Clinical Study In The Treatment Of Patients With Advanced Breast Cancer

Background and Objection:Breast cancer is the first cancer of female cancer in our country, and it is the main cause of death in female. And the annual incidence rate increases, the incidence of breast cancer in our country is 89/10 million per year. Stage I breast cancer after treatment,5-year disease-free survival rate was 90%, stage II breast cancer after treatment,5 years’ disease-free survival rate of 70-80%, stage III breast cancer after treatment,5 years disease-free survival rate is 60% to 70%, stage IV breast cancer after treatment,5 years over-all survival rate is about 30%.At present around 40% of all patients with breast cancer suffer a recurrence; most of them die from it. Breast cancer thus remains the most common cause of cancer-related death in women. The risk of recurrence is highest in the first 2-3 years and then decreases continuously, although it never reaches zero. Ten percent to 20% of all recurrences are isolated locoregional recurrences, while 60% to 70% are distant metastases in one "anatomical structure," or else in multiple locations. The incidence and location of recurrences depend on the initial tumor stage, previous therapy, tumor biology, and the sensitivity of the diagnosis.The prognosis of primary metastatic breast cancer depends on the location of the metastases, but is generally regarded as poorer than that of secondary metastatic tumors. In primary metastatic breast cancer, resection with tumor-free margins (tumorectomy, mastectomy) improves 5-year overall survival by 40% to 50%. The role of axillary surgery is unclear.Today, endocrine treatment is the first line of therapy for all patients with metastatic breast cancer and positive or unknown hormone receptor status whose disease is not at a life-threatening stage. A delay of 10 to 12 weeks must be allowed for before the endocrine treatment will start to take effect.Extensive visceral metastases, CNS metastases and/or an urgent need for remission (pain) are reasons not to undertake endocrine treatment. Concurrent chemoendocrine therapy must be avoided, as this is no more effective than the separate therapies but has more side effects. Endocrine maintenance therapy following a response to chemotherapy improves not only disease-free survival but also overall survival.HER2 status is not in itself a decision criterion for or against endocrine treatment. All endocrine therapies are less effective when there is overexpression of HER2 than when there is not. Compared to anastrozole treatment alone the combination of anastrozole with trastuzumab significantly improved the remission rate and the progression-free interval.Compared with an aromatase inhibitor alone, in patients not previously treated with trastuzumab, letro-zole combined with the dual tyrosine kinase (HER2, EGFR) inactivator lapatinib showed a significantly higher remission rate (15% versus 28%) and a longer progression-free interval.Nevertheless, the combination of chemotherapy with trastuzumab remains the standard for all HER2-positive patients. Combinations of hormone therapy and trastuzumab should only be considered for selected patients (e.g., with comorbidities or in whom chemotherapy is contraindicated).For premenopausal women, the standard treatment is suppression of ovarian function combined with a second endocrine treatment step (aromatase inhibitor, fulvestrant) by analogy to postmenopausal patients. Endocrine treatment in postmenopausal patients with metastatic breast cancer depends on which treatment was previously given, and for how long. At present, there are four clinical situations. After treatment with tamoxifen, aromatase inhibitors, and fulvestrant, gestagens (medroxyproges-terone acetate, megestrol acetate), with their anabolic, analgesic, and euphorizing side effects, show positive effects in patients in the final stage of the disease. Otherwise, endocrine treatment starts again from the beginning.There are no real predictors of responsiveness to chemotherapy. If chemotherapy is indicated, it should be continued so long as the therapeutic index is favorable, i.e., so long as the benefit is greater than the side effects. Disease progression and untreatable side effects are signs that warrant treat-ment cessation.The first-line treatment with the highest recommendation grade for previously untreated metastatic breast cancer is anthracyclines and taxanes. Docetaxel appears to be better when given at 3-weekly intervals and paclitaxel at weekly intervals. Many patients have already received anthracyclines and taxanes as adjuvant treatment. If there has been a long period (more than 2 to 3 years) between the adjuvant treatment and metastatic recurrence, it is certainly acceptable to give a taxane or anthracycline. To reduce the risk of cumulative cardio-toxicity, in this situation the liposomal encapsulation of doxorubicin or epidoxorubicin can be used. When the patient has been previously treated with anthracyclines, taxanes are