tbuckley/cabot-search huggingface dataset:
The impact of oral anticancer drugs on recurrence pattern after adjuvant chemotherapy in colorectal cancer patients.
Authors: Takehiro Shimada, Masashi Tsuruta, Hirotoshi Hasegawa, Koji Okabayashi, Ryo Seishima, Hidena Takahashi, Shimpei Matsui, Toru Yamada, Takayuki Kondo, Mutsuhito Matsuda, Masashi Yahagi, Yusuke Yoshikawa, Yusuke Asada, Kiyoaki Sugiura, Yoshiyuki Suzuki, Yuki Tajima, Junpei Nakadai, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2015)

610 Background: In colorectal cancer (CRC), liver metastasis is one of the critical prognostic factors. However, its pathogenesis still remains unclear. “Stream line theory” is known to be in the liver, where the bloodstream from superior and inferior mesenteric vein make a laminar flow in portal vein, and pour into the right and left hepatic vein, respectively. Recently we have elucidated that stream line theory might affect the pattern of liver metastasis in CRC. We anticipated that the way how to administrate anticancer drug also influence on the effectiveness for liver metastasis in CRC, namely oral administrated drug is absorbed in small intestine and delivered to the right lobe in the liver mainly. We hypothesized that oral intake of anticancer drug suppressed especially recurrence in the right hepatic lobe. The aim of this study is to elucidate the specific pattern of recurrence after curative resection of CRC depending on the way to administrate anticancer drug as adjuvant chemotherapy (AC). Methods: Between January 2003 and September 2013, of 365 patients who were received AC following R0 excision of primary CRC in our institution, we analyzed 94 patients who were diagnosed recurrence. They were divided into 2 groups: 64 patients were received only oral anticancer drug as AC following curative resection of CRC (PO group), and the others are distributed into IV group. A comparative review of clinicohistopathological factors and recurrence pattern were statistically performed. Results: Preoperative CEA levels were significantly higher in IV group than PO group (3.3 vs. 7.6, p=0.03). No other difference was observed in background factor of 2 groups. Comparing the recurrence pattern, 11 (17.2%) were diagnosed recurrence in the right hepatic lobe in PO group while 11 (36.7%) in IV group. There was significantly lower incidence of recurrence in the right hepatic lobe in PO group comparing with IV group (HR=2.79, 95% CI=0.92 to 8.37; p=0.04). Conclusions: AC by oral anticancer drug might specifically suppressed recurrence in the right hepatic lobe behind “stream line theory” in which oral anticancer drug is absorbed in small intestine and mainly drained into the right hepatic lobe.
Multicenter phase II study of modified FOLFIRI in patients in a Chinese population with advanced colorectal cancer (CRC) refractory to fluoropyrimidine and oxaliplatin
Authors: W. Zhang, Z. Y. Zhao, Q. Wu, J. Li, Q. Fu, J. Cheng, N. Xu, C. Xu, C. P. Wu, L. G. Xu
Journal: Journal of Clinical Oncology (2005)

3686 Background: CRC is one of the leading causes of cancer-associated death in China. The irinotecan, leucovorin(LV), and bolus and infusional 5-FU (FOLFIRI) regimen has been shown to be effective against advanced CRC in first-line and second-line treatments in Western countries. This multicenter phase II study assessed the efficacy and safety of modified FOLFIRI in patients in a Chinese population with advanced CRC refractory to fluoropyrimidine and oxaliplatin. Methods: The modified FOLFIRI consisted of irinotecan 180 mg/m2 d1 +LV 200 mg/m2 d1 + 5-FU 400 mg/m2 bolus d1 plus 5-FU 2400 mg/m2 as a 46-hour infusion, every 2 weeks. The main inclusion criterion was the advanced CRC refractory to fluoropyrimidine and oxaliplatin. Results: 83 patients with the Eastern Cooperative Oncology Group PS 0–1 =94% were enrolled. 44 were men and 39 were women. The median age was 54 years (range, 30–72). 80 patients were evaluable for efficacy: 10 (12.5%) had a partial response, 51 (63.7%) had stable disease, and 19 (23.8%) had progressive disease. The median time to progression was 96 days (95% CI: 68 -120). Survival data will be presented. Safety analysis was based on the 83 enrolled patients. The most frequent NCI grade 3/4 toxicities were neutropenia (24.1%), nausea/vomiting (8.4%), and diarrhea (2.4%). Conclusions: Modified FOLFIRI is well tolerated in patients in a Chinese population with advanced CRC refractory to fluoropyrimidine and oxaliplatin. The clinical benefit of modified FOLFIRI seen in a Chinese population is consistent with those previously reported in a second-line setting. No significant financial relationships to disclose.
A phase II study of MK-2206, an allosteric inhibitor of AKT as second-line therapy for advanced gastric and gastroesophageal junction (GEJ) cancer: A SWOG Cooperative Group trial (S1005).
Authors: Ramesh K. Ramanathan, Shannon L McDonough, Hagen F. Kennecke, Syma Iqbal, Joaquina Celebre Baranda, Tara Elisabeth Seery, Howard John Lim, Aram F. Hezel, Gina M. Vaccaro, Charles David Blanke
Journal: Journal of Clinical Oncology (2014)

