bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrence after surgery for concurrent metastatic colorectal cancer: The perspective of bioinformatics and machine learning.
Authors: Luo Zhiwen , Bi Xinyu
Published: May 2020

4043

Background: Recurrence of concurrent metastatic colorectal cancers (mCRCs) after surgery is still a challenge. But mCRCs’ outcomes are heterogeneous, and no clinicopathological methods can predict its recurrence and guide postoperative treatment from an intrinsic cell activities and extrinsic immune microenvironment perspective. We aimed to identify such gene models. Methods: Gene expression analysis on CRCs. Based on metastasis-related genes, a metastatic evaluation model (MEM) was developed, dividing mCRCs into high and low recurrence risk clusters. Machine learning tested MEM’s importance to predict recurrence. Further investigating MEM’s two clusters made an immune prognostic model (IPM) with immune genes differentially expressed between MEM clusters. The predictive performance of MEM and IPM on prognosis was comprehensively analyzed and validated. The mechanism of IPM on the immune microenvironment and response to immuno/chemotherapy was analyzed extensively. Results: RNA data of 998 CRCs were analyzed. High postoperative recurrence risk in mCRCs was owing to immune response’s down-regulation, which was influenced by 3 MEM genes ( BAMBI, F13A1, LCN2) and their related 3 IPM genes ( SLIT2, CDKN2A, CLU). MEM and IPM were developed and validated on 239 mCRCs to differentiate a low and high recurrence risk (AUCs > 0.7). Functional enrichment analysis showed immune response and immune system diseases pathway represented the major function and pathway related to IPM gene. IPM high-risk group (IPM-high) had higher fractions of Tregs ( P= 0.04), lower fractions of resisting memory CD4+ T cells ( P= 0.02) than IPM-low. And stroma and immune cells in IPM-high samples were scant ( P= 0.0002, 0.001, respectively). In IPM-high, MHC class II molecules all down-expressed, and DNA methylation disordered. TIDE algorithm and GDSC analysis discovered IPM-low was more promising to respond to both anti-CTLA4 therapy ( P= 0.005) and common FDA targeted drugs ( P< 0.05), while IPM-high had nonresponse to both of them. But anti-CDKN2A agent with activation of MHC class II response might reverse the dilemma of this refractory mCRCs subgroup. Conclusions: Postoperative recurrence of mCRC is strongly related to immune microenvironment. Our two relative gene models could identify subgroups of mCRC with different recurrence risk, and stratify mCRCs sensitive to immune/chemotherapy, even highlight the ignored importance of MHC class II molecules on immunotherapy in mCRCs for the first time.
Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Five-year long-term results.
Authors: Moniz Camila Motta Venchiarutti , Riechelmann Rachel Pimenta , Braghiroli Maria Ignez , Ribeiro Suilane Coelho , Rivelli Thomás Giollo , Bariani Giovanni M. , Chen Andre Tsin Chih , Nahas Caio , Bonadio Renata Colombo , Ortega Cinthia , Franco Rejane , Meireles Sibele , Pereira Allan Andresson Lima , Sabbaga Jorge , Coudry Renata A. , Hoff Paulo Marcelo
Published: May 2020

4053

Background: Chemoradiation (CRT) is a curative treatment for SCCAC. However, some patients (pts) present primary CRT resistance. As a rare tumor, there is a lack of prospective studies of prognostic factors in this setting. Methods: This prospective cohort study was aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status, and tumor DNA mutations) in SCCAC. We published the 6 months (m) response rate (RR) of this cohort showing that HIV- were 5.7 times more likely to achieve response 6m post CRT (OR 5.72, CI 95% 2.5-13.0, P < 0.001). Now we report the long-term follow-up results of 5-year progression-free survival (PFS) and overall survival (OS). Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. DNA mutations were analyzed by next-generation sequencing (NGS). HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for PFS and OS. The median age was 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. HPV was evaluated in 67 and found in 47 (70.1%); HPV16 was the most common. PD-L1 was tested in 61; 10 (16.4%) had positive expression > 1%. Ki-67 was performed in 65, with a median of 50% (range 1-90%). The median follow up is 66m. 5-year PFS and OS rates were 63.3% (95% CI 51.2-73.2%) and 76.4% (95% CI 64.8-84.6%), respectively. In a multivariate analysis, age (HR 1.06, P = 0.022, IC 95% 1.01-1.11) and absence of complete response at 6m (HR 3.36, P = 0.007, IC 95% 1.39-8.09) was associated with inferior OS. The OS rate was 62.5% in HIV+ group (95% CI 22.9-86%) in comparison with 78% (95% CI 65.7-86.3%) among HIV- pts, although this difference was not statistically significant (P = 0.400). A tendency to inferior OS was observed among pts with p53 codon 72 polymorphism (HR 2.83, P = 0.181, 95% CI 0.61-13.02). Other tumor mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: HIV- pts were 5.7 times more likely to achieve response 6m post CRT. The absence of complete response at 6m was the main factor associated with poor 5-year OS. New strategies of follow up and complementary treatment should be studied in late responders and HIV+ pts to ensure the success of curative treatment. Clinical trial information: 36211 .
17-year incidence trends of anal squamous cell carcinoma.
Authors: Jhaveri Khushali , Surani Salim , Shah Shailja , Talati Shailesh S. , Shah Maya
Published: May 2020

