Takeshi Kotake

The combination of HLA-B*15:01 and DRB1*15:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer

PurposeIn a phase III study of gemcitabine plus erlotinib for advanced pancreatic cancer conducted in Canada, the incidence of interstitial lung disease (ILD) was 3.5xa0%. However, the incidence of ILD was reported as high as 8.5xa0% in a Japanese phase II study. These results suggest the influence of ethnic factors in the association of the use of gemcitabine plus erlotinib with the incidence of ILD. Here, we conducted a prospective study to analyze the relationship between human leukocyte antigen (HLA) alleles and ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.MethodsPatients were treated with gemcitabine (1000xa0mg/m2; administered by intravenous infusion on days 1, 8, and 15 every 4xa0weeks) and erlotinib (given orally at 100xa0mg/day). We compared the frequencies of HLA alleles in patients who did and did not develop ILD.ResultsA total of 57 patients were treated, and 4 patients (7.0xa0%) developed ILD. The combination of HLA-B*15:01 and DRB1*15:01 was observed in 2 of 4 patients (50xa0%) with ILD and in only 1 of 53 patients without ILD (2xa0%) resulting in odds ratio of 52.0 (95xa0% CI 3.2–842.5; pxa0=xa00.011).ConclusionThese results suggest that the combination of HLA-B*15:01 and DRB1*15:01 is associated with ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.

Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study

BackgroundFOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC).MethodsPatients received combination therapy consisting of panitumumab (6xa0mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85xa0mg/m2, and folinate (LV) 200xa0mg/m2] on day 1, followed by fluorouracil (5-FU) 3200xa0mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2xa0weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165xa0mg/m2).ResultsSeven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9–100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4–7.3) months.ConclusionThe FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

Abemaciclib for the treatment of breast cancer

ABSTRACT Introduction: There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy. However, currently, besides oestrogen receptor expression, there is a definite lack of predictive biomarkers for response and/or tolerance to abemaciclib, which is important for patient selection. Another problem is that its contribution to overall survival (OS) has not been shown. And while two large the phase 3 study highlighted the anti-tumour effect of abemaciclib, the OS results are awaited. Furthermore, the effect on brain metastases is expected to be unique to abemaciclib as the response of brain metastasis in HR-positive breast cancer patients has been confirmed in a few cases with case collection still ongoing.

Gene expression profile of peripheral blood mononuclear cells may contribute to the identification and immunological classification of breast cancer patients

BackgroundIt has been reported that the gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits a unique gene expression signature in several types of cancer. In this study, we aimed to explore the breast cancer patient-specific gene expression profile of PBMCs and discuss immunological insight on host antitumor immune responses.MethodsWe comprehensively analyzed the gene expression of PBMCs by RNA sequencing in the breast cancer patients as compared to that of healthy volunteers (HVs). Pathway enrichment analysis was performed on MetaCoretm to search the molecular pathways associated with the gene expression profile of PBMCs in cancer patients compared with HVs.ResultsWe found a significant unique gene expression signature, such as the Toll-like receptor (TLR) 3- and TLR4-induced Toll/interleukin-1 receptor domain-containing adapter molecule 1 (TICAM1)-specific signaling pathway in the breast cancer patients as compared to that of healthy volunteers. Distinctive immunological gene expression profiles also showed the possibility of classifying breast cancer patients into subgroups such as T-cell inhibitory and monocyte-activating groups independent of known phenotypes of breast cancer.ConclusionsThese preliminary findings suggest that evaluation of gene expression patterns of PBMCs might be both a less invasive diagnostic procedure and a useful way to reveal immunological insight of breast cancer, including biomarkers for cancer immunotherapy, such as immune checkpoint inhibitor therapy.

Prevalence and risk factors of hepatitis B virus reactivation in patients with solid tumors with resolved HBV infection

Reports of hepatitis B virus (HBV) reactivation in solid tumors are very limited, and their frequencies and risk factors were previously unknown.

