bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic characterization of rectal cancer and molecular determinants of response to neoadjuvant chemoradiotherapy.
Authors: Chatila Walid Khaled , Marco Michael , Qu Xuan , Walch Henry S. , Luthra Anisha , Chen Chin-Tung , Kundra Ritika , Schultz Nikolaus , Yaeger Rona , Smith Jesse Joshua , Sanchez Vega Francisco , Garcia-Aguilar Julio
Published: February 2020

192

Background: Rectal cancers are clinically different from colon cancers and have not yet been molecularly characterized due to the scarcity of pretreatment specimens. Discovery of molecular determinants of response to chemotherapy and radiation in patients with locally advanced rectal cancer (LARC, stage II and III) are needed to select those who can avoid surgery and benefit from watch-and-wait strategies. Methods: We profiled 371 pre-treatment specimens using targeted-exome sequencing of 468 cancer genes (n = 325), whole-exome sequencing (n = 100), and RNA-sequencing (n = 113). The targeted-sequencing cohort included patients with stage I (n = 44), II (n = 41), III (n = 176), and IV (n = 64) disease. Primary tumors were divided into lower (LR: 0-4 cm to anal verge, n = 62), middle (MR: 4-8 cm, n = 115), and upper rectum (UR: 8-12 cm, n = 107). We examined molecular determinants of complete response (CR) and relapse free survival (RFS) in LARC patients treated with chemoradiotherapy only (CRT: n = 39), induction chemotherapy + CRT (INCT: n = 87) and consolidation chemotherapy after CRT (CCNT: n = 63). Results: Among MSS cases, oncogenic gene and signaling pathway alterations did not vary by clinical stage. WNT pathway alterations, driven by APC mutations, were more frequent in the UR (89% UR v 86% MR v 60% LR, p < 0.001) while RTK/RAS alterations were more frequent in the LR (54% UR v 69% MR v 72% LR, p < 0.03). A set of genes enriched in mTOR signaling, G2M checkpoint, EMT transition, and DNA repair were overexpressed in the UR (FDR < 0.1). The 5-yr RFS rate for LARC was 75% (CI: 68%-82%) and 24% of the cases had a CR (n = 45). MSI cases had a higher rate of CR compared to MSS cases (50% v 23%, p = 0.07) and none relapsed (n = 8). KRAS-altered MSS tumors exhibited worse RFS in cases treated with CNCT (5-yr: 74% v 97%, p = 0.01), but not in cases treated with INCT (5-yr: 67% v 72%, p = 0.7). Conclusions: WNT alterations are more frequent in the UR while RTK/RAS alterations are more frequent in the LR, suggesting differences in tumor biology between proximal and distal rectal cancer. Further, we report correlations between distinct molecular profiles and response to treatment paradigms that could guide the design of future clinical trials.
Results of a fifty-gene breast cancer RNA subtype classifier applied to 167 colorectal cancer (CRC) patients.
Authors: Reddy Sandeep K. , Seery Tara Elisabeth , Szeto Christopher
Published: February 2020

20

Background: ERBB2 (HER2) is thought to be a target in <10% of CRC patients versus 20% of breast cancers, 15% of gastroesophageal cancers, and 10% of biliary cancers, based on FISH or IHC. Intrinsic molecular subtype is used to classify cancers into distinct biologic subtypes (eg. CMS 1-4 in CRC). A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. The HERACLES trial (trastuzumab plus lapatinib) resulted a 32% ORR and median TTP of 5.5 months in heavily pre-pretreated HER2+ CRC patients. We determined molecular subtypes using the 50-gene breast cancer classifier to identify an expanded CRC patient population eligible for HER2 therapy. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) data from NantHealth was performed. Breast Cancer Intrinsic Subtypes based on RNAseq was used to classify CRC into 5 BC subtypes. Results: 167 CRC patients were classified using the Nant50 Breast Cancer classifier: 15.0% as Luminal B, 13.1% as Luminal A, and 1.8% as Basal-like. Surprisingly, 117/167 (70%) classified as HER2-enriched (HER-E). 15/167 (9.0%) had over-expression of ERBB2 by RNAseq or CN gain, which is consistent with published data of HER2+ CRC. ERBB2 is very significantly differentially expressed in HER2-E subtyped CRC (p=<0.001), more than ERBB2 CN gain, suggesting that HER2-E may be more HER2 driven. Across subtypes APC and TP53 were the most commonly mutated genes at 65.3% and 52.6% respectively, however both were more enriched in HER2-E CRC (APC OR=3.3, p=0.001, TP53 OR=2.6, p=0.007). Other known drivers of CRC such as PIK3CA, KRAS, and BRAF, were not differentially mutated in HER2-E CRC, however NRAS mutants were significantly more enriched in non-HER2-E CRC (OR=4.6, p=0.02). Conclusions: Even after excluding known HER2 over-expression and CN gain, PAM50-like gene classifier identifies a far higher than expected percentage of HER-E subtype CRC (99/167 = 59%) which may represent an under appreciated population for HER2 directed therapy and clinical trials.
Establishing novel mutation subtypes in peritoneal carcinomatosis of appendiceal origin.
Authors: Garland-Kledzik Mary , Scholer Anthony Joseph , Khader Adam , Santamaria-Barria Juan , Orozco Javier , Pigazzi Alessio , Marzese Diego M.
Published: February 2020

