Resectable gastric cancer: should we apply a tailored surgical strategy according to microsatellite status?

244 Background: Subgroup analysis of trials data suggested a favorable prognostic role for microsatellite instability high (MSI-high) status in resectable gastric cancer, but a lack of survival benefit from neoadjuvant/adjuvant chemotherapy; questioning current standard of care for MSI-high locally advanced gastric cancer. To help guide treatment decision making, we retrospectively studied the interaction between MSI status and chemotherapy on survival in a single institution. Methods: All clinically advanced (tumor stage 3-4 or positive lymph nodes) gastric cancer patients that underwent gastrectomy between 2000-2018 with MSI status available from immunohistochemistry (IHC, deficient mismatch repair protein expression (dMMR) vs proficient (pMMR)) or DNA next generation sequencing testing (NGS, MSI-high vs low/stable (MSS)) were included. Clinicopathological characteristics and overall survival (OS) was compared between patients with neoadjuvant/adjuvant chemotherapy and without, stratified for MSI status, by Kaplan-Meier and Cox regression analysis. Results: From a total of 1,844 clinically advanced patients with resection, MSI status was available in 559 as determined by IHC in 420, NGS in 88, and both in 51 with a concordance rate of 50/51 (98%). Tumors were dMMR/MSI-high in 84 (15%) and pMMR/MSS in 475 (85%). Patients with dMMR/MSI-high tumors were more often older, female, and had distal tumors with intestinal subtype. Neoadjuvant and/or adjuvant chemotherapy was administered in 53 (63%) in the dMMR/MSI-high group and 367 (77%) in the pMMR/MSS (p = 0.006). Median (interquartile range) time of follow-up was 32 (19-57) months. In the total cohort, OS after 3 years was 82% in the dMMR/MSI-high and 59% in pMMR/MSS (p < 0.001). In the patients with neoadjuvant/adjuvant chemotherapy only, the dMMR/MSI-high had improved OS (3-years OS: 80% vs 60%, p = 0.001), and after adjustment for age and clinical tumor stage in multivariable analysis, dMMR/MSI-high status was associated with improved OS (HR 0.38 95%CI 0.22-0.68). In the dMMR/MSI-high group only, 3-year OS was 80% with chemotherapy vs 86% without (p = 0.374), and chemotherapy was not associated with a difference in OS after multivariable analysis (HR 1.03 95%CI 0.40-2.66). In case of neoadjuvant chemotherapy, grade 1 pathological response ( > 90%) was observed in 1/41 (2.4%) of the dMMR/MSI-high tumors vs 43/278 (16%) of the pMMR/MSS tumors respectively (p = 0.026). Conclusions: The incidence of MSI-high tumors in our cohort of clinically locally advanced, resectable, gastric cancers was 15%. Patients with MSI-high tumors had worse pathological treatment response to neoadjuvant chemotherapy, but better OS, compared to microsatellite stable tumors. However, in patients with MSI-high tumors, OS was not altered by neoadjuvant/adjuvant chemotherapy. We recommend assessing MSI status in locally advanced gastric cancer.

Background: To determine the frequency and prognostic impact of ALK-rearrangements in gastric cancer patients who underwent curative surgical resection with extensive (D2) lymph node dissection. Patients and methods: We concurrently analyzed the ALK-rearrangements and HER2 overexpression in whole tumor sections of 455 curatively resected gastric cancers. We performed immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), and analyzed the relationship between ALK positivity and clinical survival outcome. Results: Of the 455 tumors that were screened, 38 (8.4%) were ALK+ by IHC, which consisted of 1+ (24, 7.5%), 2+ (3, 0.7%), and 3+ (1, 0.2%), but no cases were confirmed by FISH. ALK+ patients were significantly younger (57 vs. 61 years, P=0.02) and showed similar patterns of ALK+ lung adenocarcinoma. ALK+ patients were significantly more likely to have abundant signet ring cells (defined as ≥ 10% of tumor cells). Moreover, as the ALK intensity (measured by IHC) increased, so did the density of signet ring cell in tumors (Ptrend = 0.02). Also, the disease free survival (DFS) and overall survival (OS) of ALK+ patients in stages were shorter than ALK- patients (DFS: 21.2 vs.100.5 months; P = 0.007, OS: 34.3 months vs. median survival time unattainable; P=0.016) Conclusions: ALK+ is an independent negative prognostic factor in surgically resected gastric cancers and is associated with signet ring cell histology. Furthermore ALK+ might be a relevant therapeutic target in gastric cancer patients. Citation Format: Hongjae Jeon, HyeRyun Kim, Sung Hoon Noh, Hyun Cheol Chung, Sun Young Rha. The clinicopathological features and prognostic impact of ALK-positivity in resected gastric or gastro-esophageal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 566. doi:10.1158/1538-7445.AM2014-566

