tbuckley/cabot-search huggingface dataset:
Phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy for resectable pancreatic cancer.
Authors: Katherine Y. Fan, Aaron Tyler Wild, Daniel A. Laheru, Timothy M. Pawlik, Lei Zheng, Dung Thi Le, Phuoc T. Tran, Avani Satish Dholakia, Rachit Kumar, Susannah G. Ellsworth, Amy Hacker-Prietz, Zeshaan Rasheed, Ana De Jesus-Acosta, Matthew Weiss, Martin Makary, John L. Cameron, Ralph H. Hruban, Elliott K. Fishman, Christopher Lee Wolfgang, Joseph M. Herman
Journal: Journal of Clinical Oncology (2013)

269 Background: Amplification and overexpression of the EGFR gene and surface protein have been described in up to 80% of pancreatic tumors, making EGFR an attractive target in developing new adjuvant therapy for pancreatic adenocarcinoma (PDAC). Inhibition of EGFR has been suggested to provide additive activity when combined with capecitabine and radiation. Here we evaluate the antitumor activity and toxicity profile of erlotinib combined with adjuvant chemoradiotherapy (CRT) and chemotherapy. Methods: 50 patients with resected stage I/II PDAC were enrolled in a phase II trial of adjuvant erlotinib and capecitabine administered concurrently with IMRT (50.4 Gy), followed by 4 cycles of erlotinib and gemcitabine. Results: Median length of follow-up was 18.2 months (IQR, 13.8-27.1). Seventy-nine percent of tumors were of the pancreatic head, 85% had nodal involvement, and 17% had positive margins. Median RFS was 15.6 months (95% CI, 14.1-17.1), local RFS 21.1 months (95% CI, 17.1-25.1), and OS 24.4 months (95% CI, 17.1-31.6). Local recurrence was only observed in 19% patients and synchronous recurrence in 8%. Patients with maximum tumor diameter of ≤3 cm showed superior RFS (17.9 vs. 14.0 months; P=0.049), as did patients with cutaneous reaction to erlotinib (16.3 vs. 9.3 months, P=0.021). Superior OS was associated with less than median (32.3U/mL) pre-CRT CA19-9 values (28.2 vs. 19.0 months, P=0.012). During CRT, 31% patients experienced grade 3 toxicity and 2% grade 4, while 31% patients required a treatment break/stopped treatment early. During post-CRT chemotherapy, 35% patients experienced grade 3 toxicity and 8% grade 4, while 30% required a dose reduction. Conclusions: Results of this phase II trial suggest erlotinib combined with standard adjuvant CRT and chemotherapy provides excellent local disease control and reasonable tolerability compared with existing adjuvant regimens. Patients with maximum tumor diameter of ≤3 cm, cutaneous reaction to erlotinib, and less than median pre-CRT CA19-9 values appear to especially benefit from this new adjuvant regimen. Clinical trial information: NCT00962520.
Adherence to head and neck cancer guidelines: Multidisciplinary conference recommendations and care delivered.
Authors: Zhannat Nurgalieva, Randal S. Weber, Stephen Yenzen Lai, Erich M. Sturgis, Beth Michelle Beadle, William William, Carol M. Lewis
Journal: Journal of Clinical Oncology (2012)

202 Background: Adherence to clinical guidelines, such as those developed by the National Comprehensive Cancer Network (NCCN), can serve as a quality measure for delivered care. We aimed to determine NCCN guideline compliance of and concordance between multidisciplinary conference (MC) treatment recommendations and treatment received. Methods: A retrospective review of 71 consecutive previously untreated patients from 1/1 to 4/1/2006 evaluated whether MC recommendations were compliant with 2006 NCCN treatment guidelines, what treatment was actually provided, and whether this treatment was congruent with MC recommendations and/or adhered to 2006 NCCN guidelines. Results: TNM staging was documented in 94.4% of MC notes and treatment recommendations were documented for 98.6% of patients. Of enrolled patients, 53% had oropharyngeal cancer, 22.7% had oral cavity cancer, 18.2% had laryngeal cancer, and 6.1% had nasopharyngeal cancer. The mean age at presentation was 57.4 years. Forty-eight patients (72.7%) were men. MC recommendations were not compliant with NCCN guidelines in 7 (10.6%) patients. Reasons for non-compliance were recommended definitive radiation alone for T1/2N2 oropharyngeal cancer (3 patients), recommended over-use of induction chemotherapy (2 patients) or adjuvant therapy (1 patient), and incomplete documentation (1 patient). Actual treatment deviated from MC recommendations in 25 (38.5%) patients, although in 14 of these patients, treatment remained guideline-adherent. Actual treatment was not compliant with guidelines in 9 patients; 4 of these patients had treatment congruent with MC recommendations, which were not NCCN guideline-compliant. Reasons for guideline-discordance in the remaining patients were individual. Conclusions: Discordance with NCCN guidelines for head and neck cancer treatment planning and delivery was observed in this cohort; while some deviations were due to incomplete documentation, areas for improvement were identified. Further study is warranted to determine whether treatment deviating from NCCN guidelines impacts patient outcome.
Implications of <i>BRCA1</i>and <i>BRCA2</i> mutations on taxane sensitivity in patients (pts) with advanced ovarian cancer.
Authors: D. S. P. Tan, T. A. Yap, M. M. Hutka, P. Roxburgh, E. Grzybowska, C. Gourley, M. E. Gore, S. B. Kaye
Journal: Journal of Clinical Oncology (2011)