200

Background: Appendiceal cancer (AC) is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare genetic make-up of primaries and metastases, and to find novel targetable alterations. Methods: The analysis involved the curation and normalization of mutation panels from adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than two patients and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Non-negative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed by using the Pearson’s χ2 test. Results: AC patients were stratified into five mutation subtypes. AC0 had no mutations in the 41 genes in the study. The most frequently mutated genes varied between the subtypes. AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% v 50.0-74.2%, p < 0.001) and had a higher mutation frequency (3.6 v 0-3.1, p < 0.001). There were no differences between primaries and metastases (p = 0.35). Conclusions: Characterization of these subtypes suggest a need for molecular rather than anatomic staging for AC. Histone regulation by KMT2D and EP300 may be considered for targeted therapy for patients with AC3. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed.
Prognostic and predictive value of DNA mismatch repair status in patients with locally advanced rectal cancer following neoadjuvant therapy.
Authors: Hu Huabin , Wang Chao , Wu Zehua , Huang Yan , Zhang Jianwei , Cai Yue , Xie Xiaoyu , Ling Jiayu , Deng Yanhong
Published: February 2020

210

Background: DNA mismatch repair deficient (dMMR) is a distinct molecular phenotype of colon cancer related to favorable outcome and resistant to 5-FU based adjuvant chemotherapy, however, little is known about dMMR rectal cancers. We investigated the value of dMMR on prognosis and predicted response to neoadjuvant therapy in rectal cancer patients. Methods: Between January, 2013 and December, 2018, a total of 855 consecutive patients with determined MMR status who underwent neoadjuvant therapy followed by curative surgery for locally advanced rectal cancer were included this retrospective study. Associations of MMR status with clinicopathologic variates and response to neoadjuvant therapy were determined using Chi-square or Fisher Exact tests. Local recurrence-free survival (LRFS) and disease-free survival (DFS) were analyzed using Cox proportional hazard models. Results: In this study population, dMMR was detected in 69 of 855 (8.1%) cases. Patients with dMMR showed similar clinicopathological characteristics including grade of differentiation, location from anal verge, clinical stage, neoadjuvant therapy regimen, pathological stage and postoperative chemotherapy to those who with pMMR, except younger age ( < 65 years, 89.1% vs. 77.7%, P = 0.034) and more mucinous adenocarcinoma in dMMR tumors. MMR status were not predictive for response to neoadjuvant therapy including pCR rate (18.8% vs. 12.9%, P = 0.185), downstaging rate (76.6% vs. 68.9%, P = 0.200) and tumor regression grade 0-1 (31.3% vs. 43.7%, P = 0.052), regardless of chemoradiation or chemotherapy. Multivariable analysis revealed that patients whose tumors had dMMR vs. pMMR had significantly longer DFS (HR = 0.39, 95%CI = 0.18 - 0.83, P = 0.014), but the correlation was not observed for LRFS (HR = 0.81, 95%CI = 0.25 - 2.60, P = 0.724). In the subgroup analysis, dMMR was a statistically significant prognostic factor for DFS only in patients with ypstage II-III (HR = 0.39, 95%CI = 0.17 - 0.88, P = 0.024). Conclusions: dMMR was significantly associated with longer DFS in patients with locally advanced rectal cancer, whereas was not a predictive marker for neoadjuvant therapy.
Wild-type APC and prognosis in metastatic colorectal cancer.
Authors: Wang Chongkai , Ouyang Ching , Sandhu Jaideep Singh , Kahn Michael , Fakih Marwan
Published: February 2020

223

Background: Somatic mutations at adenomatous polyposis coli ( APC) gene, found in ~75% of colorectal cancers (CRC), are under-represented in microsatellite instable (MSI-H) tumors. While several studies have suggested worse outcomes for CRC patients (pts) with wild-type APC ( APC-WT), the prognostic implication of this genomic alteration in metastatic CRC (mCRC) is not well defined. Methods: APC prognostic value was evaluated in 331 stage IV microsatellite stable (MSS) CRC pts treated in our institution. Next-generation genomic analysis (FoundationOne) was used to characterize the molecular characteristics of APC-WT and mutant APC ( APC-MT) pts. Findings were validated on a public database of stage IV colon cancer from MSKCC. Results: APC-WT was present in 26% of mCRC patients. In comparison to APC-MT population (n = 244), APC-WT pts (n = 87) tended to be younger (median age: 49 vs. 58 years), right-sided (44% vs. 24%), BRAF-V600E mutated (25% vs. 5%), p53 WT (38% vs. 21%) and RAS WT (66% vs. 53%). APC-WT tumors were associated with other Wnt activating alterations ( CTNNB1, FBXW7, RNF43, ARID1A and SOX9). Among those, RNF43 and CTNNB1 were more significantly represented in the APC-WT vs APC-MT population (12% vs 1% and 11% vs 3%, respectively). APC-WT pts had a worse overall survival (OS) than APC-MT pts (30 vs 48 months, HR = 1.809, 95% CI 1.260-2.596, p < 0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (HR = 1.7, p = 0.001) in our data set. The prognostic implication of APC-WT on OS were confirmed further in a similar multivariate model of 433 stage IV pts from MSKCC public database (HR = 1.6, P = 0.01). Conclusions: APC-WT is associated with poor OS in MSS mCRC regardless of RAS, BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other activating alterations of Wnt pathway, including RNF43 and CTNBB1.
Polymorphisms of genes encoding for regulatory proteins in the coagulation cascade to predict outcome for stage II and III colon cancer.
Authors: Berger Martin D. , Zlobec Inti , Cao Shu , Miyamoto Yuji , Suenaga Mitsukuni , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Battaglin Francesca , Zhang Wu , Lugli Alessandro , Lenz Heinz-Josef
Published: February 2020

