bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histopathologic response and growth patterns of colorectal cancer liver metastases (CRCLM) in patients treated with triplets plus bevacizumab (bev) or anti-EGFRs.
Authors: Marmorino Federica , Cremolini Chiara , Pietrantonio Filippo , Pellegrinelli Alessio , Zucchelli Gemma , Loupakis Fotios , Lonardi Sara , Aprile Giuseppe , Morano Federica , Prisciandaro Michele , Masi Gianluca , Mennitto Alessia , Bergamo Francesca , Cardellino Giovanni Gerardo , Fassan Matteo , Casagrande Mariaelena , Milione Massimo , Fontanini Gabriella , de Braud Filippo , Falcone Alfredo 
Published: January 2019

636 Background: The histopathological response to pre-operative chemotherapy is associated with clinical outcome in patients (pts) undergoing secondary resection of CRCLM. Three different histopathological growth patterns (HGPs) of CRCLM have been described: desmoplastic (i.e. with a capsule of stroma separating tumor and normal cells), pushing (i.e. with limited infiltration of normal hepatic plates by tumor cells) and replacement (i.e. with abundant infiltration of normal hepatic plates by tumor cells and vessel cooption). Methods: Histopathological parameters of response were evaluated in specimens from 159 pts who underwent secondary resection of CRCLM, after receiving triplet (FOLFOXIRI or COI) plus bev (N = 103) or anti-EGFR (N = 56) in 5 first-line clinical studies (TRIBE, MOMA, MACBETH, COI-B and COI-E). The aims of this analysis were to evaluate the prognostic role of histopathologic response and to investigate the prognostic role of HGPs and their potential different sensitivity to targeted agents. Results: When compared with partial (TRG 3) and no (TRG 4-5) pathologic response (N = 118), major response (TRG 1-2, N = 41) was associated with longer RFS (mRFS: 28.0 versus 11.0 mos, HR = 0.57, 95%CI = 0.39–0.86; p = 0.007) and OS (mOS: unreached versus 42.1 mos, HR = 0.54, 95%CI = 0.31-0.93; p = 0.027). No association of baseline clinical characteristics and RAS and BRAF status with major response was found. Major response was more frequent among pts treated with bev than with anti-EGFRs (OR = 2.83, 95%CI = 1.20–6.65; p = 0.015) and was associated with deepness of response as a continuous variable (HR = 1.02, 95% CI = 1.00–1.04; p = 0.011). In the desmoplastic HGP (N = 28) a higher percentage of major response was reported (57% vs 17% in pushing and 22% in replacement HGP, p < 0.001) and a numerical advantage from anti-EGFR vs bev was evident in terms of both major response and RFS. Conversely, in the pushing HGP (N = 66) a significant benefit from bev vs anti-EGFR in major response and RFS was observed. No difference was described in the replacement HGP (N = 65). Conclusions: The assessment of HGPs may be useful to predict benefit from available targeted agents.
Association of RAS mutations with race in metastatic colorectal cancer: CALGB/SWOG 80405 (ALLIANCE).
