Perceived Importance of Breast Cancer Risk Factors: A Survey on 386 Physicians in China.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience.  This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

A Phase I/II study of the combination of lapatinib and oral vinorelbine in HER2-positive metastatic breast cancer.

BACKGROUND: The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is convenient but with uncertain toxicity profiles. A Phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. METHOD: Female MBC patients with HER2 positive were eligible. Lapatinib was given once daily and oral vinorelbine was given on Days 1 and 8 of a 21-day cycle. A 3 + 3 standard dose-escalation rule was applied in the Phase I study. The primary endpoint of the Phase II study was PFS. In the Phase II part, because no DLT was observed in the first 20 patients, vinorelbine dose-escalation was permitted if no significant toxicities after the first cycle was observed. RESULT: From June 2009 to February 2013, 46 patients were enrolled in Phase I (n = 15) and II (n = 31) studies. Median age was 52.8 (range 34.3-84.0); 28 (60.9%) patients were ER positive. In the Phase I study, two patients had DLTs (neutropenia (n = 2), diarrhea (n = 1)). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the Phase II study, 11 patients safely had vinorelbine escalated to 60 mg/m2 on cycle 2. The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) patients had PR; the clinical benefit rate was 38.7%. Six patients had disease control over 2 years. CONCLUSION: Lapatinib 1000 mg and oral vinorelbine 50 mg/m2 were tolerable with manageable toxicities. Escalation to vinorelbine 60 mg/m2 is feasible if no significant toxicities after the first cycle. Clinical efficacy was demonstrated with long-term responders observed.

Increased 5α-reductase type 2 expression in human breast carcinoma following aromatase inhibitor therapy: the correlation with decreased tumor cell proliferation.

Tumor cell proliferation and progression of breast cancer are influenced by female sex steroids. However, not all breast cancer patients respond to aromatase inhibitors (AI), and many patients become unresponsive or relapse. Recent studies demonstrate that not only estrogens but also androgens may serve as regulators of estrogen-responsive as well as estrogen-unresponsive human breast cancers. However, the mechanism underlying these androgenic actions has remained relatively unknown. Therefore, in this study, we evaluated the effects of AI upon the expression of enzymes involved in intratumoral androgen production including 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5), 5α-reductase types 1 and 2 (5αRed1 and 5αRed2) as well as androgen receptor (AR) levels and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). Eighty-two postmenopausal invasive ductal carcinoma patients were enrolled in CAAN study from November 2001 to April 2004. Pre- and post-treatment specimens of 29 cases were available for this study. The status of 17ßHSD5, 5αRed1, 5αRed2, and Ki67 in pre- and post-treatment specimens were evaluated. The significant increments of 5αRed2 as well as AR were detected in biological response group whose Ki67 LI decreased by more than 40% of the pre-treatment level. This is the first study demonstrating an increment of 5αRed2 and AR in the group of the patients associated with Ki67 decrement following AI treatment. These results suggest that increased 5αRed2 and AR following AI treatment may partly contribute to reduce the tumor cell proliferation through increasing intratumoral androgen concentrations and its receptor.

Spatholobus suberectus inhibits cancer cell growth by inducing apoptosis and arresting cell cycle at G2/M checkpoint.

AIM OF THE STUDY: Although herbs have long been alternatively applied for cancer treatment in China, its treatment effects and their potential mechanisms have not been sufficiently investigated. The chinese herb Spatholobus suberectus (SS) is commonly prescribed to cancer patients. In this study, the anti-cancer effect of SS and its molecular mechanisms have been investigated. MATERIALS AND METHODS: The effect of SS on cell proliferation was studied by cell growth assay and flow cytometry on breast cancer cell lines MCF-7 and colon cancer cell line HT-29. The role of SS in apoptosis was studied by flow cytometry, DNA fragmentation assay and mitochondrial membrane potential assay. Expression of proteins associated with cell cycle and apoptosis was determined by Western blot analysis. The in vivo effect of SS was tested in nude mouse cancer xenografts. RESULTS: Cell growth assay showed that SS effectively inhibits tumor cell growth in a dose-dependent manner. Flow cytometry analysis showed that SS could arrest the cell cycle at G2/M checkpoint, which is associated with DNA damage and activation of phosphor-Chk1/Chk2. The pro-apoptotic effect of SS was demonstrated by Annexin V-PI staining and mitochondrial membrane potential assay. In vivo experiments show that the efficiency of SS alone group was superior to docetaxel or to docetaxel and SS combined. No obvious body weight loss or blood toxicity was observed in SS tested animals. CONCLUSIONS: Our data demonstrates that SS is a potential herb for cancer treatment by inhibiting tumor growth via induction of apoptosis and arrest of the cell cycle at G2/M phase.

