bluuebunny/crossref_metadata_2025 huggingface dataset:
A French prospective pilot study for identifying dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients (pts) receiving capecitabine (cap).
Authors: Etienne-Grimaldi Marie-Christine , Ferrero Jean-Marc , Thomas Fabienne , Bobin-Dubigeon Christine , Merlin Jean Louis , Pinguet Frederic , Ferrand Christophe , Boyer Jean-Christophe , Romieu Gilles , Bachelot Thomas , Pivot Xavier , Dieras Veronique , Largillier Remy , Mousseau Mireille , Goncalves Anthony , Roche Henri Hubert , Bonneterre Jacques , De Clercq Beatrice , Milano Gerard
Published: March 2020

e13519

Background: For fluoropyrimidines, and especially cap, Health Authorities point out that DPD deficiency confers a significant risk of major toxicity (tox). Identification of at-risk pts is thus relevant. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping for predicting severe cap-related tox in metastatic breast cancer pts. Methods: 303 pts were included (15 institutions), 88% received cap as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment dihydrouracil (UH2) and uracil (U) plasma concentrations were measured in 286 pts (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was done on 281 pts. Severe tox (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 tox (diarrhea, vomiting, hematoxicity, hand-foot syndrome) was observed in 19.6% of pts (one toxic death). A marked trend for higher U (median 12.7 vs 10.2 ng/ml, p=0.014) and UH2 (median 110 vs 93 ng/ml, p=0.011) concentrations was observed in pts developing severe tox vs those who didn’t. However, ROC curves showed that these differences were too small for use as reliable tox predictors. The distribution of UH2/U ratio was similar between pts with or without tox (median 9.1 vs 9.6, respectively, p=0.80). The patient with toxic death had a UH2/U ratio of 6.5 and U concentration of 17 ng/ml. Among the 7 pts with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe tox (including toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe tox was 4.60 in mut pts vs wt pts (95%CI 2.95-7.16, p=0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: These data point out that breast cancer pts harbouring a DPD variant allele are candidate to develop severe, up to lethal, cap-related tox. In contrast, pre-treatment UH2/U ratio and U measurements are not reliable predictors of cap tox. Clinical trial information: Eudract 2008-004136-20.
Focal adhesion kinase (FAK) inhibitors VS-6063 and VS-4718 target cancer stem cells.
Authors: Xu Qunli , Kolev Vihren N , Wright Quentin G , Shapiro Irina M , Vidal Christian M. , Padval Mahesh , Keegan Mitchell , Paterson Daniel , Horobin Joanna , Pachter Jonathan A
Published: March 2020

e13523

Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates cellular signaling through integrins and growth factor receptors and functions in multiple steps of tumorigenesis. Both VS-6063 and VS-4718 are potent, selective, and orally active FAK inhibitors. In a phase I clinical trial, VS-6063 was well tolerated and demonstrated preliminary clinical activity. VS-4718 is in late stage preclinical development and has been shown to inhibit tumor growth and metastasis in tumor models. We report here that the FAK inhibitors VS-6063 and VS-4718 effectively abrogate cancer stem cells (CSCs). Methods: VS-6063 and VS-4718 were evaluated in the ALDEFLUOR and Side Population (SP) CSC assays in vitro and in xenograft tumors in vivo. Results: Treating SUM159 breast cancer cells with FAK inhibitors reduced the percentage of ALDEFLUOR+ and SP CSCs. Similar inhibitory effects on CSCs were observed in the ovarian cancer cell lines OVCAR-5 and OVCAR-8 and the mesothelioma cell line H2052. In direct contrast, cytotoxic agents paclitaxel, carboplatin and pemetrexed increased the percentage of CSCs, suggesting that these agents do not effectively target CSCs. Importantly, combination of either VS-6063 or VS-4718 with cytotoxic agents blocked induction of CSCs by these agents. The effect of a FAK inhibitor on CSCs in vivo was evaluated in an MDA-MB-231 human breast cancer orthotopic model. Oral administration of FAK inhibitor substantially reduced the number of ALDH1- positive cells in tumors as assessed by immunofluorescence. Following dissociation of cells from tumors, CSCs were found to be reduced in FAK inhibitor-treated tumors as measured by multiple assays. Furthermore, cells isolated from FAK inhibitor-treated tumors showed reduced tumor-initiating capability upon re-implantation into immunodeficient mice. FAK inhibitor also decreased ALDH1-positive CSCs in an orthotopic MM87 mesothelioma model. Conclusions: Our results provide clear demonstration that FAK inhibitors target cancer stem cells both in vitro and in xenograft tumors in vivo and support the planned clinical development of VS-6063 and VS-4718 to achieve durable clinical responses for cancer patients.
Targeting PIK3CA mutant breast cancer with the combination of PIK3CA-specific inhibitor, BYL719, and IGF1-R antibody, ganitumab.
Authors: Cao Z, Alexander , Pinzon-Ortiz Maria , Chen Yan , Li Xiaoyan , Beltran Pedro J. , Gansert Jennifer L. , Peters Malte , Schlegel Robert , Schumacher Karl Maria , Huang Alan
Published: March 2020

