tbuckley/cabot-search huggingface dataset:
Phase I trial of the first-in-class EGFR antibody mixture, Sym004, in patients with advanced solid tumors.
Authors: R. Dienstmann, A. W. Tolcher, K. P. Papadopoulos, D. W. Rasco, J. Tabernero, I. Brana, A. Piera, N. J. Skartved, H. Aladdin, J. Petersen, A. Patnaik
Journal: Journal of Clinical Oncology (2011)

3089 Background: Sym004 is a recombinant antibody 1:1 mixture of two chimeric anti-EGFR mAbs, which elicits superior cancer cell growth inhibition in preclinical models. Uniquely, Sym004 mediates cell surface receptor removal by triggering EGFR internalization and degradation. Results from a first-in-human multicenter trial evaluating safety and tolerability of multiple doses of Sym004 are reported. Methods: The trial comprises a dose-escalating part A (0.4 mg/kg-12 mg/kg) with classical 3+3 design after the first 2 cohorts and an extension part B at maximum tolerated dose (MTD). Patients (pts) received weekly IV infusions of Sym004 until disease progression or unacceptable toxicity. Pharmacokinetics and safety is evaluated weekly, with dose-limiting toxicities (DLT) assessed in the first 4 weeks, and tumor response every 8 weeks. Results: In part A, 17 pts (median age 60 years) were treated with doses up to 9 mg/kg without reaching the MTD: 0.4 mg/kg (1 had 6 doses), 0.75 mg/kg (1 had 35* doses), 1.5 mg/kg (3 pts had 6, 6 and 21 doses), 3 mg/kg (3 pts had 3, 5 and 6 doses), 6 mg/kg (3 pts had 3, 12* and 13 doses) and 9 mg/kg (6 had 1, 4*, 4*, 5*, 6* and 9* doses [*ongoing]). Most common tumor types were colorectal (11 pts) and pancreatic carcinomas (3 pts). 90% of adverse events (AEs) were CTCAE grade 1 or 2. The most frequent events were skin toxicities, diarrhea, nausea, infusion related reaction and electrolyte disturbances, similar to marketed anti-EGFR mAbs. 5 pts had non-serious, grade 1 mucositis. 4 pts had serious AEs related to Sym004: grade 2 rash and grade 1 allergic reaction (6 mg/kg), grade 3 acneiform rash (6 mg/kg), grade 3 hypomagnesemia (9 mg/kg) and grade 3 infusion related reaction (9 mg/kg). The latter event led to the introduction of an intensified pre-medication scheme with steroids, antihistamines and paracetamol before the first 4 infusions and lowered infusion rate. No further infusion reactions were observed thereafter. Of the 11 pts treated with doses up to 6 mg/kg, 4 remained in the trial for more than 8 weeks. AUC and Cmax for both mAbs constituting Sym004 were similar and increased with dose. Conclusions: Sym004 is well tolerated with no unexpected toxicities and shows preliminary signs of clinical activity.
Quality and consistency in breast cancer clinical guidelines internationally: Are we globally consistent?
Authors: C. E. Simmons, S. Hogeveen, J. Nichols, S. Trudeau-Tavara, M. Quan
Journal: Journal of Clinical Oncology (2010)

6096 Background: Evidence-based guidelines are used in health care systems throughout the world to aid in treatment decisions and ensure quality and consistency in patient care. In breast oncology, guidelines for care are published by several internationally recognized organizations from the USA, Canada, and the UK. This study compared clinical breast cancer guidelines from the American Society of Clinical Oncology (ASCO, USA), Cancer Care Ontario (CCO, Can), and the National Institute of Clinical Evidence (NICE, UK) in order to determine consistency of quality and content across international organizations. Methods: A search of breast cancer guidelines published from ASCO, CCO, and NICE was completed. Guidelines of the same topic were identified across organizations and appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument by 4 independent reviewers. Content of each guideline was also scored for consistency in overall recommendations across organizations,and consistency in cited evidence. Results: The quality of breast cancer guidelines produced from these organizations was consistently good in the areas of scope and purpose, rigor of development and clarity of presentation, but were variable in quality in the domains of stakeholder involvement, applicability and editorial independence. The content of the guidelines varied slightly in strength of recommendation, but all guidelines utilized the same sources of evidence and had similar interpretations of the evidence. Conclusions: This review has demonstrated the consistency of quality and content of breast cancer practice guidelines published from different national organizations. The development of future guidelines from these organizations should focus on how to implement and measure uptake of a guideline. AGREE domain Use of adjuvant Staging and follow-up Bisphosphonate use ASCO CCO NICE ASCO CCO NICE ASCO CCO NICE Scope and Purpose 80% 89% 64% 56% 86% 81% 72% 86% 78% Stakeholder involvement 46% 52% 60% 44% 52% 77% 52% 62% 71% Rigor of development 65% 77% 56% 68% 71% 89% 77% 77% 83% Clarity of presentation 62% 85% 67% 71% 81% 92% 79% 88% 79% Applicability 8% 33% 72% 56% 58% 64% 75% 33% 64% Editorial independence 67% 100% 50% 62% 50% 62% 54% 29% 67% No significant financial relationships to disclose.
A RNA signature with high sensitivity and specificity discriminating between responder and nonresponder to cetuximab monotherapy in colorectal cancer.
Authors: A. Rosenthal, M. Becker, I. Klaman, T. Mayr, R. Pauli, K. Hertel, K. Helwig, I. Fichtner, J. Hoffmann, H. Adams, B. Hinzmann
Journal: Journal of Clinical Oncology (2011)

