bluuebunny/crossref_metadata_2025_split huggingface dataset:
De-adoption of epidermal growth factor receptor (EGFR) inhibitors following recommendations for KRAS testing to guide treatment of metastatic colorectal cancer (mCRC).
Authors: Dotan Efrat , Li Tianyu , Hall Michael J. , Meropol Neal J. , Beck Robert J , Wong Yu-Ning 
Published: March 2020

e14021 Background: KRAS mutation status is a predictive biomarker for resistance to EGFR antibodies among mCRC pts, and is recommended for use by ASCO and the FDA. Little is known about the uptake of clinical recommendations in oncology practice. We sought to study the effect of ASCO and FDA guidelines on the use of EGFR antibodies among a commercially insured population. Methods: The LifeLink Health Plan Claims Database (formerly the PharMetrics Patient-Centric Database) was used to create a cohort of >18 yo mCRC pts treated between 2004-2010. We identified treatment and diagnosis using ICD-9 or HCPCS (J) codes. We defined 1st line therapy as any chemotherapy +/- bevacizumab given after the pt had a claim for mCRC, excluding pts treated with EGFR antibodies in the 1st line. 2nd line therapy was defined as the initiation of a new chemotherapy agent (irinotecan/oxaliplatin) +/- EGFR antibody. We examined pts in two-month time intervals and calculated the fraction of pts in each interval who received EGFR antibody at any point beyond their 1st line treatment. Chi2 tests were used to compare treatment rates at the time points shown in the Table. Results: 5099 pts received 2nd line therapy of which 2603 pts received an EGFR antibody. Median age was 61 years, with 57% males. 59% received an EGFR antibody as a single agent. The remainder received this in combination with one or more of the following agents: fluorouracil 13.5%, irinotecan 36.7%, oxaliplatin 3.9%, and bevacizumab 6.1%. Rates of EGFR antibody use are outlined in the Table. Conclusions: The utilization of EGFR antibodies for mCRC treatment decreased following the presentation of clinical trial data, publication of ASCO guidelines and FDA label change. These data suggest that oncologists respond rapidly to new evidence and professional guidelines, and readily accept the use of predictive biomarkers in clinical practice. [Table: see text]
Use of germ-line variants in the WNT/β-CATENIN pathway to predict tumor recurrence in adjuvant colon cancer.
Authors: Wilson Peter M.D. , Páez David , Gerger Armin , Zhang Wu , Yang Dongyun , Labonte Melissa Janae , Benhaim Leonor , Bohanes Pierre Oliver , Ning Yan , Wakatsuki Takeru , Loupakis Fotios , Lenz Heinz-Josef 
Published: March 2020

e14034 Background: The Wnt/β-catenin signaling plays a central role in the development and progression of most colon cancers. Germline variants in Wnt/β-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/β-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. Methods: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4 genes by PCR-RFLP or direct DNA-sequencing. We also included NOTCH2 and GLI1 variants which belong to the Notch and Hedgehog pathways respectively. Results: The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (4.9vs10.7 years; HR: 2.48; 95%CI, (0.96, 6.38); p=0.044) in high-risk stage II colon cancer patients. This result remained significant in the multivariate Cox regression analysis. Conclusions: Despite the importance of Wnt/β-catenin pathway in the development of cancer, only the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for colon cancer patients after 5-fluorouracil-based adjuvant therapy.
KRAS aKtive, an Italian network for assessment of KRAS mutations in colorectal cancer patients: Results on 7,432 cases.
Authors: Marchetti Antonio , Pinto Carmine , Taddei Gian Luigi , Clemente Claudio , Troncone Giancarlo , Russo Antonio , Fontanini Gabriella , Larocca Luigi Maria , Mottolese Marcella , Giannini Giuseppe , Ruco Luigi , Roz Elena , Scarpa Aldo , Calabrese Giuseppe , Bortesi Beatrice , Vaccarella Salvatore , Cossu Antonio , Ludovini Vienna , Normanno Nicola 
Published: March 2020

