Clinical and genetic predictions of early-onset cardiac toxicity in adjuvant chemotherapy for breast cancer.

Aim: To identify clinical and genetic variants associated with early-onset cardiac toxicity with a low cumulative dose of chemotherapy drugs in breast cancer. Methods: A total of 388 recruited patients completed routine blood, liver and kidney function, D-dimer, troponin T, brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, ECG and echocardiography tests before and after adjuvant chemotherapy. 25 single-nucleotide polymorphisms (SNPs) were tested. Results: A total of 277 adjuvant chemotherapy-related cardiac toxicity events were recorded in 180 patients (46.4%). Anthracycline-containing chemotherapy (odds ratio: 1.848; 95% CI: 1.135-3.008; p = 0.014) and the SLC28A3 rs885004 GG genotype (odds ratio: 2.034; 95% CI: 1.189-3.479; p = 0.010) were found to be associated with overall cardiac toxicity. The final predictive risk model consisting of clinical risk factors and SNPs was better than SNP alone (p = 0.006) or clinical risk factor alone (p = 0.065). Conclusion: On the basis of clinical factors, a prediction model with genetic susceptibility factors can better predict early-onset cardiac toxicity.

Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population.

BACKGROUND: We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population. METHODS: We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from the China National Cancer Center and finally included 2263 MBC patients in this study, among which 809 patients presented with lung metastases at first MBC diagnosis. The risk factors for BCLM were determined using multivariate logistic regression analysis and the prognostic factors of BCLM patients were assessed by univariate and multivariate Cox regression analyses. RESULTS: Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metastases. Age ≥ 50 years, Eastern Cooperative Oncology Group (ECOG) 2, M1, hormone receptor-negative (HR-)/human epidermal growth factor receptor 2-positive (HER2) + subtype, triple-negative subtype and disease-free survival (DFS) > 2 years were remarkably associated with higher incidence of lung metastases, while invasive lobular carcinoma (ILC) and bone metastases were significantly correlated with lower odds of lung metastases at diagnosis. The median survival of BCLM patients was 41.7 months, with triple-negative subtype experiencing the worst prognosis of 26.8 months. ECOG 2, triple-negative subtype, liver metastases, multi-metastatic sites and DFS ≤ 2 years were significantly correlated with poor survival of BCLM patients. CONCLUSIONS: Our study provides essential information on clinicopathological features and survival outcomes of BCLM patients at initial diagnosis of MBC in China.

Recent advances in selective photothermal therapy of tumor.

Photothermal therapy (PTT), which converts light energy to heat energy, has become a new research hotspot in cancer treatment. Although researchers have investigated various ways to improve the efficiency of tumor heat ablation to treat cancer, PTT may cause severe damage to normal tissue due to the systemic distribution of photothermal agents (PTAs) in the body and inaccurate laser exposure during treatment. To further improve the survival rate of cancer patients and reduce possible side effects on other parts of the body, it is still necessary to explore PTAs with high selectivity and precise treatment. In this review, we summarized strategies to improve the treatment selectivity of PTT, such as increasing the accumulation of PTAs at tumor sites and endowing PTAs with a self-regulating photothermal conversion function. The views and challenges of selective PTT were discussed, especially the prospects and challenges of their clinical applications.

Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer.

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.

Functional roles of sodium-calcium exchange in autorhythmicity and action potential of murine fetal cardiomyocytes at early developmental stage.

The aim of the present paper was to study the role of sodium calcium exchanger (NCX) in the generation of action potentials (APs) in cardiomyocytes during early developmental stage (EDS). The precisely dated embryonic hearts of C57 mice were dissected and enzymatically dissociated to single cells. The changes of APs were recorded by whole-cell patch-clamp technique before and after administration of NCX specific blockers KB-R7943 (5 µmol/L) and SEA0400 (1 µmol/L). The results showed that, both KB-R7943 and SEA0400 had potent negative chronotropic effects on APs of pacemaker-like cells, while such effects were only observed in some ventricular-like cardiomyocytes. The negative chronotropic effect of KB-R7943 on ventricular-like cardiomyocytes was accompanied by shortening of AP duration (APD), whereas such an effect of SEA0400 was paralleled by decrease in velocity of diastolic depolarization (Vdd). From embryonic day 9.5 (E9.5) to E10.5, the negative chronotropic effects of KB-R7943 and SEA0400 on ventricular-like APs of embryonic cardiomyocytes gradually disappeared. These results suggest that, in the short-term development of early embryo, the function of NCX may experience developmental changes as evidenced by different roles of NCX in autorhythmicity and APs generation, indicating that NCX function varies with different conditions of cardiomyocytes.