Authors: Sehdev Amikar , Niedzwiecki Donna , Venook Alan P. , Lenz Heinz-Josef , Innocenti Federico , Mahoney Michelle R. , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Atkins James Norman , Goldberg Richard , Mayer Robert J. , Schilsky Richard L. , Bertagnolli Monica M. , Blanke Charles David , O'Neil Bert H. ,   Cancer and Leukemia Group B (Alliance) and SWOG
Published: January 2019

638 Background: Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular subtypes in part based on RAS mutational status. It is plausible that RAS mutations are differentially distributed between CC and AA and may contribute to poor outcomes in AAs with CRC. Methods: We did a retrospective analysis of CALGB/SWOG 80405 trial patients. We divided the entire cohort into 2 groups: a) Common RAS: mutation in KRAS exon 2, codon 12 or 13; b) Extended RAS: any NRAS mutations or mutation in KRAS except those listed above. We then analyzed these two subgroups for association between RAS mutations and race (3 categories: Caucasian, AA, Others) using chi-square test for univariate analyses and logistic regression for multivariate analysis. We also analyzed the effect of extended RAS testing on prognosis of metastatic CRC by estimating the overall survival (OS) using Kaplan-Meier method and 95% confidence interval (CI). Cox proportional-hazard model was used for multivariate analyses. Results: There were 1729 CRC patients in common RAS group of which 357 (20.6%) had mutations present. Extended RAS group had 621 patients of which 95 (15.5%) had mutations present. There was no significant difference in the rate of common RAS mutations between CC and AA (20.5% vs. 24%, p=0.22). However, extended RAS mutations were significantly more in AA as compared to CC (25% vs. 14%, p=0.02). Multivariate analysis adjusted for age, gender, prior adjuvant chemotherapy and pelvic radiation confirmed higher odds of extended RAS mutation in AA compared to CC (adjusted OR 1.12; 95% CI 1.01-1.23; p=0.02). The median OS in patients with an extended RAS mutation was shorter as compared to those without extended RAS mutation (25.3 vs. 31.9 months; HR 1.26; 95% CI 0.99-1.62; p=0.05). Multivariate analyses adjusted for age, gender, race, prior adjuvant chemotherapy and pelvic radiation showed a trend towards longer OS in patients without extended RAS mutation as compared those with extended RAS mutation (adjusted HR= 1.24, 95% CI, 0.97-0.1.58, p=0.08). Conclusions: Extended RAS mutations are significantly more common in AA as compared to CC. Additionally, presence of extended RAS mutation may confer a poor prognosis in CRC patients.
Clinical prognostic score of BRAF V600E mutated (BM) metastatic colorectal cancer (mCRC): Results from the “BRAF, BeCool” platform.
Authors: Intini Rossana , Loupakis Fotios , Cremolini Chiara , Sartore-Bianchi Andrea , Pietrantonio Filippo , Pella Nicoletta , Santini Daniele , Rimassa Lorenza , Formica Vincenzo , Calvetti Lorenzo , Salvatore Lisa , Antonuzzo Lorenzo , De Luca Emmanuele , Morano Federica , Tosi Federica , Moretto Roberto , Fassan Matteo , De Maglio Giovanna , Zagonel Vittorina , Di Maio Massimo 
Published: January 2019

639 Background: BM mCRCs account around 10% of mCRCs, with a dismal prognosis. Intra-group heterogeneity has been recently studied, however, an extensive prognostic clinical analysis has not been provided yet. Methods: BM mCRCs tested on primary tumor (T) or on metastases (mets) were collected from 13 Italian Oncology Units. A prognostic score was derived by an internal cross-validation procedure: the whole population was splitted in a training (67%) and in a testing (33%) sample; this process was repeated 10 times. Primary endpoint was OS. Multivariate analysis (MA) was performed on each training sample, and covariates with independent prognostic value were included in the scoring system, assigning rounded scores to the covariates. Results: A total of 395 BM mCRC patients were included. At MA, independent prognosticators for OS were ECOG PS (1 vs 0; 2-3 vs 0), Ca19.9 (high vs normal); LDH (≥300 vs low); neutrophil/lymphocyte ratio ( > 3 vs low); T grading (3-4 vs 1-2); liver mets (yes vs no); lung mets (yes vs no); lymphnode mets (yes vs no). Two different scoring systems were built: a «complete» score (0-18) with all significant covariates; a «simplified» score (0-11), selecting only significant clinico-pathological covariates, excluding laboratory values. With «complete» score, proportion of patients with low (0-4), intermediate (5-8) and high (9-18) score was 39%, 46% and 15%, respectively. Median OS was 27.6, 18.7 (HR interm. vs low 1.89, 95%CI 1.25 – 2.86, p = 0.003) and 6.6 months (HR high vs low 4.95, 95%CI 2.89 – 8.47, p < 0.0001), respectively. Similar results were observed adjusting for type of first-line treatment. Median PFS was 11.1, 8.6 (HR interm. vs low 1.36, 95%CI 0.94 – 1.97, p = 0.11) and 4.1 months (HR high vs low 3.50, 95%CI 1.98 – 6.20, p < 0.0001). Similar results were obtained with the «simplified» score. Conclusions: A simple and ready-to-use prognostic score for BM mCRC was developed. The robustness of the internal cross-validation justifies the effort of a validation study. Identification of specific prognostic factors in distinct molecular subgroups is crucial for adjusting exploratory translational analyses and future clinical trial design.
