• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.12
• /
• pp.7111-7116
• /
• 2013

Introduction: Trastuzumab, an HER2-targeting agents, has shown efficacy in metastatic HER2-positive breast cancer patients. Single-agent clinical trials have evaluated therapeutic regimens using trastuzumab for metastatic breast cancer patients. The aim of our study is to evaluate the efficacy and safety of trastuzumab in combination with chemotherapy or hormone therapy in HER2-positive metastatic breast cancer patients. Methods: A literature research was conducted in PubMed and to identify appropriate studies from relevant reviews. Randomized controlled trials comparing chemotherapy or hormone therapy regimens in combination with trastuzumab were eligible. Dadta on clinical outcomes, including safety, efficacy, and patient characteristics were collected. Results: Seven articles describing five trials were included in our systematic review and meta-analysis. Partners of trastuzumab included in trials were anthracycline, paclitaxel, docetaxel, anastrozole and letrozole. The addition of trastuzumab to chemotherapy improved the overall survival (HR=0.79, 95%CI 0.65-0.96), while to hormone therapy did not (HR=0.85 95%CI 0.56-1.30). All trastuzumab-containing regimens increased cardiac toxicity (RR=3.37, 95%CI 1.26-9.02) and grade III-IV adverse events. Conclusions: Our study supports the addition of trastuzumab to chemotherapy which is effective and tolerated for metastatic breast cancer with HER2+ patients. Of note, more adverse events will occur followed the use of trastuzumab, especially cardiac toxicity, with two treatment regimens.

• Journal of Radiopharmaceuticals and Molecular Probes
• /
• v.7 no.2
• /
• pp.105-111
• /
• 2021

⁸⁹Zr is a positron-emitting radioisotope, which has known as well-suited radioisotope for use in a monoclonal antibody-based imaging agent for immuno-PET. The purpose of this study was to quantitatively evaluate the diagnostic ability of general trastuzumab and thio-trastuzumab as HER2 positive receptors based on Df hexadentate iron chelator. Desferrioxamine-p-SCN (Df-Bz-NCS) and desferroixamine-maleimide (Df-Mal) were purchased from Macrocyclics (Dallas, TX, USA). The trastuzumab was purchased from Roche (Schweiz), and thio-trastuzumab was obtained from professor Hyo-Jeong Hong group (Kangwon National University). The radioisotope ⁸⁹Zr was produced by domestic purification system and KIRAMS using medical cyclotron (50 MeV, Scantronix). The conjugates of Df-trastuzumab and Df-thio-trastuzumab were prepared with Df-Bz-NCS and Df-Mal under basic aqueous solution (pH 8-9) at room temperature, respectively. The conjugates purified by PD-10 column were mixed with dried ⁸⁹Zr chloride. ⁸⁹Zr-labeled conjugates were purified and concentrated by Amicon ultra centrifugal filter. The preparation step and time of ⁸⁹Zr-labeled conjugates was shorted as 4 steps within 2 hours. ⁸⁹Zr-labeled conjugates showed the highly radiochemical purity of over 98%, and were very stable until 7 days by the analysis of radio-ITLC method. Each radio-labeled conjugates were also exhibited the highly stability in both PBS buffer and mouse serum. Immuno-PET imaging of ⁸⁹Zr-labeled conjugates in mice bearing gastric cancer xenograft tumors with HER2 expression showed high tumor uptake in the NCI-N87 HER2-expressing. However, ⁸⁹Zr-Df-Mal-thio-trastuzumab showed a relatively lower tumor-to-background ratio than ⁸⁹Zr-Df-Bz-trastuzumab, as well as whole-body distribution. In the results, ⁸⁹Zr-Df-Bz-trastuzumab was evaluated to have a relatively higher HER2 diagnostic ability than ⁸⁹Zr-Df-Mal-thio-trastuzumab.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.1
• /
• pp.127-131
• /
• 2013

Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.