4041 Background: The PI3K/AKT/MTOR pathway is frequently activated in gastric/GEJ cancers. This study evaluated the activity of single agent MK-2206 at the dose of 60 mg every other day in this tumor type. Methods: Eligible patients (pts) had gastric /GEJ adenocarcinoma with measurable disease, who had had progression after first-line treatment, or recurrence within six months after adjuvant therapy. Other pertinent eligibility criteria included a Zubrod performance status of 0-1, a fasting serum glucose ≤150 mg/dL, and < Grade 2 malabsorption or chronic diarrhea. Adequate hematologic, renal, hepatic, and cardiac function were required. Prior treatment with a PI3, AKT, or mTOR inhibitor was not allowed. MK-2206 (60 mg every other day) was given until progression or intolerable toxicity. Primary endpoint was overall survival (OS), secondary endpoints were safety, progression free survival (PFS) and response rate (RR). The study required 60 evaluable pts and a median OS of 6.5 months (mo) (power of 89%, significance level 0.07) to be considered encouraging for further investigation. Results: Seventy-five pts were enrolled between 1/1/11 to 5/1/13. Eight pts were ineligible and one pt withdrew; 66 pts were included in the analyses. Median age is 60.7 yrs (range 30.4-86.7), Males 70%, White 89% and Asian 6%. There were 2 deaths possibly related to study drug (cardiac arrest and respiratory failure). Gr 4 adverse events (AEs) were hyperglycemia, anemia and lung infection (1 each). Gr 3 AEs were infrequent and < 5% except for fatigue (6%). Other all Gr AEs included anemia 15%, anorexia 27%, diarrhea 24%, fatigue 48%, hyperglycemia 29%, nausea 40%, vomiting 20%, maculopapular rash 30%, and acneiform rash 8%. The RR is 2%, median PFS is 1.8 mo. (95% CI of 1.7- 1.8) and median OS is 5 mo (95% CI 4 - 10 mo). Conclusions: MK-2206 as 2nd line therapy in an unselected group of gastric/GEJ cancers was well tolerated with some evidence of activity (RR 2%, OS 5.0 mo) and in the range of other second line agents (irinotecan, docetaxel, ramucirumab). The primary study endpoint of 6.5 mo was not met. (Support: NIH/NCI cooperative group grants CA32102 and CA38926). Clinical trial information: NCT01260701.
A phase I study of AVE1642, a human monoclonal antibody–blocking insulin-like growth factor-1 receptor (IGF-1R), given as a single agent and in combination with sorafenib as first-line therapy in patients with advanced hepatocellular carcinoma (HCC).
Authors: S. J. Faivre, L. Fartoux, M. Bouattour, F. Bumsel, C. Dreyer, E. Raymond, O. Rosmorduc
Journal: Journal of Clinical Oncology (2011)