Cardiac fibroblast paracrine factors modulate mouse embryonic stem cells.

The study aims to investigate the effects of cardiac fibroblast (CF) paracrine factors on murine embryonic stem cells (ESCs). Conditioned mediums from either neonatal cardiac fibroblasts (ConM-NCF) or adult cardiac fibroblasts (ConM-ACF) were diluted by 1:50 and 1:5, respectively, to investigate whether these conditioned mediums impact murine ESCs distinctly with RT-real time PCR techniques, cell proliferation essay, ELISA and by counting percentage of beating embryoid bodies (EBs) during ESCs differentiation. The data showed that the paracrine ability of CFs changed dramatically during development, in which interleukin 6 (IL6) increased with maturation. ConM-NCF 1:50 and ConM-NCF 1:5 had opposite effects on the pluripotent markers, although they both reduced mouse ESC proliferation. ConM-ACF 1:50 promoted ESCs pluripotent markers and proliferation, while ConM-ACF 1:5 exerted negative effects. All CF-derived conditioned mediums inhibited cardiac differentiation, but with distinguishable features: ConM-NCF 1:50 slightly decreased the early cardiac differentiation without altering the maturation tendency or cardiac specific markers in EBs at differentiation of day 17; ConM-ACF 1:50 had more significant inhibitory effects on early cardiac differentiation than ConM-NCF 1:50 and impeded cardiac maturation with upregulation of cardiac specific markers. In addition, IL6 neutralization antibody attenuated positive effect of ConM-ACF 1:50 on ESCs proliferation, but had no effects on ConM-NCF 1:50. Long-term IL6 neutralization reduced the percentage of beating EBs at early developmental stage, but did not alter the late cardiac differentiation. Taken together, both the quality and quantity of factors and cytokines secreted by CFs are critical for the ESC fate. IL6 could be a favorable cytokine for ESC pluripotency and the early cardiac differentiation.

Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study.

BACKGROUND: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus. METHODS: Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing. RESULTS: In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9-6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05). CONCLUSIONS: Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus.

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis.

PURPOSE: Breast cancer is the most common cancer in females and the leading cause of death worldwide. The effects of statins on breast cancer prognosis have long been controversial; thus, it is important to investigate the relationship between statin type, exposure time, and breast cancer prognosis. This study sought to explore the effect of statins, as well as the different effects of statin solubility and variable follow-up times, on breast cancer prognosis. METHODS: We searched the MEDLINE (via PubMed), EMBASE (via OvidSP), Cochrane Library, and ISI Web of Knowledge databases using combinations of the terms "breast neoplasms[MeSH]," "statins" or "lipid-lowering drug," "prognosis" or "survival," or "mortality" or "outcome" with no limit on the publication date. We searched the databases between inception and October 15, 2016. Reference lists of the included studies and relevant reviews were also manually screened. The initial search identified 71 publications, and 7 of these studies, which included a total of 197,048 women, met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. The data were analyzed using Stata/SE 11.0. RESULTS: Overall statin use was associated with lower cancer-specific mortality and all-cause mortality, although the benefit appeared to be constrained by statin type and follow-up time. Lipophilic statins were associated with decreased breast cancer-specific and all-cause mortality; however, hydrophilic statins were weakly protective against only all-cause mortality and not breast cancer-specific mortality. Of note, one group with more than 4 years of follow-up did not show a significant correlation between statin use and cancer-specific mortality or all-cause mortality, whereas groups with less than 4 years of follow-up still showed the protective effect of statins against cancer-specific mortality and all-cause mortality. CONCLUSIONS: Although statins can reduce breast cancer patient mortality, the benefit appears to be constrained by statin type and follow-up time. Lipophilic statins showed a strong protective function in breast cancer patients, whereas hydrophilic statins only slightly improved all-cause mortality. Finally, the protective effect of statins could only be observed in groups with less than 4 years of follow-up. These findings are meaningful in clinical practice, although some conclusions contradict conventional wisdom and will thus require further exploration.

A pH-Responsive Detachable PEG Shielding Strategy for Gene Delivery System in Cancer Therapy.