e13525

Background: PI3K/AKT signaling is a critical growth and survival pathway in many human cancers. PI3Ks are lipid kinases that are important in controlling signaling pathways involved in cell proliferation, motility, cell death and cell invasion. The α isoform of PI3K (PIK3CA) is linked upstream mainly to receptor tyrosine kinases and is commonly mutated in various solid tumor types. The existing scientific evidence strongly supports the concept of targeting PIK3CA in human cancers, especially those harboring PIK3CA mutations. Sustained PIK3CA inhibition may lead to aberrant RTK signaling to attenuate PIK3CA inhibition. IGF1R is a RTK commonly expressed in human neoplasia. Its signaling has been implicated in tumor cell survival. Additionally, IGF1R/IRS signaling has been shown to be a feedback pathway to down-modulate mTOR inhibition by RAD001 in cancer cells. We reason that the efficacy of PIK3CA inhibition would be enhanced if PIK3CA inhibitor is combined with a targeted agent against a key RTK in pAKT signaling. Methods: We set out to examine whether PIK3CA inhibition would also trigger IGF1-R/IRS signaling. In addition, we explored the combination of PIK3CA-specific inhibitor, BYL719, and a fully human antibody against IGF1-R, ganitumab, preclinically against a PIK3CA mutant breast cancer model, MCF7. Results: Our data indicate that IGF1-R/IRS signaling is activated upon PIK3CA inhibition. BYL719 exhibited concentration-dependent tumor growth inhibition in vitro. Ganitumab alone had modest inhibitory activity. The combination of BYL719 and ganitumab inhibited MCF7 growth synergistically in vitro. This combination was further tested in an MCF7 xenograft in mice. BYL719 monotherapy resulted in tumor stasis. Ganitumab alone had marginal growth inhibition. The combination of BYL719 and ganitumab led to tumor regression. Conclusions: Our data suggest that the combination of BYL719 and ganitumab would act synergistically to inhibit PIK3CA mutant breast cancer cells by blocking two inter-connected pathways. The combination of BYL719 and ganitumab has now entered into clinical trial (NCT01708161). It represents a promising approach against PI3KCA mutant breast cancers.
Preclinical and clinical data for tbo-filgrastim: A short-acting filgrastim.
Authors: Buchner Anton , Mueller Udo W. , Bias Peter , Engert Andreas
Published: March 2020

e13555

Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal model studies. Clinical: The PK/PD of tbo-filgrastim and filgrastim were compared in 2 Phase I studies in 200 healthy volunteers. The safety and efficacy of tbo-filgrastim were compared with filgrastim in 3 Phase III studies in 677 patients receiving CTx for breast cancer (BC), lung cancer (LC) and non-Hodgkin lymphoma (NHL). The BC study, in which DSN was the primary parameter, was placebo controlled. Results: Preclinical: Binding affinity to the human G-CSF receptor and growth-promoting activity were comparable between tbo-filgrastim and filgrastim in vitro. In vivo, no relevant differences were seen between tbo-filgrastim and reference filgrastim in PK, PD, safety, or tolerability in animal models. Clinical and laboratory findings, gross pathology and histopathology in animal models were similar to filgrastim. Clinical: tbo-Filgrastim was safe, effective, and comparable to filgrastim in the prevention of FN. DSN, absolute neutrophil count (ANC) nadir, and time to ANC recovery were comparable. The incidence of FN was low (mean of 12.1%, 15.0%, and 11.1% in Cycle 1 of the BC, LC, and NHL studies, respectively), with no significant differences between agents. In the BC study, in Cycle 1, DSN was 1.1 vs 3.9 days for tbo-filgrastim and placebo, respectively. The efficacy of tbo-filgrastim was independent of the myelotoxic potential of CTx. Immunogenicity and incidence of binding and neutralizing antibodies were low and comparable. Conclusions: The safety profiles of tbo-filgrastim and filgrastim were similar and characteristic of filgrastims. Tbo-filgrastim was superior to placebo and equivalent to filgrastim in reducing DSN after myelotoxic CTx. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.
Phase (Ph) I study of pazopanib (P) in combination with vinorelbine (V) in patients with metastatic non-small cell lung cancer (mNSCLC) and breast cancer (mBC).
Authors: Gentzler Ryan D. , Kaklamani Virginia G. , Worden Rebekah , Zumdahl Therese , Simm Hala D , Rademaker Alfred , Johnson Melissa Lynne , Patel Jyoti D.
Published: March 2020

e13568

Background: V is an established treatment for mNSCLC and mBC, but combination 2nd line chemotherapy has not shown clear benefit for either disease. The anti-VEGF agent bevacizumab improves response rate and progression free survival (PFS) for mNSCLC and mBC. P is a tyrosine kinase inhibitor targeting the VEGF receptors. We hypothesize that because CYP3A4 is inhibited by P and responsible for metabolism of V, there may be synergy between P + V. This is a ph I study testing the combination of P + V in previously treated pts with mNSCLC and mBC. Methods: Pts with Stage IIIB/IV NSCLC or Stage IV mBC with ≤ 2 (lung) or ≤ 3 (breast) prior chemotherapies, no prior VEGF inhibitors, and PS 0-2 were treated with P + V. The objective was to determine the maximum tolerated dose (MTD) of P + V. Dose escalations followed a standard 3+3 design. After 6 pts, the protocol was amended to add an intermittent dosing cohort (2a) to improve tolerability. Response assessment (RA) occurred q 42 days (d) while on study. Pts had weekly toxicity assessments, and PK data was collected on d 1-2 of the first 2 cycles. Results: Eight pts (7 mNSCLC, 1 mBC) were enrolled in 3 of 9 planned cohorts. Pts received a median of 2 cycles. All pts experienced at least 1 grade (gr) 3/4 toxicity. Six dose-limiting toxicities occurred in 4 pts in cohort 2/2a. Five severe adverse events were reported in 4 pts and included thrombocytopenia, neutropenia, abdominal (abd) pain, pneumonia, and hepatotoxicity. Gr 3/4 toxicities were: neutropenia (6), fatigue (2), thrombocytopenia (1), hyperbilirubinemia (1), transaminitis (1), hypertension (1), abd pain (1), and pneumonia (1). 1 pt refused treatment after 1 cycle and had no RA. 5 of 8 pts expired due to progressive disease. No partial responses were noted. Median PFS was 66 d (95% CI 35 to 384 d). Conclusions: Combination of P + V in pre-treated mNSCLC and mBC results in high rates of gr 3/4 toxicities at all dose levels. The trial was suspended due to significant drug-drug interactions before the MTD could be determined. No further study of P in combination with V is warranted in either pt population. Clinical trial information: NCT01060514. [Table: see text]
Orally administrative melk (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor suppresses the growth of various types of human cancer.
Authors: Chung Suyoun , Suzuki Hanae , Miyamoto Takashi , Takamatsu Naofumi , Tatsuguchi Ayako , Ueda Koji , Kijima Kyoko , Matsuo Yo , Nakamura Yusuke
Published: March 2020

