bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms in estrogen receptor beta, interleukin-8, and interleukin-8 receptor associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5-fluorouracil/oxaliplatin
Authors: Ladner R. D. , Gordon M. A. , Zhang W. , Yang D. , Nagashima F. , Chang H. , Lurje G. , Borucka E. , Lenz H. 
Published: March 2020

4130 Background: Many factors contribute to the progression of colorectal cancer and to chemoresistance. Two factors that have recently gained attention are angiogenesis and sex hormones. Interleukin-8 and its receptors play a critical role in angiogenesis, and polymorphisms in these genes have previously been reported to predict clinical outcome and resistance to therapy in a variety of cancer types. In addition, gender and the subsequent varied levels of sex hormones between males and females may also have an impact on colorectal cancer progression. Sex hormones such as estrogen exert their effects on the cell by binding to steroid receptors such as estrogen receptor beta (ER-β). It is known that ER-β is predominantly expressed in the colon, and that differential expression of this gene is predictive of clinical outcome. Therefore, functional polymorphisms within ER-β, IL-8, and the IL-8 receptors may prove to be molecular markers for predicting clinical outcome in colorectal cancer patients. Methods: 173 patients were enrolled in this phase II study. 152 patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. Polymorphisms in estrogen receptor beta, IL-8, and CXCR2 (IL-8 receptor) were tested by PCR. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. IL-8 T251A polymorphism was predictive of time to tumor progression (p=0.04, log-rank test). ER-β CA repeat polymorphism was predictive of tumor response as well as time to tumor progression (p=0.015, p=0.012, respectively). ER-β A730G SNP was also predictive of time to tumor progression (p=0.03). Polymorphism in CXCR2 was predictive of tumor response (p=0.034). Conclusions: Our results suggest that polymorphisms within IL-8, CXCR2, and ER-β may affect the progression of colorectal cancer and subsequent clinical outcome. These results highlight the importance of angiogenesis and hormone levels in colorectal cancer. No significant financial relationships to disclose.
Personalized therapy for metastatic colorectal cancer: A closer possibility?
Authors: Pierobon M. , Calvert V. , Lipsky M. , Sheehan K. , Speer R. , Mammano E. , Belluco C. , Nitti D. , Liotta L. , Petricoin E. 
Published: March 2020

4131 Background: Colorectal cancer (CRC) is the second leading cause of cancer related death in the Western world, and survival rate is closely associated with the development of metastases. Personalized targeted therapies promise to have a dramatic impact on the treatment of cancer over the next decade. The molecular fingerprint of a patient’s tumor is the basis for specific targeted therapy. Most often, we are not measuring what we are treating. If we choose therapy based on the primary tumor, but we are treating the metastasis, we are likely giving the wrong therapy if the two microenvironments are not equivalent. In this study we employed reverse phase protein microarrays (RPPA) to compare the protein kinases signal pathway derangements in the primary CRC and in its synchronous liver metastasis. Methods: Pure cell populations of 34 cases of patient-matched CRC and hepatic metastases (collected at the same surgical time) were isolated through laser capture microdissection and then lysed. The lysed cells were evaluated using RPPA technology that allowed us to analyze the activation status of 80 different kinases. Data analysis was performed using commercially available software. Results: Of the 80 kinases only 20 endpoints were significantly (p< 0.05) altered between the two populations. These endpoints were contained within just a few signaling pathways, including the PI3K-AKT prosurvival pathway and the c-kit/PDGFr/c-abl growth factor pathway. We noted a significant increase in phosphorylation of AKT along with a decrease in phosphorylation of PTEN in the liver metastasis compared to the matched primary tumors. This is in keeping with what is known about AKT since phosphorylation of PTEN serves to destabilize the protein, which serves as a natural upstream suppressor of AKT kinase. Conclusions: Specific cell signaling pathways, such as the PI3K-AKT and the c-kit/PDGFr/c-abl growth factor signaling pathway, are significantly altered and activated in hepatic metastasis compared to the primary colorectal site. Since the data reveals elevation in kinase activity increases on a pathway-wide level, a rational hypothesis can be developed whereby combinations of drugs such as an AKT- mTOR inhibitor and/or Gleevec may be an effective and novel therapeutic strategy for the treatment of metastatic CRC. No significant financial relationships to disclose.
KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab
Authors: De Roock W. , De Schutter J. , De Hertogh G. , Janssens M. , Biesmans B. , Personeni N. , Geboes K. , Verslype C. , Van Cutsem E. , Tejpar S. 
Published: March 2020