Survival benefits from lapatinib therapy in women with HER2-overexpressing breast cancer: a systematic review.

Breast cancer is the second cause of cancer mortality worldwide and there is an unmet need for novel anticancer agents. Lapatinib is a novel tyrosine kinase inhibitor for treatment of breast cancer with human epidermal growth factor receptor 2 (HER2) amplification. Given promising results in clinical studies, we investigated the survival benefits of lapatinib use in patients with HER2-overexpressing advanced or metastatic breast cancer. We searched MEDLINE, EMBASE, American Society of Clinical Oncology Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library between 2000 and 2008 for randomized controlled trials where lapatinib was used as single agent or in combination with or following other therapies. Three trials (n=704) met the inclusion criteria. Study quality was assessed by two independent reviewers and meta-analyses were conducted. Significant differences were observed between lapatinib-containing treatments to those without lapatinib in terms of survival. Pooled estimates suggested the hazard ratios of 0.61 [95% confidence interval (CI): 0.50-0.74] for progression-free survival and 0.76 (95% CI: 0.60-0.97) for overall survival. Objective response rate and clinical benefit rate also showed significant differences in favoring the use of lapatinib with odds ratios of 2.15 (95% CI: 1.48-3.11) and 2.23 (95% CI: 1.59-3.12), respectively. Heterogeneity between studies was not observed. In conclusion, addition of lapatinib to conventional anticancer treatment might offer superior survival benefit to patients with advanced metastatic HER2-overexpressing breast cancer. Further investigations on the use of lapatinib in combination with anticancer agents are warranted.

Novel therapeutic strategy for breast cancer: mammalian target of rapamycin inhibition.

BACKGROUND: Mammalian target of rapamycin (mTOR) plays a central role in regulating cellular protein synthesis. Dysregulation of mTOR signaling pathway is strongly associated with tumorigenesis, angiogenesis, tumor progression and drug resistance. Inhibition of mTOR might not only promote cell cycle arrest, but also sensitize resistant cancer cells to chemotherapeutic and other targeted agents. OBJECTIVE: To review and summarize the mechanism of mTOR on regulation of protein synthesis and latest clinical data, and to discuss the novel therapeutic strategy for the use of mTOR inhibitors in the treatment of breast cancer. METHODS: A review of published literatures and conference abstracts obtained from MEDLINE, American Society of Clinical Oncology Meeting and San Antonio Breast Cancer Symposia proceedings for results of previous preclinical and latest clinical studies of mTOR inhibition in breast cancer was performed. CONCLUSIONS: mTOR inhibitors seemed to be potentially useful for the treatment of breast cancer with acceptable safety profile. The challenge remains the identification of suitable candidates with different phenotypes. More structured studies incorporating molecular, clinical and translational research need to be initiated. Future research on mTOR inhibitors for breast cancer should focus on the evaluation of optimal schedule, patient selection and combination strategies to maximize the use of this new class of targeted agents.

Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer.

OBJECTIVES: To evaluate the efficacy and safety of combing aromatase inhibitor (AI) and cyclooxygenase-2 (COX-2) inhibitor neoadjuvantly in postmenopausal patients with invasive hormone-sensitive breast cancer. METHODS: Eighty-two patients were randomly assigned to receive exemestane 25mg daily and celecoxib 400mg twice daily (group A, n=30), exemestane 25mg daily (group B, n=24) and letrozole 2.5mg daily (group C, n=28). RESULTS: All groups showed clinical responses (58.6% for group A, 54.5% for group B and 62.0% for group C) and decrease in tumor area (61.8% for group A, 58.1% for group B and 55.7% for group C). 3 out of 5 patients with complete clinical response were observed from group A and 2 out of 69 patients operated with pathologic complete response were observed in group C. The mean microscopic tumor size was 2.53 cm for group A, 3.05 cm for group B and 2.10 cm for group C. The differences were only statistically significant when group C was compared with group B (P=0.025). The toxicity profiles among groups were satisfactory. CONCLUSION: AI is effective in treating breast cancer and may be safely used preoperatively. The addition of COX-2 inhibitor may provide additional benefit.

