bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic impact of SOX9 in stage II colon cancer: Results from a large nationwide cohort.
Authors: Hansen Torben , Trabjerg Natacha D. , Kjaer-Frifeldt Sanne , Eriksen Ann Christina , Lindebjerg Jan , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller , Sørensen Flemming Brandt
Published: February 2020

183

Background: Up-regulation of the transcription factor SOX9 has been described in colon cancer, and it has been argued that differences in the expression levels dictates cell proliferation. The aim of the present study was to analyze the prognostic impact of SOX9 in patients with stage II colon cancer. Methods: Individual patient data and formalin fixed paraffin embedded tumor tissue were collected from a large unbiased, population-based cohort, representing all patients operated for stage II colon cancer in Denmark in 2002 and 2003. The SOX9 expression was evaluated by immunohistochemistry on whole tumor sections. Patients were classified into three groups dependent on the SOX9 expression gradient in the tumor: luminal, peripheral, and uniform for comparison with the clinical data. The endpoint was disease free survival (DFS). Results: A total of 1,153 patients were included. We detected an expression-dependent relationship between SOX9 and prognosis. Patients with tumors exhibiting a luminal expression pattern (N = 267, increasing SOX9 expression towards the luminal compartment of the tumor) were characterized by a significantly better DFS compared to the uniform (N = 846) and peripheral (N = 40) patterns, p = 0.0070. The five-year DFS rates were 74%, 67%, and 56%, respectively. Multiple Cox regression analysis, confirmed an independent prognostic advantage of the luminal SOX9 expression pattern, as compared to the uniform pattern, hazard ratio (HR) 0.7211 (95% confidence interval (CI) 0.5561-0.9351), p = 0.0137, whereas the possible disadvantage of the periphery pattern could not be verified, p = 0.1405. Conclusions: The present results support a prognostic impact of SOX9 in stage II colon cancer. The consequence of an altered SOX9 expression seems to differ between intra-tumoral compartments, and we propose that a gradient-dependent evaluation should be applied to provide the most clinically relevant information about this transcription factor.
Genomic alterations in colitis-associated cancers in comparison to those found in sporadic colorectal cancer and present in precancerous dysplasia.
Authors: Chatila Walid Khaled , Walch Henry S. , Benhamida Jamal , Hechtman Jaclyn Frances , Barriga Francisco M. , Kundra Ritika , Ismalgeci Dorina , Miller Vincent A. , Ganesh Karuna , Faleck David , Schultz Nikolaus , Tang Laura H. , Kelsen David Paul , Yaeger Rona
Published: February 2020

191

Background: Patients with inflammatory bowel disease (IBD) [Crohn’s disease (CD) and ulcerative colitis (UC)] are at increased risk for small bowel or colorectal cancers (Colitis Associated Cancers, CAC). Currently CAC is treated the same as sporadic colorectal cancer (CRC) with significantly shorter overall survival for advanced CAC compared to matched patients with CRC. In a pilot series, we found that tumors developing in IBD have distinct genomic alterations (GA) with potential implications for early detection and treatment. We now extend this analysis and characterize the relationship of GA in synchronous dysplasia and cancer. Methods: 104 CAC (54 UC-associated and 50 CD-associated) were sequenced with targeted-exome sequencing of > 300 cancer-related genes. GA in CAC were compared to those reported for sporadic CRC. Whole exome sequencing was performed on paired mucosa, dysplasia and carcinoma samples obtained from 15 colectomy specimens; in these cases, expert pathology review confirmed normal appearing mucosa intervening between areas of dysplasia and CAC. Results: TP53 mutations (89%), MYC amplifications (24%), and cell cycle copy number alterations (20%) were significantly enriched in CAC compared to sporadic CRC, while APC alterations (21%) were significantly less common in CAC compared to sporadic CRC. Distinct GA in CAC consisted of IDH1 R132 mutations (7%) and FGFR pathway alterations (7%). While IDH1 R132 mutations and PI3K pathway alterations were more common in CD-associated CAC, MAPK ( BRAF/ MEK1) alterations were more common in UC-associated CAC. GA in CACs did not significantly vary by duration of preceding IBD. GA were often shared in dysplasia and carcinoma, despite normal-appearing intervening mucosa. GA involving TP53, APC, KRAS, and IDH1 mutations were identified in dysplasia and shared between CAC and dysplasia. Conclusions: CAC exhibit distinct GA compared to sporadic CRC with near universal TP53 mutation, increased copy number alterations involving transcription factors and cell cycle genes, and unique drivers. A field effect can be seen for GA between distant dysplasia and carcinoma, but many GA remain private to CAC.
Multimodality management of brain metastasis from colorectal cancer.
Authors: Jin Zhaohui , Breen William , Jin Rui , Brown Paul D. , Hubbard Joleen Marie
Published: February 2020

