Huiping Li

Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial

BACKGROUNDnUtidelone, a genetically engineered epothilone analogue, has shown promise as a potential treatment for breast cancer in phase 1 and 2 trials. The aim of this phase 3 trial was to compare the efficacy and safety of utidelone plus capecitabine versus capecitabine alone in patients with metastatic breast cancer.nnnMETHODSnWe did a multicentre, open-label, superiority, phase 3, randomised controlled trial in 26 hospitals in China. Eligible participants were female patients with metastatic breast cancer refractory to anthracycline and taxane chemotherapy regimens. We randomly assigned participants (2:1) using computer based randomisation and block sizes of 6 to a 21-day cycle of either utidelone (30 mg/m2 intravenously once per day on days 1-5) plus capecitabine (1000 mg/m2 orally twice per day on days 1-14), or capecitabine alone (1250 mg/m2 orally twice per day on days 1-14), until disease progression or unacceptable toxicity occurred. Patients, physicians, and assessors were not masked to treatment allocation; however, an independent radiology review committee used to additionally assess response was masked to allocation. The primary endpoint was centrally assessed (by an independent radiology review committee) progression-free survival, and analysed using the Kaplan-Meier product-limit method in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Follow-up is ongoing. This study is registered at ClinicalTrials.gov, number NCT02253459.nnnFINDINGSnBetween Aug 8, 2014, and Dec 14, 2015, we enrolled and randomly assigned 270 patients to treatment with utidelone plus capecitabine, and 135 to capecitabine alone. Median follow-up for progression-free survival was 6·77 months (IQR 3·81-10·32) for the utidelone plus capecitabine group and 4·55 months (2·55-9·39) for the capecitabine alone group. Median progression-free survival by central review in the utidelone plus capecitabine group was 8·44 months (95% CI 7·95-9·92) compared with 4·27 months (3·22-5·68) in the capecitabine alone group; hazard ratio 0·46, 95% CI 0·36-0·59; p<0·0001. Peripheral neuropathy was the most common grade 3 adverse event in the utidelone plus capecitabine group (58 [22%] of 267 patients vs 1 [<1%] of 130 patients in the capecitabine alone group). Palmar-plantar erythrodysaesthesia was the most prominent grade 3 adverse event in the capacitabine alone group (in 10 [8%] of 130 patients) and was the next most frequent grade 3 event in the utidelone plus capecitabine group (in 18 [7%] of 267 patients). 16 serious adverse events were reported in the combination therapy group (diarrhoea was the most common, in three [1%] patients) and 14 serious adverse events were reported in the monotherapy group (the most common were diarrhoea, increased blood bilirubin, and anaemia, in two [2%] patients for each event). 155 patients died (99 in the combination therapy arm, 56 in the monotherapy arm). All deaths were related to disease progression except for one in each group (attributed to pericardial effusion in the combination therapy group and dyspnoea in the monotherapy group) that were considered possibly or probably treatment-related.nnnINTERPRETATIONnDespite disease progression with previous chemotherapies, utidelone plus capecitabine was more efficacious compared with capecitabine alone for the outcome of progression-free survival, with mild toxicity except for peripheral sensory neuropathy, which was manageable. The findings from this study support the use of utidelone plus capecitabine as an effective option for patients with metastatic breast cancer.nnnFUNDINGnBeijing Biostar Technologies, Beijing, China.

Efficacy and safety of trastuzumab combined with chemotherapy for first-line treatment and beyond progression of HER2-overexpressing advanced breast cancer.