5063 Background: Preclinical data suggest that BRCA1/2 mutated (i.e. homologous recombination repair deficient) tumors are exquisitely sensitive to platinum salts but resistant to microtubule-stabilising agents (Quinn et al, 2007). A retrospective study was undertaken to investigate the clinical effects of single agent paclitaxel chemotherapy in BRCA1/2 mutated ovarian cancer (BMOC) pts. Methods: Clinical data on response rates to single agent paclitaxel (3 weekly or weekly) in BMOC pts were analysed from 4 major cancer centers. Platinum resistance or sensitivity at time of treatment with paclitaxel was defined as <6mth or >6mth progression free survival interval after the last platinum-based chemotherapy respectively. Antitumor response was defined as RECIST partial or complete response (PR/CR) after 18 weeks of treatment. Results: We identified 21 pts with multiply relapsed advanced BMOC who had received first-line platinum based chemotherapy and subsequently single agent paclitaxel as second- (3/21), third- (2/21), fourth-(9/21), fifth- (6/21), and sixth- (1/21) line treatment for relapsed disease. No pts received a PARP inhibitor before treatment with paclitaxel. The overall response rate to single agent paclitaxel was 43% (9/21). 13 of 21 pts were platinum-sensitive (PS), while 8 of 21 pts were platinum-resistant (PtR). 8 of 13 (62%) PS-BMOC pts had PR/CR, in contrast to 1 of 8 (13%) PtR-BMOC pts (p=.067, Fisher’s test). Of the 9 responding pts, 2 were taxane-naïve and 7 had prior paclitaxel; of the 12 non-responders, 5 pts were taxane-naïve and 7 had prior paclitaxel. There was no difference in the median taxane-free interval between these 2 groups (36 mth [range 3-76 mth] vs 31 mth [range 20-39 mth] respectively; p=.565, Mann Whitney U). There was no difference in PR/CR rates between 3 weekly (3/7 [43%] pts) and weekly paclitaxel (6/14 [43%] pts) schedules. Conclusions: These data provide the first preliminary clinical evidence that paclitaxel is an active drug in BMOC. They also suggest that PS-BMOC pts may potentially be more sensitive than PtR-BMOC pts to single agent paclitaxel chemotherapy. These novel findings will now need to be validated in a larger series of pts with BMOC and the underlying mechanisms dissected.
An automated, sensitive, high-throughput biomarker protocol for tissue microarrays containing archival prostate specimens: The prognostic potential of an ERG EMT panel.
Authors: Mick D. Brown, Ahmad Salman, Claire Hart, Noel W. Clarke
Journal: Journal of Clinical Oncology (2014)