4058

Background: Anal Cancer is a rare neoplasm with 9 out of 10 cases being Anal Squamous Cell Carcinoma (SCCA). We did a population-based analysis to assess the incidence trends in patients with SCCA and identify any significant change in the direction of trends using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Data was extracted from SEER database for the years 2000-2016 for the US population, across all gender, ages, and races. Joinpoint regression models of SCCA incidence were fitted to identify any discrete joints (year) that represent statistically significant changes in the direction of the trend. The average annual percentage change (APC) in the age-adjusted incidence rate in the pre- and post-joinpoint era were measured. Subgroup analysis for gender, ages, and races was also done. Results: 27,721 new adult cases of SCCA were identified from 2000 to 2016. The incidence was higher amongst females (62.44%) compared to males (37.56%) with the white population contributing 85.41% to incidence compared to black (11.84%) and other (2.75%) population. The age-based incidence rate for different groups has been mentioned in Table. A significant jointpoint for SCCA incidence was observed in 2009. The APC was 4.6% (3.5-5.6 95% CI) in 2000-2009 which reduced to 2.1% (0.7-3.4 95% CI) in 2009-2016 indicating a 54% relative reduction in the average annual APC in the US population after 2009. Subgroup analysis revealed significant joinpoints for incidence decrease in Ages 40-59, 80 and above and females of all ages. No significant changes in APC were seen when stratified by race (Refer to Table). Conclusions: Our study, in our knowledge, is the first study assessing incidence trends of SCCA over 17-years. The overall incidence of SCCA is increasing but a statistically significant trend towards decreasing rate of growth in incidence was observed in 2009 and later. Further studies are needed to analyze the causality of such changes in the trend of SCCA. [Table: see text]
The role of fibroblast growth factor receptor 4 (FGFR4) signaling in anti-EGFR resistance in colon cancer.
Authors: Cho Sang Hee , Kim Jo-Heon , Hong Chang-Soo , Sun Eun-Gene , Ryu Kyung-Hyun , Hwang Jun Eul , Bae Woo Kyun , Chung Ik-Joo , Bang Hyun-Jin
Published: May 2020

4060

Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.
Initial correlative studies from a trial of cetuximab and pembrolizumab in metastatic colorectal cancer (mCRC).
Authors: Boland Patrick M , Muhitch Jason , Abrams Scott I , Maguire Orla , Minderman Hans , Bajor David Lawrence , Saltzman Joel N. , Wang Katy , Hutson Alan , Mukherjee Sarbajit , Iyer Renuka V. , Kalinski Pawel , Fountzilas Christos
Published: May 2020

4062

Background: Cetuximab is an EGFR-targeting IgG1 mAb. Pre-clinical data suggests cetuximab induces CD8+ cytotoxic T-cell (CTL) infiltration of tumors. We hypothesized that augmentation of CTLs in the tumor microenvironment (TME) may provide the proper milieu for effective PD-1 inhibition in metastatic colorectal cancer (mCRC). We conducted a phase Ib/II study of cetuximab with the PD-1 antibody, pembrolizumab, in mCRC. Correlative blood and tissue samples were collected to assess the impact of this treatment on CTLs, as well as potential compensatory alterations in regulatory T-cells (Tregs) and suppressive MDSCs (NCT02713373). Methods: 3 week treatment cycles included pembrolizumab at 200 mg on day 1 and cetuximab 250 mg/m2 following the 400 mg/m2 loading dose. Tumor biopsies were obtained at baseline and at c4d1 (Day 64). Peripheral blood (PB) was drawn at baseline, c2d1 (day 22) and c4d1 (Day 64). Flow cytometry was performed within 24 hours with additional samples stored for future analysis. In the present analysis, we assessed changes in levels of the cellular populations of interest between cycle 4 and cycle 1. Results: Forty-two RAS-wt patients were enrolled through October 2019. Paired tumor tissues were successfully analyzed for 16 patients and PB for 38. Intratumoral CTLs (CD3+CD8+) increased significantly (+47%, p < .05). In PB, there was a slight overall decrease in PB CTLs (-5%, p = NS) and a significant decrease in CD8+CD45RO+PD1+ cells (-42%, p < .05). We saw simultaneous decreases in PD-1+ CTLs in the tumor and PB. There was a trend for increase in Tregs (CD4+ Cd25+ FoxP3+) in PB (+11%, p = NS), but an overall increase in the Teff:Treg ratio (+30%, p = NS). CD4+CTLA4+ cells significantly increased (+37%, p < .05). Granulocytic MDSCs (CD11b+CD14−CD33+HLADR−) in PB decreased significantly on-treatment (-30%, p < 0.5). The sample size and tissue limitations prohibited meaningful evaluation of tissue Tregs and MDSCs via the present methods. Conclusions: Cetuximab and pembrolizumab induced dynamic changes in the TME and PB. The treatment associated increase in intratumoral CTLs was particularly pronounced, consistent with their local expansion and/or influx. This was accompanied by a decrease in PB CTLs. Decreases in multiple PD-1+ lymphoid populations were observed in both tumor and PB, notably PD-1+ CTLs. Of note, we saw a synchronous increase in immunosuppressive CD4+CTLA4+ T-cells in PB. Patient outcomes are pending maturation. Further analyses are planned, coupled with integration of clinical data. Clinical trial information: NCT02713373 .
The landscape of DNA damage response (DDR) pathway in colorectal cancer (CRC).
Authors: Arai Hiroyuki , Elliott Andrew , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Sohal Davendra , Goldberg Richard M. , Hall Michael J. , Scott Aaron James , Khushman Mohd , Hwang Jimmy J. , Lou Emil , Weinberg Benjamin A. , Marshall John , Lockhart Albert Craig , Stafford Phillip , Zhang Jian , Korn W. Michael , Lenz Heinz-Josef
Published: May 2020