227

Background: In cancer patients, an activated coagulation cascade might promote tumor cell dissemination. There are preliminary data suggesting that fibrinogen in combination with platelets can build a meshwork that entraps cancer cells enabling them to escape from immunosurveillance. We therefore hypothesize that variations in genes encoding for regulatory proteins within the coagulation pathway may predict outcome in patients with stage II and III colon cancer. Methods: The impact of three functional single nucleotide polymorphisms (SNPs) within the FGB, SERPINC1 and ITGA2B genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was isolated from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 42.8% / 57.2%; 111 patients had stage II, and 98 stage III colon cancer. The FGB rs4220 SNP showed significant association with recurrence rate in the overall population. Patients harboring any A allele had a higher 3-years recurrence rate compared to those with a G/G genotype (28% vs 17%) in both univariate (HR 1.83, 95% confidence interval (CI) 0.99-3.36, p = 0.048) and multivariate analyses (HR 1.94, 95% CI 1.05-3.57, p = 0.034). This trend was most evident among pts with stage II and especially the subgroup of high-risk stage II colon cancer. Again, A allele carriers had a higher 3-years recurrence rate compared to those having a G/G genotype (24% vs 10% and 44% vs 15% respectively) in both univariate (HR 3.32, 95% CI 1.26-8.74, p = 0.010 and HR 5.34, 95% CI 1.38-20.68, p = 0.006) and multivariate analyses (HR 3.34, 95% CI 1.27-8.78, p = 0.015 and HR 5.44, 95% CI 1.40-21.15, p = 0.015). Conclusions: Here, we demonstrate that the FGB polymorphism rs4220 might serve as a prognostic biomarker in stage II colon cancer. Assessment of FGB rs4220 might help us to identify those stage II colon cancer patients who will derive the most benefit from adjuvant chemotherapy.
Molecular landscape and prognostic value of HER2 low-expression on metastatic colorectal cancer.
Authors: Yagisawa Masataka , Sawada Kentaro , Nakamura Yoshiaki , Ishii Takahiro , Kubota Yohei , Nakajima Hiromichi , Jogo Tomoko , Sasaki Akinori , Mishima Saori , Kotani Daisuke , Kawazoe Akihito , Kuboki Yasutoshi , Shitara Kohei , Kojima Takashi , Doi Toshihiko , Ohtsu Atsushi , Fujii Satoshi , Yoshino Takayuki , Taniguchi Hiroya
Published: February 2020

229

Background: HER2 dual blockade showed the promise in clinical trials in patients (pts) with HER2-positive (HER2-Pos) metastatic colorectal cancer (mCRC). A phase I/II study of a novel anti-HER2 antibody-drug conjugate (HER2-ADC) showed promising activities across different cancer subtypes including HER2-Pos mCRC, and also showed a hint of activity for low-expressing (HER2-L) mCRC, regardless of RAS mutation. However, molecular landscape and prognostic value of HER2-L on mCRC are unclear. Methods: The eligibility included pts with mCRC who had undergone surgical resection of primary tumor. Using the specimen, HER2 expression was evaluated by immunohistochemistry (IHC) and FISH. Definition of HER2 positivity was as follows; HER2-Pos as IHC 3+ or IHC 2+/FISH positive: HER2-L as IHC 2+/FISH negative or IHC 1+: Negative (HER2-Neg) as IHC 0+. NGS tests were also done. Results: Between 2005 and 2015, a total of 370 pts were analyzed; 60% were male, with a median age of 64 y/o. Fifteen pts (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg were identified. Proportion of left-sided primary tumor was similar among groups ranging from 72% to 78%. No difference was observed in terms of major clinicopathological characteristics. The proportion of co-altered RAS mutations in HER2-L was significantly higher than HER2-Pos ( p = 0.037) and similar to HER2-Neg (27% in HER2-Pos vs. 62% in HER2-L vs. 56% in HER2-Neg). As of median follow-up of 24.8 months, median overall survival (mOS) in HER2-L was significantly better than that in HER2- Pos ( p = 0.029, 18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 pts harboring RAS wild-type who received an anti-EGFR monoclonal antibody therapy, median progression-free survival (mPFS) in HER2-L tended to be better than that in HER2- Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.5 in HER2-Neg ( p = 0.099). Conclusions: Since HER2-L mCRC had the high prevalence of co-altered RAS mutations but showed a better prognosis and might benefit more from an anti-EGFR therapy than HES2-Pos, the HER2-L mCRC seems to have a different biological behavior from HER2-Pos in terms of molecular landscape and prognostic value on mCRC.
Molecular characterization of appendiceal goblet cell carcinoid.
Authors: Arai Hiroyuki , Baca Yasmine , Johnston Curtis , Goldberg Richard M. , Philip Philip Agop , Seeber Andreas , Battaglin Francesca , Xiu Joanne , Wang Jingyuan , Soni Shivani , Zhang Wu , Hwang Jimmy J. , Shields Anthony Frank , Marshall John , Korn W. Michael , Lenz Heinz-Josef
Published: February 2020

