Cardioprotective Effect of Dexrazoxane in Patients with HER2-Positive Breast Cancer Who Receive Anthracycline Based Adjuvant Chemotherapy Followed by Trastuzumab

김인호,이지은,윤호중,송병주,채병주 한국유방암학회 2017 Journal of breast cancer Vol.20 No.1

Purpose: We intended to determine whether dexrazoxane (DZR) is cardioprotective during administration of adjuvant anthracycline- based chemotherapy followed by a 1-year trastuzumab treatment. Methods: The medical records of 228 patients who underwent surgical resection and received adjuvant chemotherapy with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer between January 2010 and December 2014 were reviewed. Approximately 25% of patients received DZR prior to each administration of doxorubicin during doxorubicin with cyclophosphamide (AC) chemotherapy. DZR was not administered during the 1-year trastuzumab maintenance period. Rates of cardiac events (reduction in left ventricular ejection fraction [LVEF] by 10% or more; reduction in absolute LVEF to <45%) and cardiac event-free duration (CFD) were examined. The trastuzumab interruption rate was also assessed. Results: Twelve percent of patients experienced a cardiac event. Repeated-measures analysis of variance for ejection fraction revealed a significant main effect of time, and a significant group (DZR)×time interaction. The group treated with adjuvant chemotherapy and DZR experienced significantly lower frequencies of cardiac events than the adjuvant chemotherapy only group. In multivariate analysis, DZR administration was associated with significantly fewer cardiac events. Moreover, DZR administration was an independent good prognostic factor for CFD. Only one patient (2.3%) experienced early interruption of trastuzumab in the adjuvant chemotherapy with DZR group due to cardiac toxicity, whereas 10 patients (7.6%) experienced a trastuzumab stop event in the adjuvant chemotherapy only group. Conclusion: DZR is cardioprotective in HER2-positive breast cancer patients who received adjuvant chemotherapy with trastuzumab. A large cohort randomized trial is needed to determine if DZR has an effect on trastuzumab interruption and completion of 12-month trastuzumab. Because cardiac toxicity has a significant negative effect on trastuzumab maintenance and quality of life, DZR administration could be considered concomitantly with anthracycline- based adjuvant chemotherapy with trastuzumab.

Efficacy and Safety of Trastuzumab Added to Standard Treatments for HER2-positive Metastatic Breast Cancer Patients

Zhu, Zhen-Li,Zhang, Jun,Chen, Mei-Lan,Li, Ke Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.12

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.

Trastuzumab-based Retreatment after Lapatinib in Heavily Pretreated HER2 Positive Metastatic Breast Cancer: an Anatolian Society of Medical Oncology Study

Uncu, Dogan,Bayoglu, Ibrahim Vedat,Arslan, Ulku Yalcintas,Kucukoner, Mehmet,Artac, Mehmet,Koca, Dogan,Oguz, Arzu,Demirci, Umut,Arpaci, Erkan,Dogan, Mutlu,Kucukzeybek, Yuksel,Turker, Ibrahim,Isikdogan, Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.9

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.

Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment

An, E.,Ock, C.-Y.,Kim, T.-Y.,Lee, K.-H.,Han, S.-W.,Im, S.-A.,Kim, T.-Y.,Liao, W.-L.,Cecchi, F.,Blackler, A.,Thyparambil, S.,Kim, W. H.,Burrows, J.,Hembrough, T.,Catenacci, D. V. T.,Oh, D.-Y.,Bang, Y.- KLUWER ACADEMIC PUBLISHERS GROUP 2017 Annals of Oncology Vol. No.