e13569

Background: We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also highly upregulated in multiple types of cancer including prostate, pancreas and lung cancers, and plays indispensable roles in cancer cell survival, particularly in the maintenance of tumor-initiating cells. In this study, we attempted to identify novel substrates of MELK and develop the small-molecule MELK inhibitor. Methods: To elucidate the MELK signaling pathway in breast cancer cells, we screened MELK substrates by 2D-PAGE and mass spectrometric analysis, and characterized two of them for their roles in mammary carcinogenesis. Furthermore, we conducted a high-throughput screening of a compound library followed by structure-activity relationship studies. We investigated the growth suppressive effect of a MELK inhibitor OTSSP167 using xenograft models in mice and a mammosphere-formation assay. Results: We identified two novel MELK substrates, DBNL and PSMA1, which plays critical roles in invasiveness of cancer cells and maintenance of mammary tumor-initiating cells. We successfully obtained a highly potent MELK inhibitor OTSSP167 with IC50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of these two substrates by MELK as well as mammosphere formation of breast cancer cells, and exhibited strong tumor-growth suppressive effects on xenografts of human breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. Conclusions: Orally administrative MELK inhibitor OTSSP167 is a promising compound to treat various types of human cancer. This compound can inhibit the phosphorylation of MELK substrates and also suppresses the formation of cancer stem cells in breast cancer cells, providing a novel strategy to cure cancer.
Multicentric survey on dose reduction in cancer drug therapy: Detection and measurement of critical phenomena as potential indicators of suspected adverse reactions.
Authors: Tenti Elena , Casadei Gardini Andrea , Amadori Dino , Fiacchi Paola , Stancari Alessandra , Zanardi Alessandra , Cherubini Chiara , Sferra Stella , Sara Simonetta , Rondoni Cristina , Maugeri Antonio , Restuccia Silvia , Gallani Maria Laura , Palazzini Simonetta , Bianchini Erika , Menozzi Silvia , Musi Eleonora , Minguzzi Martina
Published: March 2020

e13579

Background: The antineoplastics are considered drugs with a high number of side effects. Paradoxically, in the National Network of Pharmacovigilance the number of reported adverse reactions of these medicine is proportionally lower than that of normal drugs. In the field of pharmacovigilance programs promoted by the Region Emilia Romagna and funded by AIFA (Italian Medicines Agency) a project of multicenter surveillance of cancer drugs and their effect has been developed aimed at improving patient safety. The project joined 7 centers: IRCCS IRST (Coordinating Center) and the Hospitals of Ravenna, Parma, R. Emilia, Bologna, Ferrara and Rimini. Methods: All centers except one used the management software Log80 and therefore shared a database of information of analogous structure (the data presented come from the database of medication prescription). The survey included patients that started therapy in 2011 and reduced it in the same year. It was analyzed dose reduction from 10% to 50% during the first 90 days of therapy (dose reduction was counted from the actual administred dose to patient). The first 90 days of therapy have been considered as a significant time frame to intercept critical phenomena. Results: Out of a total of 12,389 patients, 1,320 have reduced the dose in the firts 3 mounth of treatment (10.7%). The drugs that have mostly resulted in a reduction of dose were Paclitaxel and Oxaliplatin (with a reduction of respectively 17.4% and 17.3% in term of number of patients ), Docetaxel (14.8%), Carboplatin (15%), Fluorouracil (10.7%) and among oral medications Capecitabine (6.9%). Conclusions: This survey has shown that patients treated with chemotherapy have had a dose reduction lower than compared to published studies. With regards to these reduction it must be highlighted that approximately 20% of patients have reduced by 30% the dose within three months of therapy. The dose reduction may underlie suspected adverse reactions; in this perspective, further investigations could show if the patients had severe adverse drug reactions.
Differential effects of selenium (Se) on normal and malignant cells treated with chemotherapy (CT) and radiation (RT).
Authors: Jameson Michael B. , Lobb Richard J , Jacobson Gregory M , Cursons Ray T
Published: March 2020

