tbuckley/cabot-search huggingface dataset:
The role of EGFR amplification in trastuzumab resistance: A correlative analysis of TBCRC003.
Authors: I. E. Krop, L. Flores, J. S. Najita, I. A. Mayer, T. J. Hobday, C. I. Falkson, C. L. Arteaga, A. C. Wolff, E. C. Dees, M. F. Rimawi, R. Nanda, K. Josephs, N. U. Lin, E. P. Winer
Journal: Journal of Clinical Oncology (2011)

528 Background: To identify mechanisms of resistance to trastuzumab (T), we developed and characterized T-resistant HER2+ breast cancer (BC) cell lines; these lines acquired EGFR amplification and were sensitive to both lapatinib (L) and gefitinib. To validate this finding, we prospectively assessed EGFR copy number in circulating tumor cells (CTC) from patients (pts) on TBCRC003, a multicenter clinical trial of L and T. Methods: Pts with measurable, HER2+ metastatic BC (MBC) were eligible. Cohort 1: No prior T, L, or chemotherapy (CT) for MBC, and > 1 yr from adjuvant T, if received. Cohort 2: 1-2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). CTC were collected using a modification of the CellSearch Profile Kit (Veridex) at baseline, 4wk, and progression. CTC were analyzed by FISH for EGFR and CEP7 and amplification was defined as EGFR/CEP7≥2. Results: EGFR amplification was present in CTC at baseline in 11/39 (28%) patients in cohort 2 (pts with prior T), but in only 2/34 (6%) of patients in cohort 1 (no prior T for MBC) (p=0.015). In cohort 2, 1/10 (10%) patients who went on to have progressive disease as best response had EGFR amplification in their CTC at baseline, while 6/18 (33%) patients with stable disease and 4/11 (36%) with partial responses had EGFR amplification. Conclusions: These data, which demonstrate the feasibility of using CTC collection as a means of evaluating resistance mechanisms in patients on clinical trials, support the hypothesis that EGFR amplification is selected for by treatment with T and can mediate resistance to this agent. The observed trend toward improved outcome in pts with EGFR amplified CTC when treated with a regimen containing L (which inhibits both EGFR and HER2) is consistent with a functional role for this amplification. Our recent observation that EGFR amplification develops in 26% of residual HER2+ cancers after preoperative treatment with T+CT (Krop et al, ASCO 2010) further supports this hypothesis. These results provide the rationale for a trial of an EGFR inhibitor specifically in pts with HER2+ MBC and EGFR amplified CTC. Additional CTC data from this study will be presented at the conference.
CPX-351 versus cytarabine (CYT) and daunorubicin (DNR) therapy in newly diagnosed AML patients age 60-75: Safety and efficacy in secondary AML (sAML).
Authors: J. E. Lancet, J. E. Cortes, T. Kovacsovics, D. Hogge, J. E. Kolitz, M. S. Tallman, M. Chiarella, A. C. Louie, E. J. Feldman
Journal: Journal of Clinical Oncology (2011)

6519 Background: CPX-351 encapsulates CYT and DNR at a 5:1 molar ratio predicted in vitro to maximize synergy. CPX-351 liposomes accumulate within bone marrow with preferential uptake by leukemia cells followed by intracellular release of drug. Multiple CRs in advanced AML patients in phase I led to a randomized phase IIb study comparing CPX-351 (85 pts) vs. standard CYT+DNR (7+3) (41 pts) for untreated elderly patients with AML. Trends favored CPX-351 vs. 7+3 in CR + CRi rates, 60d mortality and EFS. Significant improvement in OS was observed in the 51 (40%) patients entered with sAML (prior antecedent hematologic disorders (AHD): MDS, MPD, CMMoL and treatment-related AML (t-AML)) and this led to an analysis of this subpopulation. Methods: Previously untreated de novo or secondary AML patients, age 60-75, PS= 0-2, SCr < 2.0 mg/dL, total bilirubin <2.0 mg/dL, ALT/AST <3 x ULN, and LVEF >50% were eligible. Patients were randomized 2:1 to receive up to 2 induction and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5; 90 min infusion, 1 unit= 1 mg CYT + 0.44 mg DNR) or standard 7+3 treatment (CYT=100 mg/m2 and DNR=60 mg/m2). Consolidation with hematopoietic stem cell transplantation (SCT) was permitted. Endpoints included: CR + CRi rate (1° endpoint) and duration, EFS, aplasia rate, survival at 1 year, and death at day 30 and 60. Results: 2:1 randomization assigned 32 (63%) sAML pts. to CPX-351 and 19 (37%) pts. to 7+3. Most patients (45 of 51) had AHD; only 6 of 51 had t-AML. Conclusions: CPX-351 exhibited higher response rate, lower induction mortality despite higher infection rate, and improved survival (p=0.01) among sAML patients compared to standard 7+3, providing a strong rationale for a phase III study. % As of 1 February 2011 CPX-351 n=32 7+3 n=19 Demographics Sex (male) 66 47 Race (Caucasian) 92 95 Age (median, yrs) 68 68 (>70) 41 42 ECOG PS (0-1) 78 79 (2) 22 21 Cytogenetic risk (adverse) 28 32 Prior AHD MDS 59 58 CMMoL 13 11 MPD 13 16 MDS/MPD 3 5 Prior therapy for AHD 34 37 Induction mortality (60d) 6 32 Adverse events (gr 3/4) Febrile neutropenia 56 47 Bacteremia 28 10 Pneumonia 25 10 Fungal 16 5 Sepsis 3 16 Efficacy %CR + CRi 56 32 EFS (median) 3.8m 1.4m p=0.07 OS (median) 12.1m 6.1m p=0.01
Development of an oncology quality metric evaluation and prioritization tool (QMEPT).
Authors: Randall F. Holcombe, Michelle Evangelista
Journal: Journal of Clinical Oncology (2016)