Prognostic significance of microsatellite instability in patients with resectable gastric cancer

Anastomotic leak predicts diminished long-term survival after resection for gastric and esophageal cancer

4026 Background: In recent years, several studies suggest that neoadjuvant treatment improve outcomes of patients with resectable advanced gastric cancer (GC). In addition, nivolumab has demonstrated clinical efficacy in multiple types of advanced cancer, and the efficacy of neoadjuvant nivolumab monotherapy has been suggested in a past clinical trial in patients with resectable non-small cell lung cancer (NSCLC). Therefore, this phase I study was planned to evaluate the safety and efficacy of neoadjuvant nivolumab monotherapy in patients with resectable GC or NSCLC. Here we report preliminary results from GC patients. Methods: This study is a phase I, multicenter, open-label, single arm study to evaluate the safety and efficacy of neoadjuvant nivolumab monotherapy in patients with resectable GC (stage I or II [cT2 or more advanced for both], or stage III) before standard surgery. Nivolumab 240 mg was administered twice every two weeks. The primary endpoint is safety. Efficacy endpoints include major pathological response (MPR) defined as residual disease < 10% and the response of primary lesion, and surgical endpoints include proportion of patients undergoing surgery with curative intent and R0 resection rate. Biomarkers such as PD-L1 expression and MSI status are also evaluated. Results: From November 2018 to December 2019, 31 GC patients were enrolled into this study. The median age was 69 years (range, 44-84) and 21 patients (67.7%) were men. According to UICC 8th, clinical stage was stage I in 7 patients (22.6%), stage IIA in 0 patients (0%), stage IIB in 14 patients (45.2%), and stage III in 10 patients (32.3%). MSI status was high in 7 patients (22.6%), low in 4 patients (12.9%), and stable in 20 patients (64.5%). Treatment-related adverse events (TRAEs) occurred in 7 patients (22.6%). The most frequent TRAE was rash which occurred in 2 patients (6.5%); the other TRAEs occurred in 1 patient each. Asymptomatic lipase increased was the only grade 3 TRAE; the other TRAEs were all grade 1 or 2 with no new safety signal. All enrolled patients completed 2 doses of nivolumab. Five patients (16.1%) had MPRs, of whom 1 patient had pathological complete response (pCR). Four of 5 MPRs, 1 pCR included, was observed in 7 MSI-H patients (57.1%) and the remaining case of MPR was observed among 20 MSS patients (5%), whereas no MPRs was achieved in 4 MSI-L patients. Among the 31 patients, 30 patients underwent surgery. The remaining 1 patient discontinued the study before surgery due to disease progression. A total of 27 patients (90%) had R0 resection. Conclusions: Neoadjuvant nivolumab monotherapy showed acceptable safety profile and antitumor activity in patients with resectable GC. Recurrence free survival and overall survival in these patients are under follow-up. Clinical trial information: JapicCTI-183895. Clinical trial information: JapicCTI-183895.