4132 Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p<0.01; responders vs. non responders). At 12 weeks there was a mean decrease in tumor size of 23.1% (SE=7.38) in the KRAS WT and an increase of 2.6% (SE=4.13) in the KRAS MUT mCRC. At 24 weeks KRAS WT and MUT mCRC had a 45.8% (SE=8.61) and a 1.3% (SE=6.67) mean decrease respectively (p= 0.0081 at 12 weeks; p=0.0015 at 24 weeks). The mean tumor size of the KRAS WT did not decrease further after 24 weeks. In the subgroup of SD tumor size regression was observed but only in WT patients. Mean time to progression was 32 (range 12–96) and 30 weeks (range 12–84) for KRAS WT (SD + PR) and MUT respectively. Conclusion: We confirmed KRAS MUT precludes objective response to CTX in mCRC. In addition we found tumor size regression in SD patients being restricted to WT patients. We observed rapid onset of these differences suggesting an important role of KRAS MUT status in early tumor shrinkage. However the onset of progression was not different according to KRAS MUT status. [Table: see text]
Simplification of cetuximab (Cet) administration: double dose every second week as a 60 minute infusion
Authors: Pfeiffer P. , Bjerregaard J. K. , Qvortrup C. , Jensen B. V. , Yilmaz M. , Nielsen D. 
Published: March 2020

4133 Background: CetIri (Cetuximab and irinotecan (Iri)) is effective in pretreated patients with advanced colorectal cancer (ACRC). Presently it is recommended that Cet is administered weekly. Inspired by a pharmacokinetic study (Tabernero et al, ASCO 2006), and due to long waiting time to begin CetIri in our institutions, we have gradually simplified the administration of CetIri. Methods: From January to September 2005, patients received standard CetIri (Cet loading dose 400 mg/m2 as a 120 minutes infusion and then weekly Cet 250 mg/m2 in 60 minutes. Iri 180 mg/m2 every second week started 1 hour after completion of Cet). From October 2005 we gradually enhanced the simplicity of administration. Presently Cet 500 mg/m2 is administered every 2 weeks. The first course is infused in 120 minutes followed 1 hour later by Iri 180 mg/m2 as a 30 minutes infusion. Subsequent courses of Cet are infused in 60 minutes, immediately followed by Iri - resulting in a total treatment time of only 90 minutes per 2 weeks. Results: All patients had ACRC resistant to 5-FU, Iri and Ox and CetIri was offered independently of EGFR expression. 65 consecutive patients with ACRC received standard CetIri and 57 patients biweekly CetIri. There was no difference in patient characteristics. Duration of therapy (4.7 vs 4.1 months), response rate (20 vs 23 %), TTP (5.4 vs 4.8 months) and survival (10.4 vs 9.8 months) were similar. Grade 3–4 non-hematological toxicity was rare (skin toxicity: 8 vs 7%, diarrhea: 10 vs 8 %, fatigue: 8 vs 5 %). Conclusion: Salvage therapy with simplified CetIri every second week is a convenient, effective and well-tolerated regimen in ACRC patients resistant to 5-FU, Iri, and Ox. To confirm results an ongoing phase II study will include 100 patients. No significant financial relationships to disclose.
Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers
Authors: Lynch H. T. , Caldas C. , Wirtzfeld D. , Vaccaro C. , Rubinstein W. , Weissman S. , Kaurah P. , Boyd N. , Fitzgerald R. , Huntsman D. 
Published: March 2020

4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.
MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study
Authors: Hobday T. J. , Rubin J. , Holen K. , Picus J. , Donehower R. , Marschke R. , Maples W. , Lloyd R. , Mahoney M. , Erlichman C. 
Published: March 2020

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.
Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer
Authors: Narahara H. , Koizumi W. , Hara T. , Takagane A. , Akiya T. , Takagi M. , Miyashita K. , Nishizaki T. , Kobayashi O. ,   TS-1 Advanced Gastric Cancer (AGC) Clinical TrialGroup
Published: March 2020