e13583

Background: Preclinical work has demonstrated that Se compounds potentiate anticancer effects of CT and RT while reducing normal tissue toxicities. The molecular basis for the therapeutic selectivity has yet to be fully elucidated but includes modulation of intracellular glutathione (GSH) concentrations, endoplasmic reticulum (ER) stress responses, DNA repair, induction of apoptosis and cellular resistance to CT and RT. Our aim was to evaluate the dose-response relationship of the Se compound methylseleninic acid (MSA) on molecular pathways involved in the response of normal and malignant cells to CT and RT. Methods: Peripheral blood mononuclear cells (PBMC) obtained from healthy blood donors and malignant THP-1 human monocytic leukaemia cells were exposed in vitro to MSA 2.5, 5 or 15 µM in varying combinations with MSA, RT, cisplatin (Pt), doxorubicin (Dox) and cytosine arabinoside (Ara-C). GSH concentration was measured by ELISA, DNA damage and repair by COMET assay, cell viability by MTT assay and ER stress response protein expression by western blotting. Results: MSA was selectively toxic to THP-1 cells and induced a protective increase in GSH in PBMC but a decrease in high concentrations within THP-1 cells. DNA damage induced by Ara-C or Dox in the COMET assay was significantly reduced by MSA in PBMC but increased in THP-1 cells. Cell death after 2 Gy RT was increased by all doses of MSA in THP-1 cells but only by the highest dose in PBMC. The cytotoxicity of Dox and Ara-C at sublethal doses was significantly enhanced by MSA in THP-1 cells and to a lesser extent in PBMC, but MSA increased cell death from Pt only in THP-1 cells. MSA induced a protective ER stress response in PBMC exposed to Ara-C but an apoptotic response in THP-1 cells. Conclusions: MSA at clinically-relevant concentrations had a differential effect on cell survival and death responses to RT and CT with relative protection of PBMC and enhanced death of THP-1 cells. Several mechanisms mediated this therapeutic selectivity and the dose-dependence of the Se effect varied between malignant and normal cells. These assays could potentially be used in clinical trials to evaluate pharmacodynamic markers of Se effects in conjunction with CT and/or RT.
Comparison of pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer.
Authors: Yamazaki Tomoko , Ishiki Hiroto , Yajima Yoko , Kobayashi Takehiko , Enokida Tomohiro , Zenda Sadamoto , Arahira Satoko , Kawashima Mitsuhiko , Tahara Makoto
Published: March 2020

e13586

Background: S-1 is an oral fluoropyrimidine that combines tegafur (FT) with two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). CDHP augments 5-FU activity by inhibiting dihydropyrimidine dehydrogenase (DPD). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the inhibitory effect on DPD and lead to increased 5-FU concentrations, and dose modification is recommended if renal dysfunction occurs (M.Tahara et. al; Cancer Science, 2011). However, the method of dose modification has not been established. We compared the pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer. Methods: This was a prospective study at a single institution. Eligibility required histologically or cytologically confirmed carcinoma of the head and neck with unresectable locally advanced disease. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m2/day, and cisplatin at 20 mg/m2/day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. Two additional cycles of chemotherapy wereplanned after the completion of CRT. S-1 dose was reduced to 40 or 30 mg/m2/day in accordance with adverse events. Peripheral blood samples were drawn before and at 1, 2, 4, 8, and 10 hours on day 7 in the first cycle and in the cycle with dose reduction. Primary endpoint was the change in 5-FU AUCss0-10 between the initial and reduced S-1 dose. Results: Eight patients were enrolled between July 2010 and July 2011, and 30 cycles of chemotherapy were administered. Four pts required S-1 dose reduction due to mucosal infection (n=2), febrile neutropenia (n=1), or renal dysfunction (n=1). PK parameters are compared below. Conclusions: AUCss0-10 for 5FU with a reduced dose of S-1 was significantly lower than with the initial dose.Further investigation with more patients is warranted. [Table: see text]
Effect of obatoclax (GX15-070) on cell survival, apoptosis, and prosurvival autophagy in head and neck squamous cell carcinoma (HNSCC).
Authors: Yazbeck Victor Y. , Li Changyou , Johnson Daniel E
Published: March 2020

e13587

Background: Approximately 500,000 new cases of head and neck cancer are diagnosed annually worldwide, with 300,000 deaths per year. Patients with recurrent and metastatic disease have a dismal prognosis with a median survival of less than one year. Current standard of care involves a platinum-based regimen for patients with good performance status, but is usually difficult to tolerate. Novel therapeutic approaches are in great need for this patient population. The antiapoptotic BCL-2 family proteins, including BCL-2, BCL-XL, and MCL-1 are involved in oncogenesis and chemoresistance and are overexpressed in HNSCC. Obatoclax is a pan-BCL2 inhibitor capable of inhibiting MCL-1, in addition to BCL-2 and BCL-XL. Methods: We determined the activity of obatoclax in 4 well-characterized HNSCC cell lines (UMSCC-1, Cal-33, 1483, UMSCC-22A). Cell viability was determined by MTT assay and apoptosis by Annexin-V binding, FACS analysis, and immunoblotting. Autophagy was assessed by immunofluorescence and immunoblotting. Results: All 4 HNSCC cell lines were highly sensitive to single-agent obatoclax with IC50’s ranging from 50-200 nM. Obatoclax induced apoptosis in all cell lines as evidenced by increased Annexin-V binding at 48 hours in a dose-dependent manner from less than 10% in vehicle treated cells to 30-60% in cells treated with obatoclax. Processing/activation of caspase-3 and cleavage of PARP protein was also observed. In addition, obatoclax induced prosurvival autophagy in all cell lines and the addition of the autophagy inhibitor chloroquine enhanced obatoclax cytotoxicity. In vivo studies of obatoclax using human HNSCC xenograft tumors is currently underway. Conclusions: This preclinical study suggests that obatoclax might have therapeutic value in HNSCC, as a single agent or in combination with an autophagy inhibitor.
Infusion-related reactions (IRR) during NGR-hTNF therapy as potential predictors of clinical outcome.
Authors: Rossoni Gilda , Gregorc Vanesa , Bulotta Alessandra , Viganò Maria Grazia , Todisco Gabriele , Lambiase Antonio , Bordignon Claudio
Published: March 2020

