Targeted gene next-generation sequencing reveals genomic profile in a cohort of 46 Chinese patients with breast cancer.

BACKGROUND: The present study aimed to explore the genomic profile in a cohort of Chinese patients with breast cancer (BC), as well as provide potential strategies for clinic treatment in specific subset of BC patients. METHODS: Paired samples from 46 BC patients were subjected to DNA extraction and 537 gene targeted next-generation sequencing. RESULTS: In total, 742 somatic mutations were detected in these patients, which involved 303 genes. TP53 and PIK3CA were the most frequently mutated genes, with a mutation rate of 45.65% and 26.09%. C>T, T>C and C>A comprised the main single nucleotide base variation for this Chinese cohort. Triple negative breast cancer (TNBC) group had more TP53-mutated patients than the Non-TNBC group (p = 0.0229). In addition, the cohort was also divided into 'Young' and 'Old' groups based on the age of onset. Compared with the 'Young' group, the 'Old' group had more frameshift mutations (p = 0.0190), less missense mutations (p = 0.0269) and more HOXA11-mutated patients (p = 0.0197). Additionally, the HOXA11mt (HOXA11 gene mutated) group had more frameshift mutations than the HOXA11wt (HOXA11 gene without mutation) group (p < 0.0001). In KEGG (i.e. Kyoto Encyclopedia of Genes and Genomes) analysis, the HOXA11wt group had more gene mutations involved in the T cell receptor signaling pathway (p = 0.0197), Jak-STAT signaling pathway (p = 0.0380) and the HIF-1 signaling pathway (p = 0.0489) than the HOXA11mt group. In the present study, the heterogeneity of somatic mutations was revealed between different tumor subgroups, including TNBC/Non-TNBC, age of onset (Young/Old) and HOXA11 mutation (HOXA11mt /HOXA11wt ). CONCLUSIONS: The present study revealed the heterogeneity of gene mutation and clinical variables among BC subtypes and might provide guidance for developing a potential target for clinical treatment.

Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.

PURPOSE: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early stage breast cancer in China. METHODS: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman's correlation analysis, while the impact of TOP2A expression on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. RESULTS: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low expression. TOP2A over-expression was in positive associations with a higher Ki67 index (r = 0.83, P < 0.001), HER2 positive (r = 0.26, P < 0.001), a larger tumor size (r = 0.14, P < 0.001), and a higher histologic grade (r = 0.59, P < 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression (r = - 0.40, P < 0.001) in early breast cancer. TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P < 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 2.04; 95% confidence interval [95% CI] 1.30-3.18, P = 0.0018) and OS (HR = 3.54; 95%CI 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. CONCLUSION: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, Ki67 index, tumor size, histologic grade and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.

Updated efficacy of adjuvant epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes in early triple-negative breast cancer in phase 2 trial: 8.1-year median follow-up.

BACKGROUND: Paclitaxel/docetaxel after doxorubicin plus cyclophosphamide (ECT) is considered as an adjuvant chemotherapy and improves the survival of early triple-negative breast cancer (TNBC) patients. We aim to assess whether carboplatin plus taxanes (TP) is non-inferior to ECT in prolonging the survival time. METHODS: TNBC patients were randomized (1:1) to receive ECT (90 mg/m2 epirubicin + 600 mg/m2 cyclophosphamide followed by 75 mg/m2 docetaxel or 175 mg/m2 paclitaxel every 3 weeks, n = 154) or TP (75 mg/m2 docetaxel or 175 mg/m2 paclitaxel + carboplatin AUC 5 every 3 weeks, n = 154). These expression of SPARC, PD-L1, and BRCA were studied. Patients were followed up for disease-free survival (DFS), overall survival (OS), and safety. RESULTS: We recruited 308 TNBC patients (median follow-up of 97.6 months). The median DFS and OS were not reached; the 8-year DFS rate of ECT and TP arms was 78.4% and 81.7%, respectively, while the 8-year OS rate were 87.2% and 89.1%, respectively. In the SPARC (> 50%) subgroup analysis, the TP arm had longer DFS (P = 0.049) and a tendency with better OS (P = 0.06) than ECT arm. No significant differences were observed in the DFS and OS between the ECT arm and TP arm in TNBC with SPARC (≤ 50%), PD-L1 (-) PD-L1 (+), and BRCA mutation or BRCA wild (all P values > 0.05). CONCLUSION: TP showed non-inferiority for DFS and OS compared with ECT in early TNBC. TP may be an effective alternative chemotherapy for TNBC patients whom the standard ECT regimen is not being used. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT01150513.

