Impact of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) on outcomes of postoperative patients with gastric cancer

4053 Background: The clinical significance of biomarkers in resected gastric cancer (GC) remains unclear. Detailed exploratory evaluations are required to better understand the clinical implications of biomarkers. Methods: The study group comprised 87 patients who received chemotherapy for recurrent or residual GC after resection of their primary tumors at National Cancer Center Hospital. The patients received 1 to 5 regimens of chemotherapy (median: 2). Total RNA was isolated from laser-captured tumor cells of the resected cancer specimens, and the gene expressions of TS, DPD, DHFR, ERCC1, MRP1, and 22 other biomarkers related to anticancer drug sensitivity were quantitatively evaluated by a real-time RT-PCR assay. Results: The gene expressions of TS, DHFR, MTHFD, RRM1, and ERCC1 were significantly related to survival ( Table ). Multivariate analysis revealed that high DHFR (p < 0.001, RR = 1.70 [95% CI, 1.28–2.29]) and high TS (p = 0.004, RR = 1.53 [1.15–2.06]) gene expressions were independently related to poor survival. As compared with intestinal type tumors, diffuse type tumors had higher DPD (p < 0.001) and lower Her2 (p < 0.001) gene expressions. As for first line chemotherapy, an analysis of 29 patients treated with S-1, an oral DPD inhibitory fluoropyrimidine, showed that patients with diffuse type tumors tended to respond better (p = 0.13) than those with intestinal type tumors. An analysis of 29 patients treated with cisplatin plus irinotecan as first line therapy showed that low ERCC1 gene expression was slightly but not significantly related to a better response (p = 0.087). Analyses of patients treated with other first line regimens revealed no significant correlation of any biomarker with response. Conclusions: Increased gene expressions of DHFR and TS in surgical specimens are significantly predictors of poor outcomes in postoperative patients with GC. [Table: see text] [Table: see text]

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Evaluation of prognostic factors in gene expression and clinicopathologic characteristics in patients with adjuvant chemotherapy for advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.61 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 61-61

Author(s):

M. Azuma ◽

K. Ishido ◽

A. Takeuchi ◽

A. Naruke ◽

K. Higuchi ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Adjuvant Chemotherapy ◽

Prognostic Factor ◽

Intestinal Type ◽

Diffuse Type ◽

Gene Expressions ◽

Group Iii ◽

Type Group ◽

Group I

61 Background: We reported TS expression is an independent prognostic factor in patients with gastric cancer who received postoperative adjuvant chemotherapy with S-1 at 2010 ASCO GI (abstract 32). These pharmacogenomic finding will help for choosing chemotherapeutic agents for personalized therapy in the future. Our aim was to indicate association of TS expression with clinicopathological characteristics in the same patient population. Methods: 39 patients with stage II or III advanced gastric cancer who underwent gastrectomy were analyzed. These patients received adjuvant chemotherapy with S-1 after surgery. Formalin-fixed, paraffin-embedded tumor tissues were dissected by the laser-captured microdissection technique and analyzed for target gene expressions using a quantitative real-time PCR. Results: There were no significant differences between stage II and III in TS gene expressions. TS expression (low ≤ 0.72, high > 0.72) and histological type (intestinal and diffuse) are evaluated for PFS and OS. Patients were classified as Group I (n = 5); low TS and intestinal type, Group II (n = 14); low TS and diffuse type, Group III (n = 13); high TS and diffuse type and Group IV (n = 7); high TS and intestinal type. There were significant differences between these four groups (Kaplan-Meier survival analysis, log-rank test, PFS: p = 0.0112 OS: p = 0.0128). The survival curve showed longer survival both PFS and OS in Groups 1 > 2 > 3 > 4. In low TS situation (responders as Group I and II), there is a trend in patients with intestinal type had a longer survival compared to diffuse type (Group I > II). In high TS situation (non-responders as Group III and IV), the result are opposite, there is a trend in patients with diffuse type had a longer survival compared to Intestinal type (Group III > IV). Conclusions: These data suggest that TS gene expression levels may be molecular markers of prognostic factor for patients with adjuvant chemotherapy for resectable gastric cancer. S-1 might be effect different behavior by both histological type and TS expression. Prospective studies are needed to validate these preliminary findings. No significant financial relationships to disclose.

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Establishment and validation of prognostic nomograms including HER2 status in metastatic gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.24 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 24-24 ◽

Cited By ~ 1

Author(s):

Takeshi Kawakami ◽

Yukiya Narita ◽

Isao Oze ◽

Shigenori Kadowaki ◽

Nozomu Machida ◽

...