181 Background: Tissue microarrays (TMAs), linked to clinical databases containing clinical outcome data, offer a great potential for defining and validating new biomarkers in urological oncology. The long term follow up required for true clinical outcome prostate cancer results in the use of archival material for TMA construction. The use of such material has inherent problems which must be overcome to unlock the full potential of prostate TMAs. Methods: A prostate 2,450 core TMA containing normal, prostatic intraepithelial neoplasia and malignant prostate tissue from 524 archival patient specimens was constructed and analysed. Each core was independently verified histologically. An automated, high throughput fluorescent staining (Leica BOND-MAX), image capture (Carl Zeiss Microimaging Mirax scanner) and scoring (Definiens Tissue Studio) protocol was compared with standardised conventional staining and manual scoring techniques. Results: Image analysis showed excellent correlation (r=0.785) and absolute agreement between the automated and manual scoring protocols (ICC=0.769, 95% CI [0.629-0.877]). Replicate analysis demonstrated that the automated, high throughput protocol was more reliable and consistent than the standardised manual staining and scoring protocols. The increased sensitivity of fluorescent staining in the automated protocol highlighted significant (p&gt;0.0001) antigen degradation (pan-cytokeratin), hence poorly persevered regions, in 50.7% of the archival TMA cores. Using well preserved cores the potential of combining Erg expression with EMT markers as a prognostic marker will be presented. Conclusions: This study shows that archival TMAs can be utilised for biomarker characterisation and validation. However there are caveats to their use, namely antigen preservation. The use of multicolour automated protocols, which utilise a house keeping antigen, circumvents these caveats and releases the full potential of TMAs in biomarker research.
A toll-like receptor 4 agonist enhances the efficacy of trastuzumab therapy of a human ErbB-2 (HER2)-transfected syngeneic tumor in a human HER2 transgenic mouse model
Authors: Shangzi Wang, Catherine Bingham, Igor Astsaturov, R. Katherine Alpaugh, Kenneth McCarthy, Yong Tang, Bruce Littlefield, Lynn Hawkins, Sally Ishizaka, Louis Weiner
Journal: Cancer Research (2008)

LB-227  Antibodies against cancer-relevant targets can exert their activities in part by recruiting Fc-receptor bearing myeloid and natural killer cells to mediate antibody dependent cellular cytotoxicity (ADCC). Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of an adaptive immune response that can be utilized for therapeutic purposes. We have previously shown that therapy with the monoclonal antibody trastuzumab and E6020, a TLR4 agonist, protects against the outgrowth of syngeneic D5 melanoma transfected with the human tumor antigen HER2 in immunodeficient C57BL/6 SCID mice and in immunocompetent wild-type C57BL/6 mice. In order to determine if these results would be replicated in immunocompetent but immunologically tolerant mice, we created C57BL/6 ErbB-2 transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter. We treated cohorts of 7-12 human HER2 transgenic bearing human HER2-transfected D5 murine melanoma cells (D5-HER2) with the human anti-HER2 antibody, trastuzumab. These mice demonstrate immunological tolerance to the syngeneic D5-HER2 cell line, which produces tumors in the transgenic mice as well as in SCID mice, but fails to induce an antibody response in either strain. These results contrast with results in immunocompetent mice, which are more resistant to tumor challenge and mount robust anti-human HER2 antibody responses. C57BL/6 HER2 transgenic mice were inoculated subcutaneously with 103 D5-HER2 cells and received either PBS, trastuzumab+E6020, or either agent alone. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than that observed with any agent individually (P
A phase II study of KOS-862 (epothilone D) as second-line therapy in non-small cell lung cancer
Authors: L. Yee, T. Lynch, M. Villalona-Calero, N. Rizvi, N. Gabrail, A. Sandler, G. Cropp, G. Palmer
Journal: Journal of Clinical Oncology (2005)

7127 Background: KOS-862 is an epothilone produced by recombinant DNA technology. Epothilones act as tubulin stabilizing agents, like taxanes, but are non-cross resistant. This study assessed the response rate, time to progression, pharmacokinetic parameters and toxicity profile of KOS-862 in patients with pre-treated non-small cell lung cancer. Methods: Eligibility for this multi-center Phase II trial included failure of a platinum-containing regimen and ECOG performance status of 0 or 1. Patients received 100 mg/m2 of KOS-862 given weekly 3 weeks out of 4 (one cycle) until disease progression or toxicity. Patients were evaluable if they received at least one cycle. A Simon two-stage design was utilized, designed to rule out a response rate of < 8%. Results: 55 patients enrolled between 12/03 and 11/04. Data is available for the first 35. Baseline demographics were 19 male, 16 female; median age 58 (range 38, 81). 56 treatment cycles were administered; 183 doses of drug were given. 9% of doses required a dose reduction and 6% required a dose delay, secondary to toxicity. Toxicity consisted of fatigue, neurosensory (primarily paresthesias, Gr 1–2), and nausea/vomiting. Of the first 35 patients, only 4 withdrew due to toxicity. To date, 1 partial response has been reported; conditions for continuing under the Simon design were not met. Stable disease for 31 weeks and 16 weeks has been seen. The first 41 patients had PK data unchanged compared to previous phase 1 trials. New data regarding the major metabolite (seco- D) will be presented. Full data for the primary endpoints (overall response rate) and secondary endpoints (time to progression, safety, and relationship of PK parameters with toxicity) will be presented. Conclusions: Activity of KOS-862 in patients with platinum-failure NSCLC is <8%; the drug was tolerated well with a toxicity profile that may be superior to other epothilones in development. Further clinical development in breast and prostate cancer continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences Kosan Biosciences Kosan Biosciences
Activating transcription factor 3 (ATF3) as a potential biomarker of platinum sensitivity in non-small cell lung cancer (NSCLC).
Authors: J. Bar, I. Gorn-hundermann, S. Reid, A. O'Brien, N. Niknejad, G. D. Goss, J. Dimitroulakos
Journal: Journal of Clinical Oncology (2011)