4064

Background: Abnormal DDR is a hallmark of cancer, relating to genome instability, anti-tumor immunity, and sensitivity to chemotherapeutic agents and radiation. We conducted a large-scale investigation to clarify the alteration of DDR pathway in CRC. Methods: Tumor samples from 9321 CRC patients were retrospectively reviewed. Next-Generation Sequencing (NGS) on a custom-designed panel enriching 592 gene targets was performed. Samples with mutations detected in any of 29 DDR-related genes were deemed DDR-mutant (DDR-MT); the rest DDR-wild type (DDR-WT). Microsatellite instability (MSI) status was tested with a combination of immunohistochemistry (IHC), fragment analysis and NGS. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. PD-L1 was tested by IHC (SP142). Consensus molecular subtype (CMS) was developed using RNA sequencing data. Results: Of 9321 cases, 1290 (13.8%) were DDR-MT. DDR-MT frequency was higher in right vs. left sided (20.9% vs 10.8%, p < 0.001) and MSI-H vs. MSS (76.4% vs 9.5%, p < 0.001) cases. In the MSS cases, right-sided had marginally higher frequency of DDR-MT than left-sided (10.6% vs 9.1%, p = 0.055), with much higher frequency of Fanconi anemia pathway alteration in right-sided (1.5% vs 0.7%, p < 0.01). CMS1 subtype had the highest frequency of DDR-MT (34.8%); CMS2 had the lowest (7.1%). DDR-MT cases (vs. DDR-WT) had higher mutation rate of ARID1A (55.0% vs 19.1%, p < 0.0001), PIK3CA (22.6% vs 15.8%, p < 0.0001) and BRAF (20.4% vs 7.3%, p < 0.0001), and lower mutation rate of TP53 (48.2% vs 76.1%, p < 0.0001), APC (60.5% vs 74.5%, p < 0.0001) and KRAS (44.0% vs 49.8%, p < 0.001). Mean TMB was much greater in DDR-MT than DDR-WT (All: 20.9/Mb vs 7.7/Mb, p < 0.0001; MSS: 13.7/Mb vs 7.6/Mb, p < 0.05). PD-L1 positivity was also higher in DDR-MT compared to DDR-WT (All: 10.1% vs 2.7%, p < 0.0001; MSS: 4.8% vs 2.4%, p < 0.0001). Conclusions: Alteration of the DDR pathway was strongly associated with MSI status in CRC. The primary tumor sidedness might also be related, as DDR-MT was more prevalent in right-sided tumors. Elevated TMB and PD-L1 expression in DDR-MT CRC indicate more activated anti-tumor immune profiles compared to DDR-WT, regardless of MSI status, suggesting possible therapeutic benefit from immune checkpoint inhibitors in DDR-MT CRC.
Association of postoperative serum carcinoembryonic antigen (CEA) with disease-free survival in patients with stage III colon cancer: ACHIEVE phase III randomized clinical trial.
Authors: Kotaka Masahito , Manaka Dai , Eto Tetsuya , Hasegawa Junichi , Takagane Akinori , Nakamura Masato , Kato Takeshi , Munemoto Yoshinori , Nakamura Fumitaka , Bando Hiroyuki , Taniguchi Hiroki , Gamoh Makio , Shiozawa Manabu , Nishi Masayasu , Horiuchi Tetsuya , Mizushima Tsunekazu , Yamanaka Takeharu , Yoshino Takayuki , Ohtsu Atsushi , Mori Masaki
Published: May 2020

4069

Background: ACHIEVE, as part of the IDEA collaboration, was a multicenter trial randomizing patients with stage 3 resected colon cancer to either 3 versus 6 months of adjuvant FOLFOX/CAPOX. We previously reported that the hazard ratios (HRs) in disease-free survival (DFS) of 3 versus 6 months duration according to risk stage (low-risk [T1-3 and N1] or high-risk [T4 or N2]) and regimen (FOLFOX or CAPOX) as well as in overall population were consistent with those observed in the whole IDEA. This study aimed to clarify the significance of post-operative serum carcinoembryonic antigen (CEA) on DFS in stage 3 colon cancer. Methods: Eligibility included post-operative serum CEA value of ≤10 ng/ml at registration in the ACHIEVE trial, which enrolled 1313 patients between 2012 and 2014, out of whom 1291 pts were the modified ITT (mITT) population and used in this study. The cutoff values of CEA analyzed for prognostic analyses were the median value (1.8 ng/ml) in the mITT, the upper limit of normal (ULN) level (5.0 ng/ml), and the half of ULN (2.5 ng/ml). The association of post-operative CEA with DFS were measured by Cox regression analyses. Results: Of the 3 cutoff values, the ULN (5.0 ng/ml) was associated with DFS more strongly than the median (1.8 ng/ml) or half of ULN (2.5 ng/ml), with a HR of 1.75 (95%CI, 1.24-2.46) (Table). The 99 patients (7.7%) were identified as the CEA > ULN and 1192 (92.3%) as < ULN. In univariate analysis, regimen (CAPOX or FOLFOX), ECOG PS (0 or 1), T factor (T1-3 or T4), N factor (N1 or N2-3) and CEA ( < ULN or > ULN) were significantly associated with DFS. Multivariate Cox regression identified CEA > ULN as an independent poor risk factor (HR = 1.45; 95%CI, 1.03-2.05). Shorter DFS in patients with CEA > ULN than in those with CEA < ULN was consistently observed in each subgroup of baseline factors, including treatment duration, regimen, age, gender, PS, T-stage, N-stage, no of lymph nodes examined, and tumor location; no interaction was observed between CEA and these factors. Conclusions: Post-operative serum CEA is also a strong prognostic factor for DFS in stage 3 colon cancer. Clinical trial information: 000008543 . [Table: see text]
Efficacy of third-line anti-EGFR-based treatment (tx) versus (vs) Regorafenib/TAS-102 (R/T) according to primary tumor site in RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts).
Authors: Vivolo Raffaella , Bria Emilio , Zurlo Ina Valeria , Bensi Maria , Dell'Aquila Emanuela , Anghelone Annunziato , Corsi Domenico C. , Caira Giulia , Santini Daniele , Ingrosso Diletta , Emiliani Alessandra , Calegari Maria Alessandra , Citarella Fabrizio , Pozzo Carmelo , Grande Roberta , Basso Michele , Tortora Giampaolo , Salvatore Lisa
Published: May 2020