Platinum-based chemotherapy in advanced triple-negative breast cancer: A multicenter real-world study in China.

Platinum-based chemotherapy (PBC) has proven benefits in phase III studies for advanced triple-negative breast cancer (TNBC) patients; however, real-world data of large samples from multiple centers are lacking. Our study was to compare the effectiveness of PBC and non-PBC in advanced TNBC patients in multicenter real-world settings. Totally, 495 patients with advanced TNBC receiving PBC (n = 350) or non-PBC (n = 145) at four cancer centers in China between 2003 and 2019 were included. Treatment responses and outcomes were compared between the two groups from first-line to third-line treatment. Of patients with PBC, 249 (71.1%) received PBC from first-line chemotherapy, 86 (24.6%) from second-line and 15 (4.3%) from third-line treatment. In first-line treatment, PBC was superior to non-PBC in objective response rate (ORR, 53.0% vs 32.1%, P < .001) and median progression-free survival (PFS, 8.4 vs 6.0 months, P = .022), whereas overall survival (OS) was similar (19.2 vs 16.8 months, P = .439). When comparing patients receiving non-PBC doublets (n = 221) with those receiving PBC doublets (n = 249), the same trend was observed in ORR (32.6% vs 53.0%, P < .001), median first-line PFS (6.5 vs 8.4 months, P = .041) and median first-line OS(17.8 vs 19.2 months, P = .568). Paclitaxel/docetaxel + platinum was more likely to be used, followed by gemcitabine + platinum. In second/third-line treatment, PBC yielded a similar response and survival compared to non-PBC. Adding PBC in the first-line therapy was better than that in the latter-line of treatment in terms of ORR, PFS and OS (P < .001). Toxic effects of PBC were tolerable and the most common adverse event was neutropenia (38.6%). PBC doublets exhibited superior efficacy and manageable toxicity compared to non-PBC doublets in the first-line treatment for Chinese mTNBC patients.

Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer.

PURPOSE: Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. METHODS: In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2 d1; carboplatin AUC = 5, day 1), or four cycles of EC (epirubicin: 90 mg/m2; cyclophosphamide: 600 mg/m2, day 1) followed by four cycles of T (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2, day 1). The primary end point was the disease-free survival (DFS) rate at 5 years. Both regimens were repeated every 3 weeks. The prognostic and predictive value of germline breast cancer gene mutations and programmed death ligand-1 (PD-L1) expression was evaluated. RESULTS: At a median follow-up of 66.9 months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority = 0.034, p log-rank = 0.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p = 0.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. CONCLUSIONS: This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients.

OBJECTIVE: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer in a real-world setting. METHODS: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival (DFS) and overall survival (OS). Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using the Cox regression model. RESULTS: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The 3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and 98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group (DFS: HR=0.50, 95% CI, 0.37-0.68; P<0.001; OS: HR=0.53, 95% CI, 0.34-0.81; P=0.004) after adjusting for covariates. In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence, and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events (incidence ≥1%) were more common in patients receiving trastuzumab (54.44%vs. 15.73%). CONCLUSIONS: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

Toremifene, rather than tamoxifen, might be a better option for the adjuvant endocrine therapy in CYP2D6*10T/T genotype breast cancer patients in China.

Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. A total of 230 breast cancer patients who received adjuvant TAM (n = 115) or TOR (n = 115) at the National Cancer Center were analyzed. The CYP2D6 *10 genotype was not significantly associated with DFS in patients who received TOR (p = 0.737). Patients treated with TOR had a higher 5-year disease-free survival (DFS) rate than those treated with TAM (89.6% vs. 80.9%, p = 0.009). TOR treatment remained an independent prognostic marker of DFS in multivariate analysis compared with TAM (hazard ratio = 0.51; p = 0.014). For all of the 50 CYP2D6 *10 T/T genotype patients, TOR treatment group had a significantly higher 5-year DFS rate than TAM group (90.9% vs. 67.9%, p = 0.031). For the remaining 170 CYP2D6 *10 C/C or C/T genotype patients, there was no significant difference between the 5-year DFS rates of the TOR and TAM groups (89.2% vs. 85.1%, p = 0.188). The advantage of adjuvant TOR over TAM in Chinese breast cancer patients might be caused by the significant benefit obtained by the CYP2D6 *10 T/T patients, who accounted for one-fifth of the overall population. TOR might be a good option for adjuvant endocrine therapy in this subgroup of patients in China.

The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population.

Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)-treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease-free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5-year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients.

Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: Phase 3 randomized trial.

BACKGROUND: In this prospective study, progression-free survival (PFS) and the safety profiles of docetaxel/capecitabine (TX) and vinorelbine/capecitabine (NX) followed by capecitabine maintenance therapy were compared in patients with metastatic breast cancer. METHODS: Patients with advanced metastatic breast cancer were randomly assigned to a TX group (n = 104) and an NX group (n = 102), both of which included capecitabine maintenance medication. The primary endpoint was progression-free survival (PFS). RESULTS: The trial met its primary endpoint and was closed to accrual subsequent to interim analysis. Forty-eight patients in the TX group (46.2%) and 42 patients in the NX group (41.2%) received maintenance medication. The median PFS (8.4 vs 7.1 months; P = .0026; 95% confidence interval, 1.18-2.3; hazard ratio, 1.65), the response duration (7.8 vs 6.6 months; P = .0451), and the median overall survival (OS) (35.3 vs 19.8 months; P = .1349; 95% confidence interval, 0.88-2.47; hazard ratio, 1.48) in the TX group appeared to be longer compared with those in the NX group, although the difference did reach not statistical significance. Patients aged ≥40 years who were postmenopausal and presented with visceral metastases were more likely to benefit from the TX regimen in terms of PFS and OS, whereas positive hormone receptor and human epidermal growth factor receptor 2 status or a history of taxane treatments did not affect differences in PFS and OS between the TX and NX groups. Hand-foot syndrome occurred more frequently in the TX group than in the NX group (47% vs 16.7%; P < .0001), but the frequencies of other minor adverse effects were similar in both groups. CONCLUSIONS: A TX regimen for advanced breast cancer followed by capecitabine maintenance medication led to longer PFS and response duration than an NX regimen, even for patients who had previously received taxane in (neo)adjuvant settings. Cancer 2015. © 2015 American Cancer Society. Cancer 2015;121:3435-43. © 2015 American Cancer Society.

[Efficacy and safety of cisplatin plus capecitabine for patients with metastatic triple negative breast cancer progressing after anthracycline and taxane treatment].

OBJECTIVE: To evaluate the efficacy and safety of cisplatin and capecitabine combination (XP) therapy for patients with metastatic triple negative breast cancer (TNBC) progressing after anthracycline and taxane treatment. METHODS: Twenty-nine metastatic TNBC patients were prospectively enrolled to receive capecitabine (1, 000 mg/m(2) twice daily on days 1-14) and cisplatin (75 mg/m(2) on day 1) , repeated every 3 weeks. RESULTS: With a median of 6 cycles of XP, all 29 patients were evaluable for response, including 18 PR (62.1%), 6 SD (20.7%), 5 PD (17.2%) and no CR. The response rate was 62.1%. Patients with earlier stage at diagnosis (stage I to IIIA), longer post-operative disease free survival (>2 years) and less metastatic sites (≤ 3) obtained significantly higher response rate than patients with later stage at diagnosis (stage IIIB to IV), shorter post-operative disease free survival (≤ 2 years) and more metastatic sites (>3). The leading side effects were grade 1/2 gastrointestinal and hematological toxicities. Grade 3/4 toxicities included neutropenia (34.5%), leukocytopenia (31.0%), anemia (6.9%), thrombocytopenia (3.4%), nausea/vomiting (20.7%), stomatitis (3.4%), and hand-foot syndrome (3.4%). CONCLUSION: Cisplatin and capecitabine combination therapy is an active and well-tolerated doublet treatment in metastatic TNBC patients progressing after anthracycline and taxane treatments.