e14049 Background: Patients (pts) with advanced, metastatic colorectal cancer (CRC) and wild-type KRAS mutation status benefit from anti EGFR antibodies cetuximab (CE) and panitumumab. Pts with CRC of UICC stage III do not benefit from CE plus FOLFOX irrespectively of the KRAS mutation status. There is a high medical need for new biomarkers that can differentiate between responder (R) and non-responder (NR) to CE therapy in the adjuvant setting. Methods: We established a panel of 148 stable, passagable CRC xenografts from 240 primary CRC tumors of all four stages (Becker et al. EORTC-NCI-AACR meeting, Berlin Nov. 2010). All xenografts were characterized by histological and molecular methods including Affymetrix array profiling and KRAS, BRAF, PIK3CA mutation analysis. Pharmacological experiments were carried out with 68 models (8 stage I, 22 stage II, 29 stage III, 9 stage IV tumors) testing therapy response to CE. In the CE group 18/68 animals responded to treatment of 50mg/kg/d given over 14 days. T/C <20 responders, T/C>20 non-responder. We isolated RNA from all 18 R and 18 NR control tumors. Labeled and amplified cDNAs (Ambion) was hybridized onto Affymetrix U133 Plus 2.0 arrays. Raw cel files were condensed (FARMS). Feature selection and classification was performed using the random forest algorithm and SVM in a nested bootstrap approach. Results: We identified a panel of signatures containing between 20 to 300 RNA markers discriminating between R and NR. The best signature containing 300 probesets showed a prospective sensitivity (S+) of 82.78% and a prospective specificity (S-) of 84.0%. A signature of 21 probesets has a S+ of 79% and a S- of 77.78%. We also assigned the response data of the mouse models to the original human tumors and developed corresponding RNA signatures that discriminated successfully the two human tumor groups and proving our model. Conclusions: We have developed highly accurate RNA signatures predicting response to CE in xenograft models carrying human CRC tumors of all four stages. This signature, if successfully validated in a larger cohort, could be applied to pts with CRC stage II and III for predicting response to CE with a PPV of 64% and a NPV of 93%.
BRCA1 mRNA expression patterns in a large lung cancer cohort.
Authors: K. Kelly, P. Mack, X. Huang, P. Lara, P. V. Danenberg, K. D. Danenberg, D. R. Gandara
Journal: Journal of Clinical Oncology (2011)

