Received Trastuzumab Treatment Research Articles

Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF < 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.

Examining the risk factors for trastuzumab-related cardiotoxicity in a predominantly Hispanic South Texas population: A descriptive study.

e24000 Background: Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), stands as first line treatment for HER2 positive breast cancer. Despite its efficacy, trastuzumab’s association with cardiotoxicity requires monitoring via serial transthoracic echocardiograms (TTEs). We aimed to evaluate the risk factors for trastuzumab related cardiotoxicity in a South Texas population that is uniquely a majority-minority Hispanic population. Methods: A retrospective chart review study was conducted of all female patients with HER2-positive breast cancer who received trastuzumab treatment from 2015-2021. A total of 180 patients were identified. Patients without baseline TTE or a baseline left ventricle ejection fraction (LVEF) less than 53% were excluded. The final sample size included 132 patients. Cardiotoxicity was defined as a decrease in LVEF of more than 10% during the 1-year study period. Results: The mean age at the time of diagnosis in the study population was 54.2 years. The average BMI of the study participants was 30.89. The incidence of cardiotoxicity in this study population was 6%. Among those who developed cardiotoxicity, 50% had hypertension, 25% had hyperlipidemia, 12.5% had type 2 diabetes mellitus, and 12.5% had previous coronary artery bypass surgery (CABG). In terms of cancer treatment, 12.5% of patients had a history of radiation, 25% had a history of anthracycline therapy, and 12.5% had their trastuzumab treatment ended prematurely. Of the cardiotoxicity population, 37.5% patients were former smokers and 25% were former alcohol users. Hispanic/Latino patients composed 58% of the study population and represented 50% of patients who experienced cardiotoxicity. Conclusions: The incidence of trastuzumab-related cardiotoxicity in this Hispanic/Latino majority-minority population was 6%, lower than the 9% observed in a predominantly white population in our previous study. However, further studies are needed to determine the factors contributing to this reduced cardiotoxicity rate in this population.

Systemic immune-inflammation index as a prognostic marker in HER2-positive breast cancer patients undergoing trastuzumab therapy

The prognostic value of SII (Systemic Immune-Inflammation Index) in HER-2-positive breast cancer (BC) patients, regardless of whether they receive trastuzumab treatment, and its potential value to distinguish patients who may benefit from trastuzumab therapy, warrant further investigation. Clinical data was collected from 797 HER-2-positive BC patients between July 2013 and March 2018. Baseline data differences were adjusted with propensity score matching. Univariate and multivariate analyses explored the correlation between clinical pathological factors, SII, and DFS. Four groups were established. Based on the baseline SII values of the participants, patients who did not receive trastuzumab treatment were divided into Group 1 (Low-SII) and Group 2 (High-SII), where SII had no predictive value for prognosis between groups. Participants who received trastuzumab treatment were also divided into two groups: the Low-SII group (Group 3) and the High-SII group (Group 4). The 5-year DFS was significantly higher in Group 3 than in Group 4 (91.76% vs. 82.76%, P = 0.017). Furthermore, multivariate analysis demonstrated a significant association between high SII and shorter DFS (HR = 3.430, 95% CI = 1.830–6.420, P < 0.001). In HER-2-positive BC patients treated with trastuzumab, those with lower SII showed a longer DFS, suggesting that SII may help in identifying patients who benefit from trastuzumab therapy.

Association between insulin resistance and cardiac remodeling in HER2-positive breast cancer patients: a real-world study

BackgroundInsulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice.MethodsHER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored.ResultsOf 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006).ConclusionInsulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.

Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy

A new therapy strategy for relapsing patients who have received trastuzumab treatment urgently needs to be explored. HER2-specific chimeric antigen receptor (CAR)-expressing NK cells are being rapidly developed for solid tumor therapy, as they have many advantages over HER2-CAR-T cells. Endogenous soluble PD-1 (sPD-1) from the PD-1 extracellular domain blocks PD-1/PD-L1 interaction to promote cancer immunology. Herein, we engineered a new HER2-CAR-NK cell that co-expresses sPD-1 (designed as sPD-1-CAR-NK cells) and assessed its cytotoxic activities toward various cancer cells, activation of immunity and sPD-1 release in vitro and in mouse models bearing breast cancer cells with high HER2 expression, with or without trastuzumab resistance. We demonstrated that sPD-1-CAR-NK cells were able to release bioactive sPD-1, thereby enhancing the cytolytic activities of HER2-CAR-NK cells against HER2 and PD-L1 highly expressing target cells accompanied by increases in the secretion of perforin, granzyme B and IFN-γ. In vivo, sPD-1-CAR-NK cells had superior immunological anticancer efficacy compared to HER2-CAR-NK cells, and they had advantages over HER2-CAR-NK cells in the intraperitoneal injection of sPD-1. Moreover, the infiltration and activation of NK and T cells into tumor tissue were increased in mice with sPD-1-CAR-NK cells. There was no significant change in the body temperature, organ tissue and body weight in all groups except for the group with the PD-1 injection. Together, these data indicate that HER2-specific sPD-1-CAR-NK cells can transport sPD-1 into cancer tissues with high HER2 expression, further improving the efficacy of HER-CAR-NK cells without obvious side effects. sPD-1-CAR-NK is a promising cytotherapeutic agent for patients bearing HER2-positive breast cancer, including those with trastuzumab resistance.

HOTAIR Competitively Binds MiRNA330 as a Molecular Sponge to Increase the Resistance of Gastric Cancer to Trastuzumab

HOTAIR, one of the most widely studied long non-coding RNAs in tumors, is closely related to tumor proliferation, migration, invasion and chemoresistance. Here, we studied the mechanism behind proliferation and chemoresistance processes. A total of 75 samples were collected from patients who underwent surgical resection of their gastric cancer and received trastuzumab treatment. Primary cells were isolated and cultured. We also developed a cell line overexpressing HOTAIR by constructing a lentiviral vector. These cell lines were studied using an array of established biomolecular methods. We found that HOTAIR levels were inversely associated with sensitivity to trastuzumab in gastric cancer and that overexpression of HOTAIR can promote the proliferation and invasion of gastric cancer cells. The sensitivity of cells overexpressing HOTAIR to two different types of human epidermal growth factor receptor 2 (HER2) inhibitors (trastuzumab and afatinib) showed that overexpression of HOTAIR is specific for trastuzumab resistance. Furthermore, luciferase reporter gene assay and western blot assay showed that there is a HOTAIR-miRNA330-ERBB4 competitive endogenous RNA regulatory network with miRNA330 as the core. HOTAIR can not only promote tumor proliferation but also enhance the resistance of tumor cells to drugs. Our experimental data not only showed strong expression of HOTAIR in gastric cancer, but also that strong expression of HOTAIR caused the sensitivity of gastric cancer cells to trastuzumab, which is a useful reference for postoperative medication.

Abstract P6-11-08: Socio-economic factors affecting trastuzumab usage in breast cancer patients belonging to hilly regions of north India

