Trastuzumab In Breast Cancer Patients Research Articles

IAM1363-01: A phase 1/1b study of a selective and brain-penetrant HER2 inhibitor for HER2-driven solid tumors.

TPS3186 Background: HER2 activation promotes carcinogenesis, prompting the development of HER2-directed therapies in cancers with HER2 alterations. There is a critical need for novel agents to treat HER2-driven cancers, as current inhibitors display significant toxicity and lack efficacy against certain mutations. IAM1363 (formerly IAM-H1 and ENT-H1) is an irreversible and brain-penetrant small molecule inhibitor targeting both wildtype HER2 and oncogenic HER2 mutants, including the recalcitrant exon 20 mutations. IAM1363, discovered through Iambic Therapeutics' AI-driven discovery platform, represents the only example of a Type II HER2 inhibitor. It was designed to avoid off-target toxicities from EGFR inhibition thus expanding the therapeutic index over existing HER2 inhibitors. In preclinical studies, IAM1363 shows preferential tumor enrichment, a unique feature observed across tumor types and anatomic sites. The promising target specificity and pharmacokinetic profile of IAM1363 offers the potential to bridge gaps left by current standard of care HER2 targeted treatments. Methods: IAM1363-01 is a first-in-human, multicenter, open-label, Phase 1/1b dose escalation and expansion trial evaluating IAM1363 as monotherapy and in combination with trastuzumab. The study will enroll patients with relapsed/refractory malignancies that have documented HER2 gene alterations (amplification or tyrosine kinase domain mutations) or protein overexpression. Prior treatment with HER2 directed therapies is allowed after a washout period. Part 1, dose escalation, will enroll patients with any tumor type. Part 2 will optimize IAM1363 dosing as monotherapy and in combination with trastuzumab. Part 3 consists of a Simon 2-Stage evaluation of IAM1363 as monotherapy in patients with colorectal, non-small cell lung, and bladder cancer with or without brain metastases and in combination with trastuzumab in breast cancer patients with brain metastases. Key objectives are to establish the safety and tolerability of IAM1363, characterize PK/PD, and determine the recommended Phase 2 dose. Exploratory analysis will correlate HER2 expression level/mutation status with tumor response and tolerability. IAM1363 will be given orally once daily at a starting dose of 120 mg/day in up to 4 planned dose levels. Dose escalation employs an accelerated titration design that transitions to a standard 3 + 3 design based on protocol-specific criteria. Up to 287 patients will be enrolled at approximately 20 sites and treated until disease progression or unacceptable toxicity. The trial is designed to establish the safety profile of IAM1363 as a single agent and in combination with trastuzumab and to provide initial proof of antitumor activity in malignancies with HER2 overexpression, gene amplification, or tyrosine kinase mutations, including in patients with brain metastases. Clinical trial information: NCT06253871 .

Left atrial strain is reduced following trastuzumab in breast cancer patients.

The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab. We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3months and after 1year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up. The mean age was 52.7±13.8years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAεres ): -4.7%; [-8.1% to -1.3%], p=.007; LA conduit strain (LAεcon ): -2.8%; [-5.3% to -.4%], p=.021); and LAεres sr: -.2/s; [-.3/s to -.09/s], p<.001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAεres : -1.7%; [-3.1% to -.3%], p=.020, LAεcon : -2.2%; [-3.3% to -1.1%], p<.001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p<.001). LA strain rates did not decline significantly in the non-CTRCD group. Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment.

Early and late onset cardiotoxicity following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors

IntroductionCardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data on longitudinal studies about early and late onset cardiotoxicity in this group of patients is scarce. The objective of the present study was to assess predictors of early and late onset cardiotoxicity in patients with breast cancer treated with A. Methods100 consecutive patients receiving anthracycline-based chemotherapy (CHT) to treat breast cancer were included in this prospective study. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years after the beginning of CHT. Clinical data, systolic and diastolic echo parameters and cardiac biomarkers including high sensitivity Troponin T (TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Heart-type fatty acid binding protein (H-FABP) were assessed. ResultsMean doxorubicin dose was 243 mg/m2. Mean follow-up was 51.8 ± 8.2 months. At one-year incidence of anthracycline related-cardiotoxicity (AR-CT) was 4% and at the end of follow-up was 18% (15 patients asymptomatic left ventricular systolic dysfunction, 1 patients heart failure and 2 patients a sudden cardiac death). Forty-nine patients developed diastolic dysfunction (DD) during first year. In the univariate analysis DD during first year was the only parameter associated with AR-CT (Table 1). In the logistic regression model DD was independently related with the development of AR-CT, with an odds ratio value of 7.5 (95% CI 1.59–35.3). ConclusionsIncidence of late-onset cardiotoxicity is high but mostly subclinical. Diastolic dysfunction early after chemotherapy is a strong predictor of anthracycline cardiotoxicity.

Abstract P6-08-13: Home-based treatment with subcutaneous (SC) trastuzumab - only a pandemic solution? Real world evidence (RWE) analysis

Abstract Background The pandemic has accelerated the introduction of more flexible and cost-effective treatment forms. The efficacy of trastuzumab in the intravenous (IV) and SC forms is similar both in early and advanced HER2-positive breast cancer (BC) patients. Compared to IV administration, SC enables reduction of treatment costs and time, and saves equipment and human resources. SC formulation is more convenient for both patients and healthcare providers and may be implemented as a home-based therapy. Recently, systemic anticancer treatment (including chemotherapy) has been increasingly performed at home, improving patient comfort and reducing the burden on the healthcare system. Poland has already implemented home-based treatment with some biologic compounds; however, they have not included trastuzumab in BC patients. Objectives This RWE analysis aims to evaluate the organizational and therapeutic procedures related to the home-based treatment with SC trastuzumab and the attitudes of patients and healthcare providers to this approach. Material and methods The study enrolled early HER2(+) BC patients treated with trastuzumab during the COVID-19 pandemic. Monitoring and treatment duration were consistent with SmPC and reimbursement regulations in Poland. The first 3-6 doses of SC trastuzumab (alone or in combination with CHT) were administered at a cancer center in outpatient and inpatient settings. Subsequent doses were administered at home by 3 qualified breast nurses. Post-injection follow-up was used for educational purposes. Data were analyzed with descriptive statistics. The study was reviewed and approved by the local Bioethics Committee. Results The analysis included 20 patients treated in two comprehensive cancer centers in Poland with a median age of 59 years (range, 36-72 years). Seven patients (35%) were professionally active. The average distance from the place of residence to the cancer center was 24 km (range, 2-65 km). A total of 232 doses were administered (mean 11.6 doses per patient; range 6-14), 133 doses at home and 99 at the cancer center. The overall tolerance of trastuzumab was good and consistent with the known safety profile described in Summary of Product Characteristics. Only 1 patient (5%) discontinued treatment prematurely due to decreased LVEF; another 19 patients completed treatment as planned. For 19 patients (95%), the benefits of SC treatment included time savings, the ability to continue working, and avoiding crowded places and infection risk. 2 patients (10%) considered the nurse’s visit privacy disturbing, while 18 (90%) would recommend home-based drug administration. The average duration of a nurse’s stay at home was 60 minutes (range 30 to 130 minutes). No logistical or technical problems were reported, except for occasional patient lateness. Nurses positively assessed the treatment provided in the nursing office, which was a source of additional knowledge, and experience. The overall impression of home-based therapy was positive for both patients and nurses. The limitation of the study is the declarative nature of the data. Conclusions Home-based treatment with SC trastuzumab should be pursued due to its safety, ease of organization, positive perception by patients and nurses, and reducing healthcare system resources. It can be particularly valuable for disabled patients who have difficulty reaching the hospital and professionally active patients. Specialized, trained nurses can self-sufficiently carry out part of the prolonged trastuzumab treatment, reducing physician involvement. Citation Format: Barbara Radecka, Hudała-Klecha Joanna, Dariusz Sawka, Jolanta Sarga, Bożena Noworolska, Jolanta Sawicka, Elżbieta Duda, Natalia Obruśnik, Patryk Zając. Home-based treatment with subcutaneous (SC) trastuzumab - only a pandemic solution? Real world evidence (RWE) analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-13.

Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab.