A pilot case control study: Could a gastric cancer risk screening tool help identify high risk patients for endoscopic screening in the United States?
Authors: In Haejin , Langdon-Embry Marisa , Gordon Lauren , Wylie-Rosett Judith , Schechter Clyde , Castle Philip , Kemeny Margaret , Rapkin Bruce D. 
Published: January 2019

64 Background: Gastric cancer incidence varies greatly among US racial/ethnic groups. Few studies have examined ethnicity, birth country, immigration and cultural diet as gastric cancer risk factors in the US. These factors, in combination with known risk factors may narrow a target population for gastric cancer screening. Methods: Two racially diverse hospital systems were used to recruit gastric cancer cases using the cancer registry, and primary care (PC) controls from waiting rooms or phone. Community controls were recruited at community gatherings. Participants were eligible if 40-85 years old, not under endoscopic surveillance and without genetic syndromes. The survey items (n = 227) included conventional risk factors, plus items about ethnicity, birth country, acculturation, and ethnic diet. Results: Of 150 participants, 39 cases, 41 PC-controls, and 44 community controls were eligible for analysis. PC-controls generally completed phone interviews (72% vs 28%), while community controls generally completed paper surveys (92% vs 8%). Gastric cancer cases were more likely to be foreign born (85% vs. 49%, p = < 0.01), from a country with gastric cancer incidence > 5 per 100,000: (62% vs. 30%, p = < 0.01) and report daily consumption of cultural food at ages 15 to 18 (69% vs. 35%, p = < 0.01) compared to controls. Cases were also older, male, Hispanic, and had stronger family history of gastric cancer. Cases and controls had similar frequency of alcohol consumption, smoking, acculturation, and barbequed food consumption. In multivariate analysis, increased age (per year, aOR 1.4, 95%CI 1.07-1.21), daily consumption of cultural foods at ages 15 to 18 (aOR 19.58, 95%CI 1.54-248.99), having less than high school education (aOR 7.24, 95%CI 1.49-35.10), and being foreign born (aOR 11.81, 95%CI 1.69-82.64) were associated with case status. Conclusions: A risk assessment tool that addresses awareness of gastric cancer risk factors, ethnicity, cultural habits and immigration patterns has potential to identify high-risk persons from multicultural areas within the US, who might benefit from endoscopic screening for gastric cancer. (Support: UG1CA189823)
Serial monitoring of ctDNA to highlight mutation profiles in colorectal cancer.