[Efficacy and toxicity of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes].

OBJECTIVE: To assess the efficacy of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes. METHODS: Clinical data of 48 patients diagnosed and treated for mTNBC between 2004 and 2012 at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) were retrospectively analyzed. All patients were pretreated with anthracyclines and at least one taxane in neo-adjuvant, adjuvant or chemotherapy for mTNBC and patients should be having at least one measurable metastatic lesion. Totally, 48 patients were included in this study, of which 21 cases received first-line chemotherapy and 27 cases received second-line chemotherapy. Based on the regimen they received, 22 patients were treated with NVB plus platinum (NP), and 26 patients with NVB plus capecitabine (NX). RESULTS: After 70 months follow-up, in the total group of patients, the objective response rate was 20.8%, clinical benefit rate was 43.8%, median progression free survival (PFS) was 4.4 months and median overall survival (OS) was 15.5 months. In addition, the ORR was significantly better in the NP arm versus NX arm (33.8% vs.7.7%, P=0.029) as well as PFS was statistically improved in the NP arm than NX arm (5.3 m vs. 3.0 m, P=0.023). Similar trend was observed in the OS, although the difference was not statistically significant (27.7 m vs. 14.8 m, P=0.077). In all, the most frequently reported adverse events were G1/2 gastrointestinal toxicity (68.8%) and neutropenia (62.5%) . No significant difference was observed between the NP arm and NX arm (P>0.05). The percentage of patients who delayed chemotherapy administration in the NP arm and NX arm was 9.1% (n=2), and 3.8% (n=1), respectively. CONCLUSIONS: NVB-based combination chemotherapy demonstrates moderate efficacy in mTNBC patients pretreated with anthracyclines and one taxane with manageable toxicity. NP regimen shows potential superiority over NX regimen, and should be further verified in randomized phase III clinical trial in larger cohort.

Efficacy of platinum-based chemotherapy in triple-negative breast cancer patients with metastases confined to the lungs: a single-institute experience.

The role of platinum-based chemotherapy (PBCT) in the treatment of triple-negative breast cancer (TNBC) is still undetermined. The aim of this study was to compare the efficacy of PBCT versus non-PBCT in patients with lung metastasis from TNBC. Clinical data on patients diagnosed and treated for lung metastasis from TNBC between 2004 and 2012 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences, were retrospectively analyzed. Of the 79 patients identified, 34 received PBCT and 45 received non-PBCT. The median progression-free survival was 10 months [95% confidence interval (CI) 6.6-13.4 months] in the platinum-based group and 5 months (95% CI 3.7-6.3 months) in the nonplatinum group (P=0.002); overall survival was also significantly improved (32 vs. 21 months, P=0.002). In the multivariate analysis for the entire cohort, first-line PBCT (hazard ratio 0.425; 95% CI 0.251-0.720; P=0.001) and presentation of symptoms related to lung metastasis (hazard ratio 2.237; 95% CI 1.180-4.240; P=0.014) were associated independently with survival. Our results support the use of PBCT in the first-line treatment of lung metastasis from TNBC.

[Clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors].