To clarify the incidence and risk factors of infusion-related reactions (IRRs) caused by trastuzumab in breast cancer patients and verify the preventive effects of dexamethasone. All breast cancer patients newly treated with trastuzumab at the Osaka Medical and Pharmaceutical University Hospital from 1 January 2017 to 31 December 2020 were included. The electronic medical records were retrospectively reviewed. The outcome measure was the occurrence of IRRs of grade 1 or higher during trastuzumab infusion. Only dexamethasone and anticancer drugs administered concomitantly before trastuzumab were used as explanatory variables. The 176 patients included in the study received 2320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the total 2320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone lowered the risk of trastuzumab-induced IRRs (mg, per 1 unit, odds ratio [OR] = 0.61, 95% confidence interval [95% CI] 0.43-0.85, P = .003). In addition, preoperative status (OR = 38.9, 95% CI 5.4-278.7, P < .001) and high-dose trastuzumab (mg/kg, per 1 unit, OR = 60.6, 95% CI 20.1-182.9, P < .001) were independent risk factors for IRRs. The results of this study suggest that premedication with dexamethasone exhibits preventive effects on trastuzumab-induced IRRs in breast cancer patients. Future studies are needed to determine the optimal dose of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab in breast cancer.

Lapatinib in combination with capecitabine versus continued use of trastuzumab in breast cancer patients with trastuzumab-resistance: a retrospective study of a Chinese population

BackgroundThe efficacy and safety of lapatinib plus capecitabine (LC or LX) versus trastuzumab plus chemotherapy in patients with HER-positive metastatic breast cancer who are resistant to trastuzumab is unknown.MethodsWe retrospectively analyzed data from breast cancer patients who began treatment with regimens of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) at eight hospitals between May 2010 and October 2017.ResultsAmong 554 patients who had developed resistance to trastuzumab, the median PFS (progression free survival) was 6.77 months in the LX group compared with 5.6 months in the TBP group (hazard ratio 0.804; 95% CI, 0.67 to 0.96; P = 0.019). The central nervous system progression rate during treatment was 5.9% in the LX group and 12.5% in the TBP group (P = 0.018).ConclusionThe combination of lapatinib and capecitabine showed a prolonged PFS relative to TBP in patients who had progressed on trastuzumab.

New Cardiac Abnormalities After Radiotherapy in Breast Cancer Patients Treated With Trastuzumab

PurposeTo evaluate cardiac imaging abnormalities after modern radiotherapy and trastuzumab in breast cancer patients. Patients and MethodsAll patients treated with trastuzumab and radiotherapy for breast cancer between 2006 and 2014 with available cardiac imaging (echocardiogram or multigated acquisition scan) were retrospectively analyzed. Cardiac abnormalities included myocardial abnormalities (atrial or ventricular dilation, hypertrophy, hypokinesis, and impaired relaxation), decreased ejection fraction > 10%, and valvular abnormalities (thickening or stenosis of the valve leaflets). Breast laterality (left vs. right) and heart radiation dose volume parameters were analyzed for association with cardiac imaging abnormalities. ResultsA total of 110 patients with 57 left- and 53 right-sided breast cancers were evaluated. Overall, 37 patients (33.6%) developed a new cardiac abnormality. Left-sided radiotherapy was associated with an increase in new cardiac abnormalities (relative risk [RR] = 2.51; 95% confidence interval [CI], 1.34-4.67; P = .002). Both myocardial and valvular abnormalities were associated with left-sided radiotherapy (myocardial: RR = 2.21; 95% CI, 1.06-4.60; P = .029; valvular: RR = 3.30; 95% CI, 0.98-10.9; P = .044). There was no significant difference in decreased ejection fraction between left- and right-sided radiotherapy (9.6% vs. 2.1%; P = .207). A mean heart dose > 2 Gy as well as volume of the heart receiving 20 Gy (V20), V30, and V40 correlated with cardiac abnormalities (mean heart dose > 2 Gy: RR = 2.00; P = .040). ConclusionNew cardiac abnormalities, including myocardial and valvular dysfunction, are common after trastuzumab and radiotherapy. The incidence of new abnormalities correlates with tumor laterality and cardiac radiation dose exposure. Long-term follow-up is needed to understand the clinical significance of these early imaging abnormalities.