Authors: Loree Jonathan M. , Strickler John H. , Pereira Allan Andresson Lima , Lam Michael , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Menter David , Banks Kimberly , Nagy Rebecca J , Raymond Victoria , Overman Michael J. , Talasaz AmirAli , Lanman Richard B. , Kopetz Scott 
Published: January 2019

641 Background: Circulating tumor DNA (ctDNA) represents an ideal platform to obtain the most current genomic profile of a patient’s tumor. We aimed to investigate how stable these profiles remain during serial ctDNA assays in metastatic colorectal cancer (mCRC). Methods: In 77 patients (pts) with mCRC and serial Guardant360 assays with a detectable mutation (mt), we compared mt stability by assessing whether variants were gained/lost between serial assays and changes in relative mutant allele frequency (rMAF). rMAF of a mt was defined as (mt allele frequency / mt present at the maximum allele frequency in that assay). rMAF results were normalized to detected ctDNA concentration changes between assays to ensure changes in rMAF were not due to changes in ctDNA concentration. MAPK pathway mutations were defined as RAS, BRAF, EGFR, KIT, or MET mutations. Results: Of 77 pts, 64 (83%) had 2 serial assays and 13 (16.9%) had 3 or 4 assays performed. Serial assays occurred an average of 138 days apart (+/- SD of 111 days). Only 13/77 (17%) pts had no change in the number of mts detected between assays. A new mt was detected in 42/77 (55%) pts, while 43/77 (56%) lost a previously detected mt. Of 52 mts detected in patients with > 2 assays, 16 (31%) were gained and subsequently lost. After controlling for ctDNA concentration, mts were equally likely to have an increasing (129/308 – 42%) or decreasing (150/308 – 49%) allele frequency. Potentially clinically relevant MAPK variants were gained/lost in 29% of patients; though MAPK mts developed in a large number of pts (16/77 – 21%), many pts also lost MAPK mts (9/77 – 12%), showing ongoing subclonal dynamics. Median time between assays did not differ between pts with gain/lost mts or stable mt profiles (P = 0.73), however mt rMAF shift of > 25% was more common if assays were > 90 days apart (OR 4.3, P < 0.0001). Conclusions: Serial ctDNA assays demonstrate ongoing mutational changes in mCRC, with emergence/disappearance of MAPK variants being more common than expansion of a pre-existing clone. Our results suggest repeated sampling may be important to optimize selection of targeted therapies at each regimen alteration.
Survival outcome in HER2-amplified metastatic colorectal cancer (mCRC).
Authors: Sawada Kentaro , Okamoto Wataru , Nakamura Yoshiaki , Yamanaka Takeharu , Yuki Satoshi , Yoshino Takayuki , Komatsu Yoshito , Sakamoto Naoya , Fujii Satoshi 
Published: January 2019

642 Background: HER2 amplifications have been observed in approximately 3% of patients (pts) with metastatic colorectal cancer (mCRC). Early clinical trials with combined HER2-targeted therapies showed promising activities. However, it remains unclear whether HER2 amplification in mCRC is as prognostic as RAS or BRAF V600E mutant (mt). We aimed to evaluate survival outcome for mCRC pts with HER2 amplification compared to those with RAS or BRAF mt. Methods: mCRC pts who received a palliative resection of the primary tumor with metastatic diseases at presentation, or recurred after curative resection of the primary tumor between 2005 and 2015, were analyzed. HER2 immunohistochemistry (IHC) was performed using formalin-fixed and paraffin-embedded (FFPE) sections obtained from the primary tumor, and HER2 amplification was confirmed by fluorescence in situ hybridization (FISH) in case of IHC 2+ or 3+. Criteria for HER2 amplification were a HER2- to CEP17- signal ratio of 2.0 or higher. RAS / BRAF status was centrally assessed by a PCR-based method. The pts were classified into four subgroups based on RAS, BRAF and HER2 status: Group R , RAS mt; Group B, BRAF V600E mt; Group H, HER2 amplification with RAS / BRAF wild-type (wt); and Group W, RAS / BRAF wt. Results: Among 370 pts, 359 pts (97%) were successfully analyzed. A total of 15 pts (4%) had HER2 amplifications, out of which four pts had overlapped RAS mt (subclassified as Group R). RAS or BRAF mutations are mutually exclusive. The number in Group R, B, H and W was 204 (57%), 13 (4%), 11 (3%) and 131 (36%), respectively. There was no remarkable difference in baseline characteristics among groups. With a median follow-up time of 63 months (mos), the median overall survival of the 359 pts was 27 mos (95%CI 24 - 29 mos); Group R, 24 mos; Group B, 14 mos; Group H, 20 mos; and Group W, 39 mos. The HR of R vs. H is 0.83 (95%CI 0.41-1.70, p= 0.618), B vs. H is 1.16 (95%CI 0.47-2.84, p= 0.748), and W vs. H is 0.52 (95%CI 0.25-1.08, p= 0.080), respectively. Conclusions: This study suggests that the prognosis of mCRC pts with HER2 amplification tends to be worse as compared to those with RAS / BRAF wt, similar to those with RAS mt, and better than those with BRAF mt, although these comparisons were not statistical significant.