OBJECTIVE: To discuss the clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors. METHODS: The databases of Cancer Hospital of Chinese Academy of Medical Sciences from January 2001 to December 2012 were reviewed. 24 patients were identified with a diagnosis of metastasis to the breast from extramammary solid tumors and their clinical data were collected and analyzed. All the primary solid tumors and breast lesions were confirmed by pathology or cytology. RESULTS: Of the 24 patients, 22 were women and two were men. The median age was 54 years. The primary malignancies included non-small cell lung cancer (n = 10), small cell lung cancer (n = 4), rhabdomyosarcoma (n = 3), olfactory neuroblastoma (n = 3), ovarian cancer (n = 2), malignant melanoma (n = 1) and gastric cancer (n = 1). 15 patients (62.5%) complainted self-palpable breast nodules, two patients manifested as diffuse swollen and red of the whole breast, 7 patients (29.2%) were identified as well-defined nodules in the breast on CT images. The majority of metastases to breast presented as a solitary nodule with rapid growth, sometimes associated with axillary lymph node enlargement and occasionally with micro-calcification. Cytopathological examination could be used to differentiate the metastatic lesions from primary breast tumors. 83.3% (20/24) of the patients were concurrently accompanied with metastases in other organs and/or lymph nodes. The metastases to the breast from extramammy solid tumors were associated with a poor prognosis and the median overall survival was only 9.2 months. CONCLUSIONS: Metastasis to the breast should be considered in any patient with a known primary malignant tumor history who presents with a breast lump. Pathological examination should be performed to differentiate the primary breast cancer from metastatic tumor. An accurate diagnosis of breast metastases may not only avoid unnecessary breast resection, more importantly it is crucial to determine an appropriate and systemic treatment.

[Efficacy and safety of trastuzumab plus different chemotherapy regimens in treatment of the patients with HER-2-positive advanced breast cancer].

OBJECTIVE: To evaluate the efficacy and safety of trastuzumab plus different chemotherapy regimens in treatment of patients with HER-2-positive advanced breast cancer. METHODS: 132 patients with advanced HER-2-positive breast cancer were treated with trastuzumab plus different regimens. The clinical characteristics, efficacy and toxicity of the 132 patients were retrospectively analyzed. RESULTS: Five patients had complete response (CR), 61 patients had partial response (PR), 39 patients had stable disease (SD), and 27 patients had progressive disease (PD). The objective response rate was 50.0% and the disease control rate was 79.5%. The median progression-free survival was 9.3 months. The median overall survival time was 46.2 months. The 1-, 2-, 5- year survival rates were 98.3%, 81.9% and 40.2%, respectively. Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy (51.2% vs. 33.3%). The number of metastatic sites, efficacy, different previous treatment lines were independent prognostic factors of PFS (P = 0.002, P < 0.0001 and P < 0.0001, respectively). Visceral metastases, pathological grade, and PFS were independent prognostic factors of OS (P = 0.041, P = 0.001, P = 0.025, P < 0.001, P < 0.0001 and P < 0.0001, respectively). Regarding the toxicities, one case discontinued treatment due to the decrease of left ventricular ejection fraction to 47%, two cases had heartbeat tachycardia, 6 cases had palpitation, 17 cases had a fever during first input trastuzumab. No other serious cardiac toxicity was observed. The most common toxicities were chemotherapy-related hematological and non-hematological toxicities. CONCLUSIONS: Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy. Patients may get benefits for early use of trastuzumab. Trastuzumab plus chemotherapy is effective and well tolerated in patients with advanced HER-2 positive breast cancer. No heart failure occurred in this series of patients, and cardiac safety seems better than that in Caucasians because of younger age at the onset in Chinese advanced breast cancer patients.

[Comparison of the effectiveness of platinum-based chemotherapy versus non-platinum-based chemotherapy for triple-negative breast cancer with metastases confined to the lungs].

OBJECTIVE: To compare the effect of first-line treatment with platinum-based chemotherapy and non-platinum-based chemotherapy in patients with lung metastases from triple negative breast cancer (TNBC). METHODS: Sixty-five eligible patients were divided into platinum-treated group and non-platinum-treated group according to the first-line therapy. Factors predicting the chemotherapeutic efficacy included overall survival (OS), progression-free survival (PFS) and objective response (OR). RESULTS: In the platinum-treated group of 32 patients, 2 cases (6.3%) achieved CR, 16 cases (50.0%) achieved PR, 11 (34.4%) cases achieved SD, and 3 patients (9.4%) achieved PD. In the non-platinum-treated group of 33 patients, 2 cases (6.1%) achieved CR, 6 cases (18.2%) achieved PR, 16 cases (48.5%) achieved SD, and 9 cases (27.3%) achieved PD. Median PFS was significantly longer in the platinum-treated group than in the non-platinum-treated group (10 months vs. 6.0 months, P = 0.012), and OS was also improved (32 months vs. 22 months, P = 0.006). Multivariate analysis of several factors including local-regional lymph node involvement, lung metastasis-related symptoms, first-line platinum-based chemotherapy, disease-free interval, size and number of lung lesions, showed that first-line platinum-based chemotherapy was an independent prognostic factor for TNBC patients with lung metastases. CONCLUSIONS: Compared with non-platinum-based chemotherapy, the first-line platinum-based chemotherapy can improve PFS and OS in TNBC patients with metastases confined to the lungs.