Abstract Introduction Breast cancer is the most common malignancy in women worldwide and is a prototype of global cancer disparity. While breast cancer mortality is decreasing in developed countries, it continues to increase in low- and middle-income countries. Trastuzumab in combination with chemotherapy is the standard of care and essential drug for patients with Her2 positive breast cancer. Despite the availability of biosimilar, it is still out of reach for many patients in India for various reasons such as lack of drug funding or because of high treatment costs. This study examines access to trastuzumab and identified potential barriers to its use in a large tertiary care hospital in an underserved and resource-restricted hilly region of Northern India (Uttrakhand). Material and methods In a cross-sectional study all patients diagnosed with Her2 positive breast cancer who underwent treatment in our institute from January -December 2018 were included. All relevant details like age, stage, treatment details, receptor status (ER/PR/ Her2) were recorded. All Her2 positive patient who had 3+ score on immunohistochemistry (IHC) were considered positive. These patients were investigated to look into various factors for acceptance or non -acceptance of trastuzumab like socio-economic status, funding of treatment, education status and reasons for non-usage of the drug. Patients were categorized into high, middle and lower socioeconomic status by using an appropriate scale. The data were analyzed by using SPSS Version 20.0 and Open epi software. Chi-square test of significance was applied to test the association between variables. Results 310 patients of carcinoma breast were included in study, out of which 68 patients were Her2 positive (22%). Of these 68 patients, 24 (35%) received trastuzumab. Most trastuzumab recipients belong to upper and middle socioeconomic status as compared to the lower class (83.3% vs 16.7%, p=0.001). The treatment of maximum (91.7%) users were met by out of pocket expenditure whereas only two patients were beneficiary of government health schemes. Most of the trastuzumab user patients were well educated (above high school level) compared to those who did not take the drug (83% vs 36%, p= 0.0001). Among 44(65%) patients who did not receive the drug, the majority had education level below high school (63% vs 36%) despite high income (54% vs 37%). 26 (59%) patients reported the financial issue as the main cause of not taking trastuzumab whereas the remaining 18 (41%) patients cited the reason that they were not offered this drug by treating physician probably assuming that patient will not be able to afford this treatment. Except for two patients, all trastuzumab nonrecipient patients were also financing their treatment themselves. These two non-user patient with financial support from the government denied the use of trastuzumab due to personal reasons. Conclusions The majority of Her2 positive patients were unable to receive trastuzumab treatment due to financial constraints, non-availability of health insurance and poor government support for treatment. Patient’s socioeconomic class, monthly income &amp; their education level significantly influenced the usage of the drug. Treating oncologist should also overcome their personal biases about the socio-economic status of patients and should offer the drug wherever indicated as this was the second most common reason for non-usage of the drug. Improvement in education standard raises the socioeconomic status as well as disease awareness among the patient which would make them vigilant and receptive to life-saving beneficial but costly treatment like trastuzumab. Tremendous efforts are required for cost reduction, patient education as well as the implementation of the government health scheme to bridge this gap. Citation Format: Rajesh Pasricha, Pragya Singh, Ajas Ibrahim, Laxman Pandey, Ajeet Singh Bhadoria, Sweety Gupta, Deepa Joseph, Manoj Gupta, Bina Ravi. Socio-economic factors affecting trastuzumab usage in breast cancer patients belonging to hilly regions of north India [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-08.

Trastuzumab chemotherapy subclinical cardiotoxicity in patients with breast cancer: A two-dimensional speckle tracking echocardiography study

Trastuzumab chemotherapy has been associated with left ventricular (LV) dysfunction. We aimed to assess early changes in LV and right ventricular (RV) mechanics associated with trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)-speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity. Thirty-one patients with breast cancer who received Trastuzumab treatment were included. Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), 4 months (T1), and 12 months (T2). All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Cardiotoxicity developed in 6 of the 31 patients (19%). The mean (±SD) LVEF at T0 was 66% (± 6); at T1 60% (± 7); and at T2, 54% (± 6). Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, −14.7; sensitivity, 91%; specificity, 82%; P = 0.003). The average 2D LV GLS was −20.58% (± 2.2) with a statistically significant decrease at T1 and T2 (LVGLS −19.35 (± 2.1) and−18.55 (± 2.3), P < 0.001 respectively). The average 2D LV radial strain was 34.71% (± 7.8) and the circumferential strain was −18.92% (± 3.9). Compared with baseline (T0), LVGLS, LV circumferential strain, and right ventricular longitudinal strain at T1 and T2 were reduced significantly in patients with cardiotoxicity ( P < 0.05). Trastuzumab treatment leads to early deterioration of LV GLS and circumferential strain. Right ventricular GLS and radial strain were also affected. Early changes in GLS are good predictors of subsequent development of trastuzumab-induced cardiotoxicity.