1635PD - Accessibility and affordability to trastuzumab for breast cancer patients: Voices of the global oncology community from ONCOLLEGE 001 survey, part 2

BackgroundONCOLLEGE-001 project surveyed the global accessibility (ACC)/ affordability (AFF) to HER2-testing (H2T) & medicines for breast cancer (BC). The 1st analysis showed critical issues of ACC & AFF of H2T in lower- middle income countries. Part 2 of the survey focuses on ACC, AFF and prioritization of anti-HER2 medicines; here, we present the data for trastuzumab (T). MethodsAn internet-based survey was developed by the international ONCOLLEGE working group. Data were analyzed per country-income (World Bank groupings) and World Health Organization Regions. Responders authorized for the use of the data. ResultsResponses were received from 210 providers (78% medical or clinical oncologists) across 45 countries (all income groups, all regions). 8% of providers reported no T available in their setting, of which 60% are from low and low-middle income countries (LMICs) and the remaining from upper- middle (UMIC). Where T was available, 15% of the responders reported ACC only as out of pocket expenditure (OOP) for patients, of which almost 70% from LMICs. More than 2/3 of the responders described to order the H2T regardless ACC to affordable trastuzumab for patients, retaining the prognostic information of HER2- overexpression to inform treatment decision- making (e.g. risk grouping for early breast cancer). The patterns of reimbursement for T influenced the percentage of eligible HER2 patients receiving the anti-HER2 drug: T is received in more than 50% of the eligible population in 8%, 41% and 74% in LMIC, UMIC and HIC (high- income) settings, respectively. In 71% of settings where trastuzumab is provided only as OOP, <1/4 of the eligible patients could access affordable T. ConclusionsThe heterogeneous pattern of ACC and AFF of H2T & anti-HER2 medicines influenced the chance of breast cancer patients to receive T. Data on the use of trastuzumab biosimilars and other HER2 blockers is under analysis. International systematized cross-cutting and comprehensive efforts across the cancer continuum are warranted to inform and shape the areas of research implementation for cancer - aiming to optimize the cure and care for all cancer patients and prevent catastrophic OOP. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity.

Significant and symptomatic cardiac comorbidity is a contraindication to adjuvant trastuzumab in breast cancer patients. However, some patients with asymptomatic, nonlimiting cardiac comorbidity and normal baseline left ventricular ejection fraction (LVEF) receive adjuvant trastuzumab in the clinical practice. We sought to describe the tolerability of trastuzumab in these patients. Retrospective analysis of patients with baseline asymptomatic, nonlimiting cardiac comorbidity receiving adjuvant trastuzumab at six Institutions between July 2007 and January 2016. Thirty-seven patients with HER2-positive, surgery treated breast cancer at high risk of relapse were studied. Median age was 64years (range 36-82), median baseline LVEF 61% (range 50%-85%). Thirteen patients (35%) received trastuzumab with adjuvant anthracycline and taxane-based regimens, 19 (51%) with taxane-based, three (8%) with off-label vinorelbine and two (5%) with off-label endocrine therapy. Most frequent cardiac comorbidities were ischemic heart disease (35%), valvular disease (30%), atrial fibrillation (19%), and conduction disorders (14%). Nine patients (24.3%) experienced a cardiac event: congestive heart failure (one patient, 3%), asymptomatic LVEF reduction (six patients, 16%), and rhythm disturbances (two patients, 5%). Trastuzumab had to be discontinued either permanently (five patients, 14%) or temporarily (two patients, 5%). At the time of last follow-up visit, all patients showed LVEF within normal limits, except one who had experienced a symptomatic cardiac event (LVEF value at last follow-up 46%). Caution is needed in patients with significant ongoing cardiovascular risk factors, but when adjuvant trastuzumab is deemed beneficial on breast cancer outcomes, nonlimiting cardiac comorbidity should not preclude treatment.