e13593

Background: NGR-hTNF, a selective antivascular agent, transiently modulates the systemic release of cytokines/chemokines. Intravenous infusion of NGR-hTNF is distinguished by an early on-target effect, IRR, which mostly consists of short-lived grade 1/2 chills. Methods: Incidence, predictors of development and relationships of IRR with treatment outcome were assessed in a pooled analysis of individual patient data from 5 phase II trials with NGR-hTNF. Global data set comprised 205 previously treated patients (pts) who had received NGR-hTNF 0.8 µg/m2 every 3 weeks (q3w) or weekly (q1w) alone in mesothelioma, colon and liver cancers or in combination with doxorubicin in small cell lung and ovarian cancers. In all trials, response to therapy (RECIST) was measured q6w until progression. Regression models estimated the effect size of IRR on response rate (RR; complete and partial response), disease control rate (DCR; RR plus stable disease) and progression free survival (PFS). Results: 137/205 pts (67%) experienced IRR on treatment, while 68 pts (33%) did not. In the IRR group, 63% of pts had grade 1 and 37% grade 2. By time to onset, 88% of pts developed IRR during first 6 weeks of therapy and 12% later. According to dosing schedule, IRR rates were higher with q1w than with q3w (85% vs 62%; p=.008). Baseline characteristics were (IRR vs non-IRR groups): median age: 66 vs 64; male: 50% vs 56%; PS ≥ 1: 34% vs 35%, range of prior lines: 1-4 vs 1-5. Among baseline characteristics, logistic regression analysis retained only a lower number of prior lines associated with higher IRR rates (OR=1.4; p=.02). Onset of IRR was related to better treatment outcome. RR was 12% in the IRR and 3% in the non-IRR group (OR=4.4; p=.05), while DCR was 50% in pts who had IRR and 34% in pts who did not (OR=2.0; p=.02). In pts with or without IRR, 6-month PFS was 21% vs 7% (HR=0.62; p=.001), respectively. Improvement in PFS time remained significant in a landmark analysis set at the 6-week time point (p=.004). On multivariate analyses adjusted for baseline variables, IRR independently predicted higher odds of tumor response (p=.05) and lower risk of progression or death (p=.009). Conclusions: Onset of IRR on NGR-hTNF treatment may predict subsequent clinical outcome. Clinical trial information: NCT00483080-NCT00483509-NCT00484211-NCT00484276-NCT00484432.
Cetuximab biweekly plus mFOLFOX6 as first-line therapy in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer (mCRC): An interim analysis of the CEBIFOX trial.
Authors: Kasper Stefan , Meiler Johannes , Knipp Heike , Hoehler Thomas , Reimer Peter , Steinmetz Tilman , Berger Winfried , Linden Gabriele , Ting Saskia , Markus Peter , Paul Andreas , Schuler Martin H. , Trarbach Tanja
Published: March 2020

e14502

Background: Combination of mFOLFOX6 with weekly cetuximab is a standard first line regimen in pts with KRAS wt mCRC. Weekly application of cetuximab increases the in-hospital time of pts with negative impact on quality of life. This multicentric phase II trial evaluates the efficacy of mFOLFOX6 + biweekly cetuximab as first line therapy in KRAS wt mCRC. Methods: Pts with KRAS wt mCRC who were not candidates for primary metastasectomy received cetuximab (500 mg/m2 every 2 weeks) in combination with mFOLFOX6 (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, 5-FU 400 mg/m2 bolus and 2,400mg/m2 over 46 h q14d). Primary endpoint was objective response rate (ORR) per RECIST 1.0, secondary endpoints were safety, secondary resection rate, quality of life (QoL), progression-free survival (PFS) and overall survival. Data of a pre-specified interim analysis are presented in which 13 responders were needed in the first 37 pts (Simon stage I). Results: As of Dec 2012, 46 pts were registered. Fourty three pts received ≥1 course of treatment, and 34 pts were evaluable for response. Baseline characteristics of the ITT population and efficacy data are listed in the Table. Median follow-up was 14.6 months. Grade 3/4 adverse events occurred in 39% of pts, including leukocytopenia (11%), gastrointestinal toxicity (11%), and rash (9%). Median PFS was 9.6 months (95% CI: 5.0 to 14.1). QoL data will be presented. Conclusions: This pre-specified interim analysis supports efficacy and safety of biweekly cetuximab given in combination with mFOLFOX6 in pts with mCRC. A high rate of objective responses and secondary hepatic resections was achieved. Based on these results enrolment in CEBIFOX is continued. Clinical trial information: NCT01051167. [Table: see text]
Correlation of bone marrow micrometastases with nodal status in gastrointestinal tumors.
Authors: Nagpal Sunil , Korant Alpesh K. , Krishnamoorthy Madhumitha , Shaik Mohammed , Johnston Gregory , Dhar Vikrom K. , Arora Madan L. , Singh Trevor , Wiese David , Saha Sukamal
Published: March 2020

e14518

Background: Presence of bone marrow (BM) micrometastases (M) is a prognostic factor for patients (pts) with solid tumors. Sentinel lymph node (SLN) mapping (M) has been found to upstage pts with gastrointestinal (GI) cancers. However, a direct correlation between the presence of BMM and nodal metastases (mets) is lacking. A retrospective study was done to determine the relationship between BMM and nodal status in GI cancers. Methods: A total of 385 consecutive pts with GI cancers were studied. Pts underwent bilateral posterior-superior-iliac-spine BM aspiration. A highly sensitive staining method was used to differentiate cytokeratin postitive cells of epithelial origin from normal hematopoetic cells. Cytospin slides were stained wtih monoclonal anti-CAM 5.2 antibody. Visualization was achieved with Ventana view-Red detection system. Slides were then counterstained with haematoxylin. Automated Cellular Imaging System was used to classify cells of interest by cellular color, size and shape. SLNM was done by peritumoral injection of 1% methylene blue in the subserosal layer. Results: A total of 385 pts were analyzed. Of these 11% were found to have BMM. The three highest sites of BMM were cholangiocarcinoma 33%, Stomach 22% and esophagus 13% (Table 1A). BMM was +ve bilaterally in 44% of pts, unilaterally in 56%. In pts who underwent SLNM, BMM were detected in 8.3% of SLN +ve vs. 12% for SLN -ve pts. For a subgroup of pts with colorectal cancer undergoing SLNM, BMM were detected in 9.6% of SLN +ve pts vs. 11% for SLN -ve pts. Conclusions: BMM did not correlate with nodal status for GI malignancies suggesting a possible different mechanism for metastases. Detection of BMM may have a significant clinical value in SLN negative pts who may benefit from adjuvant therapy. [Table: see text] [Table: see text]
The utility of PET scanning in colorectal cancer liver metastases being considered for surgery.
Authors: Ismail Jeffri R. M. , Kelly Ciara Marie , Hanrick Marian , Regan Downey Cara , McCarthy Lauragh , O'Reilly Aine , MacEneaney Peter , Bennett Michael William , O'Regan Kevin N. , Mulvihill Erica , O'Sullivan Adrian , O Suilleabhain Criostoir , McCaffrey John , O'Reilly Seamus , Power Derek Gerard
Published: March 2020

