tbuckley/cabot-search huggingface dataset:
Clinical relevance of HER2 expression/activation, as measured in circulating tumor cells by a multiplexed immunoassay, in women with HER2-negative (by FISH) metastatic breast cancer (MBC).
Authors: J. D. Hainsworth, D. A. Yardley, H. A. Burris
Journal: Journal of Clinical Oncology (2010)

TPS125 Background: HER2-targeted agents markedly improve survival in women with HER2-positive breast cancer. HER2 expression is currently assessed using immunohistochemistry or FISH techniques, usually at the time of diagnosis. The ProONC assay (Prometheus, Inc.) is a multiplexed immunoassay that allows assessment of HER2 expression/activation in circulating tumor cells (CTCs) or FNA specimens, thereby enabling reassessment at multiple timepoints during the disease course. For patients with MBC, the ProONC assay correlated strongly with FISH in tumors previously identified as HER2-positive, but identified HER2 expression/activation in 29% of patients who had previously tested HER2-negative by FISH. The clinical relevance of this finding is currently unknown. The study objectives were to: 1) determine the frequency of HER2 expression/activation, as measured in CTCs by the ProONC assay, in women with HER2-negative MBC by FISH testing; 2) evaluate the efficacy of HER2-targeted treatment in this group of women with MBC. Methods: Part 1: Blood samples and/or FNA specimens from 74 women with HER2-negative MBC (by FISH) will be obtained. CTCs will be isolated and tested for HER2 expression/activation using the ProONC assay. If the incidence of HER2- positivity is ≥10%, the study will proceed to Part 2. Part 2: A sufficient number of women with HER2-negative MBC (by FISH) will be screened to identify 48 women who are HER2-positive by the ProONC assay. At the time of their next progression of MBC, these women will receive HER2- targeted treatment with either trastuzumab (HER2 overexpressed) or pertuzumab (HER2 amplified but not overexpressed). Responding patients will continue single-agent HER2-targeted therapy; stable patients after 8 weeks will have appropriate chemotherapy added. Response rate to HER2- targeted treatment will be determined. No significant financial relationships to disclose.
Hepatic artery infusion in surgical therapy of hepatic metastases from colorectal cancer
Authors: F. J. Cummings, K. Varker, G. Begossi, C. Taneja, H. J. Wanebo
Journal: Journal of Clinical Oncology (2008)

15077 Background: The gold standard in the treatment of liver metastases from colorectal cancer (CRC) is surgical resection. Unfortunately most of the patients are unresectable. The purpose of the study was to assess the role of hepatic arterial infusion in the management of these patients. Methods: Our clinical series included 274 patients with liver metastases from CRC (period 1978–2001). One hundred thirty four pts were treated surgically as follows: resection (87 pts), hepatic artery infusion (HAI) (30 pts), resection plus HAI (13 pts), and ablation plus HAI (8 pts). The remaining 139 pts received systemic therapy treatment. A separate (historic) group had supportive care only (historic) group had supportive care only (historic control). Overall and median survival was measured by Kaplan-Meier method from treatment of liver metastases in the surgical group and from diagnosis in systemic therapy/historic groups. Conclusion: A multi-option strategy is essential in surgical planning for management of liver metastases from CRC. Resection has an overall 5 year survival of 25% which is greatly enhanced by addition of adjuvant therapy with HAI. In the event of non-resectability, HAI with tumor ablation or HAI alone is associated with a median survival of 29 and 17 months respectively and provides excellent palliation ensuring that the operative procedure is maximized in these high-risk metastases and may extend survival in patients with non-resectable metastases who are failing systemic chemotherapy. Group Pts. N Surgical Intent 2 yr 5 yr Median (mo) Resection only 87 Curative 73% 25% 35 Resection & HAI 13 Curative 66% 55% Not reached HAI 30 Palliative 23% 0% 17 Ablation plus HAI 8 Palliative 57% 12.5% 29 Systemic Therapy 139 Palliative 13% 1% 11 Historic Controls 136 Supportive 8% 0% 6 No significant financial relationships to disclose.
Clinical significances of pAkt and pErk1/2 in patients with early-stage breast cancer treated with anthracycline-based adjuvant chemotherapy.
Authors: Y. Teng, W. Liu, X. Qu, L. Zhou, L. Zhang, J. Zhang, M. Zhao, P. Yu, B. Jin, Y. Luo, J. Shi, Y. Liu
Journal: Journal of Clinical Oncology (2011)