4514 Background: S-1 has been widely used against advanced gastric cancer (AGC) not only as monotherapy but also in combination with other cytotoxic compounds. Results of a phase I/II study combining S-1 + cisplatin (CDDP) were very encouraging with a high response rate (RR) of 76%, and the MST (Median Survival Time) of 383 days (Koizumi W et al, Br J Cancer, 2003). Based on these results, a phase III study comparing S-1 alone with S-1 + CDDP has been conducted to further evaluate the efficacy and safety for S-1 + CDDP as a standard treatment for AGC. Methods: This is a randomized, controlled, open-label, parallel, multicenter study. Patients (pts) are randomized to one of two treatment arms. Arm A: Pts receive oral S-1 (40 mg/m2) twice daily 28 days followed by 14 days rest. Arm B: Pts receive oral S-1 (40 mg/m2) twice daily 21 days followed by 14 days rest plus CDDP (60 mg/m2) iv on day 8. Eligibility criteria included unresectable/recurrent AGC, age 20–74, no prior chemotherapy for AGC. Primary endpoint was overall survival (OS). Main secondary endpoints included RR, time to treatment failure (TTF) and toxicity. Based on planned sample size of 284 pts, the trial was designed to have 90% power to detect an improvement in median OS from 8 to 12 months (2-sided log-rank test; significance level 0.05). Results: 305 pts (Arm A/B, 152/153) were randomized between Mar 2002 and Nov 2004. The eligible pts were 299 (Arm A/B, 150/149). Median age was 62.0/61.5 yrs. At a 2 yrs follow-up since last patient in, the MST for Arm A was 335.5 days (95%CI: 292.0 - 402.0) and for Arm B was 396.0 days (95%CI: 342.0 - 471.0). The OS for Arm B was superior to Arm A (log-rank p=0.0366, hazard ratio: 0.774, 95% CI: 0.608 - 0.985). RR was 31.1% for Arm A and 54.0% for Arm B. In Arm A vs Arm B, the most common grade 3/4 toxicities were: leucopenia, 2.0% vs 11.5%; neutropenia, 10.7% vs 39.9%; anemia (decreased Hb), 4.0% vs 25.7%; nausea, 1.3% vs 11.5%; anorexia, 6.0% vs 30.4%. No treatment related death was observed. Conclusions: The combination treatment of S-1 and CDDP met primary endpoint of OS, and was found to be effective and well tolerated in pts with AGC. Accordingly, this regimen can be regarded as one of first-line standard treatment for AGC. No significant financial relationships to disclose.
Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)
Authors: Posner M. , Chang K. J. , Rosemurgy A. , Stephenson J. , Khan M. , Reid T. , Fisher W. E. , Waxman I. , Von Hoff D. , Hecht R. 
Published: March 2020

4518 Background: TNFerade is a replication-deficient adenoviral vector carrying the transgene for human TNF-a protein, regulated by the radiation-inducible promoter Egr-1. A 50 patient (pt) phase II dose-escalation study in LAPC showed a possible dose-dependent improvement in survival. To confirm these findings, the randomized Pancreatic Cancer Clinical Trial with TNFerade (PACT) study was developed. PACT is a 330 pt study, powered to detect a 20% absolute increase in the primary efficacy endpoint (overall survival at 1 year) compared to standard of care (SOC) chemoradiation. An interim analysis of safety and efficacy was planned after the first 51 pts were randomized. Survival data to 11/15/06 has been evaluated and are reported here. Methods: The TNFerade arm pts received a five- wk treatment of weekly injections of 4 x 1011 pu TNFerade, continuous infusion 5-FU (200 mg/m2/day x 5 days/wk) and 50.4 Gy radiation. TNFerade was administered by percutaneous CT-guided transabdominal injection. The SOC arm received the same regimen, without TNFerade injections. Patients were randomized 2:1 to the TNFerade and SOC arms. The first 51 randomized pts were assessed for evidence of objective response (OR) and overall survival Results: Assessment of response data is still ongoing. TNFerade + SOC was well tolerated. One year survival, the primary endpoint of the study, was 70.5% in the TNFerade + SOC arm versus 28.0% in the SOC arm, an absolute increase of 42.5%. The median survival for TNFerade + SOC pts was 515 days compared to 335 days for the SOC pts. The logrank statistic for comparison between the two arms is X2 = 2.014 (p=0.16). Conclusions: The interim survival data is preliminary. The magnitude of the difference in survival in favor of the TNFerade + SOC arm, however, is encouraging. The data appears to corroborate previous findings from the dose-escalation study, which showed an apparent survival advantage in the 4×1011 pu dose group compared to 4 x 109 pu group. A second interim analysis is planned with larger patient numbers to determine whether this early positive trend is confirmed. No significant financial relationships to disclose.
Correlation of RTOG 9704 (adjuvant therapy (rx) of pancreatic adenocarcinoma (pan ca)) radiation therapy quality assurance scores (RTQASc) with survival (S)
Authors: Abrams R. A. , Winter K. A. , Regine W. F. , Safran H. , Hoffman J. P. , Konski A. A. , Benson A. B. , Macdonald J. S. , Rich T. A. , Willett C. G. 
Published: March 2020