231

Background: Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. There are a few reports focusing on the molecular differences between GCC and other appendiceal tumors such as adenocarcinoma and neuroendocrine tumor (NET). Methods: A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas and 14 NETs) were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) / mismatch repair (MMR) status was tested with a combination of NGS, IHC and fragment analysis. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 were tested by IHC (SP142). Molecular characteristics of GCCs are compared with those of adenocarcinomas and NETs, using Chi-square test. Results: The top five genes with most frequent mutation rate in GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), KRAS (7.5%) and CHEK2 (4.0%). Compared to adenocarcinomas, GCCs showed significantly lower mutation rates in KRAS (7.5% vs 60.4%), GNAS (3.8% vs 34.4%), APC (1.9% vs 11.7%), while significantly higher mutation rates in CDH1 (3.8% vs 0.7%), CHEK2 (4.0% vs 0.3%), CDC73 (2.0% vs 0.0%), ERCC2 (2.0% vs 0.0%) and FGFR2 (1.9% vs 0.0%). Compared to NETs, GCCs showed significantly lower mutation rate in KRAS (7.5% vs 28.6%), APC (1.9% vs 28.6%), BRCA2 (0.0% vs 7.1%) and FANCA (0.0% vs 7.1%), with all p < 0.05. In GCCs, MSI-H/dMMR, TML-high (> 17mut/Mb) and PD-L1 expression were seen in 0.0%, 0.0% and 2.0%, respectively. No significant difference was observed in these immune-related markers’ frequency, compared to adenocarcinomas and NETs. Conclusions: GCCs had considerably distinct mutational profile compared to appendiceal adenocarcinomas and NETs. Understanding these molecular characteristics may be critical for a development of effective treatment strategy in GCC.
Variation in genetic polymorphisms and gene expression of HLA-E to predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI/cetuximab: Data from the phase III FIRE-3 trial.
Authors: Naseem Madiha , Cao Shu , Stintzing Sebastian , Battaglin Francesca , Tokunaga Ryuma , Puccini Alberto , Berger Martin D. , Soni Shivani , Zhang Wu , Barzi Afsaneh , Heinemann Volker , Lenz Heinz-Josef
Published: February 2020

245

Background: HLA-E is an MHC Class I antigen which inhibits NK cell activity by binding to CD94 receptor. Overexpression of HLA-E on crc cells is associated with poor prognostic outcomes and has recently been associated with microsatellite instability. As cet enhances NK cell activity which is dependent on HLAE, this study aims to assess whether differences in HLAE gene expression and polymorphisms lead to different outcomes. Methods: Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. PFS and OS outcomes were investigated for an HLAE genetic polymorphism, rs1264457, where G > A leads to glycine > arginine, where glycine has stronger affinity for NK cell receptor. Results: FOLFIRI/cet and FOLFIRI/bev cohort characteristics: median FU (29.1/26.7mo); PFS (12.8/11.5mo); OS (49.8/31.4mo); RAS WT (64%/62%) and RAS mut (15%/16%). Overexpression of HLAE was associated with poor OS (log2 > 13, 30 vs 34 mo) in cet arm (P < .05). No significant association was observed with PFS. Multivariable analysis showed that HLAErs1264457 carriers with any A allele (n = 65) had better PFS than pts with G/G genotype (n = 18) in RAS WT pts treated with FOLFIRI/cet (12.9 vs 12.3 mo; HR = 2.36; 95%CI = 1.14-4.88; p = 0.021). A non-significant trend of improved OS was seen among carriers of A allele than G/G genotype (56.2 vs 40 mo). These effects were not observed in Ras mut pts. No significance was observed in FOLFIRI/bev overall or FOLFIRI/bev RAS WT pts. Conclusions: Overexpression of HLAE leads to poor OS among pts treated with FOLFIRI/cet. Poor PFS was seen among pts treated with cet who are RAS wt carrying polymorphisms allowing for increased binding to NK cell receptor, which in turn enhances HLAE inhibitory function of NK cell lysis. Addition of mAb against HLAE, which have been shown to restore NK cell mediated cell lysis, needs investigation in this pt population.
The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: A multicenter retrospective analysis.
Authors: Lakkunarajah Suganija , Breadner Daniel Adam , Zhang Hanbo , Spratlin Jennifer L. , Mulder Karen E. , Gill Sharlene , Sha Aaron , Abadi Shirin , Kong Shiying , Cheung Winson Y. , Loree Jonathan M. , Welch Stephen
Published: February 2020

248

Background: Colorectal cancer remains the second leading cause of cancer death in developed countries. The benefit of using fluorouracil-based chemotherapy with oxaliplatin, such as FOLFOX (fluorouracil (5-FU), leucovorin, oxaliplatin) and CAPOX (capecitabine and oxaliplatin) is well established. The optimal dose intensity (DI) under which overall survival (OS) is inferior is not established. Methods: Patients (pts) treated with adjuvant chemotherapy between 2006 and 2011 for resected stage III colon cancer (CC) from four academic cancer centres in Canada were retrospectively analysed. Patients that received CAPOX and FOLFOX were examined for the relationship between DI and OS. Results: A total of 625 pts with resected high risk stage II or stage III CC that received adjuvant chemotherapy were analysed. The median age was 63. Pts with T4 and N2 disease comprised 35.4% and 29.9% of pts, respectively. Median follow-up was 3.2 years. There was available survival data for 319 pts. The median oxaliplatin DI was 70%. The frequency of pts reaching an oxaliplatin DI of > 80% was 43%, while 76.6% of pts had a dose intensity of > 80% for their FU component. An oxaliplatin DI of > 80% was associated with a significant improvement in survival, HR = 0.42 (95%CI 0.21 – 0.81, p < 0.01). Achieving a DI of > 80% for capecitabine or 5-FU did not improve OS. Other factors associated with inferior OS included T4 (HR = 3.5, p = 0.03) and N2 (HR = 5.27, p = 0.0005) subgroups. The improvement in OS was not significant when restricting the analysis to pts with non-T4 and non-N2 disease (n = 144), HR = 0.16 (0.02 – 1.26; p = 0.08). Conclusions: Oxaliplatin DI of > 80% is associated with improved OS in patients receiving chemotherapy for high risk stage II and stage III CC.
An investigation of the relationship between tumor location and survival following colon cancer resection.
Authors: Knight Katrina , Horgan Paul G. , McMillan Donald C. , Park James Hugh , Roxburgh Campbell SD
Published: February 2020

