Trastuzumab-based Treatment Research Articles

Abstract P1-03-08: Simultaneous analyses of HER2 gene and protein status can more precisely predict pathological complete response (pCR) to neoadjuvant trastuzumab with chemotherapy in primary HER2-positive breast cancer

Abstract Background: HER2-positive breast cancer is characterized by overexpression of HER2 protein and/or amplification of the HER2 gene, assessed by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. According to the 2013 ASCO/CAP guidelines on HER2 testing in breast cancer, both protein and gene status can be classified into three categories: positive, equivocal and negative. Gene-protein assay (GPA) is a newly developed technique, in which IHC and dual color ISH (DISH) are simultaneously performed on a single slide. HER2 GPA slides allow bright-field analyses of both protein and gene expression status of each cell. Breast cancer cells can be classified into nine types based on the combination of protein and gene expression with GPA. Table 1. Three by three classification of cancer cells by the HER2 GPA analysis HER2 protein 3+ (positive)2+ (equivocal)0, 1+ (negative)HER2 gene copy number≥6 (positive)ABC 4, 5 (equivocal)DEF <4 (negative)GHI Purpose: We aimed to elucidate the relationship between the results of HER2 GPA analysis and the therapeutic effects of trastuzumab-based treatment. Methods: Fifty three (53) patients with HER2-positive breast cancer, who underwent neoadjuvant trastuzumab with chemotherapy, were analyzed for HER2 status and clinical outcome. First, HER2 protein and gene status in a pre-therapeutic biopsy material from each patient were separately assessed according to the ASCO/CAP guidelines using HER2 GPA slides. Second, all cancer cells in five representative microscopic images of GPA slides were assessed to determine protein expression and to count the gene copy number at individual cell levels. Finally, we investigated the relationship between the mixture composition of the nine cell types and pathological complete response (pCR) of trastuzumab-treated breast cancer. Results: The GPA results were concordant with the results of IHC in 98% of samples, and with DISH results in 100%. Two hundred eighty nine (289) cancer cells per patient were assessed on average, ranging from 137 to 490 cells. The mean proportion of type A cancer cells was 64%, ranging from 0% to 98%. Patients who had 50% or more of type A cancer cells achieved pCR in 72% of cases (28/39), while patients with less than 50% of type A cancer cells achieved pCR in 7% of cases (1/14) (P<0.0001). The mean proportion of type C cancer cells was 7%, ranging from 0% to 60%. Patients who had 10% or more of type C cancer cells achieved pCR in 10% of cases (1/10), while patients with less than 10% of type C cancer cells achieved pCR in 65% of cases (28/43) (P=0.0016). Conclusion: HER2 GPA analyses can more precisely predict therapeutic effect of trastuzumab-based treatment in primary HER2-positive breast cancer. Our study suggests that the HER2 GPA approach would further improve precision therapy in HER2-positive breast cancer. Citation Format: Horii R, Nitta H, Ito Y, Iwase T, Ohno S, Akiyama F. Simultaneous analyses of HER2 gene and protein status can more precisely predict pathological complete response (pCR) to neoadjuvant trastuzumab with chemotherapy in primary HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-08.

The Predictive and Prognostic Role of Stromal Tumor-infiltrating Lymphocytes in HER2-positive Breast Cancer with Trastuzumab-based Treatment: a Meta-analysis and Systematic Review.