Objective To observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing advanced breast cancer. Methods A total of 90 patients with HER2-overexpressing advanced breast cancer were enrolled in this study. All patients were diagnosed with ductal invasive breast cancer by pathological analysis, and were aged between 31–73 years with a median of 51 years. HER2-positivity was defined as 3(+) staining in immunochemistry or amplification of fluorescence in situ hybridization (FISH, ratio ≥2.0). Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a secondline, third-line, and above treatment in 90, 34, 14, and 6 patients, respectively. The chemotherapy regimen was given according to normal clinical practice. The response rate was evaluated every two cycles, and the primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival curves were estimated by using Kaplan-Meier graphs and were compared by using log-rank test statistics. Multivariate analysis was done using Cox’s proportional hazards regression model, and the level of significance was P<0.05. Results All 90 patients received at least one dose of trastuzumab, and efficacy could be evaluated in 85 patients. The median follow-up was 50 months. In total, 72 (80.00%) patients had visceral metastasis, and 43 (47.78%) patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases. The median PFS for first-line trastuzumab was 10 months (range, 2–59 months), and the median OS after metastasis or initially local advanced disease was 22 months (range, 2–116 months). Conclusions Trastuzumab combined with chemotherapy was active and well-tolerated as a first-line treatment and even beyond progression in HER2-overexpressing advanced breast cancer as a second-line or third-line treatment. However, its efficacy is certainly less beyond this point.

National consensus in China on diagnosis and treatment of patients with advanced breast cancer

The recently available guidelines on the management of advanced breast cancer (ABC) organized by Chinese Anti-Cancer Association, Committee of Breast Cancer Society (CACA-CBCS) do not elucidate ABC in details. To instruct clinicians in treatment of ABC, a Chinese expert consensus meeting on diagnosis and treatment of ABC was held in June 2014 and a consensus is developed. The following consensus provides the level of evidence and supporting documents for each recommendation, and introduces research topics to be urgently addressed. Notably, the consensus on diagnosis and treatment of ABC in China is developed to be applied nationwide. In different areas, multidisciplinary treatment (MDT) tailored to the each patient and the disease itself should be applied based on the basic principles of modern oncology.

A serum microRNA signature predicts trastuzumab benefit in HER2-positive metastatic breast cancer patients

Trastuzumab is a standard treatment for HER2-positive (HER2+) breast cancer, but some patients are refractory to the therapy. MicroRNAs (miRNAs) have been used to predict therapeutic effects for various cancers, but whether miRNAs can serve as biomarkers for HER2+ metastatic breast cancer (MBC) patients remains unclear. Using miRNA microarray, we identify 13 differentially expressed miRNAs in the serum of HER2+ MBC patients with distinct response to trastuzumab, and four miRNAs are selected to construct a signature to predict survival using LASSO model. Further, our data show that miR-940 is mainly released from the tumor cells and miR-451a, miR-16-5p and miR-17-3p are mainly from the immune cells. All these four miRNAs directly target signaling molecules that play crucial roles in regulating trastuzumab resistance. In summary, we develop a serum-based miRNA signature that potentially predicts the therapeutic benefit of trastuzumab for HER2+ MBC patients and warrants future validation in prospective clinical trials.Resistance to therapy is a significant issue for patients with metastatic breast cancer (MBC). Here the authors analyze total miRNA from serum samples of 386 MBC patients before treatment with a follow up of 31 months and define a four miRNA signature that predicts the therapeutic benefit of trastuzumab.

Clinical outcomes with first-line chemotherapy versus endocrine therapy for adjuvant endocrine therapy-resistant metastatic breast cancer

Background: Endocrine therapy resistance (ETR) is a great obstacle in the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. Patients with ETR have significantly decreased clinical benefit from endocrine therapy (ET). Therefore, it is quite important to find the clinicopathological factors that affect the outcome of patients with ETR in clinical practice. Methods: We screened 405 consecutive ER+/HER2− metastatic breast cancer (MBC) patients who were treated from 2013–2015 in our hospital. Patients with ETR (defined as relapse during adjuvant ET or within 12 months after completing adjuvant ET) were selected to explore the clinicopathological factors affecting the objective response rate (ORR) and progression-free survival (PFS). Results: We included 135 patients in the study. Chemotherapy (CT) was administered to 96 patients and ET to 39 patients as first-line treatment. Patients with liver or visceral metastasis received CT significantly more frequently than ET (P=0.001, 0.001). There was no significant difference in median PFS between the two groups (ET: 11.8 months, CT: 12.0 months, P=0.931, HR =1.029). However, patients with more than two metastatic sites had a shorter PFS than patients with less than or equal to two metastatic sites (7.5 vs. 14.5 months, P=0.031, HR =1.714). When patients on CT were further stratified, those who received ET as maintenance therapy had a longer PFS (14.3 months) compared with those that did not (7.5 months) (P=0.003). n Conclusions: ET and CT were both appropriate treatments for patients with ETR. Maintenance ET was a good choice for ER+/HER2− patients.