In this study, a pH-responsive detachable polyethylene glycol (PEG) shielding strategy was designed for gene delivery in cancer therapy. Polyethylenimine/DNA complex (PEI/DNA) was in situ shielded by aldehyde group-modified PEG derivatives. The aldehyde groups of PEG could react with the amino groups of PEI by Schiff base reaction. The Schiff base bond was stable in neutral pH but labile in slightly acidic pH, which made the PEG sheddable in tumors. PEG-coated nanoparticles (NPs) had distinct advantages compared to their mPEG counterpart, possessing decreased zeta potential, more compressed size, and enhanced stability. PEG/PEI/DNA NPs showed not only high tumor cell uptake and transfection efficiency in vitro but also efficient accumulation and gene expression in solid tumors in vivo. This pH-responsive detachable PEG shielding system has the potential to be applied to other polycationic nanoparticles that contain amino groups on their surfaces, which will have broad prospects in cancer therapy.

Ultrasensitive pH Triggered Charge/Size Dual-Rebound Gene Delivery System.

A facile strategy is developed to construct an ultrasensitive pH triggered charge/size dual-rebound gene delivery system for efficient tumor treatment. The therapeutic gene is complexed by polyethylenimine (PEI) and poly-l-glutamate (PLG), further in situ tightened by aldehyde modified polyethylene glycol (PEG) via Schiff base reaction. The generated Schiff base bonds are stable in neutral pH but cleavable in tumor extracellular pH. This gene delivery system possesses following favorable properties: (1) the tunable gene delivery system is constructed by chemical bench-free "green" and fast process which is favored by clinician, (2) PEG cross-linking shields the surface positive charges and tightens the complex particles, leading to decreased cytotoxicity, improved stability, and prolonged circulation, (3) PEG shielding can be rapidly peeled off by acidic pH as soon as arriving tumors, (4) dual charge/size ultrasensitively rebounding to higher positive potential and bigger size enhances tumor cell uptake efficiency. A series of experiments both in vitro and in vivo are carried out to investigate this gene delivery system in detail. An antiangiogenesis therapeutic gene is carried for the treatment of CT26 tumors in mice, achieving superior antitumor efficacy which is well proved by sufficient biological evidence. The system has great potentials for cancer therapy in the future.

Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.

The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, P<0.001], but not 2-year progression-free survival (OR=1.81, 95% CI: 0.61-5.36, P=0.284). Specifically, early (OR=3.32, 95% CI: 1.38-7.95, P<0.01) but not advanced (OR=3.75, 95% CI: 0.96-14.68, P=0.057) NSCLC patients were likely to gain a large benefit from the adoptive immunotherapy. Most of the adoptive immunotherapy-induced adverse effects were self-limited, mainly including fever, shiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC.

Platinum-based chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis of randomized-controlled trials.

The aim of this study was to evaluate the benefits of the addition of platinum agents for the treatment of patients with triple-negative breast cancer on the basis of randomized-controlled trials (RCTs). A fully recursive literature search was performed in the Cochrane Controlled Trials Register Databases, Medline, EMBASE, and Chinese Biomedical Literature Database in any language. RCTs were considered for inclusion. Eight randomized-controlled trials totaling 1142 patients were included. The objective response rate was reported in six RCTs, which were divided into two subgroups: palliative chemotherapy for a metastatic setting and neoadjuvant chemotherapy. Using the fixed-effects model, the difference between the platinum-based group and the non-platinum-based group was found to be statistically significant in the overall study [relative risk (RR)=1.36, P<0.00001], the subgroup of palliative chemotherapy (RR=2.42, P<0.00001), and the subgroup of neoadjuvant (RR=1.15, P=0.01). Pathological complete response rates were based on five studies, and the results between the platinum-based group and the non-platinum-based group also reached statistical significance both in the fixed-effects model (RR=1.43, P<0.0001) and in the random-effects model (RR=1.47, P=0.01). The results seemed to yield a better response rate and pathological complete response rate for platinum-based therapy in triple-negative breast cancer. However, because of the heterogeneous nature of primary trial outcomes, caution should be exercised in coming to this conclusion and further research is necessary to support these findings.

Development and validation of the NCC-BC-A scale to assess patient-reported outcomes for breast cancer patients in China.