indicated; after previous treatment with an-thracyclines and taxanes, capecitabine, vinorelbine, nab-paclitaxel (nanoparticle-albumin-bound paclitaxel, licensed in the USA), and PEG-liposomal doxorubicin are indicated. Vinorelbine is indicated above all when there are contraindications to treatment with taxanes (e.g., impaired liver function). Cytostatics not licensed in Germany are nab-paclitaxel and ixabepilone. Ixabepilone works via inhibition of the microtubule system, without the occurrence of cross-resistance with taxanes. For off-label use of ixabepilone, neuropathy and the therapeutic index must be monitored. Neither of these substances requires a solubilizer, so premedication is unnecessary. If polychemotherapy is indicated, anthracycline-taxane combinations are recommended in patients not previously treated with anthracycline, and combinations of taxanes with capecitabine or gemcitabine in patients who have previously received anthracyclines.Vascularization is a necessary part of metastasization. To that extent, inhibition of angiogenesis using the VEGF-specific antibody bevacizumab is a logical therapeutic approach. As first-line treatment in HER2-negative patients, bevacizumab in combination with docetaxel (D, once every 3 weeks) or paclitaxel (P, once a week) led to significantly higher remission rates and an increase in progression-free survival, although overall survival was not affected.The efficacy and side effects of bevacizumab depend on its early use and individual VEGF genotypes. Bevacizumab is licensed for use in combination with taxanes for first-line treatment of HER2-negative metastatic breast cancer.Patients who overexpress HER2 benefit from early use of the monoclonal antibody trastuzumab in combination with docetaxel or paclitaxel, with a significant increase in median overall survival.For this reason, trastuzumab in combination with a cytostatic should be offered as first-line therapy to all patients, with the exception of older patients and those with cardiac morbidity. Monitoring of heart function is obligatory during trastuzumab therapy. If progression occurs during trastuzumab treatment (± taxane), the present recommendation is to switch to lapatinib+capecitabine, since the combination of lapatinib+capecitabine is significantly better than chemotherapy alone in terms of tumor response and progression-free survival. Lapatinib (± capecitabine) seems to be effective in the treatment of radiotherapy-resistant brain metastases. In patients with metastatic breast cancer not previously treated with trastuzumab, the combination of lapatinib+paclitaxel led to a significant improvement in clinical benefit and progression-free survival compared to chemotherapy alone, and median overall survival was also increased.Prospective studies on continuing trastuzumab when disease progression occurs during trastuzumab therapy in combination with chemotherapy showed that continuing the antibody treatment and changing the chemotherapy had a significant advantage over chemotherapy alone, leading to a treatment response of 49% versus 25% for the combination. Continuing trastuzumab therapy when disease progression occurs and changing the chemotherapy represents an alternative to lapatinib+chemotherapy. Clinical trials are now ongoing into another HER2 monoclonal antibody, pertuzumab.In the present authors’ view, metastatic breast cancer will remain a great challenge for physicians and researchers. Although long-term remissions are possible in individual cases today, no treatment will be available in the foreseeable future that can claim to be curative.For this reason, the main aim of current treatment for metastatic breast cancer continues to be, as the authors said at the beginning, to restore and maintain quality of life by the alleviation of symptoms caused by metastases.In all solid tumors, the treatment of breast cancer is the best About 70% of patients with breast cancer after systemic treatment will have a distant metastasis or local recurrence. These patients with advanced breast cancer face palliative treatment, such as palliative chemotherapy, palliative radiotherapy, targeted therapy, biological therapy, and so on. Among them, palliative chemotherapy is the most common. The purpose of palliative chemotherapy is to improve the quality of life of patients with advanced breast cancer, reduce the pain caused by recurrent lesions, and prolong the survival time of patients.In the second line chemotherapy of breast cancer, paclitaxel is the main drug. But in clinic, there are some patients who can not obtain clinical efficacy in palliative chemotherapy including drug paclitaxel, they were forced to change the treatment plan. In this way, the patient’s treatment time was prolonged, the quality of life has not been improved. This is contrary to the principles of treatment for patients with advanced breast cancer. If you can through molecular markers were screened of taxol drug sensitive patients undergoing such palliative chemotherapy, then can improve the efficacy