Wei-Wu Chen

The Impact of Diabetes Mellitus on Prognosis of Early Breast Cancer in Asia

BACKGROUND Diabetes mellitus (DM) has been implicated in influencing the survival duration of patients with breast cancer. However, less is known about the impact of DM and other comorbidities on the breast cancer-specific survival (BCS) and overall survival (OS) outcomes of Asian patients with early-stage breast cancer. PATIENTS AND METHODS The characteristics of female patients with newly diagnosed, early-stage breast cancer were collected from the Taiwan Cancer Registry database for 2003-2004. DM status and other comorbidities were retrieved from Taiwans National Health Insurance database. The BCS and OS times of patients according to DM status were estimated via the Kaplan-Meier method. Coxs proportional hazard model was used to estimate adjusted hazard ratios (HRs) for the effects of DM, comorbidities, and other risk factors on mortality. RESULTS In total, 4,390 patients were identified and 341 (7.7%) presented with DM. The 5-year BCS and OS rates were significantly greater in DM patients than in non-DM patients (BCS, 85% versus 91%; OS, 79% versus 90%). Furthermore, after adjusting for clinicopathologic variables and comorbidities, DM remained an independent predictor of shorter BCS (adjusted HR, 1.53) and OS (adjusted HR, 1.71) times. Subgroup analyses also demonstrated a consistent prognostic influence of DM across different groups. CONCLUSION In Asian patients with early-stage breast cancer, DM is an independent predictor of lower BCS and OS rates, even after adjusting for other comorbidities. The integration of DM care as part of the continuum of care for early-stage breast cancer should be emphasized.

High Prevalence of the BIM Deletion Polymorphism in Young Female Breast Cancer in an East Asian Country.

Background A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians. Method Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs. Results Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort. Conclusions BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians.

Abstract 2984: Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Clinically, combination of anti-angiogenic agents with chemotherapeutic agents demonstrated better antitumor efficacy. Instead of merely effect on vasculature regression, careful use of anti-angiogenic therapy may cause the grossly abnormal structure and function of tumor blood vessels to return to a more normal state. Treatment with anti-angiogenic agents can primarily improve chemotherapy efficacy by normalizing tumor vasculature, decrease the intra-tumor interstitial pressure, thereby leading to a more effective drug delivery. We planned to investigate the timing and effect of tumor vascular normalization in human after the administration of anti-angiogenic agent. It may help determine the appropriate timing of administration of chemotherapeutic agents after anti-angiogenic treatment. Materials and methods: This study enrolled the last 8 consecutive patients who participated in a phase II trial for treatment of refractory brain metastases from breast cancer (Eur J Can 49:2s, 2013 suppl; abstr 1878). The protocol treatment consists of bevacizumab 15mg/kg on day 1, chemotherapy of etoposide and cisplatin on day 2 (24 hours after administration of bevacizumab), in 21-day cycles. These 8 patients specifically received four dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations. DCE-MRI was performed before treatment, 1 hour after the end of bevacizumab infusion (i.e., 2.5 hours after starting bevacizumab infusion), 24 hours and 21 days after bevacizumab infusion. This study was registered with ClinicalTrials.gov, identifier [NCT01281696][1], and was approved by the ethical review board. Results: Clinically, all the 8 patients achieved partial remission at central nervous system. All of the 4 DCE-MRI parameters decreased after bevacizumab infusion. Compared to baseline values, the mean reductions at 1 hour and 24 hours were -12.8% and -24.7% for Peak, -46.6% and -65.8% for Slope, -27.9% and -55.5% for iAUC60, -46.6% and -63.9% for Ktrans, respectively (all P values <0.05). The differences between 1 hour and 24 hours reached statistical significance (all P values <0.05) for all the parameters. However, the differences in the mean percentage change between 24 hours and 21 days did not reach significance in any of the four parameters Conclusion: Normalization of tumor vasculature induced by bevacizumab was clearly demonstrated in brain metastases in human at 1 hour after completion of bevacizumab infusion, but significantly became more obvious at 24 hours after bevacizumab administration. Citation Format: Yen-Shen Lu, Bang-Bin Chen, Ching-Hung Lin, Wei-Wu Chen, Pei-Fang Wu, Ann-Lii Cheng, Tiffany Ting-Fang Shih. Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect. [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 2984. doi:10.1158/1538-7445.AM2014-2984 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01281696&atom=%2Fcanres%2F74%2F19_Supplement%2F2984.atom