255

Background: Both tumour location and systemic inflammation (SI) have been related to survival in patients undergoing curative surgery for colon cancer. Recently, right colon cancer (RCC) has been associated with pre-existing cardiovascular disease (CVD). Comorbidity scores such as the Lee Cardiac Risk Index (LCRI) capture symptomatic disease only. Imaging-based assessment of vascular calcification can be used to identify subclinical CVD. We explored the relationship between tumour location, systemic inflammation, cardiac comorbidity and survival in patients undergoing CC resection. Methods: Patients were identified from a prospective cancer database. Clinicopathological characteristics and survival data were abstracted. Aortic calcification (AC) was quantified visually on staging CT images. SI was measured using the modified Glasgow Prognostic Score (mGPS). Results: Of 418 patients, most were female (221, 53%), over 65 (282, 67%), ASA grade II or less (66%) with RCC (230, 55%) and TNM II-III disease (320, 77%). Compared with LCC, RCC was associated with increasing age (59% vs 41%, p = 0.039), greater AC (61% vs 39%, p = 0.013) but not SI (61% vs 39%, p = 0.139). There were no significant differences between LCC with respect to ASA, smoking status or LCRI. Univariate analysis revealed TNM stage (HR 3.55 (95%CI 1.51 - 8.39) p = 0.004) and degree of AC (HR 1.77 (1.04 - 3.00) p = 0.034) were associated with cancer-specific survival (CSS) in RCC while in LCC, only TNM stage was related to CSS (HR 2.30 (0.99 - 5.30) p = 0.05). Multivariate analysis in patients with RCC confirmed AC to be a stage-independent predictor of CSS (HR 1.94 (1.15 – 3.67) p = 0.013). Conclusions: AC is associated with RCC and confers an inferior prognosis, independent of stage. Investigation of underlying mechanisms is required, but impaired perfusion may limit mucosal function, potentiating the effect of carcinogens in the right colon.
Modified Controlling Nutritional Status score: A refined prognostic indicator depending on the stage of gastric cancer.
Authors: Jeon Chul Hyo , Lee Han Hong
Published: February 2020

294

Background: The role of controlling nutritional status (CONUT) score in predicting cancer survival remains uncertain. This study aimed to investigate the predictive value of the CONUT score and to develop a more appropriate scoring system beyond CONUT for gastric cancer (GC). Methods: We retrospectively reviewed 1307 patients who underwent curative gastrectomy between 2009 and 2015. The CONUT and three modified scores with modified lipid components (L-CONUT: albumin/total lymphocyte count [TLC]/low density lipoprotein, H-CONUT: albumin/TLC/high density lipoprotein, and T-CONUT: albumin/TLC/triglyceride) were calculated. The predictive value of each scoring system on long-term survival was assessed. Results: The values of the four nutritional scores were categorized into three groups (low, medium, and high). The CONUT (P < 0.001), L-CONUT (P < 0.001), H-CONUT (P < 0.001), and T-CONUT (P < 0.001) scores showed significant differences in overall survival in the three groups. Survival analysis according to the pathological stage showed that advanced age, Eastern Cooperative Oncology Group performance status, male sex, and high H-CONUT score (HR, 3.93; 95% CI, 1.81–8.55; P = 0.001) were independent worse prognostic factors for overall survival in the stage I group. In the stage II group, CONUT score (HR, 5.077; 95% CI, 1.65–15.65; P = 0.005) was significantly associated with poor prognosis. In the stage III group, no scoring system showed significant results. Conclusions: In advanced GC (beyond stage II), the prognostic impact of the nutritional scoring system was uncertain. However, the H-CONUT score is a promising indicator of prognosis in stage I GC, and the CONUT score is useful for predicting long-term survival in stage II GC.
Real-world outcomes of first-line U.S. patients with unresectable advanced or metastatic gastroesophageal adenocarcinoma by primary tumor location.
Authors: Shankaran Veena , Xiao Hong , Bertwistle David , Zhang Ying , Abraham Pranav , Chau Ian
Published: February 2020

304

Background: Gastric cancer clinical trials are inconsistent in their inclusion of esophageal adenocarcinoma (EAC). Thus it is uncertain if outcomes are similar among subgroups of gastroesophageal adenocarcinoma. The aim of this study was to compare baseline characteristics and clinical outcomes of US patients with EAC versus Gastroesophageal Junction Cancer (GEJC) and Gastric Cancer (GC) treated in real world clinical settings. Methods: Adult patients with unresectable, advanced or metastatic GC, GEJC, or EAC diagnosed between January 2011 and November 2018 were identified from the Flatiron Health database. Patients with a positive HER2 test, or who received trastuzumab, were excluded. Overall survival (OS) was defined as time from first-line (1L) treatment initiation to death or loss of follow-up. Survival analyses were conducted using Kaplan-Meier methods with log-rank test and Cox models. Results: A total of 3052 patients (969 EAC and 2083 GEJC/GC) met eligibility criteria. Out of all EAC patients, 90% were males and 76% were white. Within the GEJC/GC patients, 67% were males and 57% were white. Median age was 66 years for both cohorts while proportion with ECOG PS of 0 or 1 was 78% for EAC and 84% for GEJC/GC among patients with ECOG scores. The proportion of patients receiving 1L treatment was comparable (78% for EAC, 76% for GEJC/GC) across groups with FOLFOX being the most frequent treatment (25% for EAC and 29% for GEJC/GC). There was no significant difference in OS between the two groups, with median OS of 9.1 and 9.6 months for EAC and GEJC/GC, respectively (HR 0.957, 95% CI: 0.863 - 1.062, p = 0.41). Conclusions: In this US real-world analysis, OS did not differ significantly between patients with EAC and patients with GEJC/GC who received 1L treatment, suggesting that these two populations may have comparable survival benefit from systemic therapy.
Change in neutrophial-to-lymphocyte ratio (NLR) in response to immune checkpoint inhibitor for advanced gastric cancer.
Authors: Chen Yang , Peng Zhi , Gong Jifang , QI Changsong , Zhang Xiaotian , Li Jian , Shen Lin
Published: February 2020

