Li Bian

Circulating tumor cells in HER2-positive metastatic breast cancer patients: a valuable prognostic and predictive biomarker

BackgroundThis study was initiated to investigate the prognostic significance of circulating tumor cell (CTC) enumeration and the predictive value of CTC HER2 expression for efficient anti-HER2 therapy in HER2-positive metastatic breast cancer (MBC) patients.MethodsSixty HER2-positive MBC patients were enrolled in the present study. Before the initiation of systemic treatment, CTCs from 7.5 ml of blood were analyzed using the CellSearch system. The progression-free survival (PFS) of the patients was estimated using Kaplan-Meier survival curves.ResultsCTCs were detected in 45% (27/60) of the patients, who had shorter median PFS than those without CTCs (2.5 vs. 7.5 months, P = 0.0125). Furthermore, referring to the standard HER2 testing that uses immunohistochemistry (IHC), we proposed a CTC HER2-positive criterion, defined as >30% of CTCs over-expressing HER2. Among patients undergoing anti-HER2 therapy, those with HER2-positive CTCs had longer PFS (8.8 vs. 2.5 months, P = 0.002). Among patients with HER2-positive CTCs, the median PFS for those receiving anti-HER2 therapy was significantly longer than those who were not (8.8 vs. 1.5 months, P = 0.001). Notably, up to 52% (14/27) of the HER2-positive patients were CTC HER2-negative, and anti-HER2 therapy did not significantly improve the median PFS in these patients (2.5 vs. 0.9 months, P = 0.499).ConclusionsOur findings underscore the necessity of a comprehensive CTC analysis, which may provide valuable prognostic and predictive information for optimizing individually tailored therapies in HER2-positive MBC patients. To test this idea, additional large cohort, multi-center and prospective clinical trials are needed.

Single-agent capecitabine maintenance therapy after response to capecitabine-based combination chemotherapy in patients with metastatic breast cancer.

We performed an analysis of the efficacy of capecitabine monotherapy as maintenance treatment for metastatic breast cancer (MBC) after response to capecitabine-based chemotherapy [capecitabine plus docetaxel (XT) or vinorelbine (XN)] as a first-line or a second-line treatment. Sixty-four Chinese patients with histologically confirmed MBC received capecitabine maintenance therapy after disease stabilization or maximal response to capecitabine-based combination chemotherapy. Single-agent capecitabine was administered at a dose of 1000 mg/m2 twice daily for 14 days, followed by a 7-day rest period, every 3 weeks. The median time to progression, the primary endpoint of the study, was 4.4 months (95% confidence interval, 3.4–5.4 months). Fifty-nine patients were evaluable for response. Capecitabine maintenance therapy produced an objective response rate of 5.1% (95% confidence interval, 3.9–6.3%). The incidence of grade 3/4 leukopenia (3.1%) and neutropenia (4.7%) was significantly lower (P<0.001) with capecitabine monotherapy than with combination chemotherapy (46.9 and 54.7%, respectively). Conversely, the incidence of grade 3 hand–foot syndrome was higher with capecitabine maintenance therapy than with combination therapy (14.1 vs. 0%, respectively; P=0.003). Capecitabine monotherapy is an effective maintenance treatment after response to capecitabine-based combination chemotherapy in MBC with a favorable safety profile.

Meaningful interpretation of serum HER2 ECD levels requires clear patient clinical background, and serves several functions in the efficient management of breast cancer patients.

BACKGROUND This study was initiated to evaluate the clinical significant of HER2 extracellular domain (ECD) in the real-time management of breast cancer patients. METHODS Five-hundred forty-six eligible breast cancer patients were divided according to their clinical background. The correlation between ECD, tissue HER2, and clinical outcome of the patients were analyzed. RESULTS Receiver operating characteristic analysis revealed that ECD measured before receiving neoadjuvant therapy yielded the highest area under the curve (0.9185; P<0.0001), indicating that ECD and tissue HER2 levels are consistent in untreated tumor-bearing patients. At cut-off of 15.0ng/ml, the prognostic value of ECD was demonstrated using univariate (HR=1.664, P<0.0001) and multivariate (HR=1.547, P=0.011) Cox regression analysis. Kaplan-Meier survival curves revealed that patients with elevated ECD had shorter progression-free survival (PFS) (4.0 vs. 6.1months, P<0.0001). Elevated ECD was also an adverse predictor for PFS in response to anti-HER2 therapy (4.3 vs. 10.2months, P=0.0155). In contrast, ≥20%, decreased ECD was associated with longer PFS in patients who received anti-HER2 therapy (10.9 vs. 2.4months, P=0.0164) and overall (10.7 vs. 2.8months, P=0.0034). CONCLUSIONS A patients clinical history can help determine whether ECD could provide added value for breast cancer management.