270 Background: AVE1642 blocks IGF-1R signaling. Previous phase I studies recommended AVE1642 doses ranged from 3 to 6 mg/kg in solid tumors. AVE1642 alone and in combination has shown in vitro and in vivo antitumor activity warranting further investigations in HCC. Methods: Dose-escalation was performed using a 3+3 design in patients with advanced HCC. AVE1642 doses were 1 mg/kg (DL1) 3 mg/kg (DL2), 6 mg/kg (DL3) given IV for 30 min every 3 weeks (w). AVE1642 was given alone for 3 w and every 3 w thereafter in combination with sorafenib (400 mg bid/day). Dose-limiting toxicities (DLT) were assessed during the first two cycles. Safety, pharmacokinetic (PK), pharmacodynamic (PD), tumor response (RECIST) were evaluated. Results: Thirteen patients (median age: 70y, M/F: 10/3, Child-Pugh A: 13/13) received 83 cycles (range 3-13) of AVE1642: 3 patients at DL1 (31 cycles), 7 patients at DL2 (38 cycles), 3 patients at DL3 (14 cycles) All patients were evaluable for safety and PK/PD. HCC was located in liver in 11 patients and was metastatic in 2. At cycle 1, exposure to AVE1642 alone led to grade 2-3 anemia in 1 patient at DL2, non febrile neutropenia in 1 at DL3. Other adverse events were grade 1-2 gastrointestinal disorders in 1 patient at DL1, in 3 at DL2 and hyperglycemia in only 1 at DL2. No liver function failure or haemorrhagic complications were observed. The frequency of sorafenib induced adverse events was not increased under combination. AVE1642 was eliminated slowly from the serum (t 1/2 : 5 to 6.7 days). There was no apparent effect of the dose on the systemic clearance of AVE1642, no effect of sorafenib treatment on the PK of AVE1642. IGF1 and IGFBP3 plasma concentrations (not of IGF2) were increased following AVE1642 administration. Most patients (11/13) presented tumor stabilization during a mean time of 13.3 w (ranging 6 to 27 w). Conclusions: AVE1642 can be safely combined with active doses of sorafenib. PK of both AVE1642 and sorafenib were not modified at these relevant concentrations. Interesting long-lasting disease stabilizations were observed in these patients with progressive disease. No significant financial relationships to disclose.
Targeting Lewis Y (LeY) in small cell lung cancer (SCLC) with a humanized monoclonal antibody, hu3S193
Authors: L. M. Krug, D. Milton, L. Chen, A. A. Jungbluth, E. Quaia, A. Nagel, J. Jones, R. Finn, C. Divgi
Journal: Journal of Clinical Oncology (2006)

7086 Background: LeY is a blood group antigen with dominant expression on the surface of epithelial tumors, including SCLC, making it a potential target for antibody-based immunotherapy. 3S193, an IgG3 mAb, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-LeY antibodies. A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m 2 demonstrated tumor targeting without serious toxicities or the development of human antihuman antibodies (Scott et al, ASCO, 2004). Methods: We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three prior chemotherapy regimens, measurable disease not previously irradiated, and tumor samples immunohistochemistry (IHC)-positive for 3S193. Patients received four weekly injections of hu3S193, 5 patients at 10mg/m 2 and 5 patients at 20 mg/m 2 . The first and fourth injections were radiolabeled with 111 Indium for gamma camera imaging. Results: Of 40 patients screened, 25/34 (74%) evaluable SCLC tumor samples were 3S193-positive by IHC: 1+ (n = 13), 2+ (n = 3), 3+ (n = 2), 4+ (n = 7). Ten patients were treated with hu3S193; eight completed all four injections (one had disease progression and one is still on treatment). At the lower dose, about 50% of lesions &gt;2 cm diameter visualized on FDG-PET were also seen on 111 In SPECT imaging. However, at the higher dose, essentially all FDG avid lesions showed targeting. The mean T 1/2 for all infusions was 2.89 ± 0.84 days at 10 mg/m 2 (n = 9) and 3.29 ± 0.66 days at 20 mg/m 2 (n = 7). No difference was noted in imaging or pharmacokinetics between the first and fourth injections. At the 20 mg/m 2 dose, patients experienced grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion. No other grade 2 or greater toxicities were observed. No objective responses were observed. Conclusions: SCLC has a high rate of Lewis Y expression. Given the strong tumor targeting, particularly at the higher dose, and the potential for immunomodulatory effects, administration of hu3S193 with chemotherapy would be warranted. Supported by the Ludwig Institute and the Experimental Therapeutics Committee of MSKCC. No significant financial relationships to disclose.
Urine cystatin C (uCyC) as a predictor for acute kidney injury (AKI) in urothelial cancer (UC) patients (pts) treated with cisplatin (CDDP).
Authors: Michael J Jelinek, Alicia J Wyche, Claudia Wing, Jay L Koyner, Walter Michael Stadler, Patrick T Murray, Peter H. O'Donnell
Journal: Journal of Clinical Oncology (2015)