Do early HER2-overexpression breast cancer patients benefit from undergoing neoadjuvant trastuzumab and mastectomy? A meta-analysis.

PurposeTo assess the overall survival (OS) of early human epidermal growth factor receptor 2 (HER2)-enriched breast cancer patients after receiving neoadjuvant trastuzumab (NAT) compared to adjuvant trastuzumab (AT) treatment and the difference in local-regional relapse (LRR) rate with this tumor and treatment between women after mastectomy and women after breast-conserving therapy (BCT).MethodsArticles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. A pooled odds ratio (OR) with a 95% confidential interval (CI) was calculated. The StataSE version 12.0 software was employed for meta-analysis.ResultsTwelve available clinical studies containing 2366 subjects were included. The OS of NAT compared with that of AT was not significantly different (pooled OR=1.04; 95% CI, 0.47–2.33). There was a significantly lower LRR rate for patients with mastectomy compared to those with BCT (pooled OR=0.58; 95% CI, 0.38–0.89); however, subgroup analysis revealed that the significant advantage of LRR for mastectomy compared to BCT was only represented in women without trastuzumab treatment (pooled OR=0.52; 95% CI, 0.31–0.88) compared to those who received trastuzumab treatment (pooled OR=0.71; 95% CI, 0.34–1.49).ConclusionEarly stage HER2-overexpression breast cancer patients benefit with an equivalent OS from NAT treatment compared to AT. Patients who underwent mastectomy and BCT experienced a similar LRR rate if they received anti-HER2 targeted therapy of trastuzumab, but the LRR rate was discernibly reduced in patients who received mastectomy compared to BCT if they did not also receive trastuzumab treatment.

Adherence to human epidermal growth factor receptor-2 testing and adjuvant trastuzumab treatment guidelines in Ontario.

We evaluated adherence of human epidermal growth factor receptor-2 testing using immunohistochemistry and fluorescence in situ hybridization, as well as adjuvant trastuzumab treatment according to Canadian guidelines, and predictors of trastuzumab use in early-stage breast cancer in Ontario. Retrospective cohort of early-stage breast cancer patients identified in the Ontario Cancer Registry. Human epidermal growth factor receptor-2 test type, sequence, result(s), tumor grade, and hormone receptor status were abstracted from Ontario Cancer Registry pathology reports. Trastuzumab treatment was determined from provincial cancer agency records. Other variables were determined from administrative data sources. Logistic regression models were used to estimate adjusted odds ratios for factors associated with guideline adherence. The first human epidermal growth factor receptor-2 test result was the strongest predictor of confirmatory testing (p < 0.05). Human epidermal growth factor receptor-2 testing by immunohistochemistry accounted for the majority of documented first tests (94%; n = 8249). Overall, 27% (n = 2360) of tested patients received a second test by fluorescence in situ hybridization (46%) or immunohistochemistry (49%) assay. Most human epidermal growth factor receptor-2 equivocal patients (89%; n = 784) received a confirmatory test. Among human epidermal growth factor receptor-2-positive patients, only 57% (n = 385) received trastuzumab treatment within the study period. Human epidermal growth factor receptor-2 status was the strongest predictor of trastuzumab use. Younger patients (<70 years at diagnosis) and negative hormone receptor status had higher odds of trastuzumab treatment (p < 0.05) compared to older and positive hormone receptor status patients. Immunohistochemistry use as a first test was largely consistent with Canadian guidelines; however, immunohistochemistry was frequently used as a confirmatory test, which is not guideline-concordant. Monitoring these testing and treating patterns is necessary to optimize health outcomes associated with trastuzumab.