First‑line chemotherapy with capecitabine/oxaliplatin for advanced gastric cancer: A phase I study

Combination chemotherapy with capecitabine and oxaliplatin for gastric cancer (G-XELOX) is considered as a potentially promising regimen. However, the use of the G-XELOX regimen in Japanese patients has not been investigated to date, and recommended doses of G-XELOX for Japanese patients with metastatic gastric cancer have not been established. The aim of the present study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for systemic chemotherapy with G-XELOX for metastatic gastric cancer. The enrolled patients received systemic chemotherapy with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day, b.i.d. for 14 days, repeated every 3 weeks. A decrease in oxaliplatin dose was planned from start level 1 (130 mg/m2). A total of 6 patients were enrolled between January and July 2015. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d. could be administered with acceptable toxicity, and all patients were treated at these doses. One case of grade 3 stomatitis was considered as a dose-limiting toxicity at level 1; however, excluding this case, no grade 3 or 4 non-hematological toxicity was observed. There were no treatment-related deaths. The median relative dose intensity was 71.3% for capecitabine and 92.1% for oxaliplatin. Of the 6 patients, 3 had measurable lesions according to the Response Evaluation Criteria In Solid Tumors; the response rate and disease control rate were both 67%. Therefore, systemic chemotherapy with G-XELOX was well-tolerated by patients with advanced gastric cancer. The RD was defined as oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d.

Phase I study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PI)

Background The prognosis of locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. One promising approach is neoadjuvant chemotherapy. Combination chemotherapy with S-1 and oxaliplatin (SOX) is recognised as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of SOX for locally advanced gastric cancer has not been reported. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with SOX for locally advanced gastric cancer. Methods Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as S-1 (80u2009mg/m2/day, twice daily) for 14 days, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph node dissection followed by adjuvant S-1 (80u2009mg/m2/day, twice daily) for 1 year. Escalation of oxaliplatin dose was planned (starting at level 0, oxaliplatin 100u2009mg/m2; level 1, 130u2009mg/m2). Results Six patients were enrolled. MTD was not reached at level 1. Oxaliplatin 130u2009mg/m2 in combination with S-1 80u2009mg/m2/day twice daily could be administered with acceptable toxicity. Peripheral neuropathy was observed in all patients but with no functional disorders. No treatment-related death was observed and the incidence of operative morbidity was tolerable. Resection with curative intent was undertaken in all patients with R0 resection performed in five (83%) and R1 in one. Two of the six patients had a pathological complete response (33%). Conclusion Neoadjuvant chemotherapy with an SOX regimen was feasible in patients with locally advanced gastric cancer. The recommended phase II dose was determined to be oxaliplatin 130u2009mg/m2 in combination with S-1 80u2009mg/m2/day, twice daily.

Abstract 3697: The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast cancer

Triple negative breast cancer (TNBC) is still difficult to treat partly because of lacking specific target. Although 50-70% of TNBC expresses EGFR, it is less sensitive to the treatment of EGFR inhibition for TNBC as compared to the efficacy of HER2 inhibition for HER2-positive breast cancer. Several phase II study on EGFR blockade treatment has been reported, however it has not applied in a clinical setting yet. It was reported that residual tumors after treatment with EGFR-targeted antibodies showed increased HER3 abundance leading to EGFR/HER3 receptor dimerization. The signals of HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and also up-regulation of PD-L1 expression. Thus, we hypothesized that up-regulation of HER3 signal caused by anti-cancer treatment might induce PD-L1 expression and inhibit host anti-tumor immunity. In this study, we tested the relationships between HER3 signal and PD-L1 expression by using three basal-like breast cancer cell line; MDA-MB-231, HCC70, and MDA-MB-468. MDA-MB-231 is HER3-negative, and HCC70 and MDA-MB-468 are HER3-positive cell lines. We added neureglin 1 (NRG1: HER3 ligand) to those three cell lines and analyzed PD-L1 expression of protein by flowcytometry and mRNA by qRT-PCR. Both protein and mRNA level of PD-L1 on HCC70 and MDA-MB-468 treated with NRG1 are increased as compared with those without NRG1 while there was no change of PD-L1 expression of MDA-MB-231 either with or without NRG1. In order to confirm the significance of potential treatment target of HER3, we evaluated HER3 expression in biopsy samples by immunohistochemistry before neoadjuvant chemotherapy (NAC) including all phenotypes. Thirteen pathological complete response (pCR) cases after NAC and 6 non pCR cases were included. We scored the HER3 stainability from 0 to 3 and found that non pCR cases showed significantly higher HER3 score than pCR cases (84.6% and 33% respectively, p=0.0149). Although further study is needed, these results suggest that HER3 signal possibly regulates PD-L1 expression in HER3-positive basal-like breast cancer and treatment with anti-HER3 targeting therapy combination with an immune checkpoint inhibition therapy for HER3 positive NAC resistant patients might be warranted. Note: This abstract was not presented at the meeting. Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Masakazu Toi. The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3697. doi:10.1158/1538-7445.AM2017-3697