306

Background: We intended to evaluate the utility of neutrophil-to-lymphocyte (NLR) in advanced gastric cancer patients treated with immune checkpoint inhibitor (ICI). Methods: We examined NLR at baseline and 6 (±2) weeks later in 139 patients between August 2015 and April 2019. Landmark analysis at 6 weeks was conducted to explore the prognostic value of NLR change on progress-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Cox and logistic regression models were adjusted for tumor differention, Lauren classification, line of therapy, type of anti-PD-1/PD-L1 therapy, and baseline NLR. Results: Median duration on therapy was 6 cycles. Median NLR was 3.33 (IQR: 2.26-4.84) at baseline and 2.93 (IQR: 1.67-4.83) at week 6. Patients with a higher baseline NLR showed a trend toward lower DCR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was significantly associated with inferior PFS [hazard ratios (HRs) 1.03, 95% confidence interval (CI): 1.00-1.06 ] and inferior OS (HR 1.08, 95%CI: 1.03-1.12). Relative NLR decrease by ≥ 25% from baseline to 6 weeks after ICI therapy was an independent prognostic factor for ORR (OR 8.11,95% CI:2.40-27.4), DCR (OR 20.03, 95% CI: 3.32-121), PFS (HR 0.37, 95% CI: 0.20-0.68), and OS (HR 0.26, 95% CI: 0.10-0.65). Conclusions: Early decline of NLR (and NLR at 6 weeks) were associated with improved clinical outcomes in advanced gastric cancer patients treated with ICI.

[Table: see text]
Construction and validation of a simple-to-use nomogram incorporating clinicopathological parameters into the TNM staging system to predict prognosis for stage II colorectal cancer.
Authors: Mo Shaobo , Li Yaqi , Peng Junjie , Cai SanJun
Published: February 2020

31

Background: Survival outcomes are significant different in stage II colorectal cancer (CRC) patients with diverse clinicopathological features. Objective of this study is to establish a credible prognostic nomogram incorporating easily obtained parameters for stage II CRC patients. Methods: A total of 1708 stage II CRC patients at Fudan University Shanghai Cancer Center (FUSCC) during 2008 to 2013 were retrospectively analyzed in this study. Cases were randomly separated into training set (n = 1084) and validation set (n = 624). Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors which were subsequently incorporated into a nomogram. The performance of the nomogram was evaluated by C-index and ROC curve to calculate the area under the curve (AUC). The clinical utility of the nomogram was evaluated using decision curve analysis (DCA). Results: In univariate and multivariate analyses, eight parameters were correlated with disease free survival (DFS), which were subsequently selected to draw prognostic nomogram based on DFS. For DFS predictions, the predicted concordance index (C-index) of the nomogram was 0.842 (95% confidence interval (CI), 0.710-0.980), and 0.701 (95% CI, 0.610-0.770) for training and validation set, respectively. The AUC values of ROC predicted 1, 3 and 5-year survival of nomogram in the training and validation groups were 0.869, 0.858, 0.777 and 0.673, 0.714, 0.706, respectively. The recurrence probability calibration curve showed good consistency between actual observations and nomogram-based predictions. DCA showed better clinical application value for the nomogram compared with TNM staging system. Conclusions: A novel nomogram based on a large population study was established and validated, which is a simple-to-use tool for physicians to facilitate the postoperative personalized prognostic evaluation and determine therapeutic strategies for stage II CRC patients.
Impact of palliative care in patients with metastatic esophageal cancer declining chemotherapy.
Authors: Manguso Nicholas , Kim Sungjin , Guan Michelle , Placencio-Hickok Veronica , Kim Haesoo , Liu Jar-Yee , Hendifar Andrew Eugene , Klempner Samuel J. , Burch Miguel , Gangi Alexandra , Chao Joseph , Kamrava Mitchell , Atkins Katelyn Mae , Gong Jun
Published: February 2020