e14042 Background: The KRAS aKtive program was started on March 2009, promoted by the Italian Association of Medical Oncology (AIOM) and the Italian Society of Surgical Pathology and Cytopathologyy (SIAPEC) to support the activity of oncologists and pathologists involved in the management of metastatic colorectal cancer patients who need the assessment of the mutational status of the KRAS gene. Methods: The program was specifically devised to facilitate the exchange of biologic material, clinicopathological data and diagnostic reports within a network of oncologist, pathologists and pathology/molecular biology reference laboratories throughout Italy, connected through the site www.kras-aKtive.it. KRAS mutation analysis was performed by Sanger sequencing (SS), real time PCR or other techniques, including pyrosequencing and hybridization strip assays. Data were collected in a common database. Results: The KRAS aKtive program has involved 478 oncologists, 144 pathologists, and 24 reference laboratories. A total of 7,432 KRAS mutations analyses were performed. The tests were informative in 7,265 cases (98%). The vast majority of tests (5,626 cases, 77.4%) were conducted by SS. In 529 (7.3%) cases a real-time PCR assay was used, other detection techniques were used in 1,110 (15.3%) cases. KRAS mutations at codons 12-13 were detected in 2,874 cases (39,6%). The frequency of mutations detected by real-time PCR or other techniques (45%, and 43%, respectively) was significantly higher (p=0.002, and p=0.008%, respectively) than that observed by SS (38%). The percentage of cases evaluated by non-SS-based methods has increased during the first three years of the program. Conclusions: The results of this large survey allow an accurate estimation of the actual prevalence of KRAS mutations and their types in caucasian colorectal cancer patients. Our data indicate that the frequency of mutations detected by non-SS-based methods is higher than that obtained by SS.
Phase I/II study of preoperative concurrent chemoradiotherapy with S-1, irinotecan, and cetuximab for locally advanced rectal adenocarcinoma.
Authors: Ota Mitsuyoshi , Goto Ayumu , Ichikawa Yasushi , Suwa Yusuke , Watanabe Jun , Watanabe Kazuteru , Tanaka Kuniya , Akiyama Hirotoshi , Fujii Shoichi , Endo Itaru 
Published: March 2020

e14050 Background: Recent studies reported that the cetuximab regimen including irinotecan has high tumor-response rates as a neoadjuvant chemotherapy for colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for irinotecan combined use of S-1 and cetuximab as a preoperative chemoradiotherapy and to evaluate the feasibility and effect in patients with locally advanced rectal cancer. Methods: Patient s with adenocarcinoma of the lower rectum were enrolled in a phase I trial. Wild type KRAS was confirmed by biopsy specimen in all eligible patients. Also, UGT1A1 gene polymorphism was examined to avoid irinotecan-induced severe neutropenia and homozygous type (*28/*28, *6/*6, *28/*6) patients were excluded from this study. A total dose of 50.4 Gy was delivered in 28 fractions over 6 weeks, and 80 mg/m2 of S-1 was orally administered twice a day on days 1–14 and 22–35. Irinotecan was given 125 mg/m2 (level 1) to 150 mg/m2 (level 2) on day 1 and 22. Cetuximab was given 400 mg/m2 on day 7 as a loading and 250 mg/m2 weekly on day 1 to 35. Surgical resection was scheduled 6–8 weeks after the completion of chemoradiation. Results: Among the 5 patients, who received 125 mg/m2 irinotecan, dose-limiting toxicity (DLT); perforation occurred in 1 patient. Grade 3 neutoropenia occurred in 2 patients, who recovered within a week. Within grade 2 of anal pain and acne-like erythema was occurred in all patients. A pathological complete response (pCR) was not observed, pathological downstaging was observed in 4/5 patients (80%), and a tumor volume reduction of 68% was obtained. Conclusions: In phase I, the maximum-tolerated dose was not reached, and the recommended dose (RD) of irinotecan was seemed to be 125 mg/m2. This new protocol referred to KRAS and UGT1A1 profile is well tolerated, and should proceed to a phase II trial to evaluate the effectiveness.
The relationship between tumor expression of phosphorylated STAT3 and pathology and outcome in colorectal cancer.
Authors: Guthrie Graeme JK , Platt Jonathan J , Mohammed Zahra MA , Roxburgh Campbell SD , Horgan Paul G , Mcmillan Donald C. , Edwards Joanne E. 
Published: March 2020