of chemotherapy and will not delay insensitive to paclitaxel in patients with follow-up treatment. This is a very meaningful research for clinical treatment. It is very necessary to know whether the patients with advanced breast cancer are sensitive to paclitaxel and to understand the related factors, so that it is very necessary to evaluate the patients with advanced breast cancer. But there is very limited understanding of the sensitivity of chemotherapy for advanced breast cancer, and further research is needed.Patients received medical treatment via intravenous route in the hospital. Only a small portion of the drug is oral agents, such as capecitabine. Patients received cancer treatment, is a long-term process. The need for repeated intravenous therapy is always exist, for example:chemotherapy, nutrition support therapy, etc. There are two main ways for the administration of intravenous route, namely, the peripheral vein and central vein. Peripheral intravenous administration, because superficial vein from the skin, superficial, thin venous wall, slow velocity of blood flow, vascular branches, less flexible, so if via a peripheral vein to long-term repeated intravenous administration, prone to injury of superficial blood vessel wall, local drug leakage or vasculitis, local tissue ulceration. The center vein with vascular elasticity, backflow unobstructed, coarse vascular diameter, blood flow speed, drug and tube wall contact time is short, both to reduce chemotherapy on local vascular irritation, and avoid the occurrence of phlebitis. Therefore, the central venous route is more suitable for patients with advanced breast cancer who need long-term and repeated intravenous therapy.Now chemotherapy drugs are strong stimulation, high concentrations of the drug, such as epirubicin, vinca alkaloids, paclitaxel, vinorelbine, and these chemotherapeutic drugs on vascular endothelium stimulation of great and if once the drug extravasation may will lead to serious consequences, then advice to drug choice Ways of central vein. Patients with symptoms of phlebitis or catheter embolism, should immediately stop the intravenous injection, and timely local symptomatic treatment.In recent years, with the continuous development of central venous catheter materials, completely implantable venous port has also become the first choice for the treatment of deep vein catheter. Intravenous infusion of venous access port with its safety, low infection rate, long retention time and recommended by clinicians. The method is simple and easy to operate, and can be used for a long time, and is especially suitable for patients who need long-term chemotherapy, or long-term intravenous nutrition support treatment. Postoperative appearance, safe and convenient, usually buried in subclavian skin area, location hidden, does not affect the daily life, no drug extravasation. The port just need simple maintenance and monthly a red pipe nursing. After the intravenous infusion port, the routine chest radiography was performed, and the location of the catheter was defined. However, the placement of intravenous fluids in venous access port as a vascular surgery, the risk of surgery and postoperative complications are still unavoidable. The total complication could be achieved about 8-10%. Some patients were forced to get twice operation because of complications, for example:thrombosis, infection. How to improve the safety and effectiveness of intravenous infusion with TIVAP is still an important issue.This study is based on the needs of patients with advanced breast cancer who are able to benefit from the drug paclitaxel, how the molecular marker screening of taxol drug sensitive effective patients received palliative chemotherapy including drug taxol. In our department, advanced breast cancer before 2013 were retrospectively analyzed, which can provide guidance in the future. Palliative chemotherapy or chronic transfusion therapy for patients with advanced breast cancer need deep venous catheter pathway selection, select appropriate venous channels receive palliative chemotherapy or nutritional support treatment, in catheter problems that may arise in the process and after catheterization, how to improve the venous transmission fluid port implantation of safety and effectiveness is worth discussing. The research is divided into two parts:Predictive value of microtubule-associated protein Tau in patients with recurrent and metastatic breast cancer treated with taxane-containing palliative chemotherapy (Section I); Implanting totally implantable venous access port via the internal jugular vein guided by ultrasonography is feasible and safe in patients with breast cancer (Section II).Section I Predictive value of microtubule-associated protein Tau in patients with recurrent and metastatic breast cancer treated with taxane-containing palliative chemotherapyObjectiveTau is a member of microtubule-associated proteins (MAPs) and expressed in normal breast epithelium and breast cancer cells. Tau expression levels