4082

Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, which a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to primary tumor site in third line. Methods: Pts affected by RAS/BRAF wt mCRC treated with third-line anti-EGFR-based tx or R/T were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to tumor site. Primary endpoint was PFS; secondary endpoints were OS and RR. PFS and OS analyses were performed using Kaplan-Meier method, and survival curves were compared using the log-rank test. RR was evaluated according to RECIST criteria and it was compared in the two groups using Fisher’s exact test. Statistical significance was set at p = 0.05 for a bilateral test. Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 76 RAS/BRAF wt mCRC pts, treated with third-line anti-EGFR-based tx or R/T, were enrolled. Of those, 19 (25%) pts had R-sided tumor (9 pts received anti-EGFR tx and 10 pts received R/T) and 57 (75%) pts had L-sided tumor (30 pts received anti-EGFR tx and 27 pts received R/T). As shown in the table, a significant PFS and OS benefit in favor of anti-EGFR tx vs R/T was observed in L-sided pts, while no difference both in PFS and OS was observed in R-sided pts. RR was significantly higher in L-sided pts treated with anti-EGFR vs R/T, no difference was shown in R-sided pts. At the multivariate analysis, tx regimen was indipendently associated with PFS in L-sided pts, but not in R-sided pts. Conclusions: Our study confirmed the results deriving from the retrospective analysis of the phase III study 20020408. Our results demonstrated a different benefit from third-line anti-EGFR tx according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T, while no difference was observed in R-sided tumors. [Table: see text]
Predictive and prognostic value of HER2 gene expression and HER2 amplification in patients with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).
Authors: Battaglin Francesca , Ou Fang-Shu , Qu Xueping , Bertagnolli Monica M. , Hochster Howard S. , Niedzwiecki Donna , Goldberg Richard M. , Mayer Robert J. , Zemla Tyler J. , Blanke Charles David , Venook Alan P. , Kabbarah Omar , Lenz Heinz-Josef , Innocenti Federico
Published: May 2020

4086

Background: The randomized phase III CALGB/SWOG 80405 trial found no difference in overall survival (OS) in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. We investigated the potential prognostic and predictive value of HER2 amplification and HER2 gene expression using NGS and Nanostring data. Methods: Primary tumor DNA from 559 patients (pts) was profiled for HER2 amplification by NGS (Foundation One). Tumor tissue from 925 pts was tested for Nanostring gene expression using an 800 gene panel. OS and progression free survival (PFS) were the endpoints as time-to-event variables. Cox proportional hazard models with gene expression fitted with linear spline (one internal knot at median) were used, adjusting for pts baseline characteristics, treatment assignment, and molecular features (microsatellite instability, BRAF, all RAS). Results: Of 505 tumors with both NGS and Nanostring data, 16 harbored HER2 amplification (copy number variation > 6), limited to microsatellite stable tumors and significantly associated with HER2 expression ( P < 0.001) and wild-type RAS ( P = 0.036). HER2 amplification was neither prognostic nor predictive for OS or PFS. Conversely, HER2 expression higher than median was associated with longer PFS ( P = 0.018) but not OS ( P = 0.13). Among pts with HER2 not amplified, higher HER2 expression was associated with better OS (hazard ratio [HR], 0.83; 95%CI, 0.72-0.97; P = 0.016) and PFS (HR, 0.85; 95%CI, 0.74-0.98; P = 0.027) when the expression was less than median. Additionally, in pts with no HER2 amplification and HER2 expression lower than median, treatment with Cet was associated with worse PFS compared to Bev (HR, 1.46; 95%CI, 1.12-1.90; P = 0.005). This effect was not observed with expression higher than median regardless of HER2 amplification status. Conclusions: To our knowledge, this is the largest analysis of HER2 amplification and gene expression in mCRC pts treated with standard therapy. Our results provide novel insight on the predictive and prognostic value of HER2 gene expression in pts treated with Cet- and Bev-based regimens. Upon validation, these findings could inform pts selection and the design of more effective treatment options for pts with low HER2 expression. Clinical trial information: NCT00265850.
Utilization of adjuvant chemotherapy in “ideal candidates” with stage III colon cancer.
Authors: Soleja Mohsin , Goksu Suleyman Yasin , Sanford Nina Niu , Beg Muhammad Shaalan , Kainthla Radhika , Sanjeevaiah Aravind , Jones Amy Little , Farkas Linda , Verma Udit , Hsieh David , Kazmi Syed Mohammad Ali
Published: May 2020