e21012 Background: NSCLC is the most common cause of cancer-related death. Platinum-based chemotherapy is the mainstay of treatment, but a variety of mechanisms lead to platinum-resistance. ATF3 is a transcription factor, activated in response to stress signals including DNA damage and hypoxia, shown to be involved in platinum-induced cytotoxicity. We hypothesized that ATF3 is a biomarker and mediator of platinum-sensitivity in NSCLC. Methods: Platinum-resistant (R) cell lines were created by cisplatin selection of sensitive (S) NSCLC cell lines. Platinum sensitivity was evaluated by MTT assays. ATF3 induction was examined by western blots and real-time RT-PCR. ATF3 levels in a set of NSCLC specimens were tested by immuno-histochemistry (IHC) of a tissue micro array (TMA). Results: Four sets of S and R cell lines were created, each consisting of a parental S line and 4-10 R sub-lines. mRNA levels of ATF3 were induced 35-120 fold by cisplatin treatment in two of four S lines. In contrast, ATF3 mRNA in the corresponding R lines was induced only 1-12 fold. ATF3 protein levels concurred with these results. This differential induction was seen also with hypoxia mimetics and other chemotherapy agents, but not under endoplasmic reticulum stress conditions, suggesting down-regulation of the mitogen-activated kinase pathways in the R lines. Indeed, phospo-ERK levels were low in the R lines compared to the parental S. MEK-ERK pathway inhibition protected S cells from cisplatin-induced cytotoxicity and prevented ATF3 induction. IHC of a TMA detected ATF3 protein in tumor nuclei of 23% (21 out of 91) of NSCLC specimens examined. Conclusions: ATF3 induction by cisplatin was significantly attenuated in R cell lines compared to its induction in S lines. The MEK-ERK pathway is down-regulated in R lines and its inhibition in S lines reduces ATF3 induction and platinum-induced cytotoxicity. Variable ATF3 protein levels were found in NSCLC specimens. Tumor ATF3 levels or its induction by chemotherapy represent a potential predictive marker of response to platinum-based treatment in NSCLC.
What does 'palliative care' mean? Diverse definitions from cancer care providers.
Authors: Erin E. Kent, Rebecca A. Ferrer, Michelle Mollica, Grace Huang, Angela Falisi, Wen-ying Sylvia Chou
Journal: Journal of Clinical Oncology (2016)

40 Background: Existing literature on the epistemology of palliative care has mostly centered on patient/family perspectives. Understanding how multi-disciplinary healthcare providers themselves define palliative care is a critical step towards addressing barriers and harnessing facilitators that affect optimal delivery. Methods: Semi-structured key informant interviews (N = 19) were conducted with members of healthcare provider teams as part of a qualitative study on goals of care for cancer patients enrolled in clinical trials. Purposive sampling included diverse roles: attending physicians/principal investigators, oncology fellows, physician assistants, research and clinical nurses, patient care coordinators, palliative care physicians, social workers, chaplains, and pharmacists. One probe asked participants, “What does palliative care mean to you in your work?” Responses were transcribed and independently coded by two raters using interview-derived deductive and emergent inductive codes. Themes were then identified and analyzed using NVivo. Results: Informants included different elements in their definitions: attributes of palliative care (“Palliative care is helpful”); structure (“We have a pain and palliative team”); patient outcomes “(comfort”), and relation to other services (“adjunct to necessary medical care”). Additional themes also included (1) the charge of palliative care to alleviate suffering; (2) the recognition that palliative care should be holistic; (3) the centrality of symptom management, in particular pain; (4) the conflation of end-of-life, hospice, and palliative care; (5) tensions between palliative and curative care. Provider role and specific team membership appear to influence perspectives on definitions of palliative care. Conclusions: Providers share a wide range of perspectives on the operationalization of palliative care in their work. In addition to soliciting input from patients and family members, the viewpoints of a diverse set of providers should be ascertained often to inform models of care, alleviate tensions between palliative and curative care provider teams, and increase optimal usage of palliative care.
Randomized, double-blind, placebo-controlled phase II study of AMG 386 in combination with cisplatin and capecitabine (CX) in patients (pts) with metastatic gastroesophageal adenocarcinoma.
Authors: M. M. Eatock, J. Szanto, N. C. Tebbutt, C. L. Bampton, A. H. Strickland, M. Valladares Ayerbes, N. Nanayakkara, Y. Sun, A. H. Adewoye, G. Bodoky
Journal: Journal of Clinical Oncology (2011)