High-Sensitivity Troponin T and NT-proBNP Kinetics in Breast Cancer Chemotherapy

Background/Aims: Doxorubicin (DOX) and trastuzumab (TRA) are associated with cardiac dysfunction. Method: High-sensitivity troponin T (hs-TnT) and brain natriuretic peptide attached to the amino acid N-terminal fragment in the prohormone (NT-proBNP) were measured before and on days +1, +2, +3, and +7 during cycles 1 and 2 of therapy with DOX or TRA in breast cancer patients. Results: Five of eleven DOX-treated women, compared with 2/11 TRA-treated women, had undetectable baseline hs-TnT. By day +1 of cycle 2, all the DOX-treated women (p = 0.03) but only 7/11 TRA-treated women (p = ns) had detectible hs-TnT. Time to peak was 1-2 days for both groups. In the DOX-treated women, hs-TnT showed significant peaks from precycle baseline, increases in precycle 1 to precycle 2 levels, and a cycle 1 to cycle 2 peak and area under the curve (AUC). hs-TnT increased from precycle (1, 4.6 ± 6.3 pg/mL) to a cycle 2 peak of 16.1 ± 15.0 pg/mL (p < 0.002). No increases were seen with the TRA treatment. Transient posttreatment increases in NT-proBNP were seen after both therapies. Conclusion: DOX was associated with increased pretreatment baseline, peak, and AUC hs-TnT levels. Both DOX and TRA acutely perturb NT-proBNP. Assessment of pre- and posttreatment hs-TnT could be a means of quantifying cumulative myocardial injury in the course of chemotherapy.

VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside.

Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences tumor drug uptake. Following bevacizumab treatment, preclinical and clinical studies have shown a decrease in tumor delivery of radiolabeled antibodies and two chemotherapeutic drugs. The decrease in vessel pore size during vessel normalization might explain the decrease in tumor drug uptake. Moreover, the addition of bevacizumab to cetuximab, or panitumumab in colorectal cancer patients or to trastuzumab in breast cancer patients, did not improve efficacy. However, combining bevacizumab with chemotherapy did increase efficacy in some cancer types. Novel biomarkers to select patients who may benefit from combination therapies, such as the effect of an angiogenesis inhibitor on tumor perfusion, requires innovative trial designs and large clinical trials. Small imaging studies with radiolabeled drugs could be used in the interphase to gain further insight into the interplay between VEGF targeted therapy, vessel normalization and tumor drug delivery.

Cardiotoxicity Associated with Trastuzumab in Breast Cancer Patients: Definition of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD)

Cardiotoxicity Associated with Trastuzumab in Breast Cancer Patients: Definition of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD)

Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients: a meta-analysis.

The HER2 655 A>G genetic variant has recently been associated with trastuzumab-induced cardiotoxicity in HER2 breast cancer patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the cardiac toxicity of trastuzumab in breast cancer patients. Our study population was composed of 78 HER2 breast cancer patients receiving trastuzumab. The HER2 655 A>G (rs1136201) genetic variant was genotyped using TaqMan allelic discrimination technology. Patients were classified on the basis of the occurrence of cardiotoxic events or the absence of cardiotoxic events during 1 year after the first infusion. The HER2 655 A>G polymorphism was significantly associated with cardiotoxicity: AG versus AA [P=0.012, odds ratio (OR)=5.12, 95% confidence interval (CI) 1.43-18.36], AG+GG versus AA (P=0.01, OR=5.72, 95% CI 1.50-21.76), AG versus AA+GG (P=0.005, OR=7.17, 95% CI 1.82-28.29). A meta-analysis combining these data with the results from previous studies confirmed this association. Our results support the role of the HER2 655 A>G polymorphism as a genetic marker of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors.

Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. At the end of follow-up (median: 12 months, interquartile range: 11.1-12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04-1.36), and age: 1.12 (95% CI: 1.03-1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI and age were independently associated with DD following anthracycline chemotherapy.