Background Tumor-infiltrating lymphocytes (TILs) are white blood cells that have left the bloodstream and migrated into a tumor, involving in the prognosis of breast cancer (BC) patients. Published studies reported the value of TILs in patients with HER2-positive receiving trastuzumab-based treatment. However, the results obtained remain controversial. Here, we conducted this study to explore the predictive and prognostic role of TILs for HER2-positive BC patients receiving trastuzumab therapies.Method To identify the related published studies, a comprehensive literature search dating up to July 2017 was performed in the databases of PubMed, PMC, Web of Science and China National Knowledge Infrastructure (CNKI) according to predefined selection criteria. The pathologic complete response (pCR) and survival outcome of patients were measured by odds ratio (OR) and hazard ratio (HR) with corresponding 95% confidence interval (95% CI), respectively. The association between TILs and trastuzumab benefit was analyzed by using STATA version 11.0.Result Eleven eligible studies comprising 3228 patients were identified in the present study. The pooled results showed that high level of TILs was associated with a significantly improved pCR rate (OR = 1.32; 95% CI = 1.10-1.60) and longer survival (HR = 0.97; 95% CI = 0.96-0.99), particularly in the subgroups of retrospective study design and 10% INC cut-off value. Moreover, stratified analysis revealed that elevated TILs was a predictor of higher pCR rate in the Asian population and improved survival in the subgroups of Caucasian population and multivariate analysis.Conclusion This meta-analysis indicated that the level of stromal TILs was an independent predictive and prognostic marker for better outcome in HER2-positive BC patients receiving trastuzumab-based treatment. High level of TILs was significantly associated with trastuzumab benefit.

Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance.

Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series. We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy. Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238-48. ©2016 AACR.

Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1.

BackgroundOverexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer.ResultsCell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy.Materials and MethodsSK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method.ConclusionsmRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.

Erratum: A miRNA-based signature predicts development of disease recurrence in HER2 positive breast cancer after adjuvant trastuzumab-based treatment.

Scientific Reports 6: Article number: 33825; published online: 21 September 2016; updated: 14 October 2016

A miRNA-based signature predicts development of disease recurrence in HER2 positive breast cancer after adjuvant trastuzumab-based treatment.

Approximately 20% of HER2 positive breast cancer develops disease recurrence after adjuvant trastuzumab treatment. This study aimed to develop a molecular prognostic model that can reliably stratify patients by risk of developing disease recurrence. Using miRNA microarrays, nine miRNAs that differentially expressed between the recurrent and non-recurrent patients were identified. Then, we validated the expression of these miRNAs using qRT-PCR in training set (n = 101), and generated a 2-miRNA (miR-4734 and miR-150-5p) based prognostic signature. The prognostic accuracy of this classifier was further confirmed in an internal testing set (n = 57), and an external independent testing set (n = 53). Besides, by comparing the ROC curves, we found the incorporation of this miRNA based classifier into TNM stage could improve the prognostic performance of TNM system. The results indicated the 2-miRNA based signature was a reliable prognostic biomarker for patients with HER2 positive breast cancer.

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.

HER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based adjuvant treatment: a systematic review and meta-analysis.

BackgroundTrastuzumab-based therapy is a standard, targeted treatment for HER2-positive breast cancer in the adjuvant setting. However, patients do not benefit equally from it and the association between HER2 amplification level and patients' survival remains controversial. A systematic review and meta-analysis was conducted by incorporating all available evidence to evaluate the association between disease free survival (DFS) and HER2 amplification level.ResultsThree cohort studies involving 1360 HER2-positive breast cancer patients stratified by HER2 amplification magnitude were eligible for meta-analysis. The combined HRs for DFS were 1.05 (95% CI: 0.80−1.36, p = 0.74) and 0.97 (95% CI: 0.73−1.29, p = 0.83) for HER2 gene copy number (GCN) and HER2/CEP 17 ratio. No evidence of heterogeneity or public bias was found.MethodsDatabases including PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL), were searched for eligible literature. HER2 amplification level was evaluated by fluorescence in situ hybridization (FISH) in terms of gene copy number (GCN) and HER2/CEP17 ratio. Hazard ratios (HRs) for DFS with 95% confidence interval (CI) according to the amplification level of HER2 were extracted. The outcomes were synthesized based on a fixed-effects model.ConclusionsHER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based targeted therapy in the clinical adjuvant setting.

Clinicopathological and surgical factors associated with long-term survival in patients with HER2-positive metastatic breast cancer.