We examined the association between surgical hospital volume and both overall survival (OS) and disease-free survival (DFS) using data obtained from the international CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. In the CRITICS trial, patients with resectable gastric cancer were randomized to receive preoperative chemotherapy followed by adequate gastrectomy and either chemotherapy or chemoradiotherapy. Patients in the CRITICS trial who underwent a gastrectomy with curative intent in a Dutch hospital were included in the analysis. The annual number of gastric cancer surgeries performed at the participating hospitals was obtained from the Netherlands Cancer Registry; the hospitals were then classified as low-volume (1-20 surgeries/year) or high-volume (≥21 surgeries/year) and matched with the CRITICS trial data. Univariate and multivariate analyses were then performed to evaluate the hazard ratio (HR) between hospital volume and both OS and DFS. From 2007 through 2015, 788 patients were included in the CRITICS trial. Among these 788 patients, 494 were eligible for our study; the median follow-up was 5.0 years. Five-year OS was 59.2% and 46.1% in the high-volume and low-volume hospitals, respectively. Multivariate analysis revealed that undergoing surgery in a high-volume hospital was associated with higher OS [HR = 0.69, 95% confidence interval (CI) = 0.50-0.94, P = 0.020] and DFS (HR = 0.73, 95% CI: 0.54-0.99, P = 0.040). In the CRITICS trial, hospitals with a high annual volume of gastric cancer surgery were associated with higher overall and DFS. These findings emphasize the value of centralizing gastric cancer surgeries in the Western world.

Helicobacter pylori (H pylori) infection is a known risk factor for gastric cancer (GC) and has been linked with gastroesophageal junction (GEJ) cancer. Studies examining the relationship between H. pylori infection, GC characteristics and prognosis are limited and have yielded conflicting results. We report on the clinicopathologic characteristics and oncologic outcomes of gastric and GEJ cancer patients with and without a history of H. pylori treated at our institution. We retrospectively reviewed the medical records of patients over the age of 18 years who underwent curative resection for GEJ and GC at Mount Sinai Hospital between 2007 and 2012 who had histopathologic documentation of the presence or absence of H pylori infection. Demographic, clinical, pathologic, treatment characteristics and outcomes including recurrence-free survival (RFS) and overall survival (OS) were compared. Ninety-five patients were identified. The majority of patients were male (61%), white (36%) or Asian (34%), with median age at diagnosis 64. Tumors were stage I (51%), stage II (23%), stage III (25%), and stage IV (1%). H pylori infection status was documented at the time of cancer diagnosis in 89 (94%) patients, and following cancer diagnosis and treatment in 6 (6%) patients. Younger age at diagnosis, Asian race and Lauren histologic classification were associated with H Pylori infection. H pylori positive patients exhibited higher 5-year OS and 5-year RFS compared to H pylori negative patients, though the difference was not statistically significant in either univariate or multivariate analyses. In this retrospective series of predominantly early stage GC and GEJ cancers, H. pylori positive patients were significantly younger at cancer diagnosis and were more frequently Asian compared to H. pylori negative patients. Other demographic and histologic classifications except for Lauren histologic classification were similar between the two groups. H pylori positive patients appeared to have improved outcomes compared to H. pylori negative patients.

Overall survival with or without adjuvant radiotherapy among different molecular subtypes of endometrial cancer (211)