Abstract P3-12-03: Risk of infectious complications in breast cancer patients treated with trastuzumab: A meta-analysis

Abstract Background Serious infections related to the anti-HER2 monoclonal antibody trastuzumab has been reported in clinical trials. It is not yet clear whether trastuzumab increases infection risk or not. We performed a systematic review and meta-analysis to assess the risk of infections associated with trastuzumab. Patients and methods We searched PubMed and the ASCO online database of meeting abstracts up to January 2014 for relevant clinical trials. Eligible studies included randomized controlled trials (RCTs) of trastuzumab for breast cancer patients that reported adequate safety data for grade 3-4 infection, febrile neutropenia, neutropenia, or leukopenia. Grade3 and 4 infection is defined as "IV antimicrobial agents, interventional radiology or operative intervention indicated" and "life-threatening consequences (e.g., septic shock)", respectively. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. RRs and summary incidence were calculated using random-or fixed-effects models depending on the heterogeneity of included studies. Prespecified exploratory subgroup analyses were performed according to treatment setting (neoadjuvant or adjuvant vs. metastatic setting) and therapy used with trastuzumab (combination vs. best supportive care (BSC) or single agent therapy) with regard to the RRs. Results A total of 10,094 patients from 13 trials of trastuzumab were included. The use of trastuzumab was associated with an increased risk of high-grade infection (RR, 1.21; 95% CI, 1.07-1.37; P=0.002) and febrile neutropenia (RR, 1.28; 95% CI, 1.08-1.52; P=0.004). The incidence of grade 3-4 infection and febrile neutropenia related to trastuzumab and control was 8.5% (95% CI 4.5-15.4%) vs. 6.9% (95% CI 4.0–11.6%) and 12.0% (95% CI, 8.1-17.4%) vs. 9.9% (95% CI, 6.6-14.6%), respectively. There was no significant increase in a risk of high-grade neutropenia (RR, 1.07; 95% CI, 0.98-1.68; P=0.15) or leukopenia (RR, 1.07; 95% CI, 0.94-1.23; P=0.31) in patients receiving trastuzumab. The results of exploratory subgroup analyses were shown in table1. RR of high-grade infection and febrile neutropenia according to treatment setting and therapy used with trastuzumab.High-grade infectionFebrile neutropeniaNo. of trialsRR (95%CI)PNo. of trialsRR (95%CI)PTreatment settingNeoadjuvant/Adjuvant setting71.21 (1.06-1.38)0.00461.27 (1.06-1.52)0.008Metastatic setting61.21 (0.82-1.79)0.3431.38 (0.79-2.42)0.26Therapy used with trastuzumabCombination therapy71.18 (1.04-1.35)0.0161.27 (1.06-1.52)0.008BSC/Single agent therapy71.47 (1.02-2.12)0.0431.38 (0.79-2.42)0.26BSC, best supportive care; RR, relative risk Conclusions Treatment with trastuzumab is associated with a 1.21-fold increased risk of high-grade infection and a 1.28-fold increased risk of febrile neutropenia compared with control. In order to obtain the maximum therapeutic benefit from trastuzumab, clinicians should be aware of the increased infection risk and perform careful monitoring especially when it is used with combination chemotherapy in the neoadjuvant and adjuvant setting. Citation Format: Tomohiro Funakoshi, Maya Suzuki, Hyman B Muss. Risk of infectious complications in breast cancer patients treated with trastuzumab: A meta-analysis [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 P3-12-03.

Abstract B20: Role of ErbB3 in tumorigenesis and drug resistance in ErbB2-driven breast cancer