4103

Background: Prior studies have observed under-utilization of adjuvant chemotherapy (ACT) in stage III colon cancer. Our aims were to observe the rate of utilization of ACT in very healthy or “ideal candidates”, identify reasons for omission and socioeconomic factors associated with ACT use, and observe patient outcomes. Methods: We queried patients from the National Cancer Database (NCDB) with stage III colon cancer, age<65, and Charlson-Deyo score of 0 who underwent resection in the United States between 2004-2015. Patients who received ACT were compared to patients who had surgery only (SO). We used chi-square test for categorical variables, Kaplan-Meier and Cox regression method for survival analyses. Results: Out of 243,388 stage III colon cancer patients during the study time, a total of 49,046 patients met the specific criteria of “ideal candidate”. Out of these, 88.5% received ACT and 11.5% underwent SO. The primary reason for chemotherapy omission was: no reason given (54.2%), patient/guardian refusal (26.7%), physician recommended against (9.3%), patient died (3%), unknown (6.7%). Patients who received ACT were more likely to be female, non-Hispanic white, have a higher level of education, travel shorter distance for cancer treatment, have private insurance or higher income as compared to counterpart ( all p<.001). Patients who received ACT had significantly better overall survival (5-year survival rate 74% vs. 54%, p<.001). This persisted after multivariable Cox regression analysis [HR:0.48 (CI:0.45-0.50), p<.001]. Conclusions: We observed a high rate of utilization (88.5%) of ACT in patients with stage III colon cancer who were under age 65 and without comorbidities. However, the omission of chemotherapy in this population remains a problem, partially due to patient refusal. Socioeconomic factors associated with lower utilization were primarily related to insurance status (private vs non-private). Patients who received ACT had significantly improved survival as compared to SO group. [Table: see text]
Pharmacokinetically-guided preoperative FOLFOX chemotherapy for locally advanced colon cancer patients.
Authors: Ceniceros Lucia , Baixauli Jorge , Aldaz Azucena , Arredondo Jorge , Pastor Carlos , Chopitea Ana , Granero Lucia , Martinez Patricia , Ponz-Sarvisé Mariano , Lapuente Fernando Manuel , Hernandez-Lizoain Jose Luis , Rodriguez Javier
Published: May 2020

4104

Background: Preliminary results from ongoing randomised trials suggest that neoadjuvant chemotherapy (NAC) may be an alternative approach to conventional adjuvant therapy. We assessed the feasibility and activity of incorporating a pharmacokinetically (PK) guided dose adjustment of 5-FU within preoperative Folfox. Methods: Radiologically staged LACC pts, T4 or T3 with extramural depth >5mm beyond the muscularis propia, were planned to receive 4-6 biweekly cycles of Oxalipatin (85mg/m²), Leucovorin (400 mg/m²), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m² in 46h and subsequent cycles tailored according to PK monitoring in order to reach a target 5-FU area under the curve (AUC) between 20-30 mg∙h∙L-1). Dihidrouracil deshidrogenase was determined before the first cycle in order to detect pts with 5-Fu intolerance. Three serum samples were obtained during the 5-Fu infusion in the first two cycles. Pathological tumor regression was graded according to the MSKCC classification and toxicity to the NCI-CTCAE 4.0. Results: From June 2012 to August 2017, 45 pts (M/F: 35/10; median age 63) with LACC (T3: 66.7%; T4: 31.1%; T2: 2.2%; N+:66.6%) were evaluated. Median dose of 5-FU was 4500 mg. 48.9% of the pts required a 5-FU dose increase to reach the target AUC. Side effects profile included G3 neutropenia (3 pts), G2 diarrhea (2 pts) and G2 asthenia (9 pts). NAC was discontinued in 3 pts due to small bowell obstruction requiring surgery (no progressive disease during NAC). R0 resection rate was 100% (93.3% laparoscopy-assited). MSKCC score included grades 4, 3+ and 3 in 11.1%, 26.7% and 28.9% of pts, respectively. A complete pathological response was found in 5 pts (11.1%). Median number of harvested nodes was 16 (7-51), 80% ypN0. Those pts with AUC 25-30 had a 3-fold higher likelihood of achieving a MSKCC 3, 3+ and 4 responses. Median time to hospital discharge was 7 days (range 4-22). After a median follow-up of 60 months (44-66), 5-year actuarial PFS is 88.8%. Conclusions: Preoperative PK-adjusted FOLFOX in LACC pts is safe and well tolerated, achieving remarkable rates of major pathological responses and R0 resections.
Tumor-informed assessment of molecular residual disease and its incorporation into practice for patients with early and advanced-stage colorectal cancer (CRC-MRD Consortia).
Authors: Kasi Pashtoon Murtaza , Dayyani Farshid , Morris Van K. , Kopetz Scott , Parikh Aparna Raj , Starr Jason Scott , Cohen Stacey , Grothey Axel , Lieu Christopher Hanyoung , O'Hara Mark H. , Loranger Kate , Westbrook Laura , Sharma Shruti , Krinshpun Shifra , Hook Nicole , Zimmermann Bernhard , Billings Paul R. , Aleshin Alexey
Published: May 2020

4108

Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p<0.0001 Chi-square: 70.33). Additionally, in patients with radiologically measurable active metastatic disease, ctDNA detection rate was 100%. On the contrary, patients with advanced/metastatic disease who had partial response to treatment or no evidence of disease (NED) showed 28.5% and 19.2% of ctDNA-positivity, respectively. Conclusions: This is the first large, real-world study reporting on the results from a clinically validated MRD assay. For the first time we delineate MRD rates and quantify ctDNA concentration in patients with early-stage and advanced CRC. Furthermore, we provide an initial readout that effective ongoing treatment in patients with CRC may be correlated with ctDNA clearance. Ongoing analysis expanded to a cohort of 1200 clinical cases including correlation with genomic and serial testing will be presented. [Table: see text]
Patient and tumor characteristics as determinants of overall survival (OS) in BRAF V600 mutant (mt) metastatic colorectal cancer (mCRC) treated with doublet or triplet targeted therapy.
Authors: Ros Montañá Javier , Martini Giulia , Baraibar Iosune , Villacampa Guillermo , Comas Raquel , Ciardiello Davide , Garcia Ariadna , Hernandez Yague Xavier , Queralt Bernardo , Salud Salvia Antonieta , Argiles Guillem , Cuadra Jose Luis , Toledo Rodrigo A , Chicote Irene , Mulet Nuria , Vivancos Ana , Palmer Hector G. , Dienstmann Rodrigo , Tabernero Josep , Elez Elena
Published: May 2020