Background: The commonly used international patient-reported outcome scales for breast cancer were developed before the advent of multiple targeted therapies and immunotherapies, rendering them potentially insufficient for current clinical practices. Therefore, it is necessary to develop a specific patient-reported outcome scale tailored for breast cancer patients in China to optimize the management model for these patients. Methods: A comprehensive literature search was performed in the PubMed, Embase, Wanfang, and CNKI databases to extract dimensions and items for a potential patient-reported outcome scale. The Delphi method was used to modify, add, subtract, and adjust the language of items until the experts reached a consensus on the first draft. This draft was further refined using a cognitive test and a presurvey. The optimized scale was used for a formal survey, and the items were further analyzed and screened using metrics such as the coefficient of variation, correlation coefficient, internal item consistency, factor analysis, reliability, and validity. Results: A total of 10,954 articles were analyzed, and 237 were used to create a pool of 277 patient-reported outcome items. Through two rounds of Delphi expert consultation, the experts' authority coefficients were 0.739 and 0.826. After a cognitive test, several items were adjusted to enhance understanding. Further adjustments were made following a presurvey of 200 advanced breast cancer patients, resulting in a 38-item patient-reported outcomes scale, termed NCC-BC-A. In the national formal survey, 588 advanced breast cancer patients participated. Principal component analysis showed good consistency among the items and sufficient difference between the dimensions. The results were normally distributed with good variation. The Cronbach's α coefficient of the scale was 0.925 and the test-retest reliability was 0.9041. Conclusion: The NCC-BC-A scale has high validity and reliability. It comprehensively considered the characteristics of systemic treatment for breast cancer, and the specific context within China. Its implementation may help clinicians to pay more attention to quality of life of breast cancer patients and to optimize the system for managing this condition.

A minimalist cancer cell membrane-shielded biomimetic nanoparticle for nasopharyngeal carcinoma active-targeting therapy.

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy, which is characterized by high incidence and aggression with poor diagnosis and limited therapeutic opportunity. The innovative strategy for achieving precise NPC active-targeting drug delivery has emerged as a prominent focus in clinical research. Here, a minimalist cancer cell membrane (CCM) shielded biomimetic nanoparticle (NP) was designed for NPC active-targeting therapy. Chemotherapeutant model drug doxorubicin (DOX) was loaded in polyamidoamine (PAMAM) dendrimer. The PAMAM/DOX (PD) NP was further shielded by human CNE-2 NPC CCM. Characterization results verified that the biomimetic PAMAM/DOX@CCM (abbreviated as PDC) NPs had satisfactory physical properties with high DOX-loading and excellent stability. Cell experiments demonstrated that the CNE-2 membrane-cloaked PDC NPs presented powerful cellular uptake in the sourcing cells by homologous targeting and adhesive interaction. Further in vivo results confirmed that this biomimetic nanoplatform had extended circulation and remarkable tumor-targeting capability, and the PDC NPs effectively suppressed the progression of CNE-2 tumors by systemic administration. This CCM-shielded biomimetic NP displayed a minimalist paradigm nanoplatform for precise NPC therapy, and the strategy of CCM-shielded biomimetic drug delivery system (DDS) has great potential for extensive cancer active-targeting therapy.

Efficient chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle as "in situ" vaccine integrated tumor ICD and immunoagonist.

INTRODUCTION: Immunotherapy has unprecedentedly opened up a series of neoteric tactics for cancer treatment. As a burgeoning approach, chemo-immunotherapy has innovatively expanded the accomplishments of conventional chemotherapeutic agents for cancer governing. OBJECTIVES: An efficacious chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle (NP) integrated tumor immunogenic cell death (ICD) and immunoagonist was developed as a watertight "in situ" vaccine for cancer therapy through convenient intratumoral administration with minimized systemic toxicity. METHODS: Chemical-modified pH-sensitive cis-aconityl-doxorubicin (CAD) and immunoadjuvant unmethylated cytosine-phosphate-guanine (CpG) were co-packaged by polycationic polyethylenimine (PEI) though electrostatic-interaction to construct PEI/CpG/CAD NP. By intratumoral injection, this positively charged NP could be detained at tumor site and endocytosed by tumor cells effortlessly. Then, doxorubicin was released through cis-aconityl cleavage induced by endosomal-acidity and further triggered tumor ICD, the moribund tumor cells could release damage-associated molecular patterns (DAMPs) to recruit dendritic cells (DCs). Meanwhile, the entire tumor debris derived into diversified antigens and cooperated with immunostimulatory CpG to excite DC maturation and activated comprehensive antitumor immunity. RESULTS: Prominent tumor suppression was achieved in aggressive mouse melanoma tumor model, which verified the feasibility and effectiveness of this minimalist CAD/CpG-codelivered NP. CONCLUSION: This study has provided a convenient and promising paradigm for potent cancer chemo-immunotherapy.

Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.

It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy (n = 11), (2) NVB plus anti-PD-1 toripalimab (n = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab (n = 27), (4) conventional cisplatin, NVB and toripalimab (n = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) (n = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 .

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

BACKGROUND: Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients. METHODS: We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers. RESULTS: A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7-93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4-12.9 months) and median OS was 31.0 months (95% CI: 16.5-45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013). CONCLUSIONS: The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT01937689, NCT02361112).

Synergistically enhanced cancer immunotherapy by combining protamine-based nanovaccine with PD-L1 gene silence nanoparticle.

Tumor vaccine has brought a new dawn for cancer immunotherapy, but disillusionary therapeutic outcomes have been achieved due to the inefficient in vivo vaccine delivery. Moreover, tumor cells customarily resort to various wily tricks to circumvent the recognition and sweeping of the immune system, the immune escape effect has badly aggravated the difficulty of cancer management. With respect to the foregoing, in this study, a promising combinational strategy which cooperated nanovaccine with immune escape inhibition was developed for synergistically enhancing the oncotherapy efficiency. On the one hand, natural polycationic macromolecule protamine (PRT) was utilized as the carrier to construct an antigen and adjuvant co-packaged nanovaccine for facilitating the ingestion in antigen-presenting cells, amplifying antigen cross-presentation and optimizing in vivo delivery. On the other hand, PD-L1 silence gene was selected and hitchhiked in a pH-responsive nanoparticle developed in our previous study. The therapeutic gene could be successfully delivered into the tumors to down-regulate PD-L1 expression and cripple tumor immune escape. The combination of nanovaccine with PD-L1 gene silence nanoparticle could synchronously stimulate antitumor immune responses and reduce immune escape, synergistically enhance the therapeutic efficiency. This study will furnish the prospective tactics for the research of cancer immunotherapy.

Pooled analyses of randomized controlled trials on pyrotinib plus capecitabine and a rethink of the first-line options for HER2-positive relapsed or metastatic breast cancer.

This pooled analysis explored the possibility and potential of pyrotinib plus capecitabine as a first-line regimen in relapsed or metastatic HER2-positive breast cancer patients who received prior adjuvant or neoadjuvant chemotherapy with trastuzumab and discussed the potential treatment options for these patients, especially for the patients relapsed during or within 6 months after adjuvant trastuzumab.

Cooperating minimalist nanovaccine with PD-1 blockade for effective and feasible cancer immunotherapy.

Introduction: Tumor vaccine has been a research boom for cancer immunotherapy, while its therapeutic outcome is severely depressed by the vulnerable in vivo delivery efficiency. Moreover, tumor immune escape is also another intractable issue, which has badly whittled down the therapeutic efficiency. Objectives: Our study aims to solve the above dilemmas by cooperating minimalist nanovaccine with PD-1 blockade for effective and feasible cancer immunotherapy. Methods: The minimalist antigen and adjuvant co-delivery nanovaccine was developed by employing natural polycationic protamine (PRT) to carry the electronegative ovalbumin (OVA) antigen and unmethylated Cytosine-phosphorothioate-Guanine (CpG) adjuvant via convenient chemical bench-free "green" preparation without chemical-synthesis and no organic solvent was required, which could preserve the immunological activities of the antigens and adjuvants. On that basis, PD-1 antibody (aPD-1) was utilized to block the tumor immune escape and cooperate with the nanovaccine by maintaining the tumoricidal-activity of the vaccine-induced T cells. Results: Benefited from the polycationic PRT, the facile PRT/CpG/OVA nanovaccine displayed satisfactory delivery performance, involving enhanced cellular uptake in dendritic cells (DCs), realizable endosomal escape and promoted stimulation for DCs' maturation. These features would be helpful for the antitumor immunotherapeutic efficiency of the nanovaccine. Furthermore, the cooperation of the nanovaccine with aPD-1 synergistically improved the immunotherapy outcome, profiting by the cooperation of the "T cell induction" competency of the nanovaccine and the "T cell maintenance" function of the aPD-1. Conclusion: This study will provide new concepts for the design and construction of facile nanovaccines, and contribute valuable scientific basis for cancer immunotherapy.