e14054 Background: Cancer-associated inflammation has recently been identified as a key determinant of disease progression and survival in colorectal cancer(CRC). The signal transducer and activator of transcription 3(STAT3) pathway is central to the inflammatory response, and has been implicated in cancer development and progression. This study aimed to evaluate tissue expression of cytoplasmic and nuclear STAT3 expression in CRC and its association with clinicopathological variables and survival. Methods: Patients were identified from a prospectively maintained CRC database. Using immunohistochemistry on a tissue microarray, cytoplasmic and nuclear expression of phosphorylated STAT3 (p-STAT3) at both the tyrosine 705(tyr705) and serine 727(ser727) phosphorylation sites was assessed using the weighted histoscore. Associations between p-STAT3 expression and clinicopathological factors and survival were examined. Results: In 273 patients, cytoplasmic and nuclear p-STAT3 expression was examined and considered positive if staining was observed in more than 15% of tumour cells. When colonic and rectal tumours were considered together, cytoplasmic and nuclear p-STAT3 expression at both phosphorylation sites (tyr705 and ser727) showed no significant relationship with clinicopathological variables. Similarly, when colonic tumours were considered alone, cytoplasmic and nuclear p-STAT3 expression showed no association with clinicopathological factors. In rectal cancer, although cytoplasmic p-STAT3 was not significantly associated with survival, nuclear p-STAT3 expression was associated with improved survival(tyr705 p=0.007, ser727 p=0.098). Similar to the colon cancer group, rectal cancer nuclear p-STAT3 expression showed no correlation with clinicopathological variables. Conclusions: Tumour nuclear p-STAT3 expression and its association with outcome appears to depend on tumour site with improved survival associated with nuclear p-STAT3(tyr705) expression in rectal but not colon cancer. The basis of this observation is not clear and further assessment of the role of p-STAT3 in the tumour microenvironment is required.
Association between a specific miRNA signature and pathological response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) patients.
Authors: Bandres Eva , Arias Fernando , Guerrero David , Lopez Ines , Gonzalez-Huarriz Marisol , Gomez Dorronsoro Maria Luisa , Montes Marta , Monzon Francisco , Torrea Natalia , Armendariz Pedro , Balen Enrique , Viudez Antonio , Asin Gemma , Chicata Victor , Hernandez Irene , Eito Clara , Garcia-Foncillas Jesus 
Published: March 2020

e14057 Background: MicroRNAs (miRNA), small non-coding RNA molecules act as post-transcriptional regulators of gene expression and have shown diagnostic and prognostic potential in cancer. We profiled miRNA expression in LARC patients treated with neoadjuvant CRT to assess whether a miRNA signature correlated with the degree of pathological response. Methods: FFPE-derived tumour samples from 85 LARC patients treated with preoperative CRT (45 Gy plus 5.4 Gy boost, 180-cGy daily fractions and concurrent capecitabine) were analyzed for miRNA signature generation and IHQ-EGFR protein expression. Pathological response was scored according to the Mandard’s TRG scale. Expression profile of 667 mature miRNAs obtained by TLDA Human MicroRNA Panel or individual TaqMan MicroRNA Assays were normalized using RNU48, selected as the best normalizer by Normfinder program. The correlation between miRNA expression profile and pathologic response was assessed by class-comparison, unsupervised hierarchical cluster analysis and U-Mann Whitney test. Results: A pathological complete response was achieved in 12 patients (14%), whereas no response (TRG 3-4) was observed in 49 patients (58%). As expected, TRG correlated with both relapse and disease-free survival (p<0.01). We identified a miRNA signature that correctly differentiated extreme-phenotype of responder patients (TRG-1 vs TRG-4). The top 10 of them were selected to be validated by individual Q-RT-PCR in the global series. While up-regulation of miR-21*, miR-99*, miR-125b, miR-125b1*, let-7c and miR-490 significantly correlated with a higher likelihood of achieving pathological response (TRG-1-2), miR-21 and miR-125a-3p downregulated levels were found to be associated with a TRG-4 response. High EGFR protein expression levels, determined by IHQ, were seen in the 93% of poor-responders patients (TRG-4). Interestingly, miR-21 and miR-21* levels inversely correlated with EGFR expression. Conclusions: A differential expression of miRNAs may predict the degree of pathological response to CRT in LARC patients. A miRNA-mediated role for EGFR pathway in CRT resistance warrants further research.
Prognostic value of KRAS in terms of efficacy and safety of bevacizumab as neoadjuvant or conversion treatment in patients with colorectal liver metastasis.
Authors: Garcia Alfonso Pilar , Muñoz Martin Andrés Jesús , Alvarez Sonsoles , Riesco M. Carmen , Blanco Codeisido Montse , Ruperez Blanco Ana Belen , Custodio Cabello Sara , Tapia Gonzalo , Mondejar Solís Rebeca , Martin Miguel 
Published: March 2020