7056 Background: Differential expression of DNA repair proteins plays a role in drug sensitivity. In lung cancer, low ERCC1 expression is associated with platinum responsiveness. Additional analyses have identified associations between ERCC1 mRNA expression levels and histology and gender (Gandara ASCO 2010). BRCA1 has emerged as another important DNA repair gene for chemosensitivity. To examine the distribution of BRCA1 expression in NSCLC, and determine relationships to ERCC1, tumor histology and patient demographics, we quantified BRCA1 mRNA levels in specimens from the extensive Response Genetics Inc (RGI) tumor collection. Methods: Previously extracted RNA from microdissected formalin-fixed paraffin-embedded lung cancer specimens in the RGI database were analyzed for BRCA1 mRNA expression by RT-PCR. mRNA expression was reported as a ratio of gene expression to β-actin. The data was correlated to patient demographics and ERCC1 mRNA expression levels. Results: 425 tumor specimens with known ERCC1 expression levels were analyzed for BRCA1 expression. Patient demographics: Median age - 66 (range 34-90); Gender - female 53%; Stage - early 4%, late 96%; Histology - adenocarcinoma (Adeno) 60%, squamous cell (SCC) 15% and not otherwise specified/other 25%. The median BRCA1 mRNA expression level was 0.81 with a range of 0 – 12.05. There was no association between age or gender and BRCA1 levels but there was a significant association with histology. Median BRCA1 gene expression was higher in SCC at 2.39 vs 0.57 for adeno (p.<0.0001). When dichotomized at the medians, there was a small but statistically significant positive correlation between BRCA1 and ERCC1 expression (P<0.001). This relationship was retained when using the clinically established cutpoint of 1.7 for ERCC1 (p<0.001). Conclusions: BRCA1 expression levels are significantly higher in SCC compared to adeno and modestly correlate with ERCC1 expression levels. A prospective trial is in development to further evaluate the clinical implications of these findings. All patients Squamous cell Adenocarcinoma P value BRCA1 N 425 72 256 Mean 1.24 2.99 0.80 P<0.0001 Median 0.81 2.39 0.57 P<0.0001 Range 0.0–12.05 0.03–12.05 0.0–3.8
Identifying palliative care beds to contribute to the integration of early palliative care (EPC) into the inpatient, private practice oncology setting in Brittany (France).
Authors: Anny Parot-Monpetit, Erik Monpetit
Journal: Journal of Clinical Oncology (2014)

71 Background: In France, since 2002, Identified Palliative Care Beds (LISP) has contributed to the diversification and development of Palliative Care. They are identified in acute unit with significant PC activity and estimated at 5000 in 2011. In our Brittany private hospital, since fall 2008, 8 Beds are dedicated to PC in the solid tumour oncology unit (47 beds) and allowed EPC integrated to oncologic care for inpatients. Our model incorporated a PC physician as a second attending on service alongside the rounding oncologist. Time for discussions with oncologists is optimized and warranted decisions about providing adequate information to the patient and the continuation of treatments, specific or not. We thought to better define the added value of Identified PC Beds. Methods: Because more financial and educational resources are attributed to Identified Beds by health authorities to offer a true interdisciplinary approach, a specific annual evaluation is required. We analysed 7 quantitative components and the number of claimed letters about the unit between 2008 and 2013. Results: The table show an increased PC activity no reduced to terminal care (increase Home Hospice Care, decrease death) and better provider satisfaction with oncology care. Conclusions: The French concept of Identified PC Beds, in our experience, may improve early integrated PC into the inpatients and quality of care. The co management of patients with advanced cancer by oncologists and palliative care physicians is the key. Formal study of our Identified PC Beds model is warranted. [Table: see text]
Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors.
Authors: L. Gandhi, R. Bahleda, J. M. Cleary, A. Hollebecque, E. L. Kwak, S. Pandya, S. Tolaney, R. Abbas, R. Ananthakrishnan, A. Berkenblit, J. Boni, J. Clancy, K. W. Turnbull, M. VoVan, G. Shapiro, J. Soria
Journal: Journal of Clinical Oncology (2011)

3027 Background: NER (HKI-272) is an irreversible pan-ErbB tyrosine kinase inhibitor with antitumor activity in pts with HER2-amplified tumors. TEM inhibits mTOR (TORC1). Hyperactivation of the PI3K-Akt-mTOR axis mediates resistance to anti-HER2 therapies. Preclinical data in mouse models of HER2-driven cancers suggest that the combination of both mTOR and HER2 inhibitors improves anti-tumor efficacy compared with HER2 inhibition alone. Methods: This open-label trial evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of NER plus TEM in pts with advanced solid tumors. A novel bi-directional ascending/descending trial design involved 4 dose levels of each drug (NER: 120, 160, 200 and 240 mg/d orally; TEM: 15, 25, 50 and 75 mg/wk iv) to determine the maximum tolerated dose (MTD) contour. Initial cohorts of 2 pts were enrolled to each tested dose level and observed for 28 days; the MTD(s) identified will enroll ≥6 pts for confirmation. For determination of NER and TEM plasma concentrations, blood samples were collected at pre-dose and at selected time points following treatments on Week 4. Results: 53 pts have been treated, including 10 with non-small cell lung cancer (NSCLC), 14 with breast cancer (BC) and 29 with other tumors. The most common dose-limiting toxicities were grade 3 mucositis, grade 3 diarrhea and grade 3 neutropenia. 12 of 16 possible dose combinations have been explored; MTDs to be confirmed are (NER/TEM) 200/25 and 160/50. PK of NER and TEM are evaluated. Of 6 pts with NSCLC HER2 exon 20 insertion mutation: 2 PR (17, 8 wks) and 2 SD (24, 13 wks). Among 9 HER2+ BC: 1 CR (32 wks), 1 PR (49 wks) and 3 SD (43, 23 and 16). Additional efficacy seen in pts with thymoma (CR), endometrial (PR) and urothelial (PR) cancers, and SD ≥24 wks in 1 pt each with NSCLC (genotype unk) and vulvar cancer. Conclusions: The combination of NER and TEM has demonstrated preliminary antitumor activity in pts with HER2-dependent NSCLC and BC, as well as other solid tumors, with an expected and manageable AE profile. HER2-mutant NSCLC, like other molecular subgroups, may be uniquely sensitive to the appropriate targeted therapy. An expansion cohort of 12 pts with NSCLC harboring HER2 mutation is planned at the 200/25 dose.
Association of bone mineral density with breast cancer and histopathologic features of the tumor.
Authors: Anurag Sharma, Elias Youssef, Meaghan Roche, Michael Maroules
Journal: Journal of Clinical Oncology (2013)