e14519

Background: Liver resection remains the only potentially curative option for a subset of patients with colorectal cancer liver metastases (CRCLM). Preoperative imaging used to determine resectability includes computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). The objective of this study was to determine the utility of PET scanning for potentially resectable CRCLM. Methods: We retrospectively reviewed a prospectively maintained database for all patients considered for resection of CRCLM from July 2010 to July 2012 in two specialist colorectal/hepatobiliary cancer centres. We extracted and analyzed data with respect to preoperative staging imaging and definitive treatment performed on completion of staging. Results: We identified 100 patients who underwent preoperative staging investigations for potentially resectable CRCLM. The imaging techniques performed included: CT (n=99, 99%), MRI liver (n=75, 75%), PET (n= 96, 96%). In 22 (22/96, 23%) patients PET scanning added to the preoperative staging information, identifying local recurrence (n=3, 3.1%), confirming liver metastases following an inconclusive CT/MRI (n=2, 2.1%), outruling liver metastases (n=1, 1%) and identifying extrahepatic sites (EHS) suspicious for disease (n=16, 16.7%). The EHS included either lung (n=6), bone (n=2), peritoneum (n=1) or lymph nodes (n=7). There were 2 false positive results. One patient with FDG-avid mediastinal lymph nodes had no cancer on endobronchial biopsy. One patient with FDG avidity at the primary anastomosis had no evidence of disease at colonoscopy. PET definitively changed the therapeutic strategy in 16 patients (16/96, 16.6%): precluding liver resection in 10 patients (10/96, 10.4%), leading to resection of extrahepatic disease in 4 patients (4/96, 4.1%), resection of local recurrence in 1 patient (1/96, 1%) and resection of hepatic metastases in one patient (1/96, 1%). Conclusions: In this small retrospective cohort the addition of metabolic imaging altered management in 16.6% of patients with potentially resectable CRCLM. There is a need for randomized evidence to support the routine use of PET in addition to cross-sectional imaging in this setting.
Capecitabine but not 5-FU worsened hepatosplenomegaly and liver function when used with oxaliplatin and cetuximab as first-line treatment in K-ras wild-type metastatic colorectal cancer.
Authors: Lee Victor HF , Fang Weijia , Lam Ka On , Choi Cheuk Wai , Ng Sherry CY , Ho Patty PY , Ho Garrett CL , Cheng Thomas KC , Liu Rico KY , Leung To Wai , Kwong Dora Lai Wan , Zheng Shusen
Published: March 2020

e14530

Background: MRC COIN study showed that OXA and CAP (CAPOX) have greater toxicities compared with OXA and 5-FU (FOLFOX) when cetuximab (C225) was added for mCRC. Meanwhile, OXA was associated with splenomegaly and hepatic sinusoidal injury. We investigated if CAPOX+C225 worsened hepatosplenomegaly and liver function compared with FOLFOX+C225 in K-rasWT mCRC. Methods: 97 patients with K-ras WT mCRC received either FOLFOX or CAPOX (n=57) or the same regimen+C225 (n=40) as 1st line treatment. CT scan of abdomen was performed at baseline and then after every 3-4 cycles. Liver excluding liver metastases if present, and spleen size at baseline and after treatment were contoured in Eclipse Treatment Planning System. Changes in liver and spleen size after treatment in all patients and subgroups (1) use of C225 and (2) CAPOX vs. FOLFOX +/- C225 were compared. Logistic regression was done for any predictors of hepatosplenomegaly and impaired liver function in all patients and subgroups. Results: 25, 32, 15 and 25 patients received FOLFOX, CAPOX, FOLFOX+C225 and CAPOX+C225 respectively.All patients had hepato- (p=0.014) and splenomegaly (p=0.000) after treatment. C225 did not further worsen hepato- (p=0.430) and splenomegaly (p=0.614). Cumulative dose of CAP was predictive of hepato- (p=0.003) and splenomegaly (p=0.008) even after adjusted for cumulative dose of OXA (p=0.021). For subgroup analysis, hepato- (p=0.040) and splenomegaly (p=0.041) were noted when CAPOX+C225 was compared with FOLFOX+C225, but not seen when CAPOX was compared with FOLFOX (p=0.270 and p=0.287 respectively). When comparing CAPOX+C225 with FOLFOX+C225, use of CAP was predictor of both hepato- (p=0.043) and splenomegaly (p=0.007). Dose intensity of CAP (p=0.036) and cumulative dose of OXA (p=0.044) are predictors of ≥grade 1 impaired liver function. However when comparing CAPOX with FOLFOX, no predictor was found for any complication. Conclusions: CAP further worsened hepatosplenomegaly and liver function when combined with OXA and C225 but not with OXA alone, suggesting that CAP and C225 together may add toxicity to liver and spleen.
Effect of postoperative chemotherapy (CT) on survival in patients (pts) with resected rectal cancer who received neoadjuvant therapy.
Authors: Wu Christina Sing-Ying , Wei Lai , Glass Katherine , Wilson John , Abdel-Misih Sherif , Williams Terence Marques , Martin Ludmila Katherine , Haraldsdottir Sigurdis , Harzman Alan , Husain Syed , Schmidt Carl Richard , Arnold Mark , Goldberg Richard M. , Bekaii-Saab Tanios B.
Published: March 2020