66 Background: AMG 386, a first-in-class investigational peptide-Fc fusion protein (peptibody), blocks angiogenesis via inhibiting the interaction between angiopoietins-1 and -2 and the Tie2 receptor. We evaluated the efficacy and tolerability of AMG 386 or placebo plus CX in the first-line treatment of metastatic gastroesophageal adenocarcinoma. Methods: Pts with confirmed metastatic adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus were randomized 1:1:1 to receive CX (cisplatin, 80 mg/m 2 IV Q3W; capecitabine, 1,000 mg/m 2 orally BID for 14 days Q3W) plus AMG 386 10 mg/kg (Arm A), 3 mg/kg (Arm B), or placebo (Arm C) IV QW. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR; in pts with measurable disease), adverse events (AEs), and pharmacokinetics (PK). Results: 171 pts were randomized (Arm A/B/C, n = 56/59/56). Efficacy results are summarized in the table. The incidence of grade ≥ 3 AEs in Arms A/B/C was 80/84/75%. Serious AEs occurred in 73/60/47% and serious AEs grade ≥ 3 in 66/60/43% of pts. AEs in Arms A/B/C included abdominal pain (30/40/17%; grade ≥ 3, 18/3/4%), peripheral edema (13/29/6%; grade ≥ 3, 0/2/0%), venous thromboembolic events (20/22/19%; grade ≥ 3, 20/19/17%), and pulmonary embolism (9/3/15%; grade ≥ 3, 9/2/13%). Median AMG 386 C max and C min values at steady state after CX coadministration were dose-proportional. Coadministration with CX did not markedly affect AMG 386 exposure. Conclusions: In this study, AMG 386 plus CX did not significantly improve PFS or ORR over placebo plus CX in this patient population. The toxicity of the combination of AMG 386 plus CX, compared with placebo, was greater but manageable. No unexpected AEs occurred. [Table: see text] [Table: see text]
Preferences in educational topics of interest to women with triple-negative breast cancer: The role of age, race/ethnicity, and stage at diagnosis in topic selection.
Authors: Kathleen Dickerson Swiger, Janine E. Guglielmino, Jeffrey D. Labban, Hope S. Rugo, Carey K. Anders, Hillary C.M. Nelson, Arin Ahlum Hanson, Hayley Dinerman, Catherine Creme Henry
Journal: Journal of Clinical Oncology (2015)

100 Background: Women diagnosed with triple-negative breast cancer (TNBC) responded to an online 80-question survey to identify their educational needs. They self-reported breast cancer subtype, demographics, and level of interest in 35 educational topics. Methods: This analysis examined whether demographic factors of women with TNBC diagnosed after 2006 (n = 611) were associated with their topic interest. Interest ratings were collapsed into “Not Interested” and “Interested or Very Interested.” Measures of association between interest in the top 10 TNBC topics and demographic factors were calculated using Phi coefficients (white/non-white) and point biserial correlations (age, cancer stage at diagnosis). False discovery rate adjustments were applied to the significance threshold to account for multiple comparisons. Results: Significant levels of association between personal factors and topic interest were observed for age; younger women were more likely to be interested in breast reconstruction (r pb = -19), parenting issues (r pb = -.36), and fertility preservation (r pb = -.33). Marginally significant associations were observed for race/ethnicity and cancer staging: non-white women were more likely to be interested in fertility preservation (r pb = -.12), and women diagnosed initially at higher stages of disease were more likely to be interested in parenting issues (r pb = .11). Conclusions: Age, race/ethnicity, and stage can influence education preferences of women with TNBC. These data point to the importance of understanding the interaction of children and cancer stage in women with triple-negative breast cancer. TNBC is proportionately more common in younger and non-white women; therefore, developing targeted interventions to address these factors could maximize healthcare team interactions, and enhance quality of life.