204

Background: More than 50% of colorectal cancer (CRC) patients will develop metastatic disease. Brain metastasis (BM) from colorectal cancer is uncommon (0.6-1.36%). This study aims to investigate the patient characteristics, treatment modalities and prognostic factors in this rare population. Methods: 104 patients with brain metastasis disease from CRC were identified from over 30,000 colorectal cancer patients at the Mayo Clinic Rochester between 1/1994 and 6/2019. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analysis utilized the Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: Among the 104 patients, 62 were male (59.6%) and 42 were female (40.4%). Median age at CRC diagnosis was 58.4 and at BM diagnosis was 61. Thirty-three patients had right-sided colon cancers, 27 patients had left-sided colon cancers and 39 patients had rectal cancer. Median time from CRC diagnosis to BM was 30.7 months. The majority of patients (58.7%) presented with a solitary brain lesion. Eighty-six patients (82.7%) had extracranial metastatic disease at BM diagnosis. Median survival was 7.0 months (95% CI 2.6-16.9) from BM diagnosis. Age <70, solitary BM, surgery, radiation, and chemotherapy were associated with statistically significant improved survival on univariate and multivariate analysis. Multi-modality treatment including surgical brain lesion resection, postoperative stereotactic radiation (SRS) with/without whole brain radiation (WBRT), and chemotherapy significantly improved median overall survival (Table). Conclusions: Although BM from CRC carries poor prognosis, multi-modality treatment (surgery, radiation and systemic chemotherapy) for patients with limited BM improves clinical outcome.

[Table: see text]
Exploratory longitudinal analysis of cfDNA to reveal potential biomarkers of CRC progression and treatment response.
Authors: Vallania Francesco , Assayag Karen , Warsinske Hayley , Ulz Peter , St John John , Brachmann Carrie , Patterson Scott D. , Thai Dung , Bhargava Pankaj , Shah Manish A. , Lenz Heinz-Josef , Bendell Johanna C. , Rubio Claudia
Published: February 2020

207

Background: Blood-based tests can predict drug response and disease progression. Many tests rely on detecting tumor DNA, which represents only a fraction of all cell-free DNA (cfDNA). Here, we used a novel methodology to infer gene activation from cfDNA. This unique platform offers the ability to identify potential non-tumor derived biomarkers that may be associated with clinical outcomes in colorectal cancer (CRC). Methods: Longitudinal plasma samples from metastatic CRC patients enrolled in NCT01803282 (andecaliximab/chemotherapy/bevacizumab; 92 samples from 12 patients) were evaluated. Patients were classified as progressors (SD+PD) or responders (CR+PR) based on best objective response. Gene activation was inferred from cfDNA fragment length and counts around transcription start sites using whole-genome sequencing. Transcription factor activity was estimated by measuring binding site accessibility across the genome. Tumor fraction (TF) was estimated using ichorCNA. Results: Gene activation profiles inferred from cfDNA across the entire genome identified several genes differentially expressed in progressors or responders. Specifically, all patients with elevated KIR2DL1, an inhibitory NK cell receptor, progressed (p = 6.35e-14). Additionally, BMPR1A activation decreased in responders (p = 0.002) while the DNA- binding activity of SMAD1, which functions directly downstream of BMPR1A in the BMP2 pathway, increased in responders post-therapy (p = 0.03). These 3 genes (i.e., KIR2DL1, BMPR1A and SMAD1) are related to NK cell maturation, suggesting an immunological mechanism. Notably, pre-therapy TF did not predict response. Conclusions: In this pilot study, we demonstrated the ability of a unique cfDNA platform to interrogate multiple features to reveal genes associated with drug response and their underlying mechanism. We identified that KIR2DL1 is associated with progression, and BMPR1A and SMAD1 are associated with response. This work highlights the potential of cfDNA to provide biological insights beyond TF and that identification of non-tumor-derived signals may benefit biomarker discovery and drug target identification.
Local immune response in colon cancer: Indicative of good or poor prognosis?
Authors: Alexander Peter G , In Jitwadee AF , Roseweir Antonia K. , Powell Arfon GMT , Edwards Joanne , Roxburgh Campbell SD , Horgan Paul G. , McMillan Donald C. , Park James Hugh
Published: February 2020

213

Background: The tumour microenvironment is an important determinant of survival in patients with colon cancer. Although the generalised inflammatory infiltrate as assessed by Klintrup-Mäkinen (KM) grade is a stage-independent prognostic marker, immunohistochemical staining for specific immune cell populations, such as T-cells, may have greater prognostic value. The present study examines the clinical utility of combined assessment of KM grade in addition to cytotoxic (CD8) and regulatory (FoxP3) T-cells. Methods: KM, CD8 and FoxP3 were assessed retrospectively in a cohort of 520 patients with stage I-III colon cancers. The relationship between KM grade, T-cell density and cancer-specific survival was examined. Results: KM was high in 33% of patients, of which: 16% had high FoxP3, 12% high CD8 and 56% both FoxP3 and CD8, while the remaining 15% were high KM alone. Conversely, 67% had low KM and of these: 47% had high CD8 alone or with FoxP3; 27% were high for FoxP3 alone and 25% had no inflammatory infiltrate. KM in the presence of other T-cells resulted in good outcome (Table), whereas CD8 with low KM with or without FoxP3 resulted in intermediate outcome. FoxP3 alone with low KM resulted in poor outcome. Similarly, KM alone without T-cells resulted in poor outcome. When no inflammatory cells were present, outcomes were comparable to KM or FoxP3 alone. Conclusions: A co-ordinated immune response results in good outcome and this can be assessed using a combination of a simple H&E based method (KM) in addition to T-cell markers. Where KM is low, despite the presence of cytotoxic T-cells, survival outcome is worse. Conversely, high KM in the absence of T-cells, or FoxP3 alone, are associated with poor outcome, comparable to no inflammatory response.