• Korean Journal of Clinical Oncology
• /
• v.14 no.2
• /
• pp.108-115
• /
• 2018

Purpose: This study aimed to compare the results of treatment with adjuvant trastuzumab for 9 months versus 12 months in human epidermal growth factor 2 (HER2)-positive breast cancer patients. The primary endpoint was disease-free survival. Secondary endpoints included cardiac safety, tolerability, and overall survival. Methods: The study included 60 non-metastatic HER2-positive breast cancer patients. All study patients underwent surgery, received adjuvant chemotherapy, radiotherapy and hormonal therapy if indicated. Thirty patients were randomized in each group. Group I patients received adjuvant trastuzumab for 12 months, while group II patients received adjuvant trastuzumab for 9 months. Patients were assessed by clinical examination and Echocardiography during treatment. Results: After median follow-up of 12 months, 90% of the patients in group I were disease free and 83.3% of patients in group II were disease free (P=0.402). All studied population in both groups I and II were alive at the end of the 1-year follow-up period after the completion of adjuvant trastuzumab treatment thus overall survival is 100%. Conclusion: Trastuzumab is tolerable and its side effects are reversible. Nine months of adjuvant trastuzumab treatment is more cost effective than the standard 12 months.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.4
• /
• pp.1643-1649
• /
• 2015

Background: The aim of the present study was to evaluate clinicopathological characteristics of our early stage breast cancer patients who are epidermal growth factor receptor 2 (HER2) overexpressed/amplified (HER2+), the efficacy of trastuzumab treatment and survival results. Materials and Methods: Patients with HER2-positive early stage breast cancer receiving adjuvant trastuzumab were investigated retrospectively. Clinicopathological features of 210 patients and treatment outcome were analysed. To evaluate survival rates, the Kaplan-Meier method was used. Univariate and multivariate analyses were conducted with the Cox regression model. Results: Mean age of the patients was 51.8, 71.9% being postmenopausal. Some 37.6% of patients were node negative, and 31% had T1 tumor size and 52.4% were positive for estrogen receptor. Of 210 patients, 89.5% completed planned 52 weeks adjuvant trastuzumab treatment. The median follow up was 27.5 months (6.0-86.0). Relapse free survival (RFS) was 68.0 months (95% CI: 62.1-74.0) and overall survival (OS) was 74.8 months (95% CI: 69.5-80.1). The 3 year OS for all patients was 92.0% and RFS was 79.6%. During follow up, relapse was detected at the rate of 14.3%. Trastuzumab associated cardiotoxicity was found at the rate of 3.3%. In univariate analyses, larger tumor size and grade III were significantly associated (p<0.05) with RFS. Multivariate analyses of covariates displaying p<0.05 identified grade III as an independent prognostic factor. Conclusions: In the present study, it was established that trastuzumab had a satisfactory safety profile and treatment efficacy as in other clinical studies and that among clinicopathological factors evaluated, only being grade 3 had a significant effect on RFS. The occurrence of relapse with adjuvant trastuzumab makes it necessary to identify molecular predictors, which will define this group better and help explain resistance to anti HER2 based therapies.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.11
• /
• pp.5915-5916
• /
• 2012

Human epidermal growth factor receptor (HER) 2 overexpression, observed in 20-25 percent of invasive breast cancers, is well known to be associated with a more aggressive phenotype and poor prognosis, with resistance to certain chemotherapeutic agents. The majority of patients with metastatic breast cancer who initially respond to trastuzumab, demonstrate disease progression within 1 year of treatment initiation. Furthermore, lack of response in some patients and relapse during the course of therapy, continue to challenge researchers and clinicians. A better understanding of the fundamental mechanisms of trastuzumab action is required so that new therapies directed at HER2 can be developed. We present here findings for mechanisms, both of Trastuzumab action and clinical resistance or escape.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.9
• /
• pp.4127-4131
• /
• 2015

Background: For HER2 positive metastatic breast cancer (MBC), continuing anti-HER2 therapy beyond progression is associated with improved outcome. However retreatment with trastuzumab after lapatinib progression is controversial. We retrospectively analyzed the efficacy of trastuzumab-based chemotherapy in HER2+ metastatic breast cancer patients whose disease progressed after lapatinib. Materials and Methods: Between October 2010 and May 2013, 54 patients whose disease progressed after lapatinib were retreated with trastuzumab-based chemotherapy. Efficacy and toxicity results were evaluated retrospectively. Results: The median age of patients was 46 (range 27-67). Fourteen patients (26%) had metastases at the time of diagnosis. All of the patients had received trastuzumab in an adjuvant or metastatic setting, while 16 (30%) had received two lines of trastuzumab. All patients had received lapatinib plus capecitabine. The median chemotherapy line for the metastatic setting was 2 (range 1-7). Cranial metastases were identified in 27 (50%) patients. 53 patients received trastuzumab-based chemotherapy following lapatinib progression while one patient received trastuzumab monotherapy. Combination chemotherapy consisted of navelbin (n=33), taxane (n=10), gemcitabine (n=2), platinum (n=2) and platinum with taxane (n=6). The median treatment cycle was 5 (range 1-44). Among 49 patients assessed for response 2 (4%) showed CR, 12 (25%) PR, 11 (22%) SD and 24 (49%) disease progression. Asymptomatic cardiotoxicity was reported in 2 (4%) of the patients. At a median follow-up of 9 months (1-39), median progression-free survival was 5 months (95% CI 4.1-5.9) and median overall survival was 10 months (95% CI 6.9-13.0). PFS and OS were not affected by the absence/presence of cranial metastases. Conclusions: Retreatment with trastuzumab-based therapy after lapatinib progression showed efficacy in heavily treated MBC patients.