Abstract Introduction: Overexpression of erbB3 is frequently observed in erbB2 altered breast cancers. Numerous studies indicate that the expression of erbB3 plays an important role in erbB2-driven breast cancer formation and progression. In this study, we take advantage of the mammary tumors derived from MMTV-neu transgenic mice and the tumor xenografts established from human erbB2-overexpressing (erbB2+) breast cancer cells to further elucidate the role of erbB3 in tumorigenesis and resistance to chemotherapy and erbB2-targeted therapy. Methods: Immunohistochemical analyses were performed to study the expression and phosphorylation of rat c-neu/ErbB2 and mouse erbB3 in mammary tumors. Co-immunoprecipitation (IP) analysis was employed to examine the heterodimerization between erbB2 and erbB3. Cell growth (MTS) assays were used to determine cell viability. Lentiviral vector containing shRNA was used to specifically knockdown erbB3. Flow cytometric assays were performed to define cell cycle distribution. Western blot analyses were performed to assess the expression and activation of proteins. The tumor xenografts were established by inoculation of BT474-HR20 cells (trastuzumab-resistant subline derived from BT474 cells) into nude mice. The tumor-bearing mice were treated with paclitaxel/trastuzumab and/or an anti-erbB3 monoclonal antibody (Ab, MM-121/SAR256212) to determine whether an erbB3-targeted therapy may enhance paclitaxel/trastuzumab's antitumor activity. Results: The expression status of erbB2 and/or erbB3 had no effect on tumor latency, however, the mammary tumors with co-expression of both erbB2 and erbB3 receptors grew significantly faster than those with either erbB2 or erbB3 expression alone. The tumors with co-expression of both receptors showed higher levels of phosphorylated-erbB2 (P-erbB2) and P-erbB3. The interaction between the rat c-neu transgene encoded erbB2 and mouse erbB3 was confirmed via IP assays in the mammary tumors. Elevated expression of erbB3 enhanced cell proliferation, whereas knockdown of erbB3 inhibited proliferation of erbB2+ breast cancer cells. The combinations of trastuzumab with an erbB3 blocking Ab significantly reduced cell viability in several erbB2+ breast cancer cell lines. Furthermore, MM-121 in combination with paclitaxel or trastuzumab (as compared to either alone) dramatically inhibited tumor growth in a mouse xenograft model. Conclusion: Activation of the erbB3 signaling plays a pivotal role in the development of erbB2-driven breast cancer. Strategies against erbB3 abrogates erbB2-mediated paclitaxel / trastuzumab resistance in breast cancer. Our data provide a strong basis to explore the therapeutic potential of erbB3-targeted therapy in combination with paclitaxel/ trastuzumab in breast cancer patients whose tumors overexpress erbB2. Citation Format: Hui Lyu, Jingcao Huang, Susan M. Edgerton, Ann D. Thor, Bolin Liu. Role of ErbB3 in tumorigenesis and drug resistance in ErbB2-driven breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B20.

Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: An observational single-centre study.

Trastuzumab is a recombinant humanized monoclonal antibody used to treat human epidermal growth factor receptor 2 positive breast cancer, with recognized associated cardiotoxicity. In this retrospective observational study, we investigated associated cardiotoxicity on clinical outcomes using trastuzumab in women referred to our clinic. The study was made up of 111 women with human epidermal growth factor receptor 2-overexpressing breast cancer who received trastuzumab in the Medical Oncology Department, between 2010 and 2013. A > 10% reduction of the baseline fraction of the left ventricular ejection fraction was observed in 18 (16.21%) women. Two individuals (1.8%) suffered from symptomatic heart failure, seven women showed cardiac symptoms and nine women showed asymptomatic decline of left ventricular ejection fraction. Risk factors for cardiotoxicity in the group included: postmenopausal status (p = 0.01), hypertension (p = 0.002), obesity (p = 0.0001), previously diagnosed coronary artery disease (p = 0.0001) and smoking (p = 0.03). The aforementioned factors pose a risk for cardiotoxicity. We found postmenopausal status, hypertension, obesity, previous coronary artery disease and smoking to be associated with an increased risk of cardiac dysfunction in women using trastuzumab. While administering trastuzumab to women who have these conditions, one must be aware of the risk of cardiotoxicity of trastuzumab.

Long-term risk of heart failure associated with adjuvant trastuzumab in breast cancer patients.

9504 Background: The late cardiac effect of adjuvant trastuzumab (T) and its potential interaction with anthracycline in the general population have not been well studied. The purpose of this retrospective population-based cohort study was to determine the long-term risk of heart failure (HF) associated with adjuvant T and chemotherapy, compared to chemotherapy alone. Methods: Female breast cancer patients in Ontario, diagnosed between 2003 and 2009 were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant T and other chemotherapy. Patients with pre-existing HF were excluded. The main endpoint was new diagnosis of HF, obtained using an algorithm of admission and physician claims data. Group differences were assessed by the Kaplan-Meier (KM) method and multivariable piecewise Cox regression. Competing risk analysis using the Fine and Gray method and propensity score matching analysis were perform...

Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer

Treatment with tyrosine kinase inhibitors (TKIs) including trastuzumab has revolutionized the management of HER2-positive breast cancer. Recent evaluation of clinical trial data suggests that a subset of HER2/ER double-positive cancers may not receive significant benefit from the TKI therapy. Here we investigate the cross talk between HER2 and ER in breast cancer and monitor the effect of trastuzumab on the tyrosine kinase effector transcription factor Myc. In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab, steroid receptor-negative status (ER and PR negative) of pre-treatment biopsies predicted pathological complete response (pCR) (n=31 patients, P=0.0486), whereas elevated Myc protein inversely associated with pCR (P=0.0446). Liquid chromatography mass spectrometry identified the corepressor SMRT as a novel Myc-interacting protein. Trastuzumab treatment enhanced Myc-SMRT interactions in HER2-overexpressing breast cancer cells (LCC1) and inhibited expression of the Myc target gene survivin. In HER2-low, ER-positive steroid-dominant cells (MCF7), trastuzumab therapy repressed Myc-SMRT interactions and upregulated survivin expression. Trastuzumab treatment induced ER-CBP interactions, enhanced ER transcriptional activity and upregulated expression of the ER target gene pS2. The absence of pS2 expression in pre-treatment biopsies predicted pCR to neoadjuvant trastuzumab in breast cancer patients (n=25, P=0.0089) and pS2 expression associated with residual cancer burden (P=0.0196). Furthermore, metastatic tissues from patients who had failed trastuzumab therapy were pS2 positive. In HER2-overexpressing cells, trastuzumab treatment can repress Myc transcriptional activity and clinical response is favorable. However, with co-expression of the steroid pathway, this inhibition is lost and response to treatment is often poor.

Safety and efficacy of the HER2-derived GP2 peptide vaccine in combination with trastuzumab for breast cancer patients in the adjuvant setting.

3096 Background: GP2 is a 9 amino acid HLA-A2/A3 restricted HER2-derived peptide. GP2 + GM-CSF has been shown to be safe and effective in eliciting anti-HER2 immune response in breast cancer patients. Preclinical data has demonstrated that pretreatment of cells with trastuzumab (Tz) enhances susceptibility to lysis by GP2-specific cytotoxic T lymphocytes (CTLs). We conducted a phase Ib study to evaluate the combination of the GP2 vaccine and Tz. Methods: HLA-A2/A3 + patients with HER2 overexpressing breast cancer receiving Tz as standard therapy were enrolled. The study was designed as a 3+3 dose escalation trial with an expansion cohort evaluating 4 dose levels of the vaccine administered as 6 inoculations given every 3 weeks in combination with Tz (6mg/kg). Toxicity was graded 48-72 hr post vaccination using NCI Toxicity Criteria. Ejection fraction (EF) was monitored every 3 mo. Immunologic response was assessed in vivo by injection site local reaction (LR) and in vitro by quantifying the number of GP2-specific CTLs by HLA-A2: IgG dimer assays and their functional activity by ELISPOT. Results: 19 patients enrolled (median age 47 yr, mean tumor size 3.4 cm, 74% were grade 3, 53% ER/PR+, 63% node positive, 74% received anthracycline based therapy). Maximum local toxicities were grade 1 (77% of patients) and grade 2 (6%), and maximum systemic toxicities were grade 1 (24%) and grade 2 (5%). There were no grade 3 or 4 local or systemic toxicities. There was no significant change in EF at 3 mo (57± 1%, p=0.23) or 6 mo (59±1%, p=0.8) compared to baseline (58±0.9%). Mean post-vaccine series LR was significantly larger than initial vaccination LR (68.2 ± 8.6 mm vs 28.0 ± 10.3 mm, p=0.0004). In vitro assays demonstrated an increase in the maximal number of post- versus pre-vaccination GP2-specific CTLs by dimer assay (1.45 ± 0.19 vs 0.96 ± 0.19%, p=0.06) and increased ELISPOT activity [median 86 range (3-194) vs 34 (range 0-295) spots/106 cells]. Conclusions: GP2 vaccine in combination with Tz is both safe and immunogenic in HER2-overexpressing breast cancer patients in the adjuvant setting. Toxicity was limited to mild local and systemic reactions. There were no dose limiting toxicities or cardiac events.