e21026 Background: Akt and extracellular signal-regulated kinase (Erk1/2) are important molecules in cell proliferation. Expression of phosphorylated Akt (pAkt) and phosphorylated Erk1/2 (pErk1/2) can result in breast cancer progression and drug resistance in vitro. But compelling evidences about the clinical significances of pAkt and pErk1/2 in early stage breast cancer are currently lacking. The purpose of this study is to determine the prognosis value of pAkt and pErk1/2 in early stage breast cancer treated with anthracycline-based adjuvant chemotherapy. Methods: Tumor specimens were obtained from 256 Chinese patients with early stage breast cancer, who had received adjuvant anthracycline-based chemotherapy. The expression of pAkt and pErk1/2 were determined by immunohisto-chemistry (IHC). The interactions between pAkt, pErk1/2 and clinical characters were assessed by Chi-square tests; survival functions were estimated using the Kaplan-Meier methods. Results: PAkt and pErk1/2 were expressed in 38.7% and 33.6% of patients, respectively. For the overall patients, after a median follow-up of 52.5 months, pErk1/2 expression was related with a decreased disease free survival (DFS) of patients (p=0.049) and chemotherapy resistance (p=0.016). The patients with pAkt negative and pErk1/2 negative tumors had a longer DFS as compared with patients of pAkt positive or pErk1/2 positive (p=0.028). In HER2 positive patients, both pAkt and pErk1/2 expression were related with a decreased DFS of patients (p=0.002). In ER and PR negative patients, pAkt expression was related with a decreased DFS of patients (p=0.034). In the patients treated with anthracycline-based chemotherapy associated with taxanes, pErk1/2 expression were related with a decreased DFS (p=0.030). Multivariate analysis showed that coexpression of pAkt and pErk1/2 was an independent predictor for DFS (p=0.032). Conclusions: In early stage breast cancer, both pAkt and pErk expression was predictive for a bad prognosis, especially in the HER2 positive patients. PErk1/2 expression was related with anthracycline resistance and it maybe a bad predictor for the efficacy of anthracycline-based chemotherapy.
Is proliferative index (Ki-67) useful to stratify patients (pts) with G2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs)? Clinicopathologic correlation.
Authors: Martin Angel, Juan O Connor, Veronica Pesce, Guillermo Ariel Mendez, Claudia Bestani, Fabiana Marmissolle, Nora Giacomi, Susana Belli, Enzo Domenichini, Matias Chacon, Victor Zamora, Ana Maria Cabanne, Patricia Parma, Enrique Luis Roca
Journal: Journal of Clinical Oncology (2015)

255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogeneous group of tumors. Several treatment options including chemotherapy and target therapy are available, but there is a lack of prospective trials assessing the role of pronostic factors in this population. Aim(s): to analyze prognostic factors and clinical characteristics in a population of patients with G2 GEP-NETs. To determine the role of ki 67 in the stratification of G2 population. Methods: Study population was obtained from our prospective database (Argentum Group). Survival was estimated using the Kaplan-Meier method and compared between Ki-67 quartiles using the log-rank test. Value of Ki-67 to discriminate mortality was assesed with a ROC curve analysis Results: 144 pts were evaluated. Mean age 54.9, 46.7% male. 102 (70.8%) with metastatic disease, mainly hepatic in 97 pts. (67.4%). 67.9 % underwent surgery. 34% received chemotherapy, and 10.9% target therapy. Median Ki-67 value was 6 (IQR 4-10), ROC curve=0.62 (95% CI 0.53 a 0.72 p=0.021. cut-off: 6.5 (sensitivity 62.2%, specificity 57.7%). Median survival was 97, 67, 51 and 27 months according stratification by quartile (p.001), 45 events (31.7%). Conclusions: Our results suggest that in the heterogenous G2 GEP-NETs there are significant differences in survival. This study was underpowered to detect differences between Ki-67 quartiles, we detected that chemotherapy was mostly used in the higher quartiles.
Second-line gemcitabine plus nab-paclitaxel (G+A) for advanced pancreatic cancer (APC) after first-line FOLFIRINOX: Single institution retrospective review of efficacy and toxicity.
Authors: Yue Zhang, Howard S. Hochster, Stacey Stein, Jill Lacy
Journal: Journal of Clinical Oncology (2014)

