Hanfang Jiang

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options.

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) remains an incurable disease, and approximately 25% of patients with HER2+ early breast cancer still relapse after adjuvant trastuzumab-based treatment. HER2 is a validated therapeutic target that remains relevant throughout the disease process. Recently, a number of novel HER2 targeted agents have become available, including lapatinib (a small molecule tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor), pertuzumab (a new anti-HER2 monoclonal antibody) and ado-trastuzumab emtansine (T-DM1, a novel antibody–drug conjugate), which provide additional treatment options for patients with HER2+ MBC. The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or T-DM1 compared with standard HER2 targeted therapy. Here we review the clinical development of approved and investigational targeted agents for the treatment of HER2+ MBC, summarize the latest results of important clinical trials supporting use of these agents in the treatment of HER2+ MBC, and discuss how these results impact therapeutic options in clinical practice.

Dendritic cells pulsed with α‐fetoprotein and mutant P53 fused gene induce bi‐targeted cytotoxic T lymphocyte response against hepatic carcinoma

Dendritic cell (DC)‐based immunotherapy is rapidly emerging as a promising treatment in cancer therapy. We had previously shown that DC pulsed with either defined mRNA of tumor antigen (Ag) such as α‐fetoprotein (AFP), or total RNA of hepatocellular carcinoma (HCC) could elicit Ag‐specific cytotoxic T lymphocyte (CTL) response. Therefore, we suggested a novel DC‐based therapeutic method, in which DCs derived from CD34+ cells enriched peripheral blood mononuclear cells were pulsed with liposome‐coated AFP and mutant P53 (mtP53) fused gene pEGFP‐C3/AFP‐mtP53 to induce bi‐targeted specific CTL responses against HCC. Three different genotype HCC cell lines, HepG2 (human histocompatibility leukocyte antigens (HLA) A2 positive, AFP expressing positive, P53 expressing negative), SMMC7721 (HLA A2 positive, neither AFP nor P53 expressing positive), and HMCC97 (HLA A2 positive, both AFP and P53 expressing positive) were selected as targets for CTL responses. An important finding was that DCs pulsed with the liposome‐coated fused gene could evoke more intensive bi‐targeted Ag‐specific CTL responses against HMCC97 than DCs pulsed with either AFP or P53 single gene (P < 0.05). This experimental therapeutic model provides a new promising cytotherapeutic approach, in that DCs pulsed with the fused gene of different Ags might induce more extensive multitargeted antitumor immunity. (Cancer Sci 2008; 99: 1420–1426)

First-line chemotherapy with docetaxel plus capecitabine followed by capecitabine or hormone maintenance therapy for the treatment of metastatic breast cancer patients.

The primary aim of the present study was to evaluate whether maintenance therapy with capecitabine or hormone replacement therapy (HRT) results in improved progression-free survival (PFS) in metastatic breast cancer (MBC) patients who had previously achieved disease control with first-line docetaxel plus capecitabine (TX) chemotherapy. Seventy-nine metastatic breast cancer patients treated between January 2008 and June 2013 with TX chemotherapy were retrospectively analyzed. Following successful initial disease control by the combination chemotherapy, 39 patients received single-agent capecitabine maintenance therapy and 40 patients received HRT as maintenance therapy. The PFS time, objective response rate, clinical benefit rate and safety of the two groups were compared. The median PFS of the total cohort (n=79) was 11.0 months. Furthermore, the median PFS time of the capecitabine (n=39) and HRT groups (n=40) were 10.9 and 11.1 months, respectively (P=0.283). Compared with the PFS time of maintenance treatment only, single-agent capecitabine treatment following TX chemotherapy prolonged the PFS time by 6.8 months and HRT following TX chemotherapy prolonged PFS time by 5.8 months (P=0.551). Of the total cohort, 49 patients did not receive palliative endocrine therapy prior to chemotherapy, including 22 patients in the capecitabine maintenance group and 27 patients in the HRT maintenance group. The PFS time from the commencement of maintenance treatment was significantly different between the two groups, 6.1 months in the capecitabine group compared with 11.5 months in the HRT group (P=0.045). For the 30 patients who underwent palliative endocrine therapy prior to TX chemotherapy, the PFS times of the capecitabine and HRT maintenance treatment groups were 7.5 and 4.1 months, respectively (P=0.043). However, the occurrence of adverse events, such as hematological and gastrointestinal toxicity, as well as hand-foot syndrome, were not significantly different between the two groups. The current study indicated that single-agent capecitabine maintenance therapy may be a potential treatment strategy for MBC patients who responded to capecitabine-based chemotherapy. In particular, capecitabine may provide a more effective maintenance treatment duration compared with HRT for patients who had previously undergone first-line palliative HRT for MBC.

Mobilization of peripheral blood stem cells using regimen combining docetaxel with granulocyte colony-stimulating factor in breast cancer patients