315

Background: Palliative care has been associated with improved overall survival (OS), but limited data exist in metastatic esophageal cancer (mEC). We investigated the impact of palliative care in patients with mEC who declined chemotherapy (CTX). Methods: The National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined CTX and had known palliative care status (surgery, radiotherapy [RT], pain management, or any combination of) were included. Cases with unknown CTX, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Univariable and multivariable Cox regressions were performed. Results: Among 140,234 EC cases, we identified 1,493 patients who declined CTX and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. Most (72.7%) did not receive palliative care. Median OS was 2.53 months (mos), with no statistically significant difference in median OS between those receiving palliative care (2.83 mos, 95% confidence interval [CI] 2.53-3.12) vs. no palliative care (2.37 mos, 2.2-2.56; p = 0.288). On univariable analysis, treatment at an academic center (hazard ratio [HR] 0.90, 0.80-1.00) and CCI ≥2 (HR 1.20, 1.00-1.42) were predictive of OS (p < 0.05). On multivariable analysis, male sex (HR 1.23, 1.08-1.40), South geographic region (HR 1.23, 1.04-1.46), CCI of 1 (HR 1.17, 1.03-1.32), higher grade (HR 1.21, 1.07-1.38), and higher T stage (HR 1.39, 1.12-1.73) were associated with poor OS (p < 0.05). Conclusions: Palliative care conferred a numerically higher, but not statistically significant difference in OS among patients with mEC declining CTX. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative care in mEC and future studies are warranted.
Should adenosquamous esophageal carcinoma be treated like adenocarcinoma or squamous cell carcinoma?
Authors: Gamboa Adriana C. , Meyer Benjamin I , Switchenko Jeffrey M. , Rupji Manali , Lee Rachel M. , Turgeon Michael K. , Russell Maria C. , Cardona Kenneth , Kooby David A. , Maithel Shishir K. , Shah Mihir M.
Published: February 2020

323

Background: Adenocarcinoma and squamous cell carcinoma of the esophagus have distinct outcomes, treatment strategies, and response profiles to therapy. Adenosquamous carcinoma (ASC) is thought to behave more aggressively than each of its counterparts. Our aim was to determine if ASC is best managed as adenocarcinoma or squamous cell carcinoma. Methods: The National Cancer Database (2004-15) was queried for patients with non-metastatic, esophageal ASC. Analysis was stratified by clinical node negative (cN0) or node positive (cN1-3) according to AJCC 8th edition. Treatment types were categorized into chemoradiation alone, surgery alone, or preoperative chemoradiation followed by surgery. Primary outcome was overall survival (OS). Results: Among 352 pts, median age was 67 yrs, 80% were male (n = 281). Median f/u was 46 mos. 43% were cN0 (n = 151), 57% were cN1-3 (n = 201). 55% had chemoradiation alone (n = 194), 15% had surgery alone (n = 53) and 30% had preoperative chemoradiation (n = 105). Of pts who had preoperative chemoradiation, 20% had pathologic complete response (n = 17). For either cN0 or cN1-3, Charlson-Deyo Comorbidity Index did not differ among the treatment groups (all p > 0.05). On KM analysis for cN0 disease, treatment with surgery alone had a comparable 5-yr OS to preoperative chemoradiation (47 vs 34% p = 0.5) and each had improved 5-yr OS compared to chemoradiation alone (30%; p = 0.02; p = 0.06). On UV analysis for patients with cN0 disease, clinical T-stage was not associated with 5-yr OS. For patients with cN1-3 disease, however, preoperative chemoradiation was associated with improved 5-yr OS when compared to chemoradiation alone or surgery alone (27 vs 19 vs 0% p < 0.001). This persisted even when accounting for age and clinical T-stage (HR 0.45 p < 0.001). Conclusions: Esophageal adenosquamous carcinoma behaves more like adenocarcinoma both in response to chemoradiation and survival outcomes based on the treatment modality. The complete response rate to chemoradiation is only 20% unlike what has been shown for squamous cell carcinoma, where chemoradiation is an acceptable definitive therapy. Esophageal adenosquamous carcinoma should be managed like adenocarcinoma and not squamous cell carcinoma.
Age-related outcomes in patients with esophageal cancer: A propensity score matched analysis.
Authors: Blinn Paige , Maramara Taylor , Shridhar Ravi , Huston Jamie , Meredith Kenneth Lee
Published: February 2020

326

Background: Esophageal cancer is increasing in incidence worldwide. It is estimated that there will be 17,650 new cases of esophageal cancer diagnosed, with 16,080 dying from the disease in the United States in 2019. There has been an increase in younger patients diagnosed with esophageal cancer. We sought to evaluate the outcomes in younger patients diagnosed with esophageal cancer. Methods: Utilizing the National Cancer Database we identified patients with esophageal cancer. We then stratified by age < 50, 51-60, 61-70, and > 70 years. Baseline univariate comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis tests as appropriate. Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. All statistical tests were two-sided and p < 0.05 was significant. Propensity score matched analysis was performed and only exact matches were allowed. Results: We identified 20,324 patients ( < 50, 2157), (51-60, 5387), (61-70, 7853), and ( > 70, 4927). T-stages and N stages were higher in the younger age groups p < 0.001 and p < 0.001 respectively. Median lymph nodes positive were highest in the < 50 group (2.2 vs 1.8 vs 1.6 vs 1.7) p < 0.001. Additionally, tumor size was largest in this age cohort (3.7 vs 3.5 vs 3.5 vs 3.2) p = 0.002. Neoadjuvant therapy was administered in 69.4% of patients in the < 50, 68.5% (51-60), 65.5% (61-70), and 49.5% > 70 patients, p < 0.001. The < 50 age group was however more likely to receive adjuvant therapy (22.9% vs 20.5% vs 16.9% vs 13.4%) p < 0.001. Median and overall survival was 49.8 mo and 45% ( < 50), 45.4mo and 43% (51-60), 45.4mo and 43% (61-70), and 35.8mo and 39% > 70, p < 0.001. After propensity score matching, multivariate analysis found that age < 50, male gender, GEJ tumor location, grade, Charleson Deyo score, T-stage N stage, margin, facility volume, neoadjuvant and adjuvant therapy were predictors of survival. Conclusions: Although younger patients present with larger tumors, higher T-stages, and N stages, they are more likely to receive neoadjuvant and adjuvant therapies. It is these therapies which are most likely contributing to improved survival compared to their older counterparts.
Self-reported patient experience and quality of care among elderly patients with colon cancer.
Authors: Snyder Rebecca A , Wardrop Rebecca , Mclain Alexander , Parikh Alexander A. , Cass Anna
Published: February 2020