4112

Background: BRAF V600 mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this targeted treated population remain to be studied. Methods: Prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines. Results: In total, 42 patients were enrolled. Median age 60.7 y (33-83), 61% female, 61% right-sided tumors, 26% received 2 or more prior chemotherapy lines. One patient (2.6%) achieved complete response and 36% had partial response with median follow-up of 14.3 months. Median progression-free survival was 5.5 months (CI95% 4.4-10.4) and median OS (mOS) was 10.7 months (CI95% 8.4-22.1). In univariate models, ECOG performance status (1 vs 0), CEA levels (high - > 3.5 ng/mL- vs low - < 3.5 ng/mL), CA 19.9 (high vs. low), LDH (high vs. low), number of metastatic sites and presence of liver metastasis were significant prognostic factors. On the other hand, MSI status and peritoneal or nodal metastasis did not associate with outcome. In multivariable model, strongest determinants of OS were ECOG and baseline CEA levels. If high-risk for both factors (ECOG 1 and CEA high, 46% of the patients), mOS was 5.6 months (CI95% 4.2-NA); if intermediate-risk (either ECOG 1 or CEA high, 33%), mOS was 13.5 months (CI95% 10.6-NA); if low-risk (ECOG 0 and CEA low, 21%), mOS not reached (CI95% 16.5-NA). Differences between intermediate- and high-risk prognostic groups compared to low-risk were significant (HR = 5.9, p = 0.03; and HR = 25.9, p < 0.001, respectively). Conclusions: Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels remain important OS determinants in BRAF V600 mt mCRC treated with doublet or triplet targeted therapy. In fact, there are not prognostic scores regarding BRAF mt mCRC treated with targeted therapies. Our study suggests that these prognostic factors may be considered as stratification factors in future clinical trials.
The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE-061.
Authors: Fuchs Charles S. , Özgüroğlu Mustafa , Bang Yung-Jue , Di Bartolomeo Maria , Mandalà Mario , Ryu Min-hee , Vivaldi Caterina , Olesinski Tomasz , Caglevic Christian , Chung Hyun Cheol , Muro Kei , Van Cutsem Eric , Kobie Julie , Cristescu Razvan , Aurora-Garg Deepti , Lu Jia , Shih Chie-Schin , Adelberg David , Cao Z. Alexander , Shitara Kohei
Published: May 2020

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Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma with tumor progression after first-line therapy (N =592). We explored the association of tissue tumor mutational burden (tTMB) status and clinical outcomes in patients with GC enrolled in KEYNOTE-061, including the relationship with PD-L1 combined positive score (CPS) and microsatellite instability-high (MSI-H) status. Methods: In patients from KEYNOTE-061 with evaluable tumor and matched normal whole exome sequencing (WES) data (N = 420; pembrolizumab, 218; paclitaxel, 202), the association of tTMB (continuous log10 scale) with confirmed ORR and PFS by blinded central radiology review per RECIST v1.1, and OS was evaluated within each treatment arm using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS). The clinical utility of tTMB was assessed using the prespecified cutoff of 175 mut/exome. Clinical data cutoff: October 26, 2017. Results: tTMB was significantly associated (α=0.05) with ORR, PFS, and OS in patients treated with pembrolizumab (one-sided P<0.001) but not paclitaxel (two-sided P>0.600). The area under the receiver operating characteristics curve for tTMB and response (pembrolizumab vs paclitaxel) was 0.68 (95% CI, 0.56-0.81) vs 0.51 (95% CI, 0.39-0.63). Patient outcomes by tTMB cutoff are reported in Table. There was low correlation between tTMB and PD-L1 CPS in both treatment arms (r<0.18). tTMB remained significantly associated with all clinical end points with pembrolizumab after adjusting for PD-L1 CPS and with PFS and OS after excluding MSI-H patients. Conclusions: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and response to pembrolizumab in patients with GC. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. Clinical trial information: NCT02370498 . [Table: see text]
Evaluation of spatiotemporal heterogeneity of PDL1 expression in gastroesophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy.
Authors: Zhou Katherine I. , Peterson Bryan , Serritella Anthony , Reizine Natalie , Wang Yan , Catenacci Daniel V.T.
Published: May 2020