[Table: see text]
Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers.
Authors: Andre Thierry , Berton Dominique , De Braud Filippo G. , Curigliano Giuseppe , Guo Wei , Danaee Hadi , Lu Sharon , Im Ellie , Starling Naureen
Published: February 2020

218

Background: Dostarlimab (TSR-042) is an investigational humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking the interaction with ligands PD-L1 and PD-L2. The ongoing GARNET trial (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F in the GARNET trial enrolled pts with dMMR or microsatellite instability high (MSI-H) non-endometrial solid tumors, the majority of which were GI in origin. Pts must have progressed following prior systemic therapy for advanced disease, assessed by independent central review (ICR). Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W thereafter. Objective response rate (ORR) and duration of response (DOR) were assessed by ICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and ≥24 weeks of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 109 pts were included in the safety analysis, with 48 dMMR pts in the efficacy analysis. Of the 48 pts, 42 (88%) had GI tumors. Confirmed ORR in dMMR pts was 43.8% (95% CI: 29.5, 58.8), with a complete response rate of 8.3%. ORR was consistent across tumor type (Table). Median DOR was not reached. The probability of maintaining response at 12 months was 85.9%. Treatment-related adverse events (TRAEs) were reported in 55% of pts; 7.3% of pts experienced grade ≥3 TRAEs, including 1 each of adrenal insufficiency, rash, diarrhea, and fatigue. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No treatment-related deaths were reported. Conclusions: Dostarlimab demonstrated robust, durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers, with an acceptable safety profile. Clinical trial information: NCT02715284.

[Table: see text]
Minimally invasive colorectal resection: Association with elevated levels of plasma TIM-3 post surgery and effect on immune tolerance and the growth of residual metastases.
Authors: Shantha Kumara Hmc , Mitra Neil , Niyagama Gamage Dasuni , Yan Xiaohong , Cekic Vesna , Baxter Kathy , Whelan Richard L.
Published: February 2020

219

Background: TIM-3 (T cell immunoglobulin and mucin domain-3) is a type I transmembrane glycoprotein expressed on CD4+ T helper 1 (Th1) and CD8+ T cytotoxic 1 (Tc1) T cells and endothelial cells. TIM-3, after binding to its ligand, Galectin-9, inhibits anti-tumor immune function. Co-expression of TIM-3 and PD-1 together is associated with enhanced dysfunctionality of tumor toxic CD8+ T cells. The combination of TIM-3 blockade with anti-PD-1 /PDL1 intervening therapy may enhance response. Tim-3 over expression has been associated with oncogenic activity in colorectal cancer(CRC). Persistently elevated plasma PDL1 levels after CRC resection have been reported. This study’s purpose was to measure plasma TIM3 levels before and during the first month after minimally invasive colorectal resection (MICR) for CRC. Methods: CRC patients (pts) in an IRB approved data/plasma bank who underwent MICR for whom plasma samples were available were studied. Clinical/pathologic data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41) and processed. TIM3 levels were analyzed in duplicate using ELISA. Wilcoxon paired t-test was used for analysis. Results: A total of 96 CRC pts who had MICR met the study criteria (colon 72%; rectal 28%; mean age 64.8± 13.3). Compared to the mean PreOp plasma TIM3 levels (2619 ± 1410,n = 96;pg/ml ), significantly higher levels (p < 0.001)were noted on (POD)1(2823±1504,n = 95), POD3 (3469±1755,n = 89), POD7-13 (4317±1957,n = 79),POD14-20 (4779±3111,n = 26), POD 21-27(4553± 1846,n = 18) and on POD 28-41 (3621±1859,n = 21). Conclusions: Plasma TIM3 levels were significantly elevated over baseline for 1 month after MICR (% change range, 8-70; peak value weeks 2-4). The acute inflammatory response might account for the early increases but late elevations are more likely associated with wound healing/tissue remodeling. Elevated plasma TIM-3 levels may exhaust tumor infiltrating T-cells which may facilitate the growth of residual tumor. Further investigation is warranted.
Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).
Authors: Sahin Ibrahim Halil , Goyal Subir , Pumpalova Yoanna S , Sonbol Mohamad Bassam , Das Satya , Haraldsdottir Sigurdis , Chen Zhengjia , Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Ahn Daniel H. , Ciombor Kristen Keon , Berlin Jordan , Bekaii-Saab Tanios S. , Draper Amber , Lesinski Gregory B. , El-Rayes Bassel F. , Wu Christina
Published: February 2020