Polymorphism in cancer-associated fibroblasts (CAFs) related genes and clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) enrolled in two independent randomized phase III trials: TRIBE and FIRE-3.
Authors: Puccini Alberto , Berger Martin D. , Tokunaga Ryuma , Naseem Madiha , BATTAGLIN FRANCESCA , Cao Shu , Millstein Joshua , Soni Shivani , McSkane Michelle , Zhang Wu , Loupakis Fotios , Stintzing Sebastian , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2019

645 Background: Tumor microenvironment plays a critical role for CRC development and progression. CAFs are the most dominant cellular components which orchestrate tumor cell proliferation, survival and invasion and have been shown to be associated with prognosis in pts with CRC. We aimed to evaluate whether single-nucleotide polymorphisms (SNPs) in CAFs related genes predict outcome in mCRC pts treated with first-line FOLFIRI/bevacizumab (bev) in TRIBE and FIRE-3 trials. Methods: The OncoArray, a custom array by Illumina including 530K SNP markers, was used to genotype genomic DNA from blood samples and served as our database, from which 15 functional SNPs within 9 genes (OPN, CD44, TCN, CD63, TIMP1, SLIT2, ROBO1, LOXL2, INHBA) related to CAF pathway were analyzed. Results: A total of 451 pts were included. Those treated with FOLFIRI/bev in TRIBE (N = 215, median PFS/OS: 9.7/26.3 months (mts)) and FIRE-3 (N = 107, median PFS/OS: 11.6/31.5 mts) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/cetuximab arm (N = 129, median PFS/OS: 12.8/49.8 mts) was used as the control. In overall pts in discovery set, OPN (osteopontin) rs11728697 any C variants showed longer PFS (median 10.8 vs 9.0 mts; HR = 0.68, 95%CI = 0.49-0.95; p = 0.025) and OS (median 30.6 vs 23.8 mts; HR = 0.69, 95%CI = 0.50-0.95; p = 0.025) than the homozygous wild type genotype (T/T) in multivariable analysis. These data were validated in the FIRE-3 cohort in OS both in univariate (median 49.3 vs 23.7 mts; HR = 0.40, 95%CI = 0.21-0.77; p < 0.001) and in multivariable analyses (HR = 0.31, 95%CI = 0.16-0.60; p < 0.001). However, the favorable impact on outcome was not shown among C allele carriers treated with FOLFIRI/cetuximab in the control arm. Conclusions: Our findings confirm that CAFs play a crucial role in mCRC and suggest that OPN polymorphisms could serve as predictive biomarkers for mCRC pts treated with first-line FOLFIRI/bev.
Genetic variants in methylation and demethylation pathways to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI/Bev: Data from TRIBE and FIRE-3 trials.
Authors: Puccini Alberto , Loupakis Fotios , Stintzing Sebastian , Berger Martin D. , Tokunaga Ryuma , Naseem Madiha , BATTAGLIN FRANCESCA , Cao Shu , Millstein Joshua , Soni Shivani , McSkane Michelle , Zhang Wu , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2019

646 Background: DNA hypermethylation in CpG islands (CIMP) has been shown to promote CRC by silencing the expression of tumor suppressor genes. However, global DNA hypomethylation is now considered a common characteristic of CRC. A new family of genes (TET) has been shown to play a crucial role in actively demethylating the DNA. We explored whether genetic polymorphisms in the genes which promote DNA methylation and demethylation are associated with outcome in pts enrolled in TRIBE and FIRE-3 trials. Methods: Genomic DNA from blood samples was genotyped through the OncoArray, a custom array by Illumina including 530K SNP markers. 