in early breast cancer were correlated with the responsiveness of taxane-containing chemotherapy. However, it is unknown whether Tau contributes to breast cancer progression. Herein, Tau expression in recurrent and metastatic breast cancer (RMBC) and its predictive significance in taxane-containing palliative chemotherapy were investigated.MethodsThe study was conducted from January 2003 to October 2013, on core needle biopsy specimens of 285 cases of recurrent and metastatic breast cancer tissues, in the Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong province. All cases were pathologically diagnosed with invasive breast cancer and had complete clinical data. All patients showed an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. All the patients have been treated with regimens, which did not include taxane drugs when they were primary breast cancer. After diagnosed with RMBC, all the patients undergo taxane-containing palliative chemotherapy. All the patients accepted physical examination, chest radiography, and computed tomography of metastatic sites. Bone scan was performed when serum levels of tumor markers were increased. Clinical response after four cycles of palliative chemotherapy was evaluated according to RECIST criteria. There are definitions of the criteria used to determine objective tumor response for target lesions. The criteria that have been accounted for the measurement of the longest diameter only for all target lesions are the following:complete response (CR)-the disappearance of all target lesions in≥4 weeks; partial response (PR)-at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter; progressive disease (PD)-at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started or the appearance of one or more new lesions; stable disease (SD)-neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since the treatment started. We set up CR and PR as effective response to treatment while PD and SD as invalid response to treatment. Material was obtained from recurrent and metastatic tumors of 285 patients and immunohistochemically stained for Tau protein. Tau staining of tumor cells was scored as follows:IHC score 0, no staining; 1+, less staining than normal epithelium; 2+, similar to normal epithelium; and 3+, uniform staining more intense than normal cells (Fig. 1a-d). Tumors with IHC scores of 0 or 1+ were considered to be Tau negative, and cases with scores 2+or 3+were considered to be Tau positive. This dichotomization of staining results was determined by using staining intensity of normal epithelial cells as a reference and without knowledge of the clinical outcome. Slides were scored without knowledge of the clinical outcome. Blind film reading by two persons was performed on each slice. The average of the two results was used as the final expression. All statistical analysis was carried out with SPSS 13.0 software for Windows (SPSS, Inc, Chicago, IL, USA). The chisquared test was used to compare the associations between Tau expression and other clinicopathologic variables; and multivariate logistic regression analysis was used to possible predictive factors associated with clinical response to treatment. A value of two-tailed P<0.05 was considered statistically significant.ResultsThe subjects consisted of 285 female patients, aged from 33 to 71 years old (average of 51.78 years old). The majority of the patients showed good ECOG status as 0 or 1. Metastatic sites were soft tissue in 285 cases (100%), including the skin, contralateral breast, lymph node; visceral in 25 cases (8.77%); and bone in 14 cases (4.91%). With adjuvant therapy of granulocyte colony stimulating factor (GCSF) and antiemetic drugs, no patient required taxane-drugs dose reduction. Among 285 patients with recurrent and metastatic breast cancer,121 (42.46%) were Tau positive. Table 2 shows Tau expression that was positively related to ER status (P<0.01). Tau expression was negatively correlated to age, menopausal status, lymph node metastasis, body mass index (BMI), progesterone receptor (PR), HER2, Ki67, and p53 (P>0.05). In addition, a positive correlation between ER+status with Tau protein expression was observed. After taxane-containing palliative chemotherapy,194 patients achieved response to treatment, and no response to treatment was found in 91 patients. Fifty-three and 68 Tau-positive patients were found in response and no response group, respectively. Tau expression, ER status, and HER2 status were positively correlated to the effectiveness of palliative chemotherapy (X 2=56.98, P<0.01; X 2=25.459, P<0.01; X 2= 15.158, P<0.01, respectively). In multivariate logistic regression analysis, Tau expression and ER status were confirmed as independent marker of sensitivity to taxanecontaining palliative chemotherapy in recurrent and metastatic breast cancer (P<0.01, P=0.021, respectively).ConclusionsTau-negative tumors are more sensitive to taxane-containing therapy than Tau-positive RMBC. The results indicate that Tau protein may be a promising predictive