<P><B>Abstract</B></P><P><B>Background</B></P><P>A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.</P><P><B>Patients and methods</B></P><P>GC patients (<I>n </I>=<I> </I>237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.</P><P><B>Results</B></P><P>Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, <I>P </I>=<I> </I>0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: <I>P </I>=<I> </I>0.504; OS = 17.5 versus 12.6 months: <I>P </I>=<I> </I>0.520). HER2 levels were not prognostic for response to chemotherapy.</P><P><B>Conclusions</B></P><P>Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.</P>

Relative Survival Benefit by Hormonal Receptor Status of Adding Trastuzumab to Neoadjuvant Chemotherapy in Breast Cancer Patients

Jean Schneider,이혁진,남석진,이수정,정진향,정성후,임승택,전예원,곽홍기 한국유방암학회 2020 Journal of breast cancer Vol.23 No.3

Purpose: Neoadjuvant chemotherapy (NAC) involving trastuzumab markedly increases pathologic complete response (pCR) rates in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Despite increasing pCR rates, long-term survival gains are controversial owing to distinctive biologic behavior mediated by the presence of hormonal receptors (HRs) that may interact with HER2 receptors. We, therefore, investigated the differences in relative survival gain provided by neoadjuvant trastuzumab-based chemotherapy on HR positive (HR+) status of patients. Methods: We retrospectively ana Patient clinical characteristics were compared usin lyzed women with stage II or III HER2+ breast cancer who underwent NAC followed by a breast cancer surgery between 2008 and 2013. The survival benefits of adding trastuzumab to NAC were analyzed by classifying patients into HR+ and HR negative (HR−) groups. Results: Of 666 patients included in the study, 374 (52.1%) were HR+ and 319 (47.9%) were HR−. In the HR+ group, trastuzumab treatment led to higher pCR rates and significantly better breast cancer specific survival (BCSS) and overall survival (OS) than no trastuzumab treatment. However, among patients with HR− breast cancer, trastuzumab treatment showed no statistically significant difference between BCSS and OS following multivariate analysis. Conclusion: We found that the addition of trastuzumab to NAC improved relative survival benefit in HER2+/HR+ patients than in HER2+/HR− patients, even though the pCR rate increases were lower. Although pCR has been regarded as a surrogate marker for estimating long-term survival benefits after NAC, it alone may not translate into real long-term oncologic outcomes in particular cancer subtypes after trastuzumab-based NAC. Further longer-term evaluation of the objective survival benefit after NAC driven by a dual HER2 block according to HR status is warranted.

유방암 환자에서의 trastuzumab 주입관련반응 발생률 및 위험인자 분석

정지혜,김유진,여미진,박애령,김순주,황보신이,나현오 한국병원약사회 2018 병원약사회지 Vol.35 No.2

Background : Trastuzumab is a monoclonal antibody for use in the treatment of the human epidermal growth factor receptor-2 (HER2) often overexpressed in breast cancer. One of its common side effects of this therapy use is the infusion-related reactions. Conversely, it is noted that there are no guidelines for preventing these side effects in patients. In this study, we aimed to find grounds to support the safe use of trastuzumab based on an analysis of the incidence and risk factor of the infusion-related reactions in breast cancer patients receiving trastuzumab. Methods : We evaluated the infusion-related reactions of the breast cancer patients receiving the first trastuzumab between Jan 1, 2014 and June 30, 2015. For the analysis of the risk factors, we collected the patient’s information retrospectively using the access to the patient’s secured electronic medical records. Results : In this study, a total of 91 patients were evaluated, and the total number of trastuzumab administration was with 270 cases. The infusion-related reactions were identified in 18 patients and the incidence was recorded at 19.8%. All infusion-related reactions were occurred during the first dose. And the symptoms began in the average timeframe of 76.5 minutes after the administration. The incidence of the infusion-related reactions was 11.1% in patients receiving premedication, and 21.9% in the patients not receiving the premedication (p=0.31). Particularly speaking, the patients who were weighing more than 70kg had a significantly higher risk of infusion-related reactions, than the patients who were known to weighing less than 70kg (odds ratio 5.23; 95% CI, 1.32 - 20.67; P=0.01). And the higher patient's body mass index tended to occur more infusion-related reactions (odds ratio 1.15; 95% CI, 0.98 - 1.35; P=0.08). Conclusion : Based on this result, in order to administer the trastuzumab safely, we suggest that the prevention guideline for the infusion-related reactions need to be utilized to consider the patient's body weight, and it is necessary to strengthen the monitoring to continue until the latter half of the drug therapy administration.