Trastuzumab-based treatment has dramatically improved the outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC) patients, with some patients achieving prolonged survival times. In this study, we aim to identify factors that are associated with long-term survival. Patients with HER2+ MBC treated with anti-HER2 target therapy were identified. Patients were grouped according to overall survival (OS) and categorized as long-term survivors (LTS, OS≥5years), or non-long-term survivors (non-LTS, OS<5years). Descriptive statistics and multivariable logistic regression modeling were used. A sensitivity analysis was carried out, including only patients diagnosed before 2007; therefore, 5years of potential follow-up was possible. 1063 patients with HER2+ MBC diagnosed between 1994 and 2012 and treated with anti-HER2 therapy were identified. Among them, 154 (14.5%) patients were categorized as LTS (median OS 92.2months). Among LTS, 63.4% were HR-positive and 32% had de novo stage IV disease. Hormone receptor positivity (OR) 1.69; 95% CI 1.17-2.44), resection of metastases (OR 2.38; 95% CI 1.53-3.69), and primary breast surgery in patients with de novo stage IV (OR 2.88; 95% CI 1.47-5.66) were associated with improved long-term survival. Greater number of metastatic sites (≥3 vs. 1, OR 0.41; 95% CI 0.23-0.72) and visceral metastases (OR 0.61; 95% CI 0.4-0.91) were associated with poor survival. Hormone receptor positivity, low burden of disease, metastasis to soft and bone tissues, and surgical management with resection of the metastatic site and the primary tumor were associated with long-term survival in patients with MBC who received anti-HER2 treatment.

Tumor Heterogeneity in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Gastric Cancer Assessed by CT Texture Analysis: Association with Survival after Trastuzumab Treatment.

BackgroundImage texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment.Methods and FindingsPatients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan–Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10−3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan–Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger population will be needed to validate the results.ConclusionsHeterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment. Therefore, texture analysis shows potential to be a clinically useful imaging biomarker providing additional prognostic information for patient selection.

Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness.

The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management.

Metastatic HER-2-positive salivary gland carcinoma treated with trastuzumab and a taxane: a series of six patients

Metastatic salivary gland carcinoma is a rare malignancy. A subset of these tumors overexpresses the human epidermal growth factor receptor 2 (HER-2), which is considered a poor prognostic marker. Targeted therapy with the monoclonal antibody trastuzumab can be a treatment option in these patients. We describe six cases of metastatic salivary gland carcinoma treated with trastuzumab in combination with a taxane. Three of these patients had salivary duct cancer, two had mucoepidermoid carcinoma and one patient was treated for acinic cell carcinoma. The therapy was well tolerated. We observed five partial responses and a median progression free survival of 10.8 months, which compares favorably with the reported outcome of combination chemotherapy. One patient achieved a complete and durable remission. When HER-2 and androgen receptor were co-expressed, trastuzumab-based treatment appeared to be more active than androgen deprivation in our experience.

HER2-amplification level and tumor-infiltrating lymphocytes in breast cancer patients treated with neoadjuvant trastuzumab.