Abstract P2-13-06: Long term clinical follow up of real world HER2-positive patients since the introduction of trastuzumab

Abstract Background: The prognosis for patients with HER2-positive early breast cancer (EBC) has improved dramatically since the introduction of adjuvant trastuzumab therapy. With the addition of pertuzumab the prognosis has improved further. However, there is a need to study how these results from clinical controlled trials are transferred to the real-world clinical setting. In this study we aim to investigate all patients with early HER2-positive breast cancer in our region since the introduction of adjuvant trastuzumab to evaluate the implementation of trastuzumab treatment regarding treatment coverage, prognosis and survival. Method: All patients with HER2-positve EBC, diagnosed between 2006 and 2014 in South-east Sweden were included in the study. The patients were identified using the Swedish national breast cancer register and then cross-referenced with data from the pathology department at each hospital in order to obtain complete coverage in a retrospective clinical follow up. In addition, data were collected from medical records for each patient to verify the actual given treatments and survival data. Results: Preliminary data is available. 611 patients were included with a median follow-up time of 5 years. During the follow-up period the number of patients diagnosed with HER2-positive EBC cancer doubled. 73% of all patients received trastuzumab treatment; however the coverage increased successively from 56% in 2006 to 83% in 2013. ER-positive patients did receive trastuzumab therapy to the same extent as ER-negative patients. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS) and breast cancer specific survival (BCSS) at 5 years were 85%, 76%, and 75% for patients not receiving trastuzumab. In the trastuzumab treated group LRFS, DRFS and BCSS was 95%, 85% and 83% respectively. The group not receiving trastuzumab was significantly older, had more frequently node negative disease and was not treated with chemotherapy to the same extent. Conclusion: A significant amount of early HER2-positive breast cancer patients did not receive adjuvant trastuzumab therapy between 2006 and 2014. In this group fewer patients received chemotherapy and despite less nodal involvement LRFS, DRFS and BCSS were poor for these patients. Citation Format: Ellegard S, Asowed M, Engvall K, Hallbeck A-L, Elander N, Stål O. Long term clinical follow up of real world HER2-positive patients since the introduction of trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-06.

FcγRIIA and IIIA polymorphisms predict clinical outcome of trastuzumab-treated metastatic gastric cancer.

Trastuzumab has substantial antitumor activity in metastatic gastric cancer. One such mechanism by which it exerts its antitumor activity is antibody-dependent cell-mediated cytotoxicity, which has been reported to be influenced by FcγRIIA and IIIA polymorphisms. This study is the first to assess their impact on trastuzumab efficacy in patients with metastatic gastric cancer. We retrospectively examined 42 Her-2-positive patients receiving fluorouracil and platinum-based chemotherapy and trastuzumab, and 68 Her-2-negative patients receiving fluorouracil and platinum-based chemotherapy only as the first-line treatment. FcγRIIA and IIIA polymorphisms were assessed, and their associations with efficacy in both settings were analyzed. In patients treated with trastuzumab, the FcγRIIA H/H genotype was associated with significantly superior progression-free survival (PFS) (hazard ratio [HR] [95% CI]: 0.36 [0.16–0.82], adjusted HR [95% CI]: 0.18 [0.07–0.48], P=0.001). When combining FcγRIIA and IIIA polymorphisms, the FcγRIIA H/H or FcγRIIIA V/V genotype was associated with a significantly improved disease control rate (P=0.04) and PFS (HR [95% CI]: 0.29 [0.13–0.67], adjusted HR [95% CI]: 0.17 [0.07–0.45], P<0.001). As expected, no association of FcγRIIA and IIIA polymorphisms with efficacy was found in patients receiving chemotherapy only. We concluded that FcγRIIA and IIIA polymorphisms might predict disease control rate and PFS in metastatic gastric cancer patients receiving trastuzumab treatment.

Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer.