260 Background: For reporting purposes and to enable ongoing quality improvement, it is essential that metrics reflective of quality oncology care delivery are tracked and reviewed on an ongoing basis. Collection of performance data and incorporation into a usable dashboard can require significant IT resources, both in personnel time and direct costs. The Tisch Cancer Institute (TCI) identified a myriad of cancer quality metrics that required prioritization in order to best allocate limited IT resources and a standardized process to facilitate comparison across different disease groups. Methods: Quality metrics were identified from various sources: CMS, PQRS, Commission on Cancer, QOPI, AHRQ and others recommended by TCI disease management teams (DMTs). All measures were evaluated with QMEPT according to the following domains: 1) Regulatory (CMS or other certifications), 2) Cost &amp; Feasibility (resource intensiveness of the collection process), 3) Patient Outcomes – (existence of standard benchmarks or known underperformance) and 4) Financial – (influence on payor contracting). All metrics were scored to generate a composite score for each metric and then weighted with 40% for Regulatory, 20% for Cost &amp; Feasibility, 40% for Patient Outcomes. Financial was not weighted but given a yes/no designation. Results: Metrics across all disease sites were scored, weighted and compared. Composite scores ranged from 1.56 to 2.67 (range 1 - 3). Weighted scores ranged from 1.4 to 2.8. In general, metrics related to breast, prostate, colorectal and lung cancers scored higher because of the required reporting and existence of evidence-based standardized benchmarks. Metrics proposed by the DMTs were frequently found to have high resource requirements for data collection. Following the scoring process, information was disseminated to the DMTs, leading to alteration of many of the quality metric requests. Metrics with the highest priority scores were submitted to the IT group for incorporation into the quality dashboard. Conclusions: The QMEPT allowed comparison of quality metrics across disparate oncology disease groups, prioritization for incorporation into a quality dashboard and rational allocation of limited IT resources.
Adenovirus-mediated siRNA targeting c-Met to inhibit proliferation and invasion of small cell lung cancer (SCLC) cells.
Authors: Z. Wang
Journal: Journal of Clinical Oncology (2011)