225

Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.
Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.
Authors: Wang Jingyuan , Xiao Yi , Loupakis Fotios , Stintzing Sebastian , Arai Hiroyuki , Battaglin Francesca , Soni Shivani , Zhang Wu , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef
Published: February 2020

232

Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis ( p < .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis ( p < .05) and had a strong trend in multivariable analysis ( p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p < .01) and multi-variable ( p = .08 and p < .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p < .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.
Stage-specific conditional survival among young versus older adults with colorectal cancer in the United States, 2004-2010.
Authors: Sanford Nina Niu , Ahn Chul , Folkert Michael Ryan , Aguilera Todd Anthony , Sher David J.
Published: February 2020

257

Background: Conditional survival (CS) is a relevant prognostic measure for cancer survivors and physicians and may be particularly important for young adult patients with CRC (colorectal cancer), whose incidence is rising. We sought to compare CS among young versus older adults with CRC. Methods: Patients diagnosed with colon or rectal adenocarcinoma between 2004-2010 were identified from the Surveillance, Epidemiology and End Results (SEER) registry. Overall survival (OS) and cancer-specific survival (CSS) were estimated, along with smoothed yearly hazards of death due to CRC, other causes and any cause, stratified by age at diagnosis ( < 50 vs. >50 years). Stage-specific conditional 5-year OS and 5-year CSS given that patients had already survived 1, 2, 3, 4 or 5 years after diagnosis was calculated, also stratified by age. Results: Among 161,859 patients with median follow-up of 54 months, 35,411 (21.9%) were aged < 50 years. Both OS and CSS were superior among younger adult as compared to older adult patients (p < 0.001). For older adults with rectal cancer, hazards of death due to non-cancer causes exceeded that of rectal and colon cancer approximately 6 and 4.5 years after diagnosis, respectively. Among younger adults, hazard of death from cancer remained greater than death from other causes throughout the entire study interval. Patients experienced improved conditional survival over time with greater improvement seen for more advanced stages. However, young adults had less CS improvement over time than older adults. For example, the 5-year overall and CSS for Stage IV colon cancer improved from 7.4% to 52.4%% (OS) and 15.1% to 78.5% (CSS) 0 to 5 years after diagnosis for older adults. In contrast, for younger adults, the 5-year overall and CSS for Stage IV colon cancer improved from 15.6% to 57% (OS) and 19.3% to 68.4% (CSS). Conclusions: Prognosis for CRC improves over time for all patients, although the increase in survival appears to be less for younger than older adults. Up to 10 years after diagnosis, the primary cause of death in younger adults with CRC remains their incident cancer.
An assessment of dose intensity of the TNT approach on outcomes in locally advanced rectal cancer.
Authors: Glode Ashley Elizabeth , Friedrich Tyler , Sandhu Gurprataap Singh , Herter Whitney , McCarter Martin , Gleisner Ana Luiza , Birnbaum Elisa , Ahrendt Steven Arthur , Vogel Jon , Goodman Karyn A. , Schefter Tracey E. , Purcell William T. , Leal Alexis Diane , King Gentry Teng , Davis S. Lindsey , Leong Stephen , Messersmith Wells A. , Lieu Christopher Hanyoung
Published: February 2020

258

Background: Patients with clinical stage II or III locally advanced rectal cancer may be treated with the total neoadjuvant therapy (TNT) approach; chemotherapy with 4 mths of FOLFOX followed by chemoradiation (chemo/XRT) with capecitabine for 5 wks administered before surgery. We hypothesized that full dose intensity is not necessary for treatment benefit. Methods: A retrospective chart review was conducted on patients with newly diagnosed rectal cancer recommended to receive TNT by the multidisciplinary (multiD) colorectal cancer tumor board at the University of Colorado Cancer Center (UCCC). The primary objective was to evaluate dose intensity of TNT and its impact on response assessed by biopsy and/or imaging (MRI). Results: Between January 31, 2016 and January 31, 2019, 80 patients were recommended the TNT approach for cancer management by the multiD team. Of those, 48 completed their neoadjuvant treatment at UCCC and were included in the analysis. The average age was 55 years (range 23-80) and 61% were male. Thirty-one patients had an ECOG of 0 and 17 had an ECOG of 1. Overall responses were 44% complete response (CR, n = 21), 15% near complete response (nCR, n = 7), 35% partial response (PR, n = 17), and 6% no response (NR, n = 3). See Table for responses seen by dose intensity for chemotherapy. Two patients did not receive their full planned XRT course, and 9 patients had their capecitabine doses held/decreased during chemoradiation. Conclusions: This single center retrospective analysis of patients receiving the TNT approach for rectal cancer provides data supporting that achieving full dose intensity is not necessary to achieve treatment benefit.