marker in patients with RMBC. It could help to select patients for taxane-containing palliative chemotherapy, which increases the targeting specificity of treatment and avoids the toxicity of the drug in those patients who are predicted to not having responsiveness to treatment. A randomized controlled study needs to be performed with larger sample sizes in the future.Section II Implanting totally implantable venous access port via the internal jugular vein guided by ultrasonography is feasible and safe in patients with breast cancer ObjectiveBecause of long-term use for chemotherapy and fluid administration in cancer patients, a totally implantable venous access port (TIVAP) has been advised as a feasible catheter. The purpose of this study was to evaluate the effectiveness and safety of ultrasound (US)-guided internal jugular vein (IJV) puncture for TIVAP implantation in patients with breast cancer.MethodsThis was a retrospective study including 492 patients with breast cancer. Patient demographics and characteristics are shown in Table 1. Of the 492 patients,5 were male and 487 were female; they had a median age of 48.66 years (range,22-73 years). All patients underwent fluid administration and/or chemotherapy. Between January 2010 and December 2013, all patients underwent TIVAP placement via the IJV or subclavian vein to the SVC. All patients were followed-up until TIVAP removal, death, or hospital discharge. The procedure and its possible complications were explained to patients, and written informed consent was obtained. Prior to surgical implantation, blood count, prothrombin time, and routine biochemistry parameters were obtained. Patients were placed in a supine position on the operative table. Catheter length was measured according to body surface prior to the procedure. Local anesthesia was administrated subcutaneously, restricted to the area of the port implantation and the venous puncture. No routine prophylactic antibiotics were administered. A standard surgical sterile technique was employed in all cases, including a surgical scrub. Statistical analysis was conducted using the SPSS 19.0 statistical analysis package. The data were analyzed using Kaplan-Meier survival analysis.ResultsTIVAP implantation was performed for chemotherapy alone (88 patients), chemoradiotherapy (387 patients), surgery (12 patients), or parenteral nutrition (5 patients). In total,176,694 catheter days (average 359 days per patient; range,28-712 days) were analyzed. Of these 492 patients,17 patients did not receive their planned intravenous chemotherapy and the TIVAPs were only effectively used for surgery or parenteral nutrition. In the remaining patients, the median number of chemotherapeutic cycles after TIVAP implantation was 5 (range,2-8). Right breast cancer was observed in 236 patients and left breast cancer in 256 patients. The median time for the implantation was 32 min (range,23-50 min). The early complications are summarized. Hematoma was observed in 12 patients (in 7 patients this occurred in the implantation site and in 5 patients in the implanted pocket) and resolved within 2 weeks. Early infection was observed in 2 patient’s Cardiac arrhythmia occurred in 10 patients, probably due to the catheter tip touching the right atrium. After replacing the catheter tip on the SVC or changing body position, the arrhythmia disappeared. The late complications are summarized. Catheter-associated thrombosis was observed in 12 patients (2.44%) approximately 12 weeks after implantation. These patients received warfarin and heparin treatment and their TIVAP continued to be used without further complications. Pulmonary thromboembolism was not observed in any patients. Catheter migration and embolization was documented in 6 patients. Port pocket infection due to cutting of the skin with the needle during repeated puncture was observed in 3 patients (0.61%) after 3 months of use for chemotherapy and fluid administration. Among the 12 patients who were converted to the subclavian vein,3 were diagnosed with pinch-off syndrome. The TIVAPs of 322 patients were removed at the end of therapy. Catheter occlusion led to the removal of TIVAP from 17 patients,4 removals were due to incurable infection with bacteremia due to penicillin-resistant staphylococcus aureus, and 1 patient (0.20%) died within 1 month of implantation because of disease progression.ConclusionAntitumor therapy including chemoradiotherapy and supportive treatments have become more important for increasing overall survival and disease free survival in patients with breast cancer. To ensure long-term central venous access, the TIVAP has been extensively used and is now widely accepted as an effective catheter [29]. Our results show that TIVAP implantation via US-guided IJV is safe and feasible in the long-term use by breast cancer patients requiring chemotherapy and parenteral nutrition. Chemotherapy and/or fluid administration on the TIVAP implantation day appear safe without an increased risk of acute and chronic complications.