4528

Background: PDL1 expression is a predictive marker for response to anti-PD1/PDL1 agents (IO) for GEA. As a prognostic biomarker, data are conflicting. Molecular heterogeneity of various biomarkers for GEA has been established. To characterize heterogeneity of PDL1 expression and its clinical relevance, we compared PDL1 expression in primary (10) and metastatic (met) tumors of newly diagnosed stage IV advanced GEA (aGEA), and before and after chemotherapy treatment (tx) for stage II–IV GEA. We assessed the prognostic relevance of PDL1 expression in aGEA. Methods: We retrospectively reviewed a cohort of 130 patients (pts) diagnosed with GEA in 2013–2019, with a total of 328 tumor samples with PDL1 expression data. PDL1 was defined as positive if combined positive score (CPS) was ≥1 using the 22C3 pharmDx assay. Analysis was performed by McNemar’s test for paired PDL1 and univariate Cox proportional-hazards model for overall survival (OS). Results: Of 328 tumors, 45% were PDL1+ and 55% PDL1-. CPS ranged 0–100 (median 1, IQR 0–5), and CPS was ≥10 for 19% of tumors. Concordance between PDL1 status of paired baseline 10 and baseline met tumors was 63% (32/51) (Table). Of 31 PDL1+ baseline 10 tumors, 52% (16/31) had PDL1- paired baseline met tumors, while of 20 PDL1- baseline 10 tumors, only 15% (3/20) had PDL1+ paired baseline met tumors. Only 35% (18/51) of met tumors were PDL1+, compared to 61% (31/51) PDL1+ 10 tumors ( p< 0.003). Post-tx tumors exhibited 62% (46/74) concordance of PDL1 status compared to pre-tx 10 tumors. Of 43 PDL1+ baseline tumors, 35% (15/43) were PDL1- post-tx; of 31 PDL1- baseline tumors, 42% (13/31) were PDL1+ post-tx ( p= 0.71). In pts with aGEA at diagnosis, OS did not significantly differ depending on baseline 10 tumor PDL1 status (median OS of 17.9 [95% CI 14.6–26.5] months for PDL1- and 16.7 [12.0–26.3] months for PDL1+; p= 0.6), nor depending on baseline met PDL1 status. Conclusions: PDL1 expression demonstrated notable baseline discordance between 10 and met tumors, particularly directional from PDL1+ 10 tumor to PDL1- met. Discordance before and after chemotherapy was also observed, but with similar proportions of PDL1+ pre-tx and post-tx tumors. These findings may have predictive IO therapeutic implications if confirmed in larger independent analyses. [Table: see text]
Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + PEGPH20 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).
Authors: Ko Andrew H. , Lee Jeeyun , ALSINA MARIA , Ajani Jaffer A. , Bang Yung-Jue , Chung Hyun Cheol , Lacy Jill , Lopez Charles D. , Oh Do-Youn , O'Reilly Eileen Mary , Siveke Jens T , Allen Simon , Al-Sakaff Nedal Jaffer Abdulla , Barak Hila , Lau Janet , Li Shi , Retiere Anne-Cecile , Shemesh Colby , Zhang Xiaosong , Kim Kyu-Pyo
Published: May 2020

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Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti–PD-L1) was tested with PEGylated recombinant human hyaluronidase (PEGPH20), an anti–stromal and extracellular matrix modulator, in patients (pts) with metastatic (m) PDAC or advanced/mGC. Methods: In 2 separate randomized trials, eligible pts with 2L mPDAC or mGC received atezo (1200 mg IV q3w) + PEGPH20 (3 µg/kg IV on D1, 8, 15). Control tx for M-PDAC (NCT03193190) was mFOLFOX6 or gemcitabine + nab-paclitaxel. In M-GC (NCT03281369), control tx was ramucirumab + paclitaxel. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. Results: Pts were followed up for ≥ 18 wk in M-PDAC (data cutoff: Aug 5, 2019) and ≥ 24 wk in M-GC (data cutoff, Jul 11, 2019). In M-PDAC, 66 pts received atezo + PEGPH20 and 42 received control in both preliminary and expansion phases. Confirmed ORRs were 6.1% (95% CI: 1.7, 14.8) and 2.4% (95% CI: 0.06, 12.6), respectively. Duration of response ranged from 5.3 to 11.3 mo in tx arm and was 3.9 mo in control. Median PFS was 1.5 mo (95% CI: 1.4, 2.6) and 2.3 mo (95% CI: 1.6, 4.0), respectively. Median OS was 7.1 mo (95% CI: 4.6, 9.5) and 6.8 mo (95% CI: 5.6, 8.3). Updated survival data will be presented. Respectively, 62.2% and 59.5% of pts had Gr 3-4 AEs; Gr 5 AEs were seen in 4.5% and 2.4% of pts; serious AEs (SAEs) occurred in 45.5% and 45.2% of pts; 16.7% and 4.8% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were myalgia (65.2%) and peripheral edema (28.8%) in the combination arm. In M-GC, 13 pts received atezo + PEGPH20 and 12 received control. Confirmed ORRs were 0% (95% CI: 0, 24.7) and 16.7% (95% CI: 2.1, 48.4), respectively. Gr 3-4 AEs were seen in 30.8% and 75.0% of pts, respectively. No Gr 5 AEs occurred in either arm. SAEs occurred in 7.7% and 50.0% of pts, respectively. Only 1 pt in the control arm had a tx-related AE leading to tx withdrawal. While tumor hyaluronan (HA) appears to be associated with poor prognosis in the M-PDAC control, there was no clear association between HA levels and response to atezo + PEGPH20. PK data will also be presented. Conclusions: Limited efficacy was seen with the chemotherapy-free combination of atezo + PEGPH20 in PDAC. No efficacy was seen in GC. The safety of atezo + PEGPH20 was consistent with each agent’s known safety profile; no new safety signals were identified. Clinical trial information: NCT03193190 .
Final analysis of single-arm confirmatory study of definitive chemoradiotherapy including salvage treatment in patients with clinical stage II/III esophageal carcinoma: JCOG0909.
Authors: Ito Yoshinori , TAKEUCHI HIROYA , Ogawa Gakuto , Kato Ken , Onozawa Masakatsu , Minashi Keiko , Yano Tomonori , Nakamura Kenichi , Tsushima Takahiro , Hara Hiroki , Okuno Tatsuya , Hironaka Shuichi , Nozaki Isao , Ura Takashi , Chin Keisho , Kojima Takashi , Seki Shiko , Sakanaka Katsuyuki , Fukuda Haruhiko , Kitagawa Yuko
Published: May 2020