ObjectiveTo evaluate the effectiveness and safety of the mobilization of peripheral blood hematopoietic stem cells by combining docetaxel with granulocyte colony-stimulating factor (G-CSF) in breast cancer patients.MethodsA total of 57 breast cancer patients were treated with docetaxel 120 mg/m2. When the white blood cell (WBC) count decreased to 1.0×109/L, patients were given G-CSF 5 μg/kg daily by subcutaneous injection until the end of apheresis. Peripheral blood mononuclear cells (MNC) were isolated by Cobe Spectra Apheresis System. The percentage of CD34+ cell was assayed by flow cytometry.ResultsAt a median 6 of days (range 3–8) after the administration of docetaxel, the median WBC count decreased to 1.08×109/L (range 0.20–2.31). The median duration of G-CSF mobilization was 3 days (range 2–7). The MNC collection was conducted 8–12 days (median 10 days) after docetaxel treatment. The median MNC was 5.35×108/kg (range 0.59–14.07), the median CD34+ cell count was 2.43×106/kg (range 0.16–16.69). The CD34+ cell count was higher than 1.00×106/kg in 47 of 57 cases (82.46%) and higher than 2.00×106/kg in 36 cases (63.16%). The CD34+ cell count was higher than 2.00×106/kg in 27 collections (23.68%). The MNC count and the CD34+ cell count were correlated with the bottom of WBC after docetaxel chemotherapy (r=0.364, 0.502, P=0.005, 0.000). The CD34+ cell count was correlated with the MNC count (r=0.597, P=0.000). The mobilization and apheresis were well tolerated in all patients. Mild perioral numbness and numbness of hand or feet were observed in 3 cases. No serious adverse events were reported.ConclusionMobilization of peripheral blood hematopoietic stem cell by combining docetaxel with G-CSF was effective and safety in breast cancer patients.

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). 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

Objective Triple-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. Methods In 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. Results Median 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). Conclusions Baseline 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.

Identification of recurrent BRCA1 mutation and its clinical relevance in Chinese Triple‐negative breast cancer cohort

Triple‐negative breast cancer (TNBC) accounts for 15–20% of all newly diagnosed breast cancers, and is enriched for germline mutation of BRCA. In Asian patients diagnosed with breast cancer, 268 deleterious mutations of BRCA1 and 242 of BRCA2 have been identified so far, including a reported BRCA1 frameshift mutation (rs80350973), apparently found only in Asian people, with a low prevalence of 0.3–1.7% in different breast cancer cohorts. Here, we reported the high prevalence (7.2%) of rs80350973 among 125 Chinese patients with TNBC, which implies its mutational predilection for certain breast cancer subtypes. Although its low prevalence had not indicated any particular clinical significance in previous studies, our results associated rs80350973 mutation with cell checkpoint malfunction, and was found to be more common in TNBC patients with high Ki‐67 indices (P = 0.004). As Ki‐67 overexpression is a predictor of poor prognosis in TNBC, inclusion of this mutation into genetic assessments may improve the clinical management of Chinese patients with TNBC.

Capecitabine maintenance therapy for XT chemotherapy-sensitive patients with metastatic triple-negative breast cancer

OBJECTIVE To investigate the efficacy and safety of capecitabine maintenance therapy (MT) after initial capecitabine plus docetaxel (XT) chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC). METHODS Fifty-five mTNBC patients treated with XT chemotherapy between May 2007 and June 2013 were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, capecitabine was continued for 32 patients (MT), while 23 patients remained without any treatment (non-MT). We compared progression-free survival (PFS) and safety of both groups. RESULTS The median PFS of 55 patients was 8.1 months, overall median PFS time of 32 patients in the capecitabine MT group and 23 in the non-MT group was 10.1 vs. 6.7 months (P=0.032), respectively. When compared PFS time of maintenance treatment, single-agent capecitabine prolonged PFS by 7.1 months, for non-MT patients, the PFS without any treatment was 3.1 months, and this between-group difference was statistically significant (P=0.003). Adverse events, including of hematologic toxicity, gastrointestinal toxicities, hand-foot syndrome and abnormal liver function were not significantly different between two groups. CONCLUSIONS After initial disease control was achieved with the XT combination chemotherapy, capecitabine MT can significantly prolong PFS time with a favorable safety profile in mTNBC patients.

Abstract 5298: Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The successful predictively treatment of metastatic breast cancer (MBC) remains a major challenge. Until now there is no definite marker to distinguish responder from non-responder and more and more important, metastasis occurred within different organs lead to serious variations of overall survival. In this study, paclitaxel and anthracyclines pretreated153 patients with MBC received 606 cycles of docetaxel plus thiotepa. 65 of 153 patients were concurrently diagnosed as MBC involved liver metastasis (LM). Among 153 patients, the response were 1 complete response (CR) (0.7%), 25 partial responses (PR) (16.3%), 73 stable diseases (SD) (47.7%), 46 progressive diseases (PD) (30.1%) and 8 unevaluable(5.2%). For LM patients, the localized liver response were 2 CR (3.1%), 20 PR (30.8%), 16 SD (24.6%), 22 PD (33.8%),5 unevaluable (7.7%). Median PFS and OS for both entire and LM subgroup were 6.5 (95% CI, 5.6 to 7.4) versus 4.2 (95%CI, 2.3-6.1), and 20.0 (95% CI, 15.6 to 24.4) versus 14.2 (95%CI, 9.5-18.9) months respectively. 79 SNPs in CYP450, whose minor allele frequency were ≥ 10% were genotyped. There was no significant difference of SNPs in therapeutic responses, PFS or OS. Of importance, there were two distinctive SNPs, rs2277119 and rs4646487 \*2/\*3 alleles, which tended to have the better liver metastases response than *1 when choosing a false discovery rate as 12%. It seemed that docetaxel plus thiotepa might be regarded as an active specific regimen for MBC with liver metastasis. The generation of conceptually specific chemotherapy targeting the organ with cancer metastasis should be considered in the future. Citation Format: Jing Yu, Ningning Dong, Ying Yan, Bin Shao, Lijun Di, Guohong Song, Li Che, Jun Jia, Hanfang Jiang, Xu Liang, Yulin Zhu, Chaoying Wang, Jie Zahng, Budong Zhu, Xinna Zhou, Xiaoli Wang, Huabing Yang, Jun Ren, Herbert Kim Lyerly. Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5298. doi:10.1158/1538-7445.AM2013-5298 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.