344 Background: Gemcitabine (G) plus paclitaxel protein-bound particles for injectable suspension (Abraxane, A) is an active first line regimen for APC based on improved efficacy compared to G (Van Hoff, DD et al. J Clin Oncol 31, 2013 [suppl;abstr 4005]). However, there is a paucity of data regarding efficacy of G+A in pts who received prior FOLFIRINOX. To assess efficacy and tolerability of 2nd line G+A, we reviewed our single institution experience with G+A in APC pts who received 1st line FOLFIRINOX. Methods: We conducted a retrospective review of dose, toxicity, efficacy of second line G+A in FOLFIRINOX-treated APC pts treated at Yale Cancer Center between 12/2011 and 08/2013. Pts were treated until progression, unacceptable toxicity, or pt preference. Doses were at treating physician’sdiscretion. Dose densities were compared to full doses (A 125 mg/m2 + G 1000 mg/m2 days 1, 8,15 q 4 wks). Response rate, med time to treatment failure (TTF), med overall survival (OS) were calculated. Results: 23 pts were treated with G+A after 1st line FOLFIRINOX. Pts characteristics: metastatic, 18; locally advanced, 5; med age, 61 (range 50-74);male, 9; ECOG PS ≤1, 22; med # FOLFIRINOX cycles, 12 (range 5-46). Med interval from FOLFIRINOX to G+A was 5 wks (range 1.7-40.3). Responses by RECIST were: PR, 2 (8.7%); SD for ≥7 wks, 8 (34.8%); PD, 10 (43.4%); ineval, 3 (13.1%). 9 (39%) and 8 (34%) pts had &gt;30% decrease in CA 19-9 and CEA, respectively. 13 pts died, 6 pts stopped G+A, 4 pts are still receiving G+A. Med TTF was 11 wks (range 1-35). Med OS was &gt;17.9 wks (range 2.1-69.6). All pts had initial dose reductions of G or A; 7 and 12 pts required further dose reductions with A and G, respectively. Dose densities were 56.9% and 63.5% for A and G, respectively. Grade ≥3 hematologic toxicities included neutropenia 17%, anemia 26%, thrombopenia 26%. Conclusions: In this single institution pt population, G+A has limited activity after FOLFIRINOX. Most of our pts received FOLFIRINOX for &gt;6 months and were still able to receive a 2nd line doublet. Most required dose reductions for cytopenias, but this sequence was tolerable. In this setting, an additional 11 wks med TTF is about half of the TTF in 1st line G+A and may be clinically valuable.
Genetic Basis of Acute Lymphoblastic Leukemia
Authors: Ilaria Iacobucci, Charles G. Mullighan
Journal: Journal of Clinical Oncology (2017)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and despite cure rates exceeding 90% in children, it remains an important cause of morbidity and mortality in children and adults. The past decade has been marked by extraordinary advances into the genetic basis of leukemogenesis and treatment responsiveness in ALL. Both B-cell and T-cell ALL comprise multiple subtypes harboring distinct constellations of somatic structural DNA rearrangements and sequence mutations that commonly perturb lymphoid development, cytokine receptors, kinase and Ras signaling, tumor suppression, and chromatin modification. Recent studies have helped to understand the genetic basis of clonal evolution and relapse and the role of inherited genetic variants in leukemogenesis. Many of these findings are of clinical importance, and ongoing studies implementing clinical sequencing in the management of leukemia are expected to improve diagnosis, monitoring of residual disease, and early detection of relapse and to guide precise therapies. Here, we provide a concise review of genomic studies in ALL and discuss the role of genomic testing in clinical management.
Clinical Characteristics and Outcomes in Patients with Multiple Myeloma and CKS1B Gene Gain/Amplification after Autologous Stem Cell Transplantation
Authors: Fabian M Bock, Gary Lu, Nina Shah, Qaiser Bashir, Krina K. Patel, Uday R. Popat, Chitra M. Hosing, Sameh Gaballa, Martin Korbling, Ruby Delgado, Gabriela Rondon, Robert Z. Orlowski, Jatin J. Shah, Elisabet E. Manasanch, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Blood (2014)
Prognostic value of duodenal invasion length in patients with gastric cancer.
Authors: N. Oshima, M. Tokunaga, Y. Tanizawa, E. Bando, T. Kawamura, J. Kondo, Y. Kinugasa, H. Kanemoto, K. Uesaka, M. Terashima
Journal: Journal of Clinical Oncology (2011)