• Journal of Digestive Cancer Research
• /
• v.3 no.1
• /
• pp.39-41
• /
• 2015

We report a case of long term survival on trastuzumab based treatment. A 51-year-old man with dyspepsia received esophagogastroduodenoscopy on another hospital and was transferred for further evaluation under the impression of advanced gastric cancer, Borrmann type III, antrum, lesser curvature. After further studies in our hospital, the patient was diagnosed with advanced gastric cancer, adenocarcinoma, moderately differentiated with pancreas invasion and lymph node metastasis. Though he was recommended with chemotherapy, he refused and left for oriental herbal medicine. After 4 months, the patient was admitted through emergency room for hematemesis. Diagnosed with gastric outlet obstruction due to gastric cancer in the antrum, he underwent the placement of pyloric metal stent insertion. Immunohistochemical staining showed HER2-positive finding, and he was treated with palliative chemotherapy of trastuzumab, capecitabine, and cisplatin, 16 times during 11 months. The patient showed neutropenia after the therapy, so cisplatin was left out, and he received combination chemotherapy of trastuzumab and capecitabine, 34 times during 25 months. Response evaluation showed no remarkable change in extent of primary stomach cancer, lymph node metastasis, and regression of metastasis site, and the patient is continuing chemotherapy.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.3
• /
• pp.1981-1984
• /
• 2013

Objective: The optimal duration of adjuvant trastuzumab treatment in patients with HER2-positive breast cancer is not known. The aim of this study was to evaluate the efficacy of 6 months of adjuvant trastuzumab treatment in patients with stage II or III HER2-positive breast cancer. Methods: The records of patients with HER2-positive stage II or III breast cancer who were admitted to the Breast Center of Taipei Medical University Hospital and Yuan's General Hospital between 2000 and 2008 were reviewed. All patients received adjuvant trastuzumab at an initial dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg/week for 22 weeks in combination with chemotherapy. Results: A total of 51 patients were included with a mean age of 46.9 years. Approximately 55% of the patients had stage III disease. The mean follow-up time from initiation of treatment was 45.2 months (range, 0.9 to 85 months). During follow-up, 46 patients (90.2%) did not experience tumor recurrence. The mean estimated disease free survival was 80.2 months. The estimated 1-, 2-, 5-, and 7-year survival rates were 97.9%, 93.1%, 93.1%, and 93.1%, respectively. The most common adverse effects were gastrointestinal symptoms (21.6%), chills (17.6%), dizziness (9.8%), and bone pain (7.8%). No cardiac or hematologic adverse events occurred. Conclusion: Adjuvant therapy with trastuzumab for 6 months resulted in a clinical benefit in patients with HER2-positive breast cancer.

• BMB Reports
• /
• v.47 no.5
• /
• pp.268-273
• /
• 2014

HER2-overexpressing breast cancers are characterized by frequent distant metastasis and often develop resistance after short-term effective treatment with the monoclonal antibody drug, trastuzumab. Here, we found that the oncogenic miRNA, miR-221, inhibited apoptosis, induced trastuzumab resistance and promoted metastasis of HER2-positive breast cancers. The tumor suppressor PTEN was identified as a miR-221 target; overexpression of PTEN abrogated the aforementioned miR-221-induced malignant phenotypes of the cells. These findings indicate that miR-221 may promote trastuzumab resistance and metastasis of HER2-positive breast cancers by targeting PTEN, suggesting its role as a potential biomarker for progression and poor prognosis, and as a novel target for trastuzumab-combined treatment of breast cancers.