Combined peripheral natural killer cell and circulating tumor cell enumeration enhance prognostic efficiency in patients with metastatic triple-negative breast cancer

ObjectivenTriple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis. Circulating tumor cells (CTCs) are a promising predictor for breast cancer prognoses but their reliability regarding progression-free survival (PFS) is controversial. We aim to verify their predictive value in TNBC.nnnMethodsnIn present prospective cohort study, we used the Pep@MNPs method to enumerate CTCs in baseline blood samples from 75 patients with TNBC (taken at inclusion in this study) and analyzed correlations between CTC numbers and outcomes and other clinical parameters.nnnResultsnMedian PFS was 6.0 (range: 1.0-25.0) months for the entire cohort, in whom we found no correlations between baseline CTC status and initial tumor stage (P=0.167), tumor grade (P=0.783) or histological type (P=0.084). However, among those getting first-line treatment, baseline CTC status was positively correlated with ratio of peripheral natural killer (NK) cells (P=0.032), presence of lung metastasis (P=0.034) and number of visceral metastatic site (P=0.037). Baseline CTC status was predictive for PFS in first-line TNBC (P=0.033), but not for the cohort as a whole (P=0.118). This prognostic limitation of CTC could be ameliorated by combining CTC and NK cell enumeration (P=0.049).nnnConclusionsnBaseline CTC status was predictive of lung metastasis, peripheral NK cell ratio and PFS in TNBC patients undergoing first-line treatment. We have developed a combined CTC-NK enumeration strategy that allows us to predict PFS in TNBC without any preconditions.

Strategies and Progress of Endocrine Therapy for Patients with Metastatic Breast Cancer

Breast cancer is one of the most prevalent cancers and the leading causes of cancer mortality in women worldwide and in China. For hormone receptor-positive (HR+) breast cancer, accounting for approximately 60-80% of breast cancer, endocrine therapy (ET) is the primary treatment strategy. For patients with HR+ metastatic breast cancer (MBC), there are many endocrine-based treatment options that can improve long-term outcomes and optimize quality of life. With the emergence and availability of new and effective agents, the options for ET have expanded in the last two decades. Although hormone therapy has been a standard of care for many decades, treatment must be individualized based on tumor biology and extent of disease. For example, the patients with impending organ failure may be treated with induction chemotherapy to improve organ function, followed by ET. For the patients who develop metastatic disease while on adjuvant ET, particularly when associated with organ failure, or for those with low expression of hormone receptors or expression of HER2, chemotherapy again may be a preferred initial treatment. ET blocks estrogen-driven tumor growth through different mechanisms; however, HR+ MBC can be intrinsically resistant or may acquire resistance to the treatment. Several targeted agents have been approved to use in combination with ET to improve response and delay development of resistance.

Palbociclib plus letrozole as first-line treatment for ER-positive and HER2-negative advanced breast cancer in Chinese women: a phase 1 study