Gastric cancer is one of the most common types of human cancer associated with a poor prognosis. MicroRNAs (miRs), a class of non-coding RNAs that are 18–25 nucleotides in length, act as key regulators in gene expression, and have been implicated in various human cancer types. miR-125b has been implicated in the malignant progression of gastric cancer. However, the association between miR-125b expression, clinicopathological characteristics and trastuzumab resistance in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains unclear. In the current study, in situ hybridization data demonstrated that 81.8% (108/132) of gastric cancer tissues exhibited positive expression of miR-125b, while only 26.3% (10/38) of non-tumor gastric tissues were miR-125b-positive. Reverse transcription-quantitative polymerase chain reaction data indicated that the expression level of miR-125b was markedly increased in gastric cancer tissues compared with non-cancerous gastric tissues. Furthermore, the miR-125b level was significantly associated with tumor (T) stage, lymph node metastasis, distant metastasis and TNM stage of gastric cancer (P<0.05). Increased miR-125b expression predicated poor prognosis in patients with gastric cancer. For HER2-positive gastric cancer, the upregulation of miR-125b expression was significantly associated with advanced malignant progression, as well as a poor prognosis (P<0.05). Furthermore, data from the present study indicated that the increased miR-125b level was significantly associated with trastuzumab resistance in HER2-positive gastric cancer (P<0.05). Therefore, the current study suggests that miR-125b may become a potential biomarker for predicting prognoses and clinical outcomes in patients with HER2-positive gastric cancer that receive trastuzumab treatment.

Association between obesity and trastuzumab-related cardiac toxicity in elderly patients with breast cancer.

PurposeTrastuzumab can improve the prognosis for patients with breast cancer, but its related cardiac toxicity is concerning. This study aimed to identify the risk factors associated with trastuzumab-related cardiac toxicity in elderly patients with HER2-positive breast cancer.Patients and methodsA total of 133 elderly (≥ 65 years) patients who were diagnosed with breast cancer between June 1, 2007, and January 31, 2016, and received trastuzumab treatment were retrospectively reviewed. Cardiac events were defined as: (1) LVEF reduction of >10% from baseline echocardiography, (2) reduction of LVEF to <50%, and (3) signs and symptoms of heart failure as defined by the Common Terminology Criteria for Adverse Events (CTCAE) accompanied by a decrease in the LVEF. Univariate and multivariate regression analyses were used to determine the contribution of different clinical variables to trastuzumab-related cardiac events.ResultsThe median age of the cohort was 71.0 years (range, 65–81 years). The median follow-up period for measurement of left ventricular ejection fraction was 11.0 months (range, 2–71 months). Fifteen patients (11.2%) experienced cardiac events during the follow-up. Multivariate regression analysis revealed that obesity (odd ratio[OR], 4.706; 95% CI, 1.984-10.147; P = 0.002) was a statistically significant risk factor associated with cardiac events.ConclusionObesity is an independent risk factor for trastuzumab-related cardiac toxicity in elderly patients with breast cancer, receiving trastuzumab. Further studies are needed to establish the independent predictive value of obesity on cardiotoxicity in these patients.

641P - FcγR IIA and IIIA polymorphisms predict clinical outcome of trastuzumab treated metastatic gastric cancer

Trastuzumab has substantial anti-tumor activity in metastatic gastric cancer, and one mechanism is antibody-dependent cell-mediated cytotoxicity (ADCC), which has been reported to be influenced by FcγR II A and III A polymorphisms. This retrospective study is the first to assess their impact on trastuzumab efficacy in patients with metastatic gastric cancer. We retrospectively included 42 Her-2 positive patients receiving fluorouracil and platinum based chemotherapy and trastuzumab, and 68 Her-2 negative patients receiving fluorouracil and platinum based chemotherapy only as first line treatment. FcγR II A and III A polymorphisms were assessed and their associations with efficacy in both settings were analyzed. In patients treated with trastuzumab, FcγR II A H/H genotype was associated with significantly superior progression-free survival (PFS) (hazard ratio (HR) and 95% confidence interval (CI): 0.36 (0.16-0.82), adjusted HR and 95% CI: 0.18 (0.07-0.48), P = 0.001). Combining FcγR II A and III A polymorphisms, FcγR II A H/H or FcγRIII A V/V genotype was associated with significantly improved disease control rate (DCR) (P = 0.04) and PFS (HR and 95% CI: 0.29 (0.13-0.67), adjusted HR and 95% CI: 0.17 (0.07-0.45), P < 0.001). As expected, no association of FcγR II A and III A polymorphisms with efficacy was identified in patients receiving chemotherapy only. FcγR II A and III A polymorphisms might predict DCR and PFS in metastatic gastric cancer receiving trastuzumab treatment.