596 Background: Trastuzumab-based neoadjuvant treatment (TNT) has shown clinical benefit in terms of both overall response and pathologic complete response (pCR). In particular, TNT is indicated for women with HER2-positive locally advanced breast cancer and allows for breast-conserving surgery. In addition, some evidences show that TIL may play a role in the response to anti-HER2 therapy. This study aims to investigate the possibility that HER2-amplification level and high level of TIL are predictive factors of response to TNT in locally advanced breast cancer. Methods: 75 HER2-positive breast cancer pts treated from 2009 to 2014 with TNT were included in this retrospective study. Preoperative biopsies or cytological samples were collected and analyzed by dual-color fluorescence in situ hybridization (FISH) to determine HER2-amplification. We used the cut-off recommended by ASCO/CAP 2013. TIL were evaluated in both pre- and post-treatment specimen; TIL score was assessed on hematossilin-eosin slides based on Salgado et al. recommendations. Clinical-pathological characteristics were recorded. Statistical analyses were performed using IBM-SPSS (V21.0). A p-value < 0.05 was considered statistically significant. Results: Among the 75 cases, HER2-amplification level was low (LA) in 14 cases (19%), intermediate (IA) in 17 cases (23%) and high (HA = gene copy number > 10 or clusters of signals) in 44 cases (59%). TNT achieved pCR in 19 of 75 tumors and correlated with HER2-amplification level (36% HA vs 6% IA vs 14% LA, p-value = 0.01). TILs levels were evaluated in 58 biopsies and surgical specimens: only 6 pts were classified as lymphocyte-predominant breast cancer (TILs ≥ 50%). The probability of developing pCR increased with TILs levels, although a statistically significant correlation was not achieved. No correlation was found between TIL and HER2-amplification levels. Age, stage, tumor grade and hormone receptor status were not significantly correlated to pCR. Conclusions: We show that while HER2-amplification level correlates positively with pCR to TNT, high level of TIL is not predictive of better response to trastuzumab in locally advanced HER2-positive disease.

A miRNA-based signature predicts development of disease recurrence in HER2 positive early breast cancer after adjuvant trastuzumab-based treatment.

e12070Background: Adjuvant trastuzumab is the standard treatment for early HER2 positive breast cancer. However, 15%-22% of patients still suffered disease recurrence after adjuvant anti-HER2 treatment. A molecular prognostic model that can reliably stratify patients by risk of developing disease recurrence is urgently needed. Methods: All the patients included were diagnosed as HER2-postive breast cancer and received radical surgery followed by adjuvant trastuzuamb treatment. Using miRNA microarrays, we analyzed the FFPE tumor tissue from14 patients (7 recurrence vs.7 non-recurrence) and identified nine miRNAs that were differentially expressed. Then, we validated the expression of these miRNAs using qRT-PCR in training set (n = 101), and built the miRNA-based classifier using the Cox regression model. We further confirmed the prognostic accuracy of this signature in an internal testing set (n = 57), and an external independent testing set (n = 53) Results: We identified a two-microRNA signature that cla...

Age is a Factor for Referral of Women With Left Ventricular Dysfunction During Trastuzumab-based Treatment for HER2-positive Breast Cancer: Single-center Retrospective Data Analysis

Age is a Factor for Referral of Women With Left Ventricular Dysfunction During Trastuzumab-based Treatment for HER2-positive Breast Cancer: Single-center Retrospective Data Analysis

Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer.

Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.

Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer

Importance Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. Objective To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. Design, Setting, and Participants In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Interventions Treatment consisted of weekly 80-mg/m 2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Main Outcomes and Measures Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Results Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Conclusions and Relevance Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.

A36 - Relationship between levels of HER-2 amplification and pathologic complete response to trastuzumab-based neoadjuvant treatment

A36 - Relationship between levels of HER-2 amplification and pathologic complete response to trastuzumab-based neoadjuvant treatment

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options.

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) remains an incurable disease, and approximately 25% of patients with HER2+ early breast cancer still relapse after adjuvant trastuzumab-based treatment. HER2 is a validated therapeutic target that remains relevant throughout the disease process. Recently, a number of novel HER2 targeted agents have become available, including lapatinib (a small molecule tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor), pertuzumab (a new anti-HER2 monoclonal antibody) and ado-trastuzumab emtansine (T-DM1, a novel antibody-drug conjugate), which provide additional treatment options for patients with HER2+ MBC. The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or T-DM1 compared with standard HER2 targeted therapy. Here we review the clinical development of approved and investigational targeted agents for the treatment of HER2+ MBC, summarize the latest results of important clinical trials supporting use of these agents in the treatment of HER2+ MBC, and discuss how these results impact therapeutic options in clinical practice.

Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration.

While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit. The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors. The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.