7080 Background: The hepatocyte growth factor receptor c-Met and its ligand hepatocyte growth factor (HGF) have been reported to be involved in cellular motility, growth, and invasion by activating mitogenic signaling pathways. The overexpression of c-Met gene has been found in many malignant cancers, but the roles of c-Met overexpression in SCLC tumors still remain unclear. The aim of the present study was to explore its roles and potential as a therapeutic target for SCLC. Methods: Quantitative real-time RT-PCR and immunohistochemistry assays were performed to detect the expression of c-Met mRNA and protein in SCLC tissue or corresponding non-tumor lung tissue samples. Adenovirus-mediated small interfering RNA (siRNA) was employed to down-regulate the expression of c-Met gene in SCLC cell line (NCI-H446). MTT and colony formation assays were performed to detect in vitro proliferation of NCI-H446 cells. In vitro wound-healing and transwell invasion assays were performed to detect in vitro invasion and metastasis of NCI-H446 cells. Finally, in vivo tumorigenicity and metastasis assays were done to analyze in vivo proliferation and metastasis of NCI-H446 cells in a xenograft model. Results: We showed that the levels of c-Met mRNA expression were significantly higher in SCLC tissue samples (0.97 ± 0.08) than those in corresponding nontumor lung tissue samples (0.21 ± 0.02; P<0.05). Additionally, the immunostaining of c-Met protein in SCLC tissues was stronger than that in corresponding non-tumor tissues. Adenovirus-mediated siRNA targeting c-Met could significantly down-regulate c-Met expression, and the specific down-regulation of c-Met expression in SCLC cells could strongly inhibit proliferation of SCLC cells both in vitro and in vivo. Moreover, c-Met down-regulation could also reduce invasion capacity in vitro and metastasis capacity in vivo of SCLC cells. Conclusions: Taken together, our results indicated that the overexpression of c-Met gene played an important role in the progression and development of SCLC, and adenovirus-mediated siRNA targeting c-Met could potentially be an experimental approach for SCLC gene therapy.
Does variation in prostate volume calculated with MRI versus TRUS lead to reclassification of men based on current PSA density threshold for active surveillance criteria? Result from a prospective cohort.
Authors: Samarpit Rai, Amil Patel, Nicola Pavan, Nachiketh Soodana-Prakash, Raymond R Balise, Bruno Nahar, Ramgopal Satyanarayana, Dipen Parekh, Sanoj Punnen
Journal: Journal of Clinical Oncology (2016)

138 Background: PSA density (PSAD) is a strong predictor of aggressive prostate cancer (PCa) and is often used as a selection criterion for active surveillance. However, measurement of PSAD can vary depending on the modality used to estimate prostate volume (PV). We analyzed a prospective cohort of men undergoing MRI−US fusion biopsy to assess the variation in PV obtained with both imaging modalities, and investigate the impact of this variation on PSAD measurement in order to determine if it led to re-classification of patients above or below the current threshold of PSAD used in clinical practice (0.15 ng/mL/cc). Methods: All men were consecutively enrolled in this prospective study and had their PV measured on MRI prior to prostate biopsy (PB), and on Trans-Rectal Ultrasound (TRUS) at the time of PB. PSAD was calculated by dividing the last PSA prior to biopsy by the PV ascertained with each imaging modality. We used paired t-tests and Wilcoxon signed−rank tests to compare the difference in PV and PSAD obtained with TRUS and MRI. We also categorized PSAD measurements on each imaging modality above and below a cut-off of 0.15 ng/mL/cc. We used the McNemar’s test for paired proportions to estimate the significance of discordance in PSAD categorization based on each imaging modality. Results: Of the 124 men, the mean PV assessed with MRI (70 cc) was 7 cc more on average (SD: 11, median = 4 cc) than that obtained with TRUS (63 cc) (P &lt; 0.0001). Furthermore, the mean PSAD obtained with MRI (0.17 ng/mL/cc), was 0.01 ng/mL/cc lower (SD: 0.07, median = 0.01) than that obtained with TRUS (0.18 ng/mL/cc) (P &lt; 0.0001). 118 (95%) men had concordant PSAD values assessed with either imaging modality using the cut-off of 0.15 ng/mL/cc. All 6 (5%) men with discordant PSAD values who were above the cut-off with PV obtained via TRUS were reclassified as being below the cut-off with PV assessed via MRI (P &lt; 0.01). Conclusions: MRI can overestimate PV compared to TRUS. This may translate to reclassification of men around the currently used PSAD threshold and have implications for treatment decision making and selection of patients for active surveillance.
Phase II study of first-line trebananib plus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Ghassan K. Abou-Alfa, Jean-Frédéric Blanc, Steven Miles, Tom M. Ganten, Jorg Trojan, Jonathan S. Cebon, Andre K. D. Liem, Lara Rachel Lipton, Charu Gupta, Benjamin Wu, Jason B. Litten, Leonard Saltz
Journal: Journal of Clinical Oncology (2014)