No consensus exists on the optimal therapy for resectable gastric cancer (GC) and gastroesophageal junction (GEJ) tumors, including the effectiveness of chemoradiotherapy versus perioperative chemotherapy (PC). Our study aimed to compare overall survival (OS) outcomes associated with the recommended treatment modalities for GC and GEJ tumors and evaluate treatment trends from 2010 to 2020. A national registry cohort identified patients with ≥ cT2 nonmetastatic GC and GEJ cancer. Treatment modalities were classified as neoadjuvant chemotherapy (NC), neoadjuvant chemoradiotherapy (NCR), PC, adjuvant chemotherapy (AC), and adjuvant chemoradiation (ACR). Kaplan-Meier curve and multivariable Cox regression models evaluated factors associated with OS. A cohort of 7665 patients were included. Patients who received PC had the highest OS (median 86.80 months, 95% CI 73.40-NE), while chemoradiotherapy in the neoadjuvant and adjuvant settings had worse OS than PC and NC (NCR median 47.15 months, 95% CI 44.58–52.27, and ACR median 52.67 months, 95%CI 42.78–63.93). The Cox proportional hazards model showed that NCR and NC had worse survival than PC (HR 1.74, 95% CI 1.50–2.02, p < 0.001 and HR 1.26, 95% CI 1.10–1.44, p = 0.0008, respectively). Additionally, the most utilized modality during 2020 was NC (35.8%), followed by PC (28.0%) and NCR (24.9%). The utilization of PC and NC had the most substantial rise between 2010 and 2020, increasing by 11.0%. The study demonstrates the association of PC with improved OS outcomes for nonmetastatic GC and GEJ tumors. Therapies combining radiation with chemotherapy and extended lymph node dissection correlated with a worse prognosis compared to PC and NC. Despite the association with improved outcomes, national data reveals low utilization rates for PC.

ABSTRACTBackgroundMolecular targeted therapy and immunotherapy have shown promise in managing gastric adenocarcinoma. The amplified expression of Human epidermal growth factor receptor‐2 (HER‐2) and microsatellite stable (MSI) status serve as indicators of response to targeted therapy and immunotherapy, respectively.AimsThis study assessed the frequency of MSI status and HER‐2 expression in a pretreated sample of Iranian patients with gastric and gastroesophageal (GE) adenocarcinoma.Methods and ResultsWe conducted HER‐2/neu expression and mismatch repair (MMR) system analyses on specimens from patients with gastric and GE adenocarcinoma at the Cancer Institute of Iran. Archival tissues from 135 mainly pre‐treated surgical specimens of gastric adenocarcinoma cases were used for HER‐2 analysis, and 66 specimens were used for MSI analysis. All specimens were tested for HER‐2 amplification, revealing that 11 patients (8.1%) had HER‐2 amplification, and three out of 66 examined patients exhibited MSI‐H. Patients with HER‐2 overexpressed specimens had a shorter median overall survival (OS) compared with HER‐2 negative cases (21 months (95% CI: 1.4–40.6) vs. 31 months (95% CI: 22.9–39), p = 0.18). The median disease‐free survival (DFS) for HER‐2 positive and negative patients was 15 and 28 months, respectively (p = 0.25). The estimated median OS and DFS for patients with negative MSI were 26 and 20 months, respectively. However, none of the patients with MSI‐positive status experienced recurrence, metastases, or death within the follow‐up period; thus, MSI‐H patients had a significantly improved OS and DFS (p = 0.018 and 0.020).ConclusionHER‐2 expression, while less common in our Iranian population compared with North American or Western European countries, showed a nonsignificant trend toward poor outcomes in patients with gastric adenocarcinoma. MSI‐H status was highly infrequent in our population, suggesting that immunotherapy may not be a beneficial treatment for a significant fraction of Iranian patients with gastric adenocarcinoma. However, a minority may still benefit from it. MSI‐H was associated with reduced perineural invasion and improved OS and DFS. Therefore, this hypothesis warrants further investigation in clinical trials to underscore the prognostic significance of HER‐2 and MSI status and the value of molecular profiling in guiding personalized treatment strategies.

