Tomohiro Matsushima

Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients

BackgroundAfter analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer.MethodsOf the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status.ResultsThe ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab.ConclusionsPatient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.

Early hypertension is associated with better clinical outcomes in gastric cancer patients treated with ramucirumab plus paclitaxel

Anti-vascular endothelial growth factor (VEGF) therapeutics such as bevacizumab, which are widely used in cancer treatment, commonly leads to hypertension. Moreover, bevacizumab-induced hypertension is associated with improved clinical outcomes in several cancers. We retrospectively analyzed 89 patients with histologically confirmed advanced gastric cancer who received the human monoclonal anti-VEGF receptor-2 antibody ramucirumab plus paclitaxel at our hospital between June 2015 and October 2016 to evaluate the impact of treatment-associated hypertension occurring within the first two treatment cycles (“early hypertension”) on outcome. The objective response rate was 40%, median progression-free survival was 5.4 months, and overall survival was 10.4 months, which is similar to previous reports. Early hypertension in patients who received more than two cycles of ramucirumab + paclitaxel was associated with longer progression-free and overall survival. Objective response rates were also higher in patients with early hypertension. These data indicate that early hypertension may be predictive of better outcomes in gastric cancer patients who receive ramucirumab + paclitaxel treatment.

Change in clinical outcomes during the transition of adjuvant chemotherapy for stage III colorectal cancer

Background There are robust data supporting the contribution of oxaliplatin (L-OHP) regarding clinical outcomes for colorectal cancer (CRC) in an adjuvant setting in European and US trials; however, there is no Japanese clinical evidence although L-OHP has been approved since 2009. We examined the transition of adjuvant chemotherapy for stage III colorectal cancer in our institute. Methods A total of 642 patients with histopathologically confirmed stage III CRC underwent curative surgery from 2005 to 2010. We examined disease free survival (DFS), overall survival (OS) and prognostic factors for stage III CRC patients who underwent adjuvant chemotherapy. Results A total of 509 patients received adjuvant chemotherapy. 3-year DFS and 5-year OS rates were 74.5% and 87.5%, respectively. The frequency of inclusion of L-OHP as adjuvant chemotherapy was increased after 2008. A total of 189 patients received adjuvant chemotherapy from 2005 to 2007 increasing to 320 patients from 2008 to 2010; the 5-year OS rates were 82.4% and 91.5%, respectively, and the 3-year DFS rates were 69.2% and 76.6%, respectively (OS, P = 0.007; DFS, P = 0.023). In univariate analysis, adjuvant chemotherapy including L-OHP was no significant deference compared to FU monotherapy. (OS: HR 0.88, 95%CI 0.4–1.91, p = 0.75, DFS: HR 0.78, 95%CI 0.21–2.3, p = 0.29). In multivariate analysis, the OS was predicted by means of N stage (HR = 2; 95%CI, 1.1–3.8; P = 0.02) and pathology (HR = 0.28; 95%CI, 0.13–0.59; P = 0.0008). The DFS was predicted by means of N stage (HR = 2.67; 95%CI, 1.82–3.9; P < 0.05), T stage (HR = 1.61; 95%CI, 1.1–2.3; P = 0.01) pathology (HR = 0.47; 95%CI, 0.29–0.75; P < 0.05) and venous invasion (HR = 2.06; 95%CI, 1.12–3.77; P = 0.01). Conclusions Clinical outcomes of stage III CRC patients receiving adjuvant chemotherapy improved. The frequency of L-OHP usage was increasing annually, however it was no influence for clinical outcomes in this study. It will be necessary to reevaluate additional effect of L-OHP with more patients.

Efficacy and safety of taxane-monotherapy in advanced gastric cancer refractory to triplet chemotherapy with docetaxel, cisplatin, and S-1: A multicenter retrospective study.

154Background: While taxane-monotherapy following fluoropyrimidine plus platinum is recognized as the standard treatment strategy for advanced gastric cancer, triplet chemotherapy with docetaxel, cisplatin and S-1 (DCS) is another option for first-line therapy in Japan. However, efficacy of taxane after DCS therapy has not been sufficiently evaluated. Methods: We retrospectively evaluated the efficacy and safety of taxane-monotherapy after DCS between January 2010 and April 2015 for advanced gastric cancer. The taxane-monotherapy included weekly paclitaxel (PTX) (80 mg/m2, day 1, 8 and 15 of a 28-day cycle) and triweekly nab-PTX (260 mg/m2, day 1). Other selection criteria were: ECOG PS < 2; adequate organ function; no severe ascites; HER2-negative. Results: Thirty of 92 patients who had been treated with DCS received taxane-monotherapy. Fifteen and 15 patients received taxane-monotherapy as the second and third-line treatment, respectively. Patients characteristics of each group (2nd/3rd) were; median ag...

Association between intratumoral HER2 heterogeneity (IHH) and trastuzumab (T-mab) efficacy in HER2 positive–gastric cancer (GC).

92 Background: ToGA study showed superiority of adding T-mab to standard chemotherapy and a positive correlation between HER2 expression levels and the T-mab efficacy. In gastric cancer IHH is frequently recognized but its clinical impact on T-mab efficacy is unclear. Methods: Patients who were treated with T-mab and had surgical specimens available for IHC test were retrospectively examined. When all tumor cells overexpressed HER2 protein by IHC, the tumor was defined as non-HER2-heterogeneous. The others were defined as HER2-heterogeneous. Progression-free survival (PFS) and overall survival (OS) were estimated using by Kaplan-Meier methods and compared by the log-rank test. The level of significance was set to p<0.05 and all statistical tests were two-sided. Results: 23 patients were enrolled. Their median age was 68 years and 83% were male. PS 0, GEJ cancer, intestinal type histology, visceral metastasis (lung or liver), and previous chemotherapy were found in 57%, 35%, 83%, 57%, and 57% of them, resp...

ACEIs/ARBs to improve survival in advanced gastric cancer patients receiving S-1 plus cisplatin.

174 Background: Gastric cancer is heterogeneous disease and male predominant incidence is recognized across the world. Interactions between tumor cells and microenvironments, such as cancer-associated fibroblasts (CAFs) and M2 macrophage, play an important role in cancer progression and CAFs and M2 macrophage predict worse outcomes in several types of cancer. Angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are widely used in cardiovascular disease because these drugs reduced cardiovascular events via inhibiting fibroblasts and inflammation. Moreover these drugs improved survival in advanced pancreatic cancer gemcitabine (Br J Cancer, Nakai, 2010). Given that CAFs and M2 macrophage are associated worse outcomes and ACEIs/ARBs may inhibit these factors, we hypothesized that these drugs may improve survival in advanced gastric cancer. Methods: Two-hundred and twenty advanced gastric cancer patients were enrolled between Jan. 2007 and Dec. 2011. These pati...