317 Background: CDDP-based treatment is limited by AKI. We aimed to test whether a novel AKI biomarker, uCyC, measured before and immediately after CDDP administration could permit earlier identification of UC pts at risk for AKI. Methods: In a nested case-control study, pts treated with CDDP were prospectively enrolled. uCyC was measured 2 hours pre- and 3 hours post-CDDP doses, with values normalized to urine creatinine. AKI was defined as an increase in serum creatinine (sCr) by ≥50% (severe cases) or ≥0.3 mg/dL above pre-CDDP baseline. Controls were pts with no significant sCr rise (sCr change &lt;25% and &lt;0.3 mg/dL). A sample size of 98 patients provided 80% power to detect a true difference in biomarker change pre- and post-CDDP between cases and controls. Results: 102 pts were enrolled: 47 had UC, and 55 had other cancers; 76 were male; 82 Caucasians/15 African Americans. 4 pts not providing urine samples were excluded from analysis. For the entire cohort, average pre-CDDP sCr was 0.98 mg/dL and mean cumulative CDDP dose was 220 mg/m 2 . Controls were younger (mean 59.2 vs 65.9 yrs, p=0.01). 25 pts (26%) developed AKI; 15 (15%) were severe cases. UC pts had a significantly increased risk of AKI compared with non-UC pts (UC n=17 [37%] vs non-UC n=8 [16%], Relative Risk 2.2, 95% CI 1.08-4.73; p=0.03). AKI risk did not correlate with total CDDP dose received. In AKI pts, uCyC increased temporally in accordance with sCr and did not increase in controls, but immediate uCyC changes (3 hrs post-CDDP) were not detectable in cases or controls. However, in UC severe cases, pre-CDDP uCyC was consistently higher than in UC controls (183 ng/mg vs 109 ng/mg, p=0.04). Additionally, in UC AKI pts compared to UC controls, average maximum (peak) uCyC was higher (1812 ng/mg vs 244 ng/mg, p=0.04). Baseline uCyC did not correlate with age, and there were no significant differences in age or baseline sCr between UC cases and controls. Conclusions: UC pts are over two times more likely to develop AKI with CDDP chemotherapy than pts with other cancers, even when pre-CDDP sCr is normal. Pre-treatment uCyC levels may have value in predicting which UC pts are at highest risk of developing CDDP-induced renal injury.
Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.
Authors: Andrew X. Zhu, Baek-Yeol Ryoo, Chia-Jui Yen, Masatoshi Kudo, Ronnie Tung-Ping Poon, Davide Pastorelli, Jean-Frédéric Blanc, Hyun Cheol Chung, Ari David Baron, Tulio Eduardo Flesch Pfiffer, Takuji Okusaka, Katerina Kubackova, Jorg Trojan, Javier Sastre, Ian Chau, Shao-Chun Chang, Paolo Abada, Ling Yang, Yanzhi Hsu, Joon Oh Park
Journal: Journal of Clinical Oncology (2015)

232 Background: REACH was a global, multicenter, randomized, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for the treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for REACH was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p=0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. The pre-specified subgroup analysis of baseline AFP (cutoff 400 ng/mL) suggested AFP is a predictive marker for RAM survival benefit. Methods: Pre-specified subgroup analysis was performed based on baseline AFP with a cutoff of 400 ng/mL. Additional analyses were conducted using stratified/unstratified cox regression models and corresponding log rank test to evaluate the relationship between baseline AFP and RAM treatment effect. Results: In 250 pts with baseline AFP ≥400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059). Median OS was 7.8m for RAM vs 4.2m for PBO. In 417 pts with a baseline AFP ≥1.5 × upper limit of normal (ULN; RAM 205; PBO 212), mOS was 8.6m for RAM vs 5.7m for PBO and the HR was 0.749 (95% CI: 0.603, 0.930) (p=0.0088). The interaction testing of baseline AFP and RAM treatment effect on OS using both cutoffs (400 ng/mL and 1.5 xULN) are significant (p-value = 0.0272 and 0.0372, respectively). The safety profile in these pt populations was similar to that observed in the overall safety population. Additional REACH analyses demonstrating the predictive value of baseline AFP for RAM treatment effect on OS will be presented. Conclusions: A clinically meaningful improvement in OS was observed in populations with a baseline AFP ≥400 ng/mL or ≥1.5 × ULN. Additional analyses demonstrated a consistent RAM OS benefit for the pt population with baseline AFP over a wide range of values above the normal range. Baseline AFP is a likely predictive marker for RAM OS benefit. Clinical trial information: NCT01140347.
Primary breast sarcoma: Clinical and retrospective analysis of cases from Jerez General Hospital, Spain
Authors: A. Moreno-Vega, N. Chavarría, J. Rubio, I. Villandiego, R. Estepa, M. Gordon, J. Salvador, E. Jimenez
Journal: Journal of Clinical Oncology (2009)