A Retrospective Study on the Efficacy of Trastuzumab in HER2-Positive and Tamoxifen-Refractory Breast Cancer with Brain Metastasis.

The role of trastuzumab in breast cancer with brain metastasis is still in discussion. This study was conducted to investigate the efficacy of trastuzumab in the management of human epidermal growth factor receptor 2 (HER2)-positive, tamoxifen-refractory breast cancer with brain metastasis. This retrospective study was conducted between January 2008 and December 2012. A total of 33 patients receiving trastuzumab treatment for HER2-positive, tamoxifen-refractory breast cancer with brain metastasis were assigned to the experimental group, while a matched group of 35 patients who received systemic therapy without trastuzumab were assigned to the control group. Data on the patient characteristics and clinical outcomes were collected and evaluated. Patients in the trastuzumab group showed a significantly better response to treatment than those in the control group (p = 0.025). Univariate and multivariate Cox proportional regression analyses indicated that progression-free survival was significantly longer in patients receiving trastuzumab therapy than in the control group (hazard ratio [HR] 2.213 [p = 0.003] and HR 3.056 [p < 0.001], respectively) and significantly shorter in patients with two or more extracranial metastases (HR 0.417 [p = 0.002] and HR 0.317 [p < 0.001], respectively). Furthermore, patients on trastuzumab treatment experienced longer overall survival than patients in the control group (HR 2.844 [p < 0.001] and HR 4.017 [p < 0.001], respectively), while shorter overall survival was seen in patients with two or more extracranial metastases (HR 0.524 [p = 0.021] and HR 0.430 [p = 0.005], respectively) and in those receiving capecitabine-based therapy as compared with anthracycline-based therapy (HR 0.558 [p = 0.030] and HR 0.449 [p = 0.011], respectively). Trastuzumab was found to benefit patients with HER2-positive, tamoxifen-refractory breast cancer with brain metastasis by improving progression-free and overall survival.

Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer.

We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab. Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy. Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002). Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.

Red-Brown Plaques and Papules in a Patient With Breast Cancer.

A 55-year-old woman diagnosed with invasive ductal carcinoma of the left breast (T3N1M0, stage IIIA) in December 2012 was treated with neoadjuvant chemotherapy comprising docetaxel (75 mg/m) and trastuzumab (8 mg/kg initially, then 6 mg/kg every 3 weeks), followed by 3 courses of epirubicin (90 mg/m) and cyclophosphamide (600 mg/m), prior to modified radical mastectomy of the left breast. In September 2013, she began receiving trastuzumab treatment and received adjuvant radiotherapy (5000Gy in 25 fractions) 1 month later. In June 2014, she developed a generalized nonpruritic, nontender rash, without fevers or other constitutional symptoms. Physical examination showed multiple red-brown plaques and papules of various sizes on the chest, abdomen, back, and limbs (Figure 1). Laboratory evaluation revealed pancytopenia (white blood cells, 1460/μL; hemoglobin, 8.3 g/dL; and platelets, 99 000/μL [leukocyte differential: 0% blasts, 0% promyeloctes, 0%myelocytes, 0%metamyelocytes, 0% banded neutrophils, 30.1% segmented neutrophils, 4.1% eosinophils, 0.7% basophils, 0.7% monocytes, 64.4% lymphocytes]). A follow-up computed tomography scan of the chest and abdomen showed no evidence of local recurrence or distant metastasis. Quiz at jama.com Figure 1.Generalizedmultiple red-brown plaques and papules of various sizes on patient’s torso.