e14058 Background: Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, only a small proportion has initially resectable metastases. Bevacizumab (BEV) added to chemotherapy (CT) is active for metastatic CRC. This study aimed to assess efficacy and safety of BEV as neoadjuvant or conversion treatment in patients with CRC liver metastases. Methods: Observational retrospective review in CRC patients with liver metastases who have undergone neoadjuvant or conversion CT with BEV as first or second line treatment. Results: 34 patients analyzed: 53% male; median age 55; 77% had metastases at diagnosis; ECOG 0-1 (38-62%); primary tumor location: 52% colon, 37% rectum, 11% colon/rectum; 84% had synchronic metastases; 16% initially resectable metastases 9% irresectable and 75% potentially resectable. 77% and 24% received first and second line BEV prior surgery respectively. Complete resection was achieved in 85%. All patients with initially unresectable metastases become resectable. 44% suffered post-operative complications; most frequent being abdominal and wound infection (12-9%). Complete pathologic response of liver metastases was seen in 7% and 61% reached major response. Median OS after surgery was 46 months. Disease free survival (DFS) since surgery was 8.8 months without significant differences between those receiving BEV as first or second line treatment. 88% of patients did not expeirence grade 3-4 toxicity. KRAS mutation was detected in 10 of 26 patients with available KRAS status (39%). Median DFS was significantly longer in wild type wt-KRAS patients compared with those mutated m-KRAS (12 vs 7 months p<0.001) thus confirming KRAS as a prognostic biomarker. Major pathologic response rate was significantly improved in wt-KRAS patients vs m-KRAS (84% vs 25% p<0.001). Conclusions: Neoadjuvant or conversion CT with BEV is an active treatment option for patients with CRC liver metastases with an adequate safety profile and without an apparent increase of surgical complications. While both wt-KRAS and m-KRAS patients benefit from treatment with BEV, wt-KRAS patients obtain greater pathologic response and significant longer DFS.
Phase II trial of preoperative radiotherapy (RT) and panitumumab (PAN) in KRAS wild type (wt) rectal cancer (RC).
Authors: Mardjuadi Feby Ingriani , Canon Jean-Luc , Coche Jean-Charles , Jouret-Mourin Anne , Sempoux Christine , Goeminne Jean-Charles , Delaunoit Thierry , Carrasco Javier , Vuylsteke Peter , Humblet Yves , Meert Nicolas , Van den Eynde Marc , Moxhon Anne , Machiels Jean-Pascal H. 
Published: March 2020

e14060 Background: The addition of anti Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mabs) to preoperative chemoradiation in RC has produced low pathological complete response (pCR) rate. The postulated reasons for the poor outcome are: lack of patient selection, suboptimal treatment sequencing, and potential negative interaction between anti EGFR mabs and chemotherapy (CT) when used concurrently as radiosensitizers. Given these issues, we conducted a phase II trial of PAN in combination with preoperative RT in Kras wt RC. Methods: We studied several treatment sequences in murine models of Kras wt human colorectal cancer. Next, we used our preclinical results to design the treatment schedule of the phase II trial. PAN (6mg/kg/q2w) was combined with RT (45 Gy) to treat T3-4, Kras wt RC. Surgery was done 6-8 weeks after the end of RT. The primary endpoint, the pCR rate on surgical specimen, was assessed centrally (Simon: H0=5%, H1=17%, α=0.05, β=0.2). Results: In our murine models, the addition of anti EGFR mabs to RT significantly improved response when anti EGFR mabs were started during RT and extended after the end of RT (p<0.05). No benefit was found when anti EGFR mabs were given before the start of RT. In the phase II trial, we therefore started RT on day 1 and introduced PAN 7 days later (day 8). After RT ended (day 36), PAN treatment was continued to day 50. To fully explore PAN’s potential as radiosensitizer, CT was not given during RT but postoperatively. 19 patients were evaluable for pCR. 47% of tumours were cT3N+. Hypomagnesemia (16%) and hypophosphatemia (16%) were most common grade ≥3 toxicities. As no pCR was found, the study was closed prematurely for lack of efficacy according to the statistical rule. 7 patients (41%) had >50% pathological tumour regression (grade 3 Dworak) and 12 (70%) showed >2mm of tumour-free circumferential resection margin. Conclusions: Preclinical data confirm the need of optimal treatment sequencing to potentiate synergism between anti EGFR mabs and RT. However, the pCR rate in our phase II trial remains low despite adequate patient selection and optimized study design. Thus, we do not recommend the concurrent use of anti EGFR mabs and RT in the neoadjuvant treatment of RC.
Predictors of survival during treatment of metastatic colorectal cancer with an intermittent chemotherapy regimen.
Authors: Kronborg Camilla J S , Jensen Anni Ravnsbæk 
Published: March 2020