23 Background: To validate the prognostic relevance of macroscopic serosal changes in patients with resected GC, we analyzed prospectively collected databases of two multicenter randomized phase III trials on adjuvant chemotherapy. Methods: In total, 655 patients in the control groups of AMC 0101 (NCT00296322) and 0201 (NCT00296335) trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time-to-peritoneal recurrence were analyzed. Results: About two-thirds of the patients were male (69%), and the median age was 55 years (range = 29–70 years). According to Lauren’s classification, 215 patients (33%) showed intestinal type. After a median follow-up period of 61.6 months (range = 2.6–113.9 months), the 5-year RFS and OS rates were 55.0% (95% CI = 51.2–58.9%) and 59.9% (95% CI = 56.2–63.6%), respectively. Intraoperatively assessed macroscopic serosal changes were identified in 432 patients (66%). This was significantly associated with multifocal or diffuse gastric cancer (p = 0.001), Borrmann type IV (p = 0.005), advanced pathological T stage (p &lt; 0.001), advanced pathological N stage (p &lt; 0.001), advanced pathological stage (p &lt; 0.001), and total gastrectomy (p &lt; 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopically serosal changes were significantly associated with poor RFS (hazard ratio [HR] = 2.0, 95% CI 1.4–2.7; p &lt; 0.001) and OS (HR = 2.1, 95% CI 1.5–3.0; p &lt; 0.001). It was also significantly related with shorter time-to-peritoneal recurrence (HR = 2.9; 95% CI = 1.7–5.0; p&lt; 0.001). Conclusions: Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence in patients with curatively resected GC. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected GC in terms of prognosis and peritoneal recurrence.

Patients who receive trastuzumab (T-mab) plus chemotherapy for stage IV HER2-positive gastric or gastroesophageal junction cancer sometimes respond remarkably well and can undergo radical surgery. However, the clinical outcomes of preoperative T-mab combined chemotherapy with radical gastrectomy remain unclear. We conducted this study to investigate the clinical outcomes of this multimodal treatment. From among a total of 199 patients who received T-mab-based chemotherapy for stage IV HER2-positive gastric or gastroesophageal junction cancer between 2011 and 2018, the subjects of this retrospective analysis were 20 patients who subsequently underwent radical gastrectomy. Seven patients had gastroesophageal junction cancer and 13 had gastric cancer. Eleven patients had unresectable stage IV cancer and 9 had resectable metastatic disease. Chemotherapy regimens included capecitabine, cisplatin + T-mab (11 patients), and S-1, oxaliplatin + T-mab (nine patients). The median number of chemotherapy cycles before surgery was three (range, 2-62). During preoperative chemotherapy, grade 3/4 adverse events developed in six patients. None suffered grade ≥ 3b postoperative complications. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 58.9% and 89.5%, respectively. Combined preoperative T-mab-based chemotherapy and surgery appears to be safe and effective for stage IV HER2-positive gastric or gastroesophageal junction cancer, with a clinically meaningful impact on RFS and OS.

BackgroundThe occurrence of a venous thromboembolism (VTE) is common in patients with cancer. Gastric cancer has been associated with one of the highest risks for VTE. Chemotherapy, especially cisplatin has been associated with a high VTE risk. In this study, risk factors for VTE occurrence and their potential impact on subsequent therapeutic interventions were investigated in patients who underwent preoperative chemotherapy, in the CRITICS gastric cancer trial.Patients and methodsPatients with resectable gastric cancer were preoperatively treated with three cycles of 3‐weekly epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC). VTE was defined as any thrombus in the venous system, excluding superficial and/or device related VTEs. Potential risk factors were analyzed in a multivariable regression model with age, gender, Body Mass Index (BMI), tumor localization, Lauren classification, type of chemotherapy (ECC/EOC), (cardiovascular) comorbidity, and previous VTE as independent risk factors. The impact of VTE on completion rate of preoperative chemotherapy, surgical resection rate, postoperative complications, and start of postoperative therapy were investigated.ResultsOf 781 patients, 78 (10%) of 781 patients developed a VTE during preoperative chemotherapy. On multivariable analysis, BMI ≥ 30 kg/m2 and previous VTE were associated with VTE occurrence (reference BMI < 25 kg/m2; OR 2.190; 95% CI 1.152‐4.164; P = .017/previous VTE; OR 3.617; 95% CI 1.201‐10.890; P = .022). Treatment with cisplatin was, compared to oxaliplatin, not significantly associated with VTE occurrence (OR 1.535; 95% CI 0.761‐3.094; P = .231). VTE occurrence did not affect completion of preoperative chemotherapy, surgical resection rate, postoperative complications, or start of postoperative therapy.ConclusionHigh BMI and previous VTE were independent risk factors for VTE occurrence during preoperative chemotherapy in patients with resectable gastric cancer. VTE occurrence in the preoperative setting did not affect receipt of further treatment.