286 Background: Trebananib is a first-in-class antiangiogenic therapy that sequesters Ang1 and Ang 2, preventing their interaction with the Tie 2 receptor. A previous study of the combination of trebananib with sorafenib in renal cell carcinoma showed an acceptable toxicity profile. Elevated Ang 2 levels have been associated with a poor prognosis in HCC. We thus evaluated the safety and efficacy of trebananib plus sorafenib in HCC. Methods: Patients with HCC, ECOG ≤ 2, Childs-Pugh A, and adequate organ function received IV trebananib at 10mg/kg weekly (cohort 1) or 15 mg/kg weekly (cohort 2) plus sorafenib 400 mg PO twice daily. Thirty patients were accrued to each cohort to provide a power of 80% with the 1-sided exact test for single proportion at α = 0.20 to show a ≥ 78% PFS rate at 4 months relative to 62% reported in the sorafenib historical control. Secondary endpoints included safety and tolerability, progression free survival, objective response rate, disease control rate, time to progression, and overall survival. Results: See table. Conclusions: Trebananib at 10 mg/kg and 15 mg/kg plus sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, study results did not show an improvement in PFS rate at four months. Clinical trial information: NCT00872014. [Table: see text]
Serum proteins marker for early detection of ovarian cancer
Authors: G. Mor, I. Visintin, H. Zhao, P. Schwartz, T. Rutherford, L. Yui, P. Bray-Ward, D. C. Ward
Journal: Journal of Clinical Oncology (2005)

9508 Introduction: A major limitation in the treatment of ovarian cancer (OC) is the lack of early detection tumor markers. Early diagnosis would significantly decrease the morbidity and mortality rate from this disease. CA 125, the only available test is elevated in only 40–50% of women with early stage disease with a positive predictive value of only 10%. Sensitive and specific methods of early stage OC detection are urgently needed. Here we report a new blood test, based on four analytes, which can discriminate between disease-free, and OC patients, including Stage I/II patients. Methods: 169 proteins were measured in serum samples (28 healthy controls and 36 OC patients) using a microarray immunoassay (Nat. Biotech (2000) 20:359). Ten proteins showing the greatest concentration differences between patients and controls were evaluated by independent ELISA assays and four were found to correctly classify all serum samples in this training set. The four biomarkers then were validated in a blind study of serum samples collected from 106 healthy females and 100 OC patients (24% Stage I/II disease and 76% Stage III/IV). The results of the selected analytes then were compared using three different classifiers: support vector machines, K-nearest neighbor classifiers and classification trees. Results: None of the 169 analytes used individually could correctly classify cancer patients and healthy controls. However, in a blind study with analysis of 4 biomarkers, 100 of the 106 women (94%) in the normal (disease-free) group had no more than one marker out of the normal range, while 99 of 100 OC patients (99%) had two or more markers out of normal range. The sensitivity of the test is 96%, specificity 97%, PPV 97% and NPV 96%. All 24 Stage I/II sera were correctly identified. Conclusion: We describe a multiplex serum protein screening assay that more accurately discriminates between normal women and OC patients and has the ability to detect early stage I and II OCs. No significant financial relationships to disclose.
Stress biomarkers in advanced cancer patients experiencing the pain, fatigue, sleep disturbance symptom cluster.
Authors: Kristine L Kwekkeboom, Erin S. Costanzo, Toby Christopher Campbell
Journal: Journal of Clinical Oncology (2015)

5 Background: Cancer symptom clusters such as co-occurring pain, fatigue, and sleep disturbance, are common and debilitating for patients with advanced disease. Stress-related neuorendocrine system alterations are thought to play a significant role in symptom co-occurrence. While studies have documented relationships between stress biomarkers and symptoms in persons with cancer, few have done so in the context of a specific symptom cluster or among persons receiving treatment for advanced disease. Objectives: This preliminary analysis describes biomarkers of neuroendocrine stress systems – salivary cortisol and salivary alpha amylase (sAA) – and their relationship with the pain, fatigue, sleep disturbance symptom cluster in cancer. Methods: We analyzed baseline data from 14 participants of a RCT of a cognitive-behavioral symptom cluster intervention. Participants were receiving chemotherapy for recurrent or metastatic cancer. The sample was largely female (93%), aged 50-74 years old (M=63.57), with lung (57%), breast (14%), GYN (22%) or prostate (7%) cancer. Participants reported symptom cluster severity and collected saliva over two days prior to a new chemotherapy cycle. Cortisol concentrations were determined by luminescence immunoassay and salivary alpha-amylase by enzyme kinetic reaction assay using standardized kits (Salimetrics, State College, PA). Results: Mean (SD) cortisol and sAA levels were within normal range and followed typical diurnal patterns (Table 1); although evening levels of cortisol appeared higher in this sample compared to those of healthy adults. Low to moderate observed correlations between symptom cluster severity and stress biomarkers (evening cortisol r = -.204; evening sAA r = .326) were not significant in this small sample. Conclusions: Elevated evening cortisol levels may suggest dysregulation of the stress response in this population. The ongoing study will further evaluate if alterations in neuroendocrine function contribute to the symptom cluster experience. Clinical trial information: NCT01954420. [Table: see text]
Long-term surveillance and preventive practices among healthy young adult cancer survivors.
Authors: E. M. Del Giudice, L. F. Paszat, L. Rabeneck, R. Sutradhar, D. Urbach, D. Wilton, N. N. Baxter
Journal: Journal of Clinical Oncology (2011)