e14535

Background: Pts with stage II/III rectal cancers are treated with neoadjuvant chemoradiation and surgical resection followed by adjuvant CT per practice guidelines. It is unclear whether adjuvant CT provides survival benefit, and the purpose of this study was to measure outcome in pts who did and did not receive adjuvant CT. Methods: We used a prospectively collected database for pts treated at The Ohio State University and analyzed overall survival (OS), time to recurrence (TTR), pt characteristics, tumor features, and treatments. Survival curves were estimated using Kaplan-Meier method and compared by the log-rank test. Age was compared using the Wilcoxon test, and other categorical variables were compared using Chi-square test or Fisher’s exact test. Results: Between August, 2005 to July, 2011, 110 pts were identified and 71 pts had received adjuvant CT. There was no significant difference in sex, race, pathologic tumor (T) stage, and pathologic complete response between the two groups. Pts receiving adjuvant CT were significantly younger (median age 54.3 vs. 62 years, p=0.01) and had more advanced pathologic nodal (N) stage (43 vs. 19% N1 or N2, p=0.02). Median OS was 72.6 months with CT vs. 36.4 months without CT (p=0.0003). Median TTR has not yet been reached. Conclusions: In this retrospective analysis, adjuvant CT was associated with a longer OS despite more advanced pathologic nodal staging. Prospective randomized studies are warranted to determine whether adjuvant CT provides a survival benefit for pts across the spectrum of stage II and III rectal cancer. [Table: see text]
Influence of KRAS mutations on outcome in patients with curatively resected stage III colon cancer treated with adjuvant chemotherapy.
Authors: Saletti Piercarlo , Nucifora Martina , De Dosso Sara , Spitale Alessandra , Sahnane Nora , Riveiro Maria Eugenia , Bertolini Valentina , Bucci Eraldo , Crippa Stefano , Ghielmini Michele E. G. , Frattini Milo
Published: March 2020

e14536

Background: Adjuvant chemotherapy improves survival in patients with stage III colon cancer (CC) after curative resection, and oxaliplatin in combination with fluoropyrimidine-based regimens has been established as a standard treatment. KRAS mutations could predict oxaliplatin sensitivity in CC cells, as recently demonstrated. Here, we profiled KRAS and correlated it with outcome in stage III CC patients who underwent adjuvant chemotherapy. Methods: Eligible patients were those with resected stage III CC who underwent 6-months adjuvant chemotherapy, either with single-agent fluoropyrimidine (FP: modulated 5FU or capecitabine) or with oxaliplatin-based regimens (O-FP: FOLFOX or XELOX). DNA extraction was performed on formalin-fixed paraffin-embedded sections, and KRAS mutations were analyzed by direct sequencing. Disease-free survival (DFS) and overall survival (OS) analyses were computed using the Kaplan-Meier method and the Log-rank test. Results: The study population included 261 patients: 115 treated with FP, 146 O-FP. We identified KRAS mutations in 71/261 (27.4%) cases, of which 33 (46.5%) received FP, and 38 (53.5%) O-FP. In wild-type (wt) KRAS cases, DFS and OS group did not significantly differ between the two treatment modalities [in months, FP vs O-FP - median OS: 62.0 vs 49.6, HR: 1.12 (95% CI: 0.65; 1.92); median DFS: 57.1 vs 44.4, HR: 0.93 (95% CI: 0.55; 1.56)]. In patients treated with FP, a worse DFS [in months, mutant vs wt - median DFS: 46.0 vs 57.1, p=0.04; HR: 1.86 (95% CI: 1.01; 3.41)] and a trend toward a worse OS in months, mutant vs wt - median OS: 56.1 vs 62.0, p=0.08; HR: 1.71 (95% CI: 0.94; 3.10)] were observed in KRAS mutated patients. On the contrary, DFS and OS were not statistically different for mutated and wt KRAS patients treated with O-FP [in months, mutant vs wt - median DFS: 43.7 vs 44.4, p=0.62; HR: 1.17 (95% CI: 0.63; 2.18); median OS: 48.9 vs 49.6, p=0.77; HR: 1.11 (95% CI: 0.55; 2.23). Conclusions: Our results suggest that curatively resected stage III CC patients exhibiting wt KRAS status might benefit from FP alone. On the contrary, an oxaliplatin-containing regimen should be recommended in KRAS mutated patients.
Risk of tumor-related death in stage I-III colon cance based on gender and tumor location.
Authors: Ladner Robert D. , Kahn Michael , Yang Dongyun , Stintzing Sebastian , Zhang Wu , Wakatsuki Takeru , Ning Yan , Volz Nico Benjamin , Li Joseph Ethan , Labonte Melissa Janae , Wilson Peter M. D. , Kardosh Adel , Lenz Heinz-Josef
Published: March 2020