[Table: see text]
Trastuzumab + fluoropyrimidine maintenance in the frontline setting for non-progressing advanced HER-2 positive gastroesophageal adenocarcinoma.
Authors: Abdelhakeem Ahmed , Rogers Jane Elizabeth , Wang Xuemei , Thomas Irene , Blum-Murphy Mariela A. , Trail Allison , Zhao Meina , Ajani Jaffer A.
Published: February 2020

291

Background: In untreated patients with HER2 positive advanced gastroesophageal adenocarcinoma (AGEA), trastuzumab plus active cytotoxic combination is the standard of care. Our objective was to assess the role of maintenance therapy (trastuzumab + fluoropyrimidine) in the absence of cancer progression. Methods: We retrospectively analyzed HER2 positive AGEA patients (between August 2008 and October 2018) who received first-line trastuzumab-based therapy followed by maintenance therapy. The primary objectives were to assess the time to maintenance failure (TTMF), the first progression-free survival (PFS), and overall survival (OS). Results: Of 70 patients analyzed, 80% were men with a median age of 60.5 years. Primary tumor commonly involved the gastroesophageal junction (65.7%). More than 1 sites of metastases were frequent (88.6%). The best response was complete in 17%, partial in 70%, and stable in 11.4%. The median follow-up time for survivors was 2.1 years (range, 0.6 to 9.2). The median TTMF was 0.7 years (95% CI; 0.4 to 1.1 years). One-year TTMF-free rate was 41%. The median PFS was 1.3 years (95% CI, 0.8-1.6). The median OS was 3.2 years (95% CI, 2.3 years–4.5 years), with a 3-year survival rate of 55% (95% CI, 40%-67%). Conclusions: Our results showed that the OS of this unique population of HER2 positive AGEA patients who qualify for maintenance therapy is excellent. The contribution of the maintenance therapy can be clarified only by prospective investigations.
Propensity-score-matched analysis of a multi-institutional dataset to compare the postoperative complications after distal gastrectomy between Billroth I and Roux-en-Y.
Authors: Nakanishi Koki , Kanda Mitsuro , Ito Seiji , Mochizuki Yoshinari , Teramoto Hitoshi , Ishigure Kiyoshi , Mmurai Toshifumi , Asada Takahiro , Ishiyama Akiharu , Matsushita Hidenobu , Shimizu Dai , Tanaka Chie , Kobayashi Daisuke , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2020

292

Background: Billroth I (B-I) or Roux-en-Y (R-Y) are common reconstruction technique after distal gastrectomy, each with advantages and disadvantages and which is the most successful remains unclear. The aim of the present study was to clarify the difference of postoperative complications between the two techniques. Methods: A multi‐institutional retrospective database comprising clinical information of 3484 patients who received resection of gastric cancer from 2010 to 2014 at nine institutions. Using propensity scores to strictly balance the significant variables, and we compared the overall and severity postoperative complications. We considered Clavien–Dindo grade ≥ II postoperative complications clinically relevant, and grade ≥ III severe postoperative complications. Results: After matching, we enrolled 1086 patients (n=543 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (28% vs 17%, respectively; P<0.0001). The incidence of intra-abdominal abscess (4.2% vs 1.7%, P=0.0120), pancreatic fluid leakage (3.1% vs 1.1%, P=0.0204), bowel obstruction (2.8% vs 0.7%, P=0.0109), and delayed gastric emptying (5.0%s 0.9%, P<0.0001) in the R-Y group was significantly higher vs the B-Ⅰ group, respectively; but not significant difference in leakage (3.2% vs 3.3%, respectively; P=0.8636). The incidence of severe postoperative complications in the R-Y group was also significantly higher vs the B-I group (15% vs 6.3%, respectively; P<0.0001). Multivariable analysis for severe postoperative complications found that R-Y reconstruction was an independent risk factor (odds ratio, 2.20, P=0.0005). Subgroup analysis found that R-Y reconstruction was associated with a greater risk of severe postoperative complications in most subgroups, but not the subgroup of patients receiving intraoperative transfusions. Conclusions: R-Y reconstruction was associated with increasing overall postoperative complications, as well as grade ≥ III severe postoperative complications.
Prognostic value of modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ration (NLR) after curative resection for gastric cancer.
Authors: Shimodaira Yusuke , Koike Sachie , Takahashi Yusuke , Okada Masao , Hayashibara Kaori , Sekino Yasushi , Sakon Masahiro , Takata Manabu , Seki Hitoshi , Munakata Yasuhiro
Published: February 2020