24 Background: Duodenal invasion (DI) has been considered as a poor prognostic factor of gastric cancer patients. Not all the patients would be able to undergo curative operation. Neoadjuvant chemotherapy (NAC) may improve the rate of curative operation of these patients. In this study, we investigated whether the length of duodenal invasion preoperative diagnosis can be one of factor to decide indication of NAC. Methods: A total of 118 gastric cancer patients with clinically evident DI, who underwent laparotomy at our center, were enrolled in this study. 42 patients with DI length 20 mm or longer were categorized into long invasion group (LI), 76 patients with DI length shorter than 20 mm were categorized into short invasion group (SI). Clinicopathologic features, rate of direct invasion and lymph nodes involvement, R0 resection, and survival rate were compared between two groups. Results: Resection rate was significantly different between two groups: SI group (85.5%; 65/76), LI group (69.0%; 29/42). Direct invasion to adjacent organs was significantly more frequently observed in LI group (21%; 6/29) than SI group (4 %; 3/65, p = 0.02). In LI group, pancreas invasion was observed in all patients except for one patient. Multivariate analysis to predict the adjacent organ invasion revealed that CT diagnosis (p = 0.005) and invasion length (p = 0.01) were selected as risk factors of direct invasion to adjacent organs. There was no significant difference of nodal involvement between LI group (83%; 24/29) and SI group (83%; 54/65 p = 0.99). The 5-year survival rate was 19% in LI group and 43% in SI group (p = 0.23). The number of patients who underwent R0 resection was more frequently in SI group (75.4%; 49/65) than SI group (69.1%; 16/29). The factors of R1 or R2 resection were metastasis of peritoneum or direct invasion to adjacent organs. Conclusions: In patients with long duodenal invasion, direct invasion to the pancreas was more frequently observed, and resulted in low curative resection rate and poor survival. Preoperative chemotherapy may improve the curative resection rate and survival in these patients. Prospective study is warranted to evaluate the efficacy of NAC for these patients. No significant financial relationships to disclose.
Final results of a translational phase l study assessing a QOD schedule of the potent AKT inhibitor MK-2206 incorporating predictive, pharmacodynamic (PD), and functional imaging biomarkers.
Authors: T. A. Yap, L. Yan, A. Patnaik, D. Olmos, I. Fearen, R. D. Baird, K. P. Papadopoulos, N. Tunariu, A. Biondo, H. Keilhack, L. M. Delgado, A. Taylor, S. C. Blackman, C. L. Carpenter, S. Decordova, S. Heaton, M. D. Garrett, D. Sullivan, J. S. De Bono, A. W. Tolcher
Journal: Journal of Clinical Oncology (2011)

3001^ Background: MK-2206 is a novel allosteric inhibitor of all 3 isoforms of AKT, which are targets implicated in malignant progression. Methods: The investigational agent MK-2206 was given orally QOD to patients (pt) with advanced solid tumors. PD studies of AKT and downstream protein phosphorylation (p) were carried out in tumor biopsies and platelet-rich plasma with MesoScale Discovery (MSD) ELISA, and hair follicles with immunofluorescence. Tumor biopsies were sequenced with Sequenom Oncocarta panel for putative predictive biomarkers and stained with IHC for PTEN expression. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopy (MRS) and diffusion weighted imaging (DWI) were conducted. Results: 71 pt (37 M; median age 59y; ECOG PS 0/1: 22/49) received MK-2206 at 30, 60, 75, 90 mg QOD. G3 rash (n=6) was dose limiting at 75-90 mg QOD, establishing MTD at 60mg QOD. Four MTD expansion cohorts were then undertaken: paired tumor biopsies (n=14), functional imaging (n=13), ovarian cancer (n=11) and castration resistant prostate cancer (n=14). MK-2206 related toxicities included rash, nausea, fatigue, and hyperglycemia. C-peptide levels increased on MK-2206. No G5 toxicities were seen. PK was dose proportional. Steady state trough MK-2206 concentrations ≥60mg QOD were above those required for both pAKT inhibition and antitumor activity in preclinical models. PD studies in patients treated at the MTD demonstrated that on commencement of MK-2206: 1) pAKT was inhibited in all on-treatment tumor biopsies (p=.002); 2) pAKT, pPRAS40, and pGSK3β were suppressed in platelet-rich plasma from 3h to 48h (all p<.05); 3) pPRAS40 was inhibited 6h to day 15 in hair follicles (p=.03). Median tumor DWI apparent diffusion coefficients increased significantly in 4 pt at day 7 and 2 pt at Day 21 of MK-2206, supporting intratumoral necrosis; DCE-MRI and MRS did not change post MK-2206. 9 pt had RECIST stable disease >4 months with minor responses in 3 pt and CA125 declines observed. Conclusions: MK-2206 can safely induce significant and sustained AKT pathway blockade at the MTD with early signs of clinical activity observed.
The influence of self-reported conflicts of interest on the conclusions of editorial authors of phase III cancer trials.
Authors: M. C. Miranda, A. T. Lera, A. Ueda, B. Briones, T. Lerner, A. Del Giglio, R. P. Riechelmann
Journal: Journal of Clinical Oncology (2011)