Vinflunine: clinical perspectives of an emerging anticancer agent.

BACKGROUND: Vinflunine is a novel second generation of Vinca alkaloid. The binding of vinflunine to tubulin and subsequent cellular arrest in mitosis is the core mechanism of this antineoplastic agent. In addition, its potential vascular-disrupting and antiangiogenic activities uphold further clinical development of this compound. OBJECTIVE: To review and summarise the pharmacological and latest clinical data, and discuss the impact of vinflunine on current treatment regimens. METHODS: A review of published literature and conference abstracts for results of previous preclinical and latest clinical studies in all cancer types was performed. RESULTS/CONCLUSIONS: Noteworthy results from Phase II studies for treatment of non-small cell lung cancer (NSCLC), breast cancer and bladder cancer supported Phase III studies. One of the Phase III studies for treatment of advanced NSCLC showed important results. Encouraging results of combination use of vinflunine and other biologic agents also opened areas to investigate its synergistic or auxiliary role to existing therapies.

Evaluation of neoadjuvant inhibition of aromatase activity and signal transduction in breast cancer.

PURPOSE: To evaluate the efficacy and safety of combing aromatase inhibitor (AI) and signal transduction inhibitor neoadjuvantly in postmenopausal patients with invasive hormone-sensitive breast cancer. PATIENTS AND METHODS: Postmenopausal women with hormone-sensitive breast cancer were given three months of letrozole 2.5mg daily and imatinib 400mg twice daily preoperatively. End-points of this study included clinical and pathologic responses, toxicities, and change in [(18)F]fluorodeoxyglucose (FDG) uptake in tumor. Expression of c-Kit was also evaluated in breast cancer tissue by immunostaining. RESULTS: Thirteen patients, aged 52--78, were accrued. Five patients (38.5%) experienced grade 3 toxicity including neutropenia, skin rash, dermatitis, hypokalemia, shortness of breath, acute coronary syndrome, and acute chronic gastritis. Three patients were withdrawn after two months of treatment due to hematoma in tumor and toxicity. Of the ten evaluable patients, nine patients (90%) achieved clinical partial response and one patient (10%) had stable disease. One patient (10%) achieved pathologic complete response. Average relative changes of FDG uptake was -69.5% among responders. Eight out of 13 tissue samples were tested for c-Kit expression and the expression was detected in all. CONCLUSIONS: In this pilot study, the dramatic response to this neoadjuvant combination treatment warrants further clinical trials. Further investigation on the involvement of c-Kit pathway in the treatment response is also suggested. However, dosage reduction of imatinib may be required to avoid its potential toxicity.

A phase II trial of vinorelbine and pegylated liposomal doxorubicin in patients with pretreated metastatic breast cancer.

The objective of the present study is to investigate the clinical efficacy and tolerance of vinorelbine and pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) with prior taxane and/or anthracycline treatment. A total of 25 patients who previously received taxane- and/or anthracycline-based chemotherapy as first- and/or second-line treatment of MBC were entered into the study and were treated with 20 mg/m2 vinorelbine on day 1 and 8 and 30 mg/m2 PLD on day 1 every 3 weeks. All were evaluated for efficacy, quality of life, and tolerance. Three complete and 6 partial responses were observed in 25 patients for an objective response rate of 36% (95% confidence interval: 17-55%). Eight patients (32%) had stable disease of not less than 3 months and 8 patients (32%) had disease progression. The median progression-free survival was 6.7 months (range, 2-18 months), and the median overall survival was 13.2 months (range, 3-31 months). Severe toxicities (grade 3 or above) were neutropenia (16%) and mucositis (8%). The health-related quality of life assessed before each cycle by specific questionnaire did not differ significantly over the treatment period. The combination of vinorelbine and PLD for anthracycline- and/or taxane-pretreated patients with MBC is an active and safe regimen that does not compromise the quality of life.