e21526 Background: Primary sarcomas of the breast (PBS) are a heterogeneous group of tumors from stromal breast, infrequent (0.1% of BC). Diagnosis and treatment is unclear. We analyzed all cases of PBS from BC diagnosed at our institution from 2004 to 2008. Methods: Histopathological specimens of PBS were reviewed (excluded phylloides, metaplastic and sarcomatoids carcinomas). A single-independent pathologist revised biopsies to confirm histology features (H&amp;E) and inmunohistochemistry (IHC) setting: p53, ki67, vimentine, oestrogen and cerbB2 receptors, CD31/34, cito-keratins (CK) and histology grade. We revised image methods (mammography, ultrasound or IRM/TC) and surgery make. We analysed diseases outcomes (disease free survival, DFS) by histology high risk factors (tumor size, histology, and proliferation index). Heterogeneous chemotherapy/radiotherapy schedules was evaluated . Statistical analysis with G-Stat 2.0 was performed. Results: Seven cases of PBS (1 male/6 female) were reviewed, from 790 BC diagnosed (0.8%): 2 angiosarcomas (AS), 1 malignant fibrous histiocytoma, 2 undifferentiated, one osteoclastic and other spindle-cell sarcoma. Mean age was 63 years, 3 image-techniques used in 71.4% patients (pts), lumpectomy was performed in 71.4%. IHC: vimentine + and CK- in all cases, CD31/CD34+ in AS. P53 and Ki67 were not significantly associated with DFS (p=0.33 and p=0.88 respectively), tumor size (mean 7.4 cm) neither (T-Student test, p=0.80). Adjuvant therapy was radiation 57.14% pts; and chemotherapy (doxorubicin 4/liposomal doxorubicin 2 pts) in recurrence. Three pts have died with distant metastases (DFS mean: 11.7 months; Kaplan-Meier method). Contralateral low grade AS in one woman, and lung adenocarcinoma in the man, had been diagnosed 2 years later. Conclusions: PBS are rare and difficult diagnosis tumors. There are few series published, without prospective studies to evaluate an adequate therapy, diagnosis and valuable prognostic factors. Our incidence was high, but the independent pathology analysis confirmed all histopathological diagnosis. This review included novel IHC and IRM images, considered necessary for diagnosis and personalized treatment. No significant financial relationships to disclose.
Notch-associated expression profiles in basal-like and claudin-low breast cancer molecular subtypes
Authors: A. Prat, O. Karginova, C. Fan, C. M. Perou
Journal: Journal of Clinical Oncology (2009)

11017 Background: An attractive candidate target for breast cancer (BC) and BC tumor-initiating cells is the Notch signaling pathway. To better understand the potential dependence of breast cancer upon Notch-signaling, we used a genomic approach to study the activation of this pathway in the different molecular subtypes. Methods: Breast basal-like, luminal and HER2+ cell lines were examined for sensitivity to gamma-secretase inhibition (GSI). Gene expression data from the most sensitive cell line was analyzed during treatment and upon releasing from GSI (4h, 8h and 24h post-treatment). Using an unsupervised analysis, all time points were hierarchically clustered and genes that changed in expression were identified (SAM one-class). This Notch-associated signature identified in vitro was used to classify 2 distinct sporadic breast tumor populations (UNC and NKI, n=495). Each tumor sample was categorized into 6 molecular subtypes (basal-like, claudin-low [submitted], luminal A/B, HER2-enriched and normal-like). Results: In vitro, breast basal-like cell lines SUM102 and SUM149 were more sensitive to GSI (IC50, 0.3 and 1.5μM, respectively) compared to the luminal MCF7 (&gt;10μM) and HER2+ SKBR3 (&gt;5μM) cell lines. Over 340 genes that changed in expression (FDR&lt;0.03%) were identified in SUM102, including known targets of the canonical Notch pathway (Hes1 and Hey2). Selected GO terms overrepresented in this signature were the following (EASE score, p&lt;0.01): Wnt and Hedgehog signaling, embryonic development and cell differentiation. In vivo, 2 distinct gene clusters were evident in both populations, one of which was predictive of poor patient outcome. This Notch-associated poor prognostic signature was highly expressed in &gt;90% of basal-like tumors. The second cluster was highly expressed in the recently identified claudin-low subtype, and was uniquely enriched with genes involved in cell differentiation (Sox7/9, Hey2, Dll1, Fzd5) and cell adhesion. Conclusions: Notch associated expression profiles are associated with basal-like and claudin-low BC subtypes, providing additional biological insight of pathway activation. GSI could represent a novel strategy for both subtypes, which represent the vast majority of the “triple negative” population. No significant financial relationships to disclose.