Keyword(s):

Gastric Cancer ◽

Prognostic Factors ◽

Group Performance ◽

Eastern Cooperative Oncology Group ◽

Metastatic Gastric Cancer ◽

Cancer Center ◽

Her2 Status ◽

First Line ◽

Center Hospital ◽

Line Chemotherapy

24 Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer (MGC). There are few reports on nomograms in MGC, while several studies have been published on nomograms for other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors for predicting survival outcome of individual patients with MGC starting first-line treatment. Methods: We used a training set of 838 consecutive patients with MGC starting first-line chemotherapy between 2005 and 2012 in Aichi Cancer Center Hospital (ACC) to establish nomograms that calculate the predicted probability of survival at different time points; overall survival (OS) at 1 and 2 years. The covariates analyzed in this model by Cox proportional hazard models included HER2 status, Eastern Cooperative Oncology Group performance status (PS), history of gastrectomy, serum lactic acid dehydrogenase (LDH), and serum alkaline phosphatase levels (ALP). Nomograms were independently validated using data on 269 consecutive patients with MGC who underwent first-line chemotherapy between 2010 and 2012 in Shizuoka Cancer Center Hospital (SCC). Missing covariate data were estimated using multiple imputation methods. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2-positive. Results: Patient characteristics were as follows: median age, 64 vs. 66 years; ECOG PS 0/1/2, 34%/51%/15% vs. 45%/44%/11%; prior gastrectomy, 42% vs. 39%; 1/ > 1 metastatic sites, 56%/44% vs. 43%/57%; high LDH, 76% vs. 27%; high ALP, 22% vs. 26%; and positive/negative HER2 status, 10%/45% vs. 7%/53%, respectively. At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, 782 and 248 patients had died, and median OS was 12.5 and 12.4 months (P= 1.00), respectively. The nomograms were capable of predicting an OS with a c-index of 0.68 and 0.58. Conclusions: These nomograms may provide objective and approximate prediction of OS for individual MGC patients in clinical settings.

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Is there a role for histology based treatment choice in advanced gastric cancer (GC)?

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.135 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 135-135

Author(s):

Rosalba Barile ◽

Michela Squadroni ◽

Federica Brena ◽

Eleonora Cerchiaro ◽

Valeria Zurlo ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Predictive Factors ◽

Signet Ring Cell ◽

Histological Diagnosis ◽

Intestinal Type ◽

Diffuse Type ◽

First Line ◽

Signet Ring ◽

Ring Cell

135 Background: Medical management of advanced GC is mostly dependent on prognostic assessment based on tumor stage (TNM) and clinical patients (pts)’ characteristics, other than HER2 expression. Prognostic and predictive factors are clearly needed, and histotype could be proposed as a surrogate marker of disease biology. Methods: We retrospectively analyzed pts with advanced GC treated with first line chemotherapy (CT) at Oncology Unit of Humanitas Gavazzeni (Bergamo) and Policlinico Gemelli (Roma). Pts were divided in three subgroups according to histological diagnosis: diffuse type carcinoma, intestinal type carcinoma and signet ring cell carcinoma. HER2 positive tumors were excluded from the analysis. The aim of our analysis was to compare clinical outcomes of metastatic GC pts receiving first line CT according to histological classification (overall survival: OS and Progression Free Survival: PFS). Results: We analyzed 170 pts. Histological diagnosis was as follows: 24.1% (n=41) signet ring cell, 54.4% (n=92) diffuse type, 21.1%(n=37) intestinal type. Pts received a fluoropyrimidine-based doublet containing cisplatin, oxaliplatin or irinotecan; in three drugs regimen anthracycline was added. In diffuse type subgroup OS was: 11.3 months with oxaliplatin based CT, 7.3 months in cisplatin and 6.2 months in irinotecan (p=0.0054); PFS was 5.2, 3.5 and 4.4 months for oxaliplatin, cisplatin and irinotecan based CT respectively (p=0.0036). In signet ring cell carcinomas OS was 12.1 months with oxaliplatin 13.9 with irinotecan, and 5.6 months with cisplatin (p=0.04), and PFS was 6.5, 8.5 and 2.9 months in pts treated with oxaliplatin, cisplatin and irinotecan respectively (p=0.0008). Among pts with intestinal type we did not detect any significant difference in term of OS and PFS comparing first line schedules. Conclusions: Based on our results, histology may be used as a simple, costless and easy tool in advanced gastric cancer treatment management. Clinical use of biomarkers (with the exception for HER2) which are being evaluated as prognostic or predictive factors in GC, is still controversial. In this scenario, the prognostic / predictive value of histology could play a significant role in treatment decision making.

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