6039 Background: The oncology drug development enterprise is highly resource-consuming, what has led to a straightening of the relationships between the pharmacy industry and researchers. Such interactions could interfere with the scientific validity of clinical trials and their interpretation by medical experts. Methods: We defined medical experts as authors of editorials of phase III cancer clinical trials published in high-impact oncology journals. We aimed to describe the frequency and types of self-reported conflicts of interest of editorial authors as well as investigate possible associations between their opinion stated in the articles and the presence of conflicts of interest. Eligible studies were editorials of phase III clinical trials of antitumor drugs or symptom management published from January 2007 to December 2009. Relevant data from the editorials and related trials were collected and each editorial conclusion was classified as favorable, neutral or unfavorable with respect to the experimental therapy. Authors’ conclusions were independently analyzed by two blinded authors. Results: 54 editorials and 54 related trials were eligible: 83% were published in the Journal of Clinical Oncology and 42% reported at least one type of conflict of interest (mostly consultancy fees and honoraria). Authors’ conclusions on the experimental therapy were neutral in 39% of editorials, favorable in 37% and unfavorable in 24%. With respect to phase III related articles, 93% were anticancer drug trials and more than half were positive trials. There was no significant association between editorial favorable opinion and self-reported conflict of interest of the editorial author (p = 0.224) or industry sponsorship of phase III trial (p = 0.251). Conclusions: Authors of editorials of phase III trial cancer trials were not influenced by self-reported conflicts of interest or trial sponsorship. Such findings reflect the transparency on the part of editorial authors and also the measures adopted by journals to improve the critical analysis of the cancer literature.
Classification of oncocytic papillary renal cell carcinoma.
Authors: Stephen Hembree Culp, Yunchuan Delores Mo, Mairo Diolombi, Helen P Cathro
Journal: Journal of Clinical Oncology (2013)

467 Background: Over the past decade, genitourinary pathologists have increasingly recognized an oncocytic variant of papillary renal cell carcinoma (PRC) that can complicate classification as Type 1 or Type 2 PRC. The International Society of Urological Pathology recently proposed reclassifying oncocytic papillary renal cell carcinoma (OPRC) as a separate subtype. We set out to test the validity of separating oncocytic tumors from other PRC. Methods: 70 consecutive cases of PRC with sufficient tissue for analysis were reviewed from patients undergoing surgery at The University of Virginia (1992 to 2007). All cases were classified by type, including those with oncocytic features. Histologic, clinical, and outcomes data were analyzed based on type and the presence of oncocytic features. Results: A total of 15 (21.4%) tumors displayed oncocytic differentiation, the majority of which were Type 2 tumors (11 or 73.3%) (p &lt; 0.001). The male to female ratio of OPRC cases was nearly 1:1 in contrast to a significant male bias historically seen in PRC. The presence of oncocytic features was significantly associated with higher Fuhrman grade (p &lt; 0.001) and no OPRC tumors were multifocal as opposed to 13 (23.6%) of non-OPRC tumors. At a median follow-up of 79.9 months for the entire cohort, 5-yr disease specific survival (DSS) for OPRC patients was 79.0% which was intermediate between patients with Type 1 (93.4%) and Type 2 (44.4%) tumors. By Cox proportional hazards regression analysis, DSS of OPRC patients was significantly better than Type 2 patients (HR 0.12; 95% CI 0.03, 0.52, p = 0.004), but tended to be worse than Type 1 patients (HR 2.58; 95% CI 0.78, 8.50, p = 0.12). Conclusions: We report the largest cohort of OPRC patients to date. Patients with OPRC demonstrate a survival rate intermediate between that of patients with non-oncocytic Type 1 and Type 2 PRC. Though the majority of OPRC tumors were classified as Type 2 PRC, oncocytic features complicate histomorphologic typing. Therefore, classification of OPRC separately would clarify typing of PRC and improve the validity of Fuhrman nuclear grading for PRC. Our results support separation of OPRC from Type 1 and Type 2 PRC, based on both histomorphologic typing and patient survival.