To investigate the expression and prognostic role of pyruvate dehydrogenase (PDH) in gastric cancer (GC). This study included 265 patients (194 male, 71 female, mean age 59 years (range, 29-81 years) with GC who underwent curative surgery at the First Affiliated Hospital of China Medical University from January 2006 to May 2007. All patients were followed up for more than 5 years. Patient-derived paraffin embedded GC specimens were collected for tissue microarrays (TMAs). We examined PDH expression by immunohistochemistry in TMAs containing tumor tissue and matched non-neoplastic mucosa. Immunoreactivity was evaluated independently by two researchers. Overall survival (OS) rates were determined using the Kaplan-Meier estimator. Correlations with other clinicopathologic factors were evaluated by two-tailed χ(2) tests or a two-tailed t-test. The Cox proportional-hazard model was used in univariate analysis and multivariate analysis to identify factors significantly correlated with prognosis. Immunohistochemistry showed that 35.47% of total cancer tissue specimens had cytoplasmic PDH staining. PDH expression was much higher in normal mucosa specimens (75.09%; P = 0.001). PDH expression was correlated with Lauren grade (70.77% in intestinal type vs 40.0% in diffuse type; P = 0.001), lymph node metastasis (65.43% with no metastasis vs 51.09% with metastasis; P = 0.033), lymphatic invasion (61.62% with no invasion vs 38.81% with invasion; P = 0.002), histologic subtypes (70.77% in intestinal type vs 40.0% in diffuse type; P = 0.001) and tumor-node-metastasis (TNM) stage (39% in poorly differentiated vs 65.91% in well differentiated and 67.11% in moderately differentiated; P = 0.001) in GC. PDH expression in cancer tissue was significantly associated with higher OS (P < 0.001). The multivariate analysis adjusted for age, Lauren classification, TNM stage, lymph node metastasis, histological type, tumor size, depth of invasion and lymphatic invasion showed that the PDH expression in GC was an independent prognostic factor for higher OS (HR = 0.608, 95%CI: 0.504-0.734, P < 0.001). Our study indicated that PDH expression is an independent prognostic factor in GC patients and that positive expression of PDH may be predictive of favorable outcomes.

Human epidermal growth factor receptor 2 (HER2) is a key pathological characteristic of gastric cancer (GC). However, the clinical significance of HER2 expression in gastric carcinoma remains controversial. The purpose of this study was to analyze the clinicopathological characteristics of HER2 protein expression, Lauren classification and tumor protein p53 (P53) expression and to evaluate the clinical significance of HER2 protein expression. A total of 176 consecutive patients were prospectively recruited between January 2014 and December 2016 at the Second Affiliated Hospital of Zhejiang University School of Medicine. Histological analysis of the resected tissue was performed for HER2 protein expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Additionally, the expression status of HER2 protein and clinicopathological features were analyzed using the chi-squared (χ2) test. Survival analysis was performed using the Kaplan–Meier method, and differences between the survival curves were determined using the log-rank test. All statistical analyses were conducted using SPSS 22.0 statistical software program (IBM Corp., Armonk, NY). A total of 176 patients with GC were enrolled in this study. Intratumoral heterogeneity of HER2 protein overexpression was observed in 42 of 176 cases with IHC grade 2+, accompanied by FISH positivity and IHC grade 3+. HER2 protein expression was correlated with tumor differentiation (P < .001), Lauren classification (P = .001), Borrmann type (P = .003) and P53 expression (P < .001). HER2 protein positivity was associated with significantly higher overall survival (OS) (P = .038). Overexpression of HER2 protein was observed in 23.9% of the cases and was significantly related to the Lauren intestinal subtype and P53 negative expression. HER2 protein overexpression was independently associated with higher OS.