Ki-67 index as a prognostic factor of subsequent lapatinib-based therapy in HER2-positive metastatic breast cancer with resistance to trastuzumab

Prognostic factor analysis has been conducted to determine whether the parameters of clinical data and biomarkers would predict differential progression-free survival (PFS) or overall survival (OS) from lapatinib-based therapy in patients with primary or acquired resistance to trastuzumab. Treatment with lapatinib plus capecitabine for HER2-positive metastatic breast cancer (MBC) with primary or acquired resistance to trastuzumab was analyzed retrospectively. Tumor biomarkers, which came from the biopsies before the starting of lapatinib therapy, were evaluated by immunohistochemistry (IHC). Prognostic factors related to PFS or OS of the lapatinib therapy were assessed by univariate and multivariate analysis. Ki-67 index and liver metastases were the significant prognostic factors for predicting PFS of subsequent lapatinib therapy in the univariate analysis and the multivariate analysis. The risk for disease progression in patients who had a Ki-67 index < 40% was 59% less than that in patients had Ki-67 ≥ 40 (HR = 0.41, 95% CI, 0.23–0.74, P = 0.003). TTP of prior trastuzumab therapy, liver metastases, and the number of metastatic sites were three independent prognostic factors of subsequent lapatinib therapy. Ki-67 index was the significant prognostic factors for predicting PFS of the subsequent second line targeted therapy in patients with trastuzumab resistance.

Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer

Background: The addition of anti-human epidermal growth factor receptor 2 (HER2)-targeted drugs, such as trastuzumab, lapatinib, and trastuzumab emtansine (T-DM1), to chemotherapy significantly improved prognosis of HER2-positive breast cancer patients. However, it was confused that metastatic patients vary in the response of targeted drug. Therefore, methods of accurately predicting drug response were really needed. To overcome the spatial and temporal limitations of biopsies, we aimed to develop a more sensitive and less invasive method of detecting mutations associated with anti-HER2 therapeutic response through circulating-free DNA (cfDNA). Methods: From March 6, 2014 to December 10, 2014, 24 plasma samples from 20 patients with HER2-positive metastatic breast cancer who received systemic therapy were eligible. We used a panel for detection of hot-spot mutations from 50 oncogenes and tumor suppressor genes, and then used targeted next-generation sequencing (NGS) to identify somatic mutation of these samples in those 50 genes. Samples taken before their first trastuzumab administration and subsequently proven with clinical benefit were grouped into sensitive group. The others were collected after disease progression of the trastuzumab-based therapy and were grouped into the resistant group. Results: A total of 486 single-nucleotide variants from 46 genes were detected. Of these 46 genes, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), proto-oncogene c-Kit (KIT), and tumor protein p53 (TP53) were the most common mutated genes. Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy. In addition, we detected a HER2 S855I mutation in two patients who had persistent benefits from anti-HER2 therapy. Conclusion: Targeted NGS of cfDNA has potential clinical utility to detect biomarkers from HER2-targeted therapies.

Abstract P3-13-10: The maintenance treatment after xeloda contained regimens with xeloda or endocrine for HR positive and HER2 negative MBC patients

Objective To discuss the optimizing selection of maintenance treatment after xeloda-contained chemotherapy regimen being applicated in HER-2 negative, HR positive relapsing metastatic breast cancer(MBC) patients, and contrast the curative effect of maintenance treatment with xeloda or endocrine. Methods 119 patients with HER-2 negative, HR positive were enrolled during 2009-2013.All patients taking the xeloda contained chemotherapy regimens to obtain CR,PR or SD were randomly divided into group A(65 cases, maintenance capecitabine therapy 800-1000mg/ m2 bid, orally, Days 1 ∼ 14, q3w)and group B(54 cases, a switch to maintenance endocrine therapy). Endpoints include overall survival (OS) and progression-free survival (PFS). Results The ages, menopausal status, number of metastases and treatment line numbers had no statistical differences between two groups, and the p value of two therapy co-operative groups was 0.002. There were 37 patients(56.9%)using TX and 28(43.1%)using NX in therapy co-operative group A. There were 39 patients (72.2%)using TX, 9(16.7%)using NX and 6(6%) using regimen containing xeloda in therapy co-operative group B. Progression-free survival was 8 months in patients who follow by xeloda and 12 months in those who follow by endocrine (p Citation Format: Zefei Jiang, Fan Qi, Shaohua Zhang, Li Bian, Tao Wang, Lei Li. The maintenance treatment after xeloda contained regimens with xeloda or endocrine for HR positive and HER2 negative MBC patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-10.