e14063 Background: Patients with metastatic colorectal cancer (mCRC) undergo month to year-long therapy with different chemotherapy regimens and biological agents. We aimed to identify predictors of mortality during an intermittent treatment regimen in an unselected cohort of patients with mCRC. Methods: Consecutive patients, treated from August 2007 until June 2011, were included. Standard 1st line treatment was biweekly FLIRI plus Bevacizumab. Clinical information was obtained from patient files. The outcome was overall survival. Cox regression analysis was used to identify predictors of outcome. We analyzed reduction in chemotherapy dosage (no reduction, ≤75% or >75%), administration of Bevacizumab to ≤50% of chemotherapy treatments, best response during the first 6 months of treatment (NC, RD or PD), and local treatment of metastases (any type). We adjusted for following baseline variables: Gender, age, PS, primary tumor site, resection of primary tumor, metachronous metastases, more than two metastatic sites, liver-only metastases, and low albumin Results: We included 314 patients (median age 64.5 IQ (57-70) years, 194 (61.8%) male). Median follow-up for survival was 471 IQ (257-708) days. One-year survival was 79%, CI (74-84%). Median overall survival was 676 days, CI (577-750). Chemotherapy reduction did not influence outcome, ≤75%: HR 1.08 CI (0.64-1.83), p=0.77, >75%: HR 0.66 CI (0.29-1.5), p=0.32. Local treatment of metastases was borderline significant: HR 0.45 CI (0.20-1.00), p=0.051. Bevacizumab was administered in 262 patients and a reduction in bevacizumab treatments was associated with increased mortality: HR 1.90 CI (1.12-3.23), p=0.018. Regression vs. NC improved outcome HR 0.48 (0.30-0.78), p=0.003, whereas PD vs. NC increased mortality HR 3.84 (1.75-8.42), p=0.001. Conclusions: In an unselected cohort of mCRC patients, using an intermittent treatment regimen, administration of Bevacizumab to less than 50% of chemotherapy treatments and PD were associated with increased mortality. Regression improved outcome compared to stable disease. Local treatment of metastases was borderline significant. Reduction in chemotherapy dosage did not influence outcome.
PPP1R13L variant as a prognostic factor in patients with rectal cancer.
Authors: Chae Yee Soo , Kim Jong Gwang , Sohn Sang Kyun , Lee Soo Jung , Kang Byung Woog 
Published: March 2020

e14074 Background: Genetic variants related with apoptosis and DNA repair pathways may play a meaningful role in cancer progression as well as carcinogenesis. Among them, PPP1R13L and ERCC1 polymorphisms was found to synergistically affect these pathways. The aim of this study was to investigate the association between these genetic variants and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 349 CRC patients underwent curative surgery between March 2003 and August 2006 were consecutively enrolled. DNA was extracted from fresh frozen normal tissue and each polymorphism (PPP1R13L rs1005165 and rs967591; ERCC1 rs11615 and rs735482) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: No statistical significance between these 4 variants and survival in a multivariate analysis for all CRC patients. However, the CC genotype of the PPP1R13L rs1005165 was significantly associated with worse survival in 164 patients with rectal cancer (HR = 2.10 and p = 0.037 for RFS; HR = 2.27 and p = 0.039 for DSS, respectively) as a recessive model of the C allele in a multivariate analysis. Meanwhile, no statistical differences in clinicopathologic characteristics were observed according to the rs1005165 genotype in rectal cancer patients. Conclusions: Our results suggest that PPP1R13L variant is possible prognostic marker in Korean patients with operated rectal cancer.