25%-30% if the sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS), and dose reductions. Results: Between August 2014 and April 2016, a total of 60 patients were enrolled, and 59 were treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events that are at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea, or HFS when compared to historical data from trials employing a 4/2 schedule. Efficacy data were comparable to studies employing a 4/2 schedule. Clinical trial information: NCT02060370.
Survival following stage II/III colon cancer (CC): Accent-based comparison versus matched general population (MGP).
Authors: Lindsay A. Renfro, Axel Grothey, David J. Kerr, Daniel G. Haller, Thierry Andre, Eric Van Cutsem, Leonard Saltz, Roberto Labianca, Charles L. Loprinzi, Steven R. Alberts, Hans-Joachim Schmoll, Chris Twelves, Greg Yothers, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2014)

3601 Background: The post-treatment survival experience of CC patients (pts) is well described in the literature, which states that cure is a probable outcome for some pts; formal survival comparisons vs. MGP are limited. Methods: Data from 32,745 pts enrolled to 25 randomized adjuvant trials conducted from 1977-2012 in 41 countries were pooled and 8 years of follow-up considered. The observed long-term survival experience of ACCENT pts was compared to the expected survival from a sex, age, country, and year MGP, overall and by stage (II, III), sex, treatment (surgery, 5FU, 5FU+oxaliplatin), age (< 70, 70+), year (pre/post 1990), and recurrence (Y/N). Comparisons were made at randomization (rand) and repeated conditional on survival to 1, 3, 5 years. CC/MGP equivalence was tested and observed Kaplan-Meier rates compared with expected MGP rates 3 years out from each landmark. Results: Within each ACCENT cohort, long-term survival of CC pts remained statistically worse than the MGP, though it improved over time given survival to certain landmarks. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free pts achieved subsequent 3 year survival rates within 5% of the MGP; pts without recurrence had subsequent 3 yr. survival within 0.5% of MGP. Conclusions: Among CC pts on clinical trials who survive up to 5 years, subsequent long-term survival remains poorer than a MGP, but notably stage II, age 70+, received oxal, and recurrence-free pts achieve similar rates. These findings emphasize the need for access to quality care and the continued need for improved treatment/follow-up strategies. % Diff (MGP - CC) survival 3 yrs post baseline time point. Baseline time point All Stage Trt Age Sex 1990 Recur II III Surg 5FU Oxal <70 70+ M F Pre Post Y N Rand 14 4.8 18 19 14 8.6 15 12 13 15 17 14 - - 5 yr 5.2 2.8 6.6 7.1 5.2 4.5 5.7 3.1 5.2 5.3 5.8 5.1 46 0.5
Primary metastatic breast cancer in elderly: An international comparison.
Authors: Willemien Van De Water, Esther Bastiaannet, Kathleen Egan, Anton J.M. de Craen, Cornelis J. H. Van De Velde, Gerrit-Jan Liefers, Martine Extermann
Journal: Journal of Clinical Oncology (2013)

e20545 Background: In primary metastatic breast cancer in elderly, both advanced age and advanced disease limit life expectancy. It remains a challenge to balancing the benefit from therapy and risk of adverse events impeding quality of life or survival. Our aim was to compare management and outcome of primary metastatic breast cancer in elderly treated in two health care settings. Methods: The first cohort comprised a hospital based series in the United States (US, n=73 women diagnosed between 2003 and 2012); the second comprised a population based series in The Netherlands (NL, n=125 women diagnosed between 2008 and 2012). All were ≥65 years at the time of diagnosis. Country was used as an instrumental variable, as a proxy for randomization to either care setting. Multivariable survival analyses were adjusted for age, comorbidity, T stage, nodal stage and hormone receptor status. Results: Characteristics of US and NL patients were similar, except for age (median 72; 79 years, p&gt;0.001). US patients more often received breast surgery and chemotherapy in particular, less often endocrine therapy as monotherapy (Table), and received more lines of treatment (median 4; 2, p&lt;0.001). Adverse events rarely were a reason for a next line of therapy (6% in each cohort). Three-year survival tended to be higher in US patients (HR for US patients was 0.71 (95% CI 0.48-1.05), p=0.089). Multivariable analyses revealed no survival differences (HR for US patients was 0.86 (95% CI 0.53-1.38), p=0.523). Results were similar after stratifying by age at diagnosis (&lt;70; ≥70 years). Conclusions: Treatment of elderly with primary metastatic breast cancer varied considerably between the NL and the US cohort. However, no differences in overall survival were observed. These results warrant further studies to evaluate the extent of treatment in this population. [Table: see text]
Discriminatory power of a 25-item distress screening tool CancerSupport Source: A cross-sectional study of 251 cancer survivors.
Authors: Melissa F Miller, C. Daniel Mullins, Ebere Onukwugha, Christopher Gayer, Mitch Golant, Joanne S. Buzaglo
Journal: Journal of Clinical Oncology (2013)