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Background: Definitive chemoradiotherapy (dCRT) consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) with 60 Gy radiotherapy (RT) for clinical (c) Stage II/III esophageal carcinoma (EC) is a standard treatment for patients (pts) refusing surgery (S) in Japan based on the previous trial (JCOG9906). However, poor survival, high incidence of late toxicities, and severe complications of salvage S are problems. We conducted a single-arm confirmatory study of CRT modifications including salvage treatment (ST) to reduce CRT toxicities and facilitate ST to improve survival. We reported the 3-year survival at 2018 ASCO Annual Meeting. We report the final data after 5-year follow-up. Methods: EC pts with cStage II/III (UICC 6th, non-T4), PS 0-1, and age 20-75 years were eligible. Chemotherapy (CT) was CDDP (75 mg/m2 on days 1, 29) and 5-FU (1000 mg/m2/d on days 1-4, 29-32). RT was administered to a total dose of 50.4 Gy with elective nodal irradiation of 41.4 Gy. Good responders after dCRT received additional 1-2 cycles of CT. For residual or recurrent disease, salvage endoscopic resection (ER) or S was performed based on the prespecified criteria. Planned sample size was 95, with one-sided alpha of 5% and power of 80%, expected and threshold 3-year overall survival (OS) as 55% and 42%. Key secondary endpoint was ST related toxicity. Final analysis was planned after 5-year follow-up for all pts. Results: From 4/2010 to 8/2014, 96 pts were enrolled, two were ineligible and 94 were included in efficacy analysis (cStage IIA/IIB/III, 22/38/34). Complete response was achieved in 55 pts (59%). Salvage ER and S were performed in 5 (5%) and 27 pts (29%). R0 resection of salvage S was achieved in 23 (85%). With a median follow-up of 5.95 years, 3- and 5-year OS was 74.2% (90% CI 65.9-80.8%) and 64.5% (95% CI 53.9-73.3%). 5-year progression-free survival and esophagectomy-free survival were 48.3% (95% CI 37.9-58.0%) and 54.9% (95% CI 44.3-64.4%). 5-year OS after salvage S was 31.0% and hazard ratio of R1-2 to R0 was 5.635 (95% CI: 1.818-17.467). No complications occurred after salvage ER. Five pts (19%) showed ≥ grade 3 operative complications and 1 treatment related death due to bronchus-pulmonary artery fistula occurred after salvage S. Only 9 pts (9.6%) showed grade 3 late toxicities. And no late operative complications more than grade 3 were observed. Conclusions: This combined modality treatment of dCRT with ST showed acceptable toxicities, favorable 5-year survival, and promising esophageal preservation. Clinical trial information: jRCTs031180110 .
Evaluation of spatiotemporal heterogeneity of tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy.
Authors: Zhou Katherine I. , Peterson Bryan , Serritella Anthony , Reizine Natalie , Wang Yan , Catenacci Daniel V.T.
Published: May 2020

4546

Background: Tumor mutational burden (TMB) may be a predictive marker for response to anti-PD1/PDL1 agents (IO). Molecular heterogeneity of various biomarkers for GEA has been established. To characterize heterogeneity of TMB and its clinical relevance, we compared TMB in primary (10) & metastatic (met) tumors at baseline newly diagnosed stage IV advanced GEA (aGEA), and before & after chemotherapy treatment (tx) for stage II–IV GEA. We assessed the prognostic relevance of TMB in aGEA. Methods: We retrospectively reviewed a cohort of 127 patients (pts) diagnosed with GEA in 2012–2019, for a total of 280 tumor samples with TMB data. TMB level was defined as low (≤5/Mb), intermediate (int) ( > 5/Mb, ≤15/Mb), or high (hi) (≥15/Mb), determined by Foundation One. Analysis was performed by Fisher’s exact test for PDL1/TMB, McNemar’s test for paired TMB, and univariate Cox proportional-hazards model for overall survival (OS). Results: Of 280 tumors, 50% (140/280) had low TMB, 45% (125/280) int TMB, & 5% (15/280) hi TMB. TMB ranged 0–58.6/Mb (median 5.3/Mb). Of tumors with hi TMB, 53% (8/15) were MSI-Hi, while of MSI-Hi tumors, 100% (8/8) were TMB hi. TMB level did not correlate with PDL1 status ( p= 0.83). Concordance between TMB levels of paired baseline 10 and baseline met tumors was 66% (29/44) (Table). TMB level was lower in the met than in the 10 in 23% (10/44) of cases, and higher in the met in 11% (5/44). Of 4 TMB hi baseline 10 tumors, 2 were not TMB hi in the met; of 40 TMB low/int baseline 10 tumors, 0 were TMB hi in the met ( p= 0.16). Post-tx tumors exhibited 71% (42/59) concordance of TMB levels compared to pre-tx 10 tumors. Of 2 TMB hi baseline tumors, 1 was not TMB hi in the post-tx tumor; of 57 TMB low/int baseline tumors, 0 were TMB hi in the post-tx tumor ( p= 0.32). In pts with aGEA at diagnosis, OS did not significantly differ depending on baseline 10 tumor TMB level (median OS of 21.4 [95% CI 15.4–27.9] months for TMB low, 14.6 [10.9–23.5] months for TMB int, and 9.6 [3.9–NA] for TMB hi; p= 0.3), nor depending on baseline met TMB level. Conclusions: Notable baseline spatial discordance of TMB was observed, particularly TMB hi 10 to low/int met. Discordance was also observed before & after tx, without significant increase towards TMB hi temporally. Spatiotemporal heterogeneity may impact the role of TMB as a predictive biomarker & warrants further study. [Table: see text]