Abstract P6-08-53: Her2 FISH amplification in ER/PR/Her2 IHC negative breast cancer

Abstract Background: Triple negative (ER negative, PR negative, Her2 negative) breast cancer is an aggressive cancer that is not likely to respond to endocrine or anti-Her2 therapy. While Her2 positivity is a poor prognostic factor, patients with Her2 positive tumors are eligible for anti-Her2 therapy. Her2 positivity is based on either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) result. Her2 IHC scores of 0+ and 1+ are negative, 2+ is equivocal, and 3+ is positive. The Her2 gene is amplified when the Her2/CEP17 ratio is ≥2.0. While most tumors will show IHC/FISH concordance, some tumors may show discordant findings between IHC staining and FISH. Previous studies have shown benefit from anti-Her2 therapy in tumors with discordant IHC/FISH results. The purpose of this study was to determine the frequency of Her2 amplification in triple IHC negative breast cancer to determine whether routine Her2 FISH testing is necessary in this subset of patients. Methods: After Institutional Review Board approval, the pathology databases were searched for cases of triple IHC negative breast cancer from 2003-August 2013. All cases of triple IHC negative with corresponding Her2 FISH testing were included in this study. The results of Her2 FISH were correlated with Her2 IHC. The clinical history and IHC slides for all discordant Her2 cases were reviewed when available. Results: A total of 659 triple IHC negative breast cancer cases from 516 patients were found. The patients’ age at diagnosis ranged from 26-92. The cases were classified using the ratio of Her2/CEP17 per the 2013ASCO/CAP guidelines: non-amplified &amp;lt; 2.0, amplified ≥ 2.0. As the copy number for Her2 was not always available, the 2013 ASCO/CAP criterion for amplification based on the copy number was not used in reclassifying the cases. Based on the ratio, 20 tumors were amplified, 631 tumors were not amplified, and 8 tumors had insufficient tissue for Her2 FISH testing. The Her2/CEP17 ratio for amplified cases ranged from 2.0 to 11.1 and for non-amplified cases from 0.5 to 1.9. Of these 20 patients, 10 received some trastuzumab treatment, 6 did not receive any trastuzumab, and in 4 patients, there was no additional information available regarding treatment with trastuzumab. Of the 10 who received trastuzumab treatment, 2 died of disease (DOD), 26 months and 45 months after their diagnosis. The overall survival of the other patients in this group was 23-106 months. Of the 6 who did not receive trastuzumab, one DOD after 76 months. The other 5 patients have overall survival ranging from 15-93 months. Of the patients with unknown Her2 targeted therapy status, one is deceased, the status of 2 is unknown, and one patient is alive at 110 months. Discussion: Our study showed 3% of triple IHC negative breast cancers to be Her2 FISH amplified. Of the 20 tumors, 19 showed Her2/CEP17 between 2.0 to 4.2 with one case showing Her2/CEP17 of 11.1. Firm conclusions on the efficacy of trastuzumab treatment in this small subset of patients with Her2 amplification but no protein overexpression cannot be drawn. However, the overall survival of those treated and not treated is similar. Based on the small number of cases with Her2 IHC/FISH discordance, a compelling case for routine testing of all Her2 IHC negative tumors cannot be made. Citation Format: Sunati Sahoo, Helena Hwang. Her2 FISH amplification in ER/PR/Her2 IHC negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-53.

Change in Percentage of Left Ventricular Ejection Fraction in Breast Cancer Patients Received Trastuzumab Treatment.

Change in Percentage of Left Ventricular Ejection Fraction in Breast Cancer Patients Received Trastuzumab Treatment.