Abstract Background Palbociclib, a cyclin-dependent kinase 4 and 6 inhibitor, is approved in many countries for the treatment of ER-positive and HER2-negative advanced breast cancer in combination with endocrine therapy. We aimed to evaluate the pharmacokinetics, safety, and efficacy of palbociclib combined with letrozole as first-line treatment for ER-positive and HER2-negative advanced breast cancer. Methods This is a phase 1, open-label, single-arm study in Chinese women with ER-positive and HER2-negative advanced breast cancer. From cycle 1 day 1, patients received letrozole 2·5 mg orally once daily continuously plus palbociclib 125 mg orally once daily for 3 weeks followed by 1 week off treatment. Blood samples for pharmacokinetic evaluation of palbociclib were collected up to 120 h after a single dose of palbociclib in a lead-in phase and after palbociclib dose on cycle 1 day 21 for multiple dose pharmacokinetic evaluation. Predose blood samples for pharmacokinetic evaluation of palbociclib and letrozole were collected on days 19–21 of cycle 1 and cycle 2 day 1 (letrozole only). Disease assessments were done every 12 weeks from cycle 1 day 1. Safety was assessed per Common Terminology Criteria for Adverse Events, version 4.0. This study is registered with ClinicalTrials, number NCT02499146, and is ongoing but not recruiting. Findings As of March 16, 2016, the cutoff date, the study completed enrolment with 26 patients. All patients completed single dose pharmacokinetic evaluation and 13 completed multiple dose pharmacokinetic evaluation. After multiple doses, the steady-state palbociclib geometric mean area under the concentration–time curve from 0 to 24 h was 2005 ngu2008×u2008h/mL and maximum observed concentration was 112·3 ng/mL, similar to those obtained in Caucasian patients following the same dosing regimen. Comparisons of single dose and multiple dose pharmacokinetic data indicated linear pharmacokinetics of palbociclib. The geometric mean accumulation ratio of palbociclib exposure after multiple dose compared with single dose was 2·1, consistent with a terminal half-life of 23·4–27·5 h. Trough concentrations of letrozole were similar to concentrations obtained in Caucasian patients. No deaths or permanent discontinuations due to adverse events were reported. One serious adverse event occurred but was not considered to be treatment-related. The most common clustered adverse events were neutropaenia (n=20, 77%), leukopaenia (n=19, 73%), and anemia (n=11, 42%), with neutropaenia (n=15, 58%) and leukopaenia (n=8, 31%) the most common grade 3–4 adverse events. Interpretation No dose adjustment for palbociclib is needed based on the Chinese population. The toxicity of palbociclib in combination with letrozole treatment was tolerable and manageable. Funding Pfizer Inc.

Peptide-Functionalized Nanomaterials for the Efficient Isolation of HER2-Positive Circulating Tumor Cells

The detection of circulating tumor cells (CTCs) with a specific antigen expression is necessary in therapeutic response monitoring and targeted therapy guidance. The existence of human epidermal growth factor receptor 2 (HER2) and the concentration of HER2-positive CTCs are strong indicators for patient diagnosis, prognosis, and therapeutic monitoring. Herein we report the direct isolation of HER2-positive CTCs by peptide-functionalized nanomaterials. We designed and screened out a peptide as an HER2 antibody alternative demonstrating high HER2 affinity and selectivity. This HER2 recognition peptide bound efficiently with HER2 at the ligand-binding domain. Efficient HER2-positive CTC capture and detection were demonstrated using magnetic nanoparticles functionalized with the HER2 recognition peptide.

Interpreting Advanced Breast Cancer Consensus Guidelines for Use in China

Abstract 58Background:In 2011, an international panel of breast cancer experts developed the first Advanced Breast Cancer (ABC) Consensus Guidelines to provide standards and improved care for the multidisciplinary care of patients with this common disease. We sought to adapt the ABC guidelines for China, incorporating cultural standards and available Chinese resource, and identifying suitable formed guideline.Methods:We organized the Chinese Consensus Guidelines Conference for ABC (CABC) yearly from 2013 through 2015 in Beijing as a joint effort between the China Medical Womens Association, the Organization of Beijing Sunshine Great Wall Oncology Program, Peking University, The panel included 50 breast oncology and surgery experts from 20 provinces, as well as two external consultant oncologists from the U.S. and Singapore. Permission was obtained from the ABC Chair to use the guidelines as a basis for our discussion. All questions were presented and discussed in detail, including a review of current app...