6121 Background: Due to advances in cancer therapy, many young adult cancer survivors (YACS) will be cured. As time lapses from active treatment, it is unknown whether YACS remain engaged in the health care system by participating in recommended preventive and screening practices. Methods: This is a population-based study using cancer registry and administrative data. We identified all adults aged 20 - 44 diagnosed with a malignant tumor between 1992 and 1999 in the Ontario Cancer Registry. We excluded individuals who died or showed evidence of recurrence within 5 years of diagnosis. Patients were matched 1:5 according to age, sex and geography to randomly selected controls who were cancer free prior to observation. Using administrative data, we identified preventive maneuvers including screening for hypercholesterolemia, cervical, breast and colorectal cancer (CRC), influenza shots and general health examinations occurring more than 5 years after diagnosis in survivors and controls. Relative health service use between survivors and controls was estimated using Poisson regression models, adjusting for income and time from diagnosis. Survivors were censored if there was evidence of recurrence. Results: 20,320 YACS and 101,571 controls were identified. Women with a history of breast cancer had more annual mammograms compared to their controls: aged 40-49 (relative rate ratio [RR] 3.46, 95% confidence interval [CI] 3.34-3.60, P<0.001); and aged 50-59 (RR 2.03, 95% CI 1.93-2.13, P<0.001). The table provides RR and CI of preventive practices, survivors compared to controls. Conclusions: Compared to controls, YACS are more likely to participate in many healthy preventive and screening practices more than 5 years after diagnosis. Preventive practice Rate ratio 95% CI P value Cervical cancer screening Screening mammogram Age 40-49 Age 50-59 CRC screening FOBT Endoscopy Flu vaccination General health exam Cholesterol screening Females 50-59 Males 40-49 Males 50-59 1.06 1.25 1.07 0.95 1.29 2.37 1.09 1.01 1.04 1.01 1.05, 1.07 1.21, 1.29 1.03, 1.11 0.90, 1.01 1.24, 1.35 2.10, 2.68 1.07, 1.10 0.99, 1.03 1.02, 1.07 0.97, 1.05 <0.0001 <0.0001 0.0002 0.08 <0.0001 <0.0001 <0.0001 0.38 0.0008 0.65
Bio-identical hormones replacement therapy and the quality of life for breast cancer patients.
Authors: TS Wiley
Journal: Journal of Clinical Oncology (2015)

87 Background: Many treatments for breast cancer block the estrogen receptor or the androgen conversion of estrogen to reduce the risk of relapse. This results in a change in the hormonal milieu. Although most women tolerate the change in hormonal status, problems can arise from this change. Without estrogen, clinical symptoms include hot flashes, sleeplessness, insulin sensitivity, and mood changes. Here, it is examined that the use of estrogen and progesterone bio-identical hormone replacement therapy (BHRT) for women in the normal physiological pattern of reproductive women is expected to coincide with increased well-being and better quality of life for women with breast cancer. Methods: This BHRT approach uses bio-identical estrogen and progesterone to restore the woman’s body to normal serum levels through twice daily transdermal application. Using real “bio-identical” or plant-derived human molecular hormones compounded via a standard formula, concentration, and packaging of transdermal creams (Estradiol E2) of 1 mg/0.1ml and progesterone P4 of 20 mg/0.1 ml). Furthermore, through an understanding of hormonal mechanisms, this BHRT mimics the female reproductive cycle by following a 28 day cycle. Results: Throughout the study, women were asked to how gauge their general well-being and quality of life. Most women reported resolution of menopausal symptoms, better sleep, decreased migraines and incontinence, increased focus, and increased libido. Most patients were pleased to be on the treatment and showed general improvement in the quality of life. Conclusions: We present the general mechanisms of action for BHRT and explain clinical trials conducted over the past decade have been examining the impact on the overall well-being and quality of life for 112 patients, as well as the impact on various cancers as well as other chronic conditions. Patients reported increased energy and overall well-being. BHRT provided resolution of most all of the patients subjective anti-estrogenic complaints. It is also observed that the recurrence rate of various breast cancers was no higher than national averages. Therefore, BHRT and rhythmic dosing seems to greatly improve well-being with no increase of cancer risk.