Abstract P4-01-19: The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients

Background: Circulating tumor cell (CTC) and serum HER2 ECD can all reflect an aggressive tumor behavior. We performed this prospective, monocenter, double-blinded study to investigate the potential clinical significance of combined detection of CTC and serum HER2 ECD for advanced breast cancer patients with histological HER2-positivity. Methods: A total of 88 eligible patients were enrolled in the present study from April 2012 to October 2013. We used Cell search system and ADVIA Centaur System to detect CTC and serum HER2 ECD respectively. Patients received systemic treatment according to national and international guidelines. Results: Twenty nine (33%) patients had ≥5 CTC, seventy three (83%) patients had serum HER2 ECD values of at least 15ng/ml, twenty seven (30.7%) patients had both elevated CTC and ECD values and fourteen (15.9%) patients had both normal CTC and ECD values. Patients with both normal CTC and serum HER2 ECD values exhibited a significantly longer median PFS than patients with both elevated values (9.0 months versus 2.8 months, p=0.023) and exhibited a trend toward longer PFS compared with patients with elevated CTC or ECD values (9.0 months versus 4.2 months, p=0.065), patients with both or one elevated values showed similar median PFS (2.8 months versus 4.2 months, p=0.211) (Figure1). Conclusions: The combined detection of CTC and serum HER2 ECD showed prognostic significance for HER-2 positive advanced breast cancer patients, patients with both normal values exhibited longer median PFS than others. Citation Format: Zefei Jiang, Jinmei Zhou, Tao Wang, Yi Liu, Lei Li, Huiqiang Zhang, Shaohua Zhang, Li Bian, Santai Song. The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-19.

Abstract OT1-1-04: HER2 status of circulating tumor cells in HER2-positive metastatic breast cancer patients: A valuable biomarker in anti-HER2 therapy

Background: In the earlier study which we have conducted, we observed that: among the patients who were histologically positive for HER2 and received anti-HER2 therapy, only those with HER2-positive circulating tumor cells (CTCs) have benefited. We also demonstrated that CTC enumeration with a modified cut-off is a valuable prognostic tool for HER2-positive MBC patients, and formulated the criterion for evaluating CTCs HER2 status. Although the number of cases was not adequate enough so as to make the persuasion of the statistical analysis limited, it was still a valuable innovative study worthy of further exploring. Purpose: we conducted a prospective study in order to find out whether HER2 expression in circulating tumor cells (CTCs) influenced anti-HER2 therapy in those HER2-positive metastatic breast cancer (MBC) patients. Trial design Patients: All the patients randomly enrolled in the trial were diagnosed with metastatic breast cancer, and the metastasis of all eligible subjects can be measured or evaluated, the Eastern Cooperative Oncology Group (ECOG) performance status score is 0 to 3. Each patient had a pathology report confirmed that this was a HER2-positve patient by the means of an immunohistochemistry (IHC) score or a fluorescent in situ hybridization (FISH) ratio, the researcher was also informed of the histological type, nodal status, estrogen receptor (ER), progesterone receptor (PgR) statuses. All of the patients would receive a new line or a new cycle of systematic therapy which must include the anti-HER2 therapy. The blood sample (10 ml) was drawn with an interval of Detection method: CTC isolation, enumeration and characterization were performed by using the CellSearch technology. HER2 expression intensity in CTC was given a score of 0, 1+, 2+, or 3+, according to the trial we have conducted previously, the CTC HER2 positive criterion was defined as >30% of CTCs over-expressing HER2 (3+). Statistical method: PFS was measured as the time between the baseline CTC assessment and the documentation of disease progression or death. Patients who were alive without progression at the time of analysis, PFS was calculated by the most recent follow-up evaluations. Kaplan-Meier survival curves were generated based on the CTC levels at baseline and the HER2 status of CTC, the curves were compared using the log-rank test. Present accrual and target accrual: 174 eligible patients were enrolled during September 2010 to April 2013, 76 patients were detected with CTC 3 1, 50 patients received a new line or a new cycle of anti-HER2 therapy within 7days. Among the 50 patients, 40 patients received Trastuzumab and others received Lapatinib. With the ongoing of the trial, we’ll continue following up with PFS and other data of the patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-04.

Randomized, controlled phase II trial of exemestane compared with medroxyprogesterone after nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer.

e11088 Background: The third-generation nonsteroidal aromatase inhibitors(AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive breast cancer. Because many patients subsequently experience progress or relapse, it is important to identify agents with efficacy after AI failure. This study is in order to understand efficacy and safety of exemestane and medroxyprogesterone for the advanced breast cancer after AI failure. METHODS Evaluation of exemestane versus medroxyprogesterone study is a randomized, controlled phase II clinical trial in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteriodal AI. The primary end point was progress free survial (PFS). Exemestane 25mg orally was administered once daily and medroxyprogesterone 1000mg orally once daily. RESULTS A total of 40 women were randomly assigned to exemestane (n=20) or medroxyprogesterone (n=20). Approximately 60% of patients had received at least two prior endocrine therapies. Median PFS was 6 months in exemestane group and 3 months in medroxyprogesterone group (P= 0.790). Overall response rate (0 vs 15%) and clinical benefit rate (30% vs 35%, P= 0.736) was similar between exemestane and medroxyprogesterone respectively. Both treatments were well tolerated. There are 6 patients who have grade 1 and grade 2 weight gain in medroxyprogesterone group. There are 2 patients who experienced grade 2 blood sugar increasement. CONCLUSIONS Exemestane and medroxyprogesterone can be used as the treatment choices in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteriodal AI. We need to carry on the phase III clinical trial to prove the efficacy and safety of the two drugs.