Adjuvant Trastuzumab Therapy Research Articles

ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) and endocrine therapy.

TPS661 Background: Approximately 50% of human epidermal growth factor receptor 2 positive (HER2+) breast cancers are also hormone receptor-positive (HR+). For patients with HER2+/HR+ disease, combining the aromatase inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) has been shown to improve outcomes vs letrozole alone. Similar results were found for the combination of trastuzumab (T; a humanized monoclonal antibody targeting HER2) and anastrozole vs anastrozole alone. Finally, the combination of L and T has been shown to improve outcomes vs L alone. Methods: This phase III, randomized, open-label, multicenter trial (ALTERNATIVE) will enroll postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have not received prior treatment for MBC, have received neo/adjuvant T and endocrine therapy, and are not candidates for chemotherapy. Patients will be randomized 1:1:1 to 1 of 3 treatment arms: L plus T plus an AI; T plus an AI; or L plus an AI. The AI can be letrozole, anastrozole, or exemestane, to be selected by the investigator. The primary objective of ALTERNATIVE is to examine the efficacy of L/T/AI compared with T/AI alone. The primary efficacy endpoint is overall survival (OS; time from randomization until death due to any cause) for L/T/AI vs T/AI. Secondary efficacy objectives include: comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI, comparisons of progression-free survival, overall response rate, time to response, duration of response, safety, and tolerability for all 3 treatment groups. The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) vs T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the ITT population. This study is currently recruiting, with a target of 525 patients. If its objectives are reached, it will provide a valuable, chemotherapy-free treatment option for HER2+/HR+ MBC patients. Clinical trial registry number: NCT01160211.

Nine-weeks of adjuvant trastuzumab in HER2-positive breast cancer: A single center experience.

e11080 Background: Trastuzumab is an effective adjuvant targeted therapy in patients with HER-2 positive breast cancer. However, effect of this therapy on survival is not well described in literature. In this study, we aimed to show characteristics of patients treated with nine week trastuzumab therapy for breast cancer and survival analysis. Methods: We analyzed the data of 2.218 breast cancer patients treated and followed up in our medical oncology department. There were 165 patients treated with 9 weeks of adjuvant trastuzumab therapy in this cohort. Patients’ characteristics, prognostic factors, and survival data were analyzed by using SPSS 18.0 version. Results: The mean age of the patients at the time of diagnosis of breast cancer was 47.3 ± 10.0 years. Sixty two (37.6%) patients were postmenopausal, eighty two patients (49.7%) were premenopausal and twenty patients (12.1%) were peri-menopausal. Invasive ductal carcinoma was the most common pathological type and was observed in 87.9% of the patients. ER and PR was positive in 49.1% of the patients and 54.5 % of the patients, respectively. Percentage of stage of the patients was 10.9 in stage I, 21.1 in stage IIA, 17.6 in stage IIB, 21.2 in stage IIIA, 0.6 in stage IIIB, 23.6 in stage IIIC. Mean follow up time of the patients was 30.9 ± 13.4 months. Numbers of the patients with progression were eighteen (10.9%). Eight (4.8%) patients died due to disease progression. Two-year survival rate was 98.3%. Disease free, progression free and overall survival times could not be obtained due to inadequate number of events. Conclusions: The superiority of nine weeks of adjuvant trastuzumab therapy to standard one year regimen of adjuvant trastuzumab is not well described in literature. The studies comparing 9-weeks and one year of adjuvant trastuzumab use with large numbers of patients are needed to show which regimen is superior.

High-sensitivity C-reactive protein (hs-CRP) as a biomarker for trastuzumab-induced cardiotoxicity in HER2-positive early-stage breast cancer: a pilot study

Monitoring of left ventricular ejection fraction (LVEF) is the current standard for detection of trastuzumab-induced cardiotoxicity; however, time-to-diagnosis and cost of assessment are suboptimal in women with early-stage breast cancer. We assessed the utility of B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin I (cTnI) as serum biomarkers for early detection of trastuzumab-induced cardiotoxicity. Fifty-four women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were prospectively enrolled, and the relationship between elevated serum BNP, hs-CRP, and cTnI levels and clinically significant decreases in LVEF was examined. LVEF was monitored at 3-4 month intervals during trastuzumab treatment. Laboratory testing for candidate biomarkers was repeated every 3 weeks with each cycle of trastuzumab. Trastuzumab-induced cardiotoxicity was defined as a decrease in LVEF of ≥15% or to a value below 50%. A clinically significant decrease in LVEF was observed in 28.6% of women. Abnormal hs-CRP (≥3 mg/L) predicted decreased LVEF with a sensitivity of 92.9% (95% CI 66.1-99.8) and specificity of 45.7% (95% CI 28.8-63.4), and subjects with normal hs-CRP levels (<3 mg/L) have 94.1% negative predictive 94.1% (95% CI 70.3-99.9) suggesting that normal hs-CRP levels may be associated with low future risk for decreased LVEF; however, no association with BNP or cTnI was observed. A false positive would have a relatively low associated cost in breast cancer patients undergoing adjuvant trastuzumab therapy and would indicate continuation of routine observation during treatment through traditional means. The maximum hs-CRP value was observed a median of 78 days prior to detection of cardiotoxicity by decreased LVEF, and those with normal levels were at lower risk for cardiotoxicity. Regular monitoring of hs-CRP holds promise as a biomarker for identifying women with early-stage breast cancer at low risk for asymptomatic trastuzumab-induced cardiotoxicity. To our knowledge, this is the first study documenting the utility of a less expensive, reproducible, easily obtainable biomarker with rapid results for evaluating cardiotoxicity related to trastuzumab therapy.