e14538

Background: Survival of metastatic colon cancer has recently been linked to gender and location of the primary. Data on these factors in the stage I-III is still sparse. We aimed to demonstrate the influence of gender and tumor location of tumor related survival, using SEER database. Methods: 288,640 patients diagnosed with stage I-III colon cancer during 1988 through 2009 identified from SEER database were included in this study. Cox proportional hazards models were used to evaluate the effects of tumor site (left vs right-sided colon) on colorectal cancer specific survival. Age, race, T stage, N stage, histology (adenocarcinoma, mucinous tumor), grading, numbers of lymph nodes resected and type of surgery were used as covariates. Results: A total of 85,131 (stage I), 110,667 (stage II) and 92,842 (stage III) patients were identified to have data on all the factors to be looked at. In the total population female gender was statistically significant for longer TSS for all three stages (HR 0.82; HR 0.86 and HR 0.89). Furthermore, in UICC I and UICC III left side was favorable (HR 0.82 and HR 0.91) but in stage II, right sided colon cancer patients had a longer TSS (HR 1.2 for left side). This was independent of gender. Conclusions: Different prognoses of right versus left colon cancer reflect different biology. Furthermore the influence of gender points to an estrogen effect in female patients. As there is emerging knowledge about the differences in right versus left colon cancer biology, the modulating effect of SMAD4 on estrogen driven TGFß signaling might be one explanation to those differences.
Genetic variants in EGFR and its ligands to predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.
Authors: Sebio Ana , Páez David , Salazar Juliana , Tobena Maria , Martin-Richard Marta , Barnadas Agust , Baiget Montserrat
Published: March 2020

e14541

Background: Epidermal growth factor receptor (EGFR) activation via ligand binding results in signaling through several pathways that fundamentally contribute to cell proliferation. Increased cell proliferation has been proposed as a radioresistance mechanism that would occur upon EGFR activation by radiation therapy. In this study we have analyzed the potential role of single nucleotide polymorphisms (SNPs) in the EGFR gene and its ligands as pharmacogentic markers of response to chemoradiation in locally advanced rectal cancer. Methods: Seventy stage II and III rectal cancer patients treated with capecitabine plus radiotherapy were analyzed. Nineteen TagSNPs in three EGFR ligands (amphiregulin, epiregulin and epidermal growth factor) were selected using HapMap database and Haploview software. One functional SNP (R521K) in the EGFR gene was also analyzed. DNA was extracted from peripheral blood and genotype was performed using the BioMarkTM System (Fluidigm). The main end point of the study was to analyze the possible association of these polymorphisms with the pathologic complete response after neoadjuvant chemoradiotherapy. Results: In the amphiregulin gene region, the rs11942466 C>A SNP was associated pathological complete response (37% in C/C vs. 21% in C/A and 0% in A/A; p=0.023). In the EGFR gene the R521K G>A SNP was associated with response in the dominant model (35 % of patients harbouring an A allele achieved complete response compared to 13 % of patients with a G/G genotype; p=0.025). In the multivariate analysis the R521K G>A polymorphism remained statistically significant with an odds ratio of 0.14 (95%CI: 0.026-0.76; p=0.023). Conclusions: EGFR and amphiregulin genetic variants might help identify patients who would benefit the most from neoadjuvant chemoradiotherapy based on capecitabine.
Association of a polymorphism in amphiregulin with worse prognosis in metastatic colorectal cancer patients treated with cetuximab.
Authors: Wilson Peter M. D. , Wakatsuki Takeru , Loupakis Fotios , Zhang Wu , Yang Dongyun , Stintzing Sebastian , Ning Yan , Volz Nico Benjamin , El-Khoueiry Rita Elie , Li Joseph Ethan , Labonte Melissa Janae , Sunakawa Yu , Maus Martin K. H. , Ladner Robert D. , Barzi Afsaneh , Iqbal Syma , El-Khoueiry Anthony B. , Lenz Heinz-Josef
Published: March 2020

e14543

Background: Accumulating data suggests that Amphiregulin (AREG) and Epiregulin (EREG), ligands of the EGFR pathway, are potential prognostic and predictive markers in metastatic colorectal cancer (mCRC). Elevated AREG and EREG gene expression levels are predictive of improved response rates in mCRC patients treated with cetuximab and longer overall survival (OS) in patients with mCRC who did not receive cetuximab. Since polymorphisms in AREG and EREG may affect their expression or function, we tested whether AREG and EREG polymorphisms were associated with clinical outcome in mCRC patients treated with cetuximab. Methods: Seventy-three patients (n=73) with histopathologically-confirmed mCRC with Kras/Braf wild type were enrolled in Italy. These patients were treated with cetuximab monotherapy or irinotecan plus cetuximab as second or third line treatment. Genomic DNA was extracted from blood and 4 SNPs in AREG and 5 SNPs in EREG were analyzed by direct DNA-sequencing. Results: The median follow-up period was 13.3 months in this cohort. The median progression-free survival (PFS) and OS were 5.2 and 12.9 months respectively. The results indicate that the intronic AREG polymorphism rs28364983 A/C was associated with shorter PFS and OS. Patients with homozygous C/C (n=2) showed a median PFS of 2.3 months vs. 5.3 months for patients harboring at least one-A allele (n=71) (HR: 4.26 [95%CI: 0.98-18.5], p=0.05). Patients with homozygous C/C showed a median OS of 3.0 months vs. 13.1 months for patients harboring at least one-A allele (HR: 3.98 [95%CI: 0.93-16.9], p=0.062). An independent cohort of thirty-three patients was used to validate these initial findings and showed that patients with homozygous C/C (n=3) had a median PFS of 2.3 months vs. 3.8 months for patients harboring at least one-A allele (n=103) (HR: 3.79 [95%CI: 1.16-12.3], p=0.027) and a median OS of 3.0 months vs. 8.4 months (HR: 3.01 [95%CI: 0.93-9.71], p=0.065), respectively. Conclusions: AREG rs28364983 predicted worse outcome in mCRC patients treated with cetuximab; however, further analyses are necessary to understand the mechanism and further validate the prognostic and/or predictive role of this polymorphism.