Safety and Tolerability of Docetaxel, Cyclophosphamide, and Trastuzumab Compared to Standard Trastuzumab-Based Chemotherapy Regimens for Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Potjana Jitawatanarat,Tracey L. O’Connor,Ellen B. Kossoff,Ellis G. Levine,Kaweesak Chittawatanarat,Nuttapong Ngamphaiboon 한국유방암학회 2014 Journal of breast cancer Vol.17 No.4

Purpose: We evaluated the tolerability and cardiac safety ofdocetaxel, cyclophosphamide, and trastuzumab (TCyH) for thetreatment of early-stage human epidermal growth factor receptor2 (HER2)-positive breast cancer and compared to the standardtrastuzumab-based chemotherapy regimens doxorubicin withcyclophosphamide followed by paclitaxel and trastuzumab (ACTH)and docetaxel, carboplatin, and trastuzumab (TCaH). Methods:We retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-basedchemotherapy at a single comprehensive cancer center between2004 and 2011. Patient characteristics, comorbidities, relativedose intensity (RDI) of each regimen, tolerability, and cardiac toxicitywere evaluated. Results: One hundred seventy-seven patientswere included in the study (AC-TH, n=114; TCaH, n=39;TCyH, n=24). TCyH was solely administered in the adjuvant setting,whereas two-thirds of the AC-TH and TCaH groups wereadministered postoperatively. Patients treated with TCyH tendedto have a more significant underlying cardiac history, higherCharlson comorbidity index, and were of an earlier stage. All patientstreated with TCyH received granulocyte colony stimulatingfactor primary prophylaxis. No febrile neutropenia or grade ≥3hematologic toxicity was observed in the TCyH group as comparedto the AC-TH and TCaH groups. There were no significantdifferences in the rates of early termination, hospitalization, dosereduction, or RDI between the regimens. The symptomatic congestiveheart failure rate between AC-TH, TCaH, and TCyHgroups was not significantly different (4.4% vs. 2.6% vs. 8.3%,respectively, p=0.57). There was also no significant difference inthe rate of early trastuzumab termination between patients treatedwith each regimen. Conclusion: TCyH is well tolerated andshould be investigated as an alternative adjuvant chemotherapyoption for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary tosupport the wider use of TCyH as an adjuvant regimen.

Patients with HER2-positive Early Breast Cancer Receiving Adjuvant Trastuzumab: Clinicopathological Features, Efficacy, and Factors Affecting Survival

Ulas, Arife,Kos, Tugba,Avci, Nilufer,Cubukcu, Erdem,Olmez, Omer Fatih,Bulut, Nilufer,Degirmenci, Mustafa Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.4

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.

A Retrospective Analysis for Patients with HER2-Positive Gastric Cancer Who Were Treated with Trastuzumab-Based Chemotherapy: In the Perspectives of Ethnicity and Histology

이준호,강정훈,황인규,안희경,백현진,이순일,임도형,원영웅,지준호,김효송,라선영,오성용,이경은,임태규,맹치훈,김문진,김승태,이지윤,박준오,박영석,임호영,강원기,박세훈 대한암학회 2016 Cancer Research and Treatment Vol.48 No.2

Purpose While the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy. Materials and Methods Data of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively. Results A total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025). Conclusion While subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer.

Prognostic and predictive values of EGFR overexpression and <i>EGFR</i> copy number alteration in HER2-positive breast cancer

Lee, H J,Seo, A N,Kim, E J,Jang, M H,Kim, Y J,Kim, J H,Kim, S-W,Ryu, H S,Park, I A,Im, S-A,Gong, G,Jung, K H,Kim, H J,Park, S Y Nature Publishing Group 2015 The British journal of cancer Vol. No.

<P><B>Background:</B></P><P>Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.</P><P><B>Methods:</B></P><P>We analysed the clinical significance of EGFR overexpression and <I>EGFR</I> gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.</P><P><B>Results:</B></P><P>Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High <I>EGFR</I> gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high <I>EGFR</I> copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.</P><P><B>Conclusions:</B></P><P>Epidermal growth factor receptor overexpression, but not high <I>EGFR</I> copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.</P>