TP53 Mutational Analysis Enhances the Prognostic Accuracy of IHC4 and PAM50 Assays

IHC4 and PAM50 assays have been shown to provide additional prognostic information for patients with early breast cancer. We evaluated whether incorporating TP53 mutation analysis can further enhance their prognostic accuracy. We examined TP53 mutation and the IHC4 score in tumors of 605 patients diagnosed with stage I–III breast cancer at National Taiwan University Hospital (the NTUH cohort). We obtained information regarding TP53 mutation and PAM50 subtypes in 699 tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. We found that TP53 mutation was significantly associated with high-risk IHC4 group and with luminal B, HER2-enriched, and basal-like subtypes. Despite the strong associations, TP53 mutation independently predicted shorter relapse-free survival (hazard ratio [HR] = 1.63, P = 0.007) in the NTUH cohort and shorter breast cancer-specific survival (HR = 2.35, P = <0.001) in the METABRIC cohort. TP53 mutational analysis added significant prognostic information in addition to the IHC4 score (∆ LR-χ2 = 8.61, P = 0.002) in the NTUH cohort and the PAM50 subtypes (∆ LR-χ2 = 18.9, P = <0.001) in the METABRIC cohort. We conclude that incorporating TP53 mutation analysis can enhance the prognostic accuracy of the IHC4 and PAM50 assays.

Abstract A080: A phase 1 study of single-agent pexidartinib in Asian patients with advanced solid tumors (NCT02734433)

Background: Pexidartinib is a novel, orally active, small-molecule kinase inhibitor that selectively targets the colony-stimulating factor-1 receptor (CSF1R), as well as the receptors c-kit and oncogenic Flt3. Based on these targets, pexidartinib may inhibit tumor growth directly by blocking oncogenic drivers such as CSF-1, c-kit, and Flt3, or indirectly by modulating the tumor microenvironment and interactions between stromal cells and tumors. This first study in Asia evaluated the safety, tolerability, and pharmacokinetic (PK) profile in an Asian population. Methods: This phase 1 non-randomized, open-label, multiple-dose study evaluated the safety and tolerability of pexidartinib in Asian patients with advanced solid tumors. This dose-escalation study employed a 3+3 design and included 2 dose levels. Patients at dose level 1 received 600 mg/day and patients at dose level 2 received 1000 mg/day for the first 2 weeks followed by 800 mg/day thereafter. Patients still receiving treatment after four 28-day cycles were eligible to continue pexidartinib in an extension phase. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Study objectives included assessment of pexidartinib safety and tolerability, PK, and pharmacodynamic effects on circulating CSF-1 and adiponectin, as well as determination of the maximum tolerated and recommended phase 2 doses (MTD and RP2D). Results: Eleven patients (6 males and 5 females, median age 64, range 23-82) were treated with pexidartinib in the dose-escalation phase. Preliminary PK data indicate that exposure (Cmax and AUC0-8h) increased proportionally with dose and the plasma concentration level increased after multiple doses. CSF-1 and adiponectin plasma concentrations increased after administration of pexidartinib. Grade ≥3 adverse events (AEs) observed were increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin, as well as anemia and lower back pain. No patients experienced dose-limiting toxicities, and the MTD was determined to be 1000 mg/day. At the time of this analysis, 7 patients had experienced disease progression, 3 patients had withdrawn from the study, and 1 patient with tenosynovial giant cell tumor continued to receive pexidartinib for more than 341 days. Conclusions: Pexidartinib was determined to be safe and tolerable at the 1000 mg/day dose for Asian patients, and the most common treatment-related AEs were elevated liver enzyme levels. Pexidartinib demonstrated clinical activity in a patient with tenosynovial giant cell tumor, and is being evaluated in a phase 3 study for patients with tenosynovial giant cell tumors in Western countries (NCT02371369). Citation Format: Chia-Chi Lin, Jih-Hsiang Lee, Chih-Hung Hsu, Wei-Wu Chen, Yu-Hsin Yen, Chih-Hsin Yang, Ling Zhang, Shun-ichi Sasaki, Lillian Chiu, Ann-Lii Cheng. A phase 1 study of single-agent pexidartinib in Asian patients with advanced solid tumors (NCT02734433) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A080.