16 Background: High bone mineral density (BMD) has been associated with increased incidence of breast cancer. We studied the differences in BMDs between females with and without breast cancer as well as the association between BMD and the histopathological features of breast cancer. Methods: Data on BMDs and Tscores of hip and spine were collected for 311 breast cancer patients from Dexa Scans available from 5 years before or within 1 year of diagnosis. The same information was collected for 1,047 females without breast cancer (age matched with study group). The following additional data was collected for breast cancer patients: TNM staging, Histology, Estrogen receptor (ER), Progesterone receptor (PR), Ki-67 and HER-2 percentages, Tumor size, and Tumor differentiation. Results: As expected, breast cancer patients were found to have higher hip/spine BMDs than women without breast cancer (p &lt; 0.001). PR percentage was positively associated with hip BMD/Tscore and spine BMD/Tscore ([r sp =0.166/0.165, 0.145/0.164, respectively], p&lt;0.05 for all [Spearman Correlation Analysis]). Tumor size was negatively associated with spine BMD/Tscore ([r sp =-0.134, p=0.06], [r sp =-0.136, p=0.04], respectively, [Spearman Correlation Analysis]). A negative trend was seen between Ki-67 percentages and BMD (although no significance was achieved). Patients with lymphovascular invasion had lower spine Tscores than patients without lymphovascular invasion (-1.22±1.45 vs. -0.84±1.37, p=0.04, [One-way ANOVA]). Conclusions: Amongst all women studied, women with breast cancer were likely to have a higher BMD. However, higher BMD in breast cancer patients was associated with favorable tumor characteristics. Higher BMD was also associated with higher percentage of PR while no significant association was seen with ER. Greater cumulative estrogen exposure in females with higher BMD might explain these results. Estrogens are known to affect proliferation of breast cancer cells and to alter their phenotypic and cytoarchitechtural features, including enhanced induction of PR and possible downregulation of ER. Future studies are needed to explore these underlying pathways, their effect on tumor behavior, and treatment implications.
Prevalence and incidence of comorbidities associated with gastric cancer.
Authors: Mark D. Danese, Michelle L. Gleeson, Wendy J. Langeberg, Juan Ke, Michael A. Kelsh
Journal: Journal of Clinical Oncology (2014)

39 Background: Understanding the burden of comorbidities in patients with gastric cancer may aid in treatment planning and evaluating the safety of new treatments. Methods: Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare combined dataset, we identified 12,612 patients diagnosed with gastric cancer 2000–2007. A cohort of 12,612 cancer-free individuals was frequency-matched by Medicare enrollment year and county of residence. Subjects were ≥66 years-old at index date to allow for ≥1 full year of Medicare coverage. Prevalence the year before index date and 3- and 12-month incidence rates (per 100 person-years) after index date were estimated for 42 common comorbidities. Results: Comorbidities with the highest (≥8%) 3-month incidence in patients with gastric cancer are shown. Conclusions: Comorbidity prevalence before index date was modestly higher, and incidence rates after index date were much higher in gastric cancer patients than in cancer-free individuals. The potential reasons for this include the increased diagnostic testing, physician visits, and reporting of morbidities that occurs with the diagnosis of cancer, as well as the effects of cancer and its treatment. [Table: see text]
Combination therapy of cytotoxic agents and COX-2 inhibitor in primary systemic therapy of breast cancer patients: A phase II study on efficacy and cardiac toxicity
Authors: L. W. C. Chow, M. Toi
Journal: Journal of Clinical Oncology (2005)