33

Background: Although studies have identified demographic and clinical factors associated with quality colorectal cancer care, the association between patient-reported experience of care and quality of care is unknown. Our primary aim was to assess the relationship between patient-reported experience of care and receipt of guideline-concordant colon cancer (CC) treatment. Methods: Fee-For-Service Medicare beneficiaries with resected stage I-III CC (2003-2013) were identified in the linked SEER registry and Consumer Assessment of Healthcare Providers and Systems patient experience survey (SEER-CAHPS) dataset. Patient-reported ratings were compared based on receipt of care consistent with recommended treatment guidelines [resection of ≥ 12 lymph nodes (LN) (stage I-III) and receipt of adjuvant chemotherapy (stage III)]. Linear regression was performed to compare mean patient experience scores by receipt of guideline concordant care, adjusting for patient and hospital factors. Results: 1010 patients with stage I-III CC were identified (mean age 76.7, SE 6.9). Of these, 58.4% of stage I (n = 192/329) and 73.4% of stage II (n = 298/406) patients underwent resection of ≥ 12 LN. Among stage III patients, 76.0% (n = 209/275) underwent resection of ≥ 12 LN and 52.4% (n = 144/275) received adjuvant chemotherapy. By multivariable analysis, patient-reported ratings of health care quality, personal and specialty physicians, customer service, physician communication, getting needed care, and getting care quickly were similar among patients who received guideline-concordant treatment compared to those who did not. However, mean ratings of overall health care quality [91.3 (SE 2.0) vs. 82.4 (SE 1.7), p = 0.0004] and getting needed care [92.8 (SE 2.4) vs. 86.8 (SE 2.0), p = 0.047] were higher among stage III patients who received guideline concordant care compared to those who did not. Conclusions: Patient-reported ratings of health care quality and ability to get needed care are associated with guideline concordant cancer care among elderly patients with stage III CC. Further investigation is needed to determine if patient-reported experience correlates with other clinical measures of quality of colorectal cancer care.
Relationship of periodic methylation patterns in the gastric mucosa and periodic stem cell replacement.
Authors: Oh Jung-Hwan , Hong Seung Jin
Published: February 2020

333

Background: The role of Helicobacter pylori-associated methylation in the inactivation of tumour-suppressor genes has been previously investigated. However, the relationship between H. pylori-associated methylation and gene inactivation is unclear. Stem cells are replaced periodically every 8 years in the gastrointestinal mucosa. Hence, age-related methylation in the gastric mucosa was studied to understand the stabilization of new stem cell phenotypes. Methods: Endoscopic biopsy specimens of the antral mucosa were obtained from 148 H. pylori-negative and 124 H. pylori-positive subjects. The methylation-variable sites of 4 housekeeping genes ( CDH1, ARRDC4, MMP2, and CDKN2A) and 2 stomach-specific genes ( TFF2 and TFF3) were examined using radioisotope-labelled methylation-specific polymerase chain reaction. Age-related methylation was evaluated at an interval of 2 years. Results: The 4 housekeeping genes were more frequently methylated in H. pylori-positive subjects than in H. pylori-negative subjects. Periodic changes in the housekeeping gene methylation were obscure. TFF2, which is highly expressed in the stomach, was periodically methylated to attain peaks at the age of 40–41, 48–49, 56–57, and 64–65 years in both H. pylori-negative and -positive subjects. TFF3, which is weakly expressed in the stomach, was methylated at the age of 46–47, 54–55, 66–67, and 72–73 years in H. pylori-negative subjects. The methylation of stomach-specific genes periodically fluctuated approximately at 8-year intervals in the gastric mucosa. Conclusions: Periodic methylation changes in the gastric mucosa may be used to estimate the replacement of new stem cells.
Early implementation of a postoperative nutrition support pathway for patients undergoing esophagectomy.
Authors: Carr Rebecca , Stella Christina , Glauner Diana , Kenny Erin , Russo Lianne , Garrity Meghan , Bott Matthew , Isbell James M. , Park Bernard , Sihag Smita , Jones David Randolph , Molena Daniela
Published: February 2020

344

Background: A significant risk of malnutrition burdens patients with esophageal cancer undergoing esophagectomy as tumor-related dysphagia and side effects of chemoradiation impair the patients’ ability to maintain adequate nutrition. Moreover, patients lose 10% or more of their preoperative body weight in the first year following surgery. Implementation of nutrition protocols may reduce postoperative weight loss and enhance recovery in these patients. Methods: This is a retrospective study examining a postoperative nutrition protocol initiated in August of 2017. Patients with esophagogastric cancer who underwent Ivor Lewis esophagectomy from July 2016 to July 2019 were identified from a prospectively collected database. Patients that underwent surgery after implementation of this protocol were compared to those operated prior to it. Results: Patients’ and tumor characteristics were similar between the two groups. The protocol included preoperative evaluation by a dietician, postoperative feeding pathway, and regular post-discharge follow up by phone with a dietician. In the post protocol group, we observed a reduction in time to initiation of diet and decreased weight loss at patient follow up (Table). There was no difference in incidence of postoperative complication, length of stay, 30-day readmission, or in hospital mortality. Conclusions: In conclusion, postoperative nutrition support programs may help reduce postoperative weight loss and may have a role in the prevention of malnutrition in these patients. Initial results suggest that more aggressive nutritional supplement program is feasible and may lead to improved postoperative outcomes in patients undergoing esophagectomy.

[Table: see text]