4523 Background: RTOG 9704 demonstrated a marginal S advantage (p=0.054) in multivariate analysis (MVA) of Gemcitabine (G) over 5FU before and after 5FU+RT for patients (pts) with pan ca resected for cure from the pan head but not from non-head sites (ASCO 2006, ASTRO 2006). This analysis was undertaken to assess the impact of RTQASc on S, S by treatment (rx) arm, and toxicity by rx arm. Methods: This is a secondary analysis of a prospective, randomized, phase III trial of the RTOG, ECOG, and SWOG. RTQASc was graded as per protocol (PP) or less than (<) PP. Using prospectively defined guidelines, <PP scores were variation acceptable (VA), variation unacceptable (VU), or incomplete/not evaluable (I/NE). I/NE pts were excluded from further analysis. Toxicities were scored by CTC, v 2.0. S is expressed as median S in yrs. Results: 416 pts had RTQASc of PP (216, 52%) or <PP (200, 48%; 42% VA, 6% VU). Frequency of PP and <PP did not differ by rx arm (PP = 55% on 5FU arm and 48% on G arm). Looking at PP vs <PP frequency of Grade 3+ Heme and Non- Heme toxicity did not vary significantly on the 5FU arm but did show a trend of < toxicity for PP pts on the G arm ( Table ). In contrast, S was increased for all (head, non-head) PP pts (median S 1.74 vs 1.47 yrs, p=0.019) and, in MVA, score of PP significantly impacted on S (p=0.02) but rx arm did not. PP and <PP S curves began to diverge at 14–15 months post surgery. For head pts, in MVA, RTQASc (PP superior to <PP) and rx arm (G superior to 5FU) both correlated with S (p=0.04, p=0.03, respectively). On the G arm PP pts had S of 1.89 yrs, significantly > than S of VA (1.41yrs) and VU (1.37yrs) pts. Conclusions: In this study prospectively defined RTQASc significantly correlated with S and effect of rx arm on S and showed a weaker effect on toxicity (G arm only). Timing of appearance of RTQASc effect on S implies effect on tumor control. In this context failure to consider RTQASc may confound observed outcomes and confuse correct understanding of the importance of RT. [Table: see text] No significant financial relationships to disclose.
Irinotecan plus S-1 (IRIS) versus S-1 alone as first line treatment for advanced gastric cancer: Preliminary results of a randomized phase III study (GC0301/TOP-002)
Authors: Chin K. , Iishi H. , Imamura H. , Kobayashi O. , Imamoto H. , Esaki T. , Kato M. , Tanaka Y. , Furukawa H. 
Published: March 2020

4525 Background: Irinotecan has single agent activity and combination activity with S-1 reportedly in phase I/II studies with advanced gastric cancer patients (pts). S-1, oral fluoropyrimidine, also has activity on gastric cancer. A multicenter, randomized phase III trial comparing IRIS to S-1 alone in advanced gastric cancer was conducted. Methods: Pts with previously untreated gastric cancer were randomized to Arm A (oral S-1 80 mg/m2/day from day 1 to 28 followed by a 14-day rest period), or Arm B (oral S-1 80 mg/m2/day from day 1 to 21 and intravenous irinotecan 80 mg/m2 on days 1 and 15 followed by a 14-day rest). Treatment was continued unless disease progression was observed. Inclusion criteria: PS (ECOG) of 0 to 2; adequate major organ functions. Primary endpoint was overall survival. Results: From June 2004 to November 2005, 326 pts were randomized to arm A (162 pts) and arm B (164 pts). Pts characteristics (arm A vs. arm B) were as follows: median age: 63 vs. 63 years, PS 0–1: 97% vs. 97%, and distribution of subtype of intestinal/diffuse/others: 44%/55%/1% vs. 41%/58%/1%. Among 187 RECIST-evaluable pts (93 vs 94) reviewed by independent review panel, best response rates were 26.9% for arm A and 41.5% for arm B(p=0.035). Among 319 toxicity-evaluable patients (161 vs 158), grade 3 or 4 toxicities for arm A vs arm B (% of pts) were as follows: neutropenia 9.3% vs 26.6%, diarrhea 5.6% vs 15.8%, anorexia 9.9% vs 15.8%, nausea 3.7% vs 7.0%, vomiting 0.6% vs 2.5%. Conclusions: IRIS is effective, and well tolerated in pts with advanced gastric cancer. Survival analysis is underway. No significant financial relationships to disclose.