3146 Background: The study was performed basing on the hypothesis that inhibition of COX-2 activities may have direct effect on cancer growth and enhance the efficacy of cytotoxic agents. This may happen through mechanisms including induction of apoptosis and inhibition of tumor-related angiogenesis. Methods: From June 2001 through August 2003, 55 patients with histologically confirmed invasive breast cancer were entered into this phase II trial. Patients were considered eligible if they had a tumor size 3 cm or greater, with no evidence of distant metastasis. Three cycles of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were administered 21 days apart. 5-fluorouracil at 500 mg/m2, epirubicin at 75mg/m2 and cyclophosphamide at 500 mg/m2 were given by intravenous injection. Celecoxib was given orally at a dose of 400 mg twice daily, starting on the first day of chemotherapy, until the morning of the surgical procedure. Restaging was performed 3 weeks after the third cycle of chemotherapy. An objective response consisted of a complete clinical response or a partial response. Venous blood samples collected throughout the treatment were analyzed for cardiac markers: pro-NT-BNP and cardiac troponin-I. Results: Thirty-eight patients (69.1%) had a major clinical response. Nine patients (16.4%) had a complete clinical response, and 29 patients (52.7%) had a partial response. Five patients (9.1%) had a complete pathologic response (pCR). Another 3 patients (5.5%) has only microinvasive disease. The serum samples from 34 patients were analyzed for changes in the cardiac markers during the period of preoperative therapy. The cardiac troponin-I levels showed a small and insignificant rise throughout the treatment period. The pro-NT-BNP levels did not change with treatment and there was a significant drop (F=6.792, p < 0.001) at the end of treatment. Conclusions: COX-2 inhibitor may enhance the response to cytotoxic agents. No major cardiac toxicity is observed during the treatment. No significant financial relationships to disclose.
Use of anti-EGFR agents among elderly patients with metastatic colorectal cancer (mCRC).
Authors: Ashley James D'Silva, Efrat Dotan, Dwight D. Kloth, Andrew Beck, Steven J. Cohen, Crystal Shereen Denlinger
Journal: Journal of Clinical Oncology (2012)

657 Background: Limited data are available regarding the tolerance of older mCRC patients to anti-EGFR therapy. To evaluate the treatment patterns and tolerability of cetuximab/panitumumab in this patient population, we conducted a retrospective review of elderly patients treated with these agents at Fox Chase Cancer Center between 2004-2010. Methods: Patients ≥ age 65 with mCRC treated with cetuximab/panitumumab were included in the analysis. Patient demographics, disease characteristics, treatment drugs and duration, KRAS status and overall survival were recorded. Toxicity evaluation included review of common hematologic and non-hematologic toxicities seen with these agents. Results: 118 patients were included; 100 received cetuximab and 18 received panitumumab therapy. The majority of patients were male (59.3%) with colon cancer (82.2%) and stage IV disease at presentation (50.8%). The median age at treatment initiation was 73 yrs (range: 65-90). Median overall survival was 510 days, and the median time on treatment 73 days. Most patients were treated prior to the incorporation of routine KRAS testing thus, KRAS status was available for 35 patients (29.7%) with 14.2% KRAS mutant tumors. 66% of cetuximab and 45% of panitumumab treatments were given in combination with another agent. The overall incidence of any grade 3/4 non-hematologic toxicity was 36% (34% for single agent; 37.8% for combination therapy). Common grade 3/4 non-heme toxicities were: hypomagnesemia-16.9%, diarrhea-10.2%, and rash-9.3%. Diarrhea and hypomagnesemia were more common among patients receiving combination therapy. The overall incidence of any grade 3/4 hematologic toxicity was 15.2% (6.8% for single agent ; 20.3% for combination therapy). Anemia was the most common heme toxicity in both single and combination therapy. Advanced age at treatment initiation was associated with higher incidence of single agent therapy (p=0.0005, ANOVA statistics). Conclusions: Our data demonstrate that elderly patients with mCRC tolerate anti-EGFR therapy, with toxicity rates similar to those reported in large clinical trials with younger patient populations. Older mCRC patients can safely receive anti-EGFR treatment as part of their therapy.