Trastuzumab‐Induced Cardiotoxicity: The Role of Two‐Dimensional Myocardial Strain Imaging in Diagnosis and Management

A 45-year-old female breast cancer patient developed heart failure during adjuvant trastuzumab therapy. Her initial left ventricular ejection fraction (LVEF) was 39% and corresponding global longitudinal and circumferential systolic strain measurements were also significantly reduced. Trastuzumab was ceased and supportive cardiac therapy commenced. The ensuing LVEF and systolic strain measurements showed consistent improvement so that trastuzumab was recommenced (while supportive cardiac therapy continued). At this point, reduced circumferential systolic strain with preserved LVEF was observed. Subsequent echocardiograms revealed further reductions in circumferential and longitudinal systolic strain without reductions in LVEF.

Pilot study evaluating the role of cardiac magnetic resonance imaging in monitoring adjuvant trastuzumab therapy for breast cancer

To explore the incidence of subclinical cardiotoxicity in women treated with adjuvant trastuzumab in the early breast cancer setting using cardiac magnetic resonance imaging (cMRI). The cardiac function and myocardial tissue characteristics of 25 women who had completed adjuvant trastuzumab therapy greater than 6 months previously was evaluated using MRI and comparing this with symptoms and routine echocardiography. Evidence of myocardial tissue damage was seen in two women in the absence of functional change or previous cardiac symptoms. Tissue characterization using cMRI may provide a useful tool in defining trastuzumab induced cardiotoxicity.

P1-08-15: Pattern of Cardiac Monitoring and Risk of Trastuzumab Associated-Cardiac Dysfunction in a Clinical Practice: A Population Based Study.

Abstract Background: Adjuvant trastuzumab therapy (ATT) in women with early-stage HER2+ breast cancer has been associated with significant reduction in the disease recurrence and mortality. Cardiac dysfunction (CD) is a known serious adverse effect of ATT. Although periodic cardiac monitoring is recommended during ATT, little is known about pattern of cardiac monitoring and incidence of CD in a clinical setting. The study aimed to determine extent of cardiac monitoring and rate of CD during ATT and to identify factors correlated with CD. Methods: Medical records of women with localized HER+ breast cancer diagnosed between the years 2005–2007 in the province of Saskatchewan was reviewed. Women with advanced or recurrent disease or if they were treated in the setting of an adjuvant trastuzumab trial were excluded. A logistic regression analysis was performed to determine various clinical variables correlated with CD. Results: A total 116 eligible women with median age of 54 yrs (range: 27–74) and median BMI of 27 (range: 44–17) were indentified. 40% had a cardiac risk factor &amp; 30% were premenopausal. 51% had node positive &amp; 53% had ER or PR+ breast cancer. 92% received anthracycline-based chemotherapy and 23% received sequential ATT. Of 62 patients with ER/PR+ breast cancer, 61% received adjuvant aromatase inhibitors. Baseline cardiac assessment was performed in 93% women. 98% women underwent periodic cardiac monitoring during ATT, 55% had monitoring performed at the interval of 3–4 months &amp; 82% women had monitoring performed at the interval of 3–6 months. Mean baseline cardiac ejection fraction (EF%) prior to the commencement of chemotherapy and ATT were 65% &amp; 63.9% respectively (p=NS). CD was observed in 32 (28%) women and only 4% were symptomatic. Trastuzumab was interrupted in 34%, and was discontinued in 20% women. Of 32 women with CD, 59% were referred to a cardiologist and 53% were treated with medication. CD was reversible in 84% cases. On multivariate analysis adjuvant aromatase inhibitor therapy was significantly correlated with cardiac dysfunction (Odd ratio 6.9 [95% CI: 1.4−33.0]). During the follow up period 18% women developed recurrent disease and 16% were died. Conclusions: Our results confirm high compliance with cardiac monitoring, though not as frequently as recommended in the clinical trial setting. Overall the rate of symptomatic decline in cardiac function was similar to the rate reported in the clinical trials, however, a relatively higher incidence of asymptomatic decline in the left ventricle EF% was noted. Among various variables examined, adjuvant