9599 Background: Distress screening and integrated psychosocial care is imperative for cancer patients, yet no tools are specifically tailored for the community provider setting where the majority of US patients are treated. Any screening tool must be validated and effective at discriminating those at risk for greater distress and the associated poorer health outcomes. The study objective was to test the discriminatory power of a 25-item distress screening tool CancerSupportSource for use among cancer survivors. Methods: A total of 251 members (90% female, median age 57 years; mixed diagnoses, 46% breast, 9% gynecologic, 7% blood, 6% colorectal, 32% other) of a community-based cancer support network completed a web-based distress screening tool. Participants were asked to rate each of 25 items according to the question “Today, how concerned are you about…?” using a five-point scale (0 not at all to 4 very seriously concerned). A summary score was calculated as the count of items rated ≥2 and the item discrimination index (IDI) as the difference between proportions of high and low scorers rating an item≥2. Cut-points at 13 and 4 yielded equal-sized groups and were used to classify participants as high (n=59) and low scorers (n=60). Results: Items with the greatest discriminatory power (IDI≥0.8) were: changes or disruptions in work, school or home life; worrying about the future and what lies ahead; feeling too tired to do the things you need or want to do; feeling sad or depressed; ability to exercise or be physically active; and feeling nervous or afraid. Conversely, items with the lowest IDI included: eating and nutrition; tobacco or substance use; transportation to treatment and appointments; considering taking your own life. Conclusions: The results highlight, among 25 items of a distress screening tool, those items with the greatest discriminatory power to identify cancer survivors with psychosocial distress. Results suggest priority areas for distress screening and referral for support services.
Up-regulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer.
Authors: Yulei Wang, Lisa Ryner, Yinghui Guan, Ron Firestein, Yuanyuan Xiao, YounJeong Choi, Christina Rabe, Shan Lu, Eloisa Fuentes, Ling Huw, Mark R. Lackner, Ling Fu, Lukas C. Amler, Carlos Bais
Journal: Journal of Clinical Oncology (2015)

e16581 Background: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Methods: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation data set containing 138 ovarian patients from the chemo-treatment arm of ICON7 trial. Results: We identified a distinct “reactive stroma” gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in post-treatment recurrent tumors. IHC and RNA ISH analyses on three of the highest-ranked signature genes (POSTN, LOX and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that high POSTN expression level predicts shorter progression free survival following front line chemotherapy. Conclusions: Our findings highlighted the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provided a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.
The effects of pioglitazone treatment on pancreatic cancer-related insulin resistance.
Authors: Jennifer Stern, Yull Edwin Arriaga, Arjun Gupta, Udit Verma, Sirisha Karri, Samira K. Syed, Leticia Khosama, John C. Mansour, Philipp Scherer, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2017)

329 Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to baseline levels at 2 weeks post-treatment (15.1±1.9 µg/ml). Markers of IR (serum glucose, insulin, glucagon, and response to an oral glucose bolus) did not correlate with tumor size, inflammatory cytokine levels, GM-CSF, or CA19-9. A dichotomous response to PIO treatment was observed between non-diabetic and T2DM patients. Fasting insulin increased 70.6±31.3% from baseline to treatment week 8 in patients with T2DM. In contrast, treatment of non-diabetic patients decreased fasting insulin by 40.2±6.3%, demonstrating a significant, P ≤ 0.01, difference in treatment response between PC patients with or without T2DM. Conclusions: We have demonstrated that PC patients respond to 8 weeks of PIO treatment with a significant rise in the insulin sensitizing adipokine, Adiponectin, with a complete wash-out after 2 weeks of cessation. PIO results in opposing fasting insulin responses in non-diabetic and DM patients suggests that diabetes status plays a significant role in the glucoregulatory effects of PIO treatment in PC patients. Clinical trial information: NCT01838317.