Abstract 5706: Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test

It is reported that gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits unique gene expression signature in cancer patients including renal cell carcinoma, pancreatic cancer and lung cancer. Since pancreatic cancer diagnosis is difficult in not only early detection of the disease but also in the diagnosis itself, development of novel diagnostic tools in addition to conventional diagnostic strategy has been awaited. On the other hand, in breast cancer, because early diagnosis by mammography and ultra sound examination on breast is established successfully, exploration of gene expression profile of PBMCs may be important in terms of insight to host antitumor immune response aspects. In the current study, we performed RNA sequencing (RNA-seq) analysis on RNA of PBMCs from 3 healthy volunteers, 6 early and 7 metastatic breast cancer patients including all phenotypes defined by ER, PgR and HER2. Genes that showed FDR These findings suggested that evaluation of gene expression patterns of PBMCs of breast cancer patients might distinguish breast cancer patients from healthy subjects and the gene expression signature of PBMCs which divided breast cancer patients into 3 groups might reveal immunologically important biologic properties such as response prediction of cancer immunotherapy including immune checkpoint inhibition treatment. Citation Format: Eiji Suzuki, Kosuke Kawaguchi, Masahiro Sugimoto, Fengling Pu, Ryuji Uozumi, Ayane Yamaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Satoshi Morita, Masakazu Toi. Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5706. doi:10.1158/1538-7445.AM2017-5706

P1-104Feasibility study of FOLFIRINOX as first-line chemotherapy for metastatic pancreatic cancer (KOBE FOLFIRINOX study)

Results: RAS mutations testing of 32 mCRC pts were 15 RAS wild-type(wt) and 17 RAS mutant type(mt) (KRAS exon2 mt: other RAS mt 11:6). The proportion of Rigt side tumor location(cecumtransverse colon) was more in RAS mt(35.3%) than in RAS wt(20.0%).Medical condition of 32 pts was ’fit’condition of 27 pts (RAS wt:mt 14:13) and ’may be unfit’condition of 5 pts (RAS wt:mt 1:4) .Among 14 RAS wt and ’fit’condition pts, 7 pts who assign treatment goal to Cytoreduction were chosen Chemothrapy (CT) doublet plus anti-EGFR and 7 pts who assign treatment goal to Disease control were chosen CT doublet plus Bevacizumab(Bmab) as first-line CT. 13 RAS mt and ’fit’condition pts were all chosen CT doublet plus Bmab as first-line CT. Among 5 ’may be unfit’condition pts, 3 pts were chosen reduced CT doublet, 1 pts fluoropyrmidine(FP)þBmab and 1 pts FP as first-line CT. Regarding first Response Rate evaluation of First-line CT(except discontinued and not evaluated pts), RAS wt and ’fit’condition group was 66.7%, RAS mt and ’fit’condition group was 44.4%,and ’may be unfit’condition group was 25.0%. By undergoing first-lineCT, 4 ’fit’condition pts who assign treatment goal to Cytoreduction became possible for Conversion surgery(RAS wt:mt 3:1).