17 functional SNPs within 11 genes related to methylation (DNMT1/3A/3B, MDM2) and demethylation pathways (TET1/2/3, IDH1/2, MBD4, TDG) were analyzed. Results: A total of 451 pts were included. FOLFIRI/bevacizumab (bev) arms from TRIBE (N = 215, median PFS/OS: 9.7/26.3 months (mts)) and FIRE3 (N = 107, median PFS/OS: 11.6/31.5 mts) served as discovery and validation cohorts respectively. FIRE-3 FOLFIRI/cetuximab arm (N = 129, median OFS/OS: 12.8/49.8 mts) served as control. In the discovery cohort, overall pts carrying TET1 rs3814177 C/C variant showed lower response rate (RR) (42.1% vs 61.8%, p = 0.026) and shorter median PFS (9.5 vs 10.3 mts; HR = 1.54, 95%CI = 1.04-2.27; p = 0.024, univariate analysis) compare to those with any T allele. The effect was more significant among KRAS mutant pts in RR (21.4% vs 60.8%, p = 0.007) and median PFS (8.6 vs 9.5 mts) both in univariate (HR = 2.00, 95%CI = 1.07-3.73; p = 0.020) and multivariable analysis (HR = 2.01, 95%CI = 1.03-3.92 p = 0.041). These findings were validated in overall pts in FIRE-3 cohort in median OS both in univariate (23.7 vs 41.9 mts; HR = 2.08, 95%CI = 1.07-4.05; p = 0.023), and multivariable analysis (HR = 2.36, 95%CI = 1.15-4.81; p = 0.019). No significant association was observed in the control arm. Conclusions: Our results provide the first evidence that TET1 polymorphism may be used as a predictive biomarker in mCRC pts treated with FOLFIRI/bev. Therefore, TET enzymes could serve as promising new treatment targets for mCRC pts.
DNA damage repair (DDR) pathway defects in gastrointestinal (GI) malignancies.
Authors: Thota Ramya , Fulde Gail , Lewis Mark Andrew , Haslem Derrick S. , Nadauld Lincoln , Moulton Bryce , Romero Robin , Abraham Tyler , Christensen Bryce , Raghunath Sharanya , Barker Tyler 
Published: January 2019

647 Background: The clinical significance of the genomic alterations associated with DDR pathway in GI tumors (besides MMR defects) is largely unknown. These patients can potentially derive benefit from targeted therapy with poly ADP ribose polymerase (PARP) inhibitors, which have already shown promising activity in ovarian, breast and prostate cancers. In this study, we investigated the frequency and clinical significance of DDR repair defects (other than MMR defects) in GI tumors. Methods: We performed a retrospective analysis of all patients who had tumor next generation sequencing performed between January 2013 and August 2017 on GI cancers harboring DDR pathway defects. Data including demographics, clinical history, and treatment were extracted from patients' records. Results: Of 299 patients with GI tumors sequenced, 35 cases (12%) were noted to have DDR defects. The most commonly mutated genes – 6 (17%) BRCA2, 5 (14%) PALB2, 4 (11%) ATM, 3 (8.6%) BRCA1, 2 (5.7%) each of NBN, MUTYH, ERCC3, PARP1 amplification and 1 (2.8%) each of ERCC2, CDK12, and PARP2 amplification. Two patients had both ATM and BRCA2 mutations. Combination of ATM and MRE11, ATM and BRCA1, BRCA1 and ERCC6, BRCA2 and CDK12 were noted in 1 patient each. Of the 23 patients with available clinical data, the median age at diagnosis was 65 (range 30–85) years with male and female prevalence rates of 60.8% and 39.2%, respectively. Stage at diagnosis was I (n = 3), II (n = 3), III (n = 8), and IV (n = 9). The primary site of tumor was found in 8 (34.8%) colon, 4 (17.4%) liver, 4 (17.4%) pancreas, 2 (8.7%) esophagus, 2 (8.7%) anus, 2 (8.7%) appendix, 1 (4.3%) rectum. Seventeen patients received platinum‐based therapy, 7 were treated with PARP inhibitors and 5 patients received both platinum and PARP inhibitor. Median overall survival from diagnosis for patients with stage I/II was 65.3 months, stage III was 23.1 months, and stage IV was 22.4 months. The median survival of patients treated with olaparib was 24.5 months. Conclusions: DDR pathway defects in GI tumors are uncommon. However, they can potentially be targeted with PARP inhibitors with durable survival. Future clinical trials are warranted to explore the role to PARP inhibitors in these unique subset of patients.