[Clinical analysis of 34 patients with adrenal metastasis from breast cancer].

OBJECTIVE: To evaluate the clinical characteristics and prognosis of adrenal metastasis from breast cancer, and to explore methods to improve prognosis. METHODS: Thirty-four breast cancer patients with adrenal metastasis were diagnosed and treated in our hospital from Jan. 1999 to Dec. 2010. SPSS 17.0 was used for survival analysis. RESULTS: During the Jan. 1999 to Dec. 2010 period, 13 595 patients with breast cancer were treated in our hospital. Among them, 34 cases had adrenal metastasis from breast cancer, with an incidence of 0.25%. The median time to progression (TTP) and overall survival of the 34 patients was 6.2 months (95%CI 3.1-9.3 months) and 21.4 months (95%CI 0-44.0 months), respectively. Eleven patients (34.4%) achieved partial response among 32 patients who received chemotherapy, and 10 (31.2%) achieved stable disease. Patients who achieved best response of PR or SD were superior in TTP and OS than patients with disease progression after chemotherapy (TTP: 18.1 months vs. 2.3 months, P < 0.001; OS: 35.2 months vs. 10.3 months, P = 0.003). Patients who received 1st or 2nd line chemotherapy were superior in TTP than patients who received over 2nd line chemotherapy (TTP: 15.7 months vs. 4.2 months, P = 0.005). CONCLUSIONS: The incidence of adrenal metastasis from breast cancer is low. Chemotherapy-based systemic therapy should be recommended to improve the prognosis for these patients.

Unfavorable pathological complete response rate of neoadjuvant chemotherapy epirubicin plus taxanes for locally advanced triple-negative breast cancer.

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer (TNBC). Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2) or docetaxel 75 mg/m(2) every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response (pCR), which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Thirty-nine (90.7%) patients were at clinical stages IIB-IIIC. Thirty-seven (86%) completed 4-6 cycles of preoperative chemotherapy, and objective response rate (ORR) was 81.4% (35/43). Forty-two patients underwent radical surgery subsequently. The pCR rate was 14.3% (6/42). The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting (88.4%, 38/43) and neutropenia (88.4%). After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally advanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

[Effects of polysomy 17 on HER-2 gene and protein expression and its clinicopathologic significance in breast cancer].

OBJECTIVE: To explore the effects of polysomy 17 on human epidermal growth factor receptor-2 (HER-2) testing and study its clinicopathologic significance. METHODS: We retrospectively analyzed the HER-2 status by fluorescence in situ hybridization (FISH) and HER-2 protein expression by immunohistochemistry (IHC) in a cohort of 619 patients with invasive breast cancer. The relationship between polysomy 17 and various clinicopathologic parameters was assessed. RESULTS: Polysomy 17 was observed in 31.8% of cases, but more frequently in the IHC(3+) (41.9%) than in the IHC(2+)(27.7%) and IHC(1+/0) (11.1%) subgroup (P = 0.001). There was no significant correlation between the frequency of polysomy 17 and HER-2 status in each IHC subgroup (P > 0.05). Among the cases without gene amplification by FISH, 9 of 15 IHC(3+) cases showed polysomy 17. As compared with the amplified group, un-amplified polysomy 17 patients were associated with such good prognostic indicators as greater hormone receptor positivity (P < 0.001) and lower Ki-67 index (P = 0.003) with a trend towards those with neither amplification or polysomy. CONCLUSION: The frequency of polysomy 17 is partially correlated with HER-2 protein expression but not HER-2 amplification. And polysomy 17 is a major factor in strong HER-2 protein overexpression in 3+ non amplified cases. Tumors displaying un-amplified polysomy 17 resemble more HER-2-negative than HER-2-positive counterparts.

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).