295

Background: Several biomarkers based on serum chemistry have been reported to be associated with the prognosis of several types of cancers. This retrospective study aimed to investigate the prognostic value of preoperative mGPS and NLR after curative resection for gastric cancer. Methods: A total of 295 patients who underwent curative gastrectomy for primary gastric cancer at our institution from January 2013 to December 2017 were enrolled in this study. The mGPS was calculated by CRP and Alb using standard thresholds ( > 0.5 mg/dL for CRP and < 3.5 g/dL for Alb). The NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. The survival curves of patients stratified by each parameter were plotted by the Kaplan-Meier method and compared by log-rank test. Multivariate Cox proportional hazards regression models were used to select parameters independently correlated with prognosis. Results: The median follow-up time was 36.7 months, and 29 patients died during follow-up. The estimated 5-year survival rate was 83.1%. Results from the univariate analyses showed mGPS2 (CRP > 0.5 mg/dL and Alb < 3.5 g/dL) was associated with poor survival while NLR and NLRc was not (P < 0.001, P = 0.506, and P = 0.423, respectively). In the multivariate analyses, the mGPS2 was identified as an independent predictive factor for OS in gastric cancer patients after curative resection (HR: 2.624; 95% CI: 1.058-6.505; P = 0.037). Conclusions: Preoperative mGPS2 was associated with worse survival after curative resection of gastric cancer patients. Based on our study, those with mPGS2 may be warranted to receive additional therapy or nutritional support to acquire better survival.
Chemoradiation-related lymphopenia and its association with survival in patients with anal cancer.
Authors: Lee Grace , Kim Daniel W. , Muralidhar Vinayak , Mitra Devarati , Horick Nora , Eyler Christine Elissa , Hong Theodore S. , Drapek Lorraine C. , Allen Jill N. , Blaszkowsky Lawrence Scott , Giantonio Bruce J. , Parikh Aparna Raj , Ryan David P. , Clark Jeffrey William , Wo Jennifer Yon-Li
Published: February 2020

3

Background: While treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, little data exists for anal cancer. We evaluated TRL and its association with survival in anal cancer patients treated with chemoradiation (CRT). Methods: A retrospective analysis of 140 patients with non-metastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by G4 TRL ( < 0.2k/μl) two months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL. Results: Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC ( > 1k/μl). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death (p = 0.013). On log-rank test, the 5-year OS rate was shorter in the cohort with versus without G4 TRL at two months (32% vs. 86%, p < 0.001). Conclusions: TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS supports the hypothesis that host immunity plays an important role in survival among patients with anal cancer. These results support ongoing efforts of randomized trials underway to evaluate the potential role of immunotherapy in localized anal cancer.
The impact of additional treatment after endoscopic submucosal dissection for esophageal squamous cell carcinoma in real-world clinical practice.
Authors: Sakaguchi Nanako , Yamaguchi Toshifumi , Ishizuka Yasunobu , Kodama Hiroyuki , Miyamoto Takahiro , Terazawa Tetsuji , Kojima Yuichi , Kii Takayuki , Sanomura Makoto , Goto Masahiro , Higuchi Kazuhide
Published: February 2020

305

Background: Endoscopic submucosal dissection (ESD) is the standard therapy for the T1a- EP/LPM esophageal squamous cell carcinoma (ESCC), although it is difficult to diagnose the invasion depth accurately before ESD. The incidence of lymph node metastases in ESCC involving the muscularis mucosae (pT1a-MM) and the submucosa (pT1b-SM) is reported to range from approximately 10% to 30%. For the patients with MM, SM or involving LVI or positive vertical margin after ESD, additional treatment (AT) is recommended to prevent local recurrence. However, the AT is not always performed to the frail or elderly patients. The aim of this study is to investigate the outcome of AT and non-AT (NAT) after ESD for ESCC in the real-world clinical practice. Methods: We retrospectively reviewed the ESCC patients who were pathologically confirmed T1a-MM or T1b-SM (UICC-TNM7th) after ESD at Osaka medical college hospital between 2004 and 2016. Results: Among 224 patients who received ESD, 52 patients were pT1a-MM (n = 36; 69.2%) or pT1b-SM (n = 16; 30.8%).Twelve of 52 patients (23%) received AT and forty patients (77%) received NAT. Six patients (AT group: 2 patients, NAT group: 4 patients) had local lymph node recurrence. Five of them underwent salvage therapy. Median follow up time were 54.3 months (range: 48.4-62.4). The 3-, 5-year RFS rate and the 3-, 5-year OS rate were 83.8%[95%CI: 68.2- 92.6], 73.4% [95%CI: 56.0- 85.7] and 94.7% [95%CI: 81.3- 98.6], 91.7% [95%CI: 77.1- 97.3] in all patients, respectively. The 5-year RFS and OS rate were 77.8%, 90.0% in the AT group and 71.6, 92.2% in the NAT group. Conclusions: Although the AT tended to prevent local recurrence, the OS was comparable with NAT because of salvage therapy. The active surveillance is recommended for T1a-MM or T1b-SM ESCC.
Treatment patterns and long-term clinical outcomes in Chinese patients with nonmetastatic gastric cancer: Results from the non-interventional EVIDENCE registry study.
Authors: Ji Jiafu , Qin Shukui , Wang Xin , Zhou Weiping , Chen Lin , Zheng Zhichao , Su Wuyun , Zhang Helong , Wang Jianhua , Luo Qi , Tang Yong , Shen Lin
Published: February 2020

307

Background: Although gastric cancer (GC) is a leading cause of cancer-related death in China, important questions about optimal management remain unanswered. The EVIDENCE registry study evaluated data from patients with GC in China to assess the pattern of treatments and long-term clinical outcomes. Methods: Five cohorts of patients with different HER2 and metastatic (m) status were evaluated from April 2013 to June 2018 in this prospective, multicenter, non-interventional, real-world study. Data from patients with operable non-mGC are reported: Cohort III (HER2+) and Cohort V (HER2−). Outcome measures included overall survival (OS), event-free survival (EFS), and disease-free survival (DFS). Results: Cohorts III/V included 758 patients (Cohort III, 271; Cohort V, 487); 75.5% were male and the mean age was 58.8 years. The majority of Cohort III/V patients (538/758; 71.0%) received only adjuvant treatment, with 215/758 (28.4%) receiving S1+oxaliplatin. Neoadjuvant or adjuvant trastuzumab was administered to 43/758 patients (Cohort III, 42; Cohort V, 1). Radiation during neoadjuvant or adjuvant treatment was administered to 23/758 (3.0%) patients. The median duration of follow-up was 515 days, during which 72 (9.5%) patients died due to progressive disease. OS rates (95% CI) for Cohorts III and V were 94% (89–96) and 95% (92–97) at 1 year, and 76% (67–83) and 70% (64–75) at 3 years, respectively. Respective EFS rates were 82% (76–87) and 86% (83–89) at 1 year, and 62% (53–70) and 57% (51–63) at 3 years; and respective DFS rates were 88% (82–93) and 86% (81–89) at 1 year and 69% (58–78) and 62% (55–68) at 3 years. Multivariate analysis indicated that the primary tumor site (p = 0.004) and overall cancer stage (p < 0.001) were associated with DFS. Regarding the primary tumor site, there was a trend towards better DFS for antrum tumors (hazard ratio 0.59; 95% CI 0.32–1.07) when evaluated against gastroesophageal junction tumors. Conclusions: This longitudinal analysis of clinicopathologic characteristics and outcomes of Chinese patients with non-mGC will provide critical information that will help to inform disease management. Clinical trial information: NCT01839500.
Association of real-world agreement between HER2 expression and ERBB2 amplification with trastuzumab therapy benefit in advanced gastric/esophageal (adv GE) cancer patients (pts).
Authors: Stein Stacey , Snider Jeremy , McCusker Margaret Elizabeth , Miksad Rebecca A. , Alexander Brian Michael , Castellanos Emily , Backenroth Daniel , Schrock Alexa Betzig , Madison Russell , Carson Kenneth Robert , Ali Siraj Mahamed
Published: February 2020

310

Background: Trastuzumab (T) plus chemotherapy is standard of care for pts with HER2+ adv GE cancer. Selection for T relies on HER2+ result by immunohistochemistry (IHC) +/- in-situ hybridization (ISH); ERBB2 amplification by comprehensive genomic profiling (CGP) also predicts benefit. As CGP use increases, it is important to explore associations of IHC/ISH and CGP result agreement with clinical outcomes in pts with adv GE cancer. Methods: Pts with adv GE cancer were selected from the Flatiron Health-Foundation Medicine (FMI) clinico-genomic database (CGDB), a nationwide de-identified EHR-derived clinical database linked to FMI genomic data. Pts treated from 01/2011-12/2018 with CGP data for tissue specimens collected before 1L were included. Agreement between HER2 status by IHC +/- ISH v ERBB2 amplification by CGP was assessed. For 1L containing T, time to tx discontinuation (TTD) and overall survival (OS) from 1L start stratified by HER2:ERBB2 agreement and ERBB2 copy number (CN) [ERBB2+ = CN >4] were estimated with unadjusted Kaplan-Meier analysis and adjusted (practice type, sex, age at adv dx) hazard ratios (aHR) from Cox proportional hazards models. Results: Of 596 HER2-tested pts with adv GE cancer in CGDB, 174 (29%) were HER2+ by IHC/ISH. Median age at adv dx was 63 y; 76.5% were male and 97% had adenocarcinoma. Overall HER2:ERBB2 agreement was 91%. Of 123 HER2+ 1L T-treated pts, median TTD and OS were longer for HER2+:ERBB2+ (concordant; n = 93) v HER2+:ERBB2- pts (discordant; n = 30): TTD, 5.2 v 0.8 months, aHR 0.46 (0.29-0.70); OS 14.8 v 7.5 months, aHR 0.38 (0.21-0.68). Median OS was 22.0 vs 8.4 months for 1L T-treated pts with ERBB2 CN > 30 (median) v CN ≤30 (aHR 0.69 [0.37-1.27]). Conclusions: In this large real-world clinico-genomic dataset, HER2:ERBB2 agreement was high in tested pts with adv GE cancer. 1L T-treated pts with discordant tests (HER2+:ERBB2-) had significantly shorter TTD and OS. Pts with higher ERBB2 CN had longer OS, but this finding was not significant after adjusting for covariates. Further research is needed to explore associations between HER2:ERBB2 agreement and clinical outcomes in this population.
Retrospective comparison of neoadjuvant chemoradiation (nCRT) +/- surgery using the CROSS trial regimen and definitive chemoradiation (dCRT) with carboplatin (C) and paclitaxel (P) in esophageal (EC), and gastroesophageal junction cancer (GEJC) in Canada.
Authors: Khalid Sidra , Hopman Wilma M. , Virik Kiran
Published: February 2020

313

Background: Trimodality therapy using the CROSS trial protocol is an accepted standard of care for locally advanced EC and GEJC. For medically inoperable patients (pts), CRT has been a standard. CRT with C and P is an option in the definitive setting. This single institution review aims to assess the application and outcomes of the CROSS trial protocol in our real world population. Methods: From June 2012 until June 2018, a retrospective review was undertaken of 83 pts who underwent CRT with C and P with trimodaility or upfront definitive intent. 65 pts underwent nCRT; 40 proceeded to surgery. 18 had upfront dCRT. Pt demographics, clinical, pathological, treatment and surgical characteristics were assessed. These factors and outcomes were analyzed in exploratory analyses. Results: Of the 83 pts: median (m) age was 69 yrs (range 48-82), 34% were ≥ 75 yrs, 80% were male, 21% had CAD, 43% GERD, 23% Barrett’s, 77% adenocarcinoma, m tumor length was 5 cm, 36% had BMI > 30 and 80% were Siewert I tumors. The m RT dose was 50.4 Gy, m chemo doses were 5, m time to CRT was 69 days and m time from CRT to surgery was 66 days. 23% nCRT pts and 72% dCRT pts were ≥ 75 yrs and 49% and 33% of these respectively had no interruptions to CRT. Pts who underwent surgery were younger (p = 0.04) and weighed more (p = 0.05). Pts ≥75 yrs were likely to have dCRT (p = 0.001). For nCRT and surgery, nCRT only and dCRT respectively, median overall survival (mOS) was 35.5, 12.1 and 17.1 months (M) (log rank p = 0.08), PFS was 32.2, 10 and 9.6M (log rank p = 0.01). Compared to the other 2 groups, pts who underwent surgery had: no COPD (p = 0.004), less CAD (p = 0.003), less renal impairment (p = 0.023) and had lower esophageal tumors (p = 0.027). mOS for pts who had nCRT was 28.9M and 17.1M for dCRT (log rank p = 0.70). Further correlative outcome data will be presented. Conclusions: Despite the broadening of CROSS trial eligibility criteria in our real world data, there appears to be a survival benefit with trimodality therapy. The use of C and P in dCRT may be of value especially in the elderly, and requires further study.
Patterns of disease, treatment, and outcomes of esophageal cancer arising within a previous radiation treatment field.
Authors: Ma Lucy Xiaolu , Sun Peiran , Espin-Garcia Osvaldo , Suzuki Chihiro , Jiang Di Maria , Lim Charles Henry , Taylor Kirsty , Chan Bryan Anthony , Sim Hao-Wen , Natori Akina , Chen Eric Xueyu , Liu Geoffrey , Knox Jennifer J. , Yeung Jonathan , Darling Gail Elizabeth , Kim John , Kalimuthu Sangeetha , Elimova Elena , Jang Raymond Woo-Jun
Published: February 2020

328

Background: Esophageal cancer arising within a previous radiation treatment field (ECRF) is rare. The patterns of disease, treatment and outcomes in these patients (pts) have not been well characterized. Methods: A retrospective analysis was performed for pts treated for esophageal cancer at the Princess Margaret Cancer Centre from 2002-2016. Electronic medical records of all pts with a histologic diagnosis of esophageal cancer occurring within the field of previous radiotherapy were reviewed. The Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Results: Of 31 ECRF pts identified, the most common prior cancer was head and neck (45%), median radiation (RT) dose 50Gy, median time to diagnosis of esophageal cancer 12 years. Features at diagnosis of ECRF included: median age 71 years, 58% male, 87% with performance status (PS) 0-1, 77% squamous cell carcinoma, 19% stage IV. Treatment intent was curative in 16 pts, palliative in 15 (Table). Reasons for palliative treatment were: 40% metastatic, 53% comorbidities/PS, 7% anatomic factors. Of resected pts, 36% had a pT1-2 tumour, 55% pN0, 69% R0. For curative pts, median PFS was 26.2 months (95%CI 10.9-34.4) with a 3 year PFS rate of 35% (95% CI 15-81). Median OS for curative pts was 26.4 months (95%CI 17.8-105.5) with a 3 year OS rate of 43% (95% CI 22-83). Most palliative pts were unable to have chemotherapy due to comorbidities and PS. Median OS for palliative pts was 9.5 months (95% CI 3.6-15.4). Conclusions: Most ECRF pts presented with earlier stage disease; however, more than a third of these could not have aggressive curative treatment due to comorbidities and/or PS. Most curative pts had surgery alone. Few palliative pts had chemotherapy, largely due to poor clinical status. Our data suggest that outcomes in both curative and palliative ECRF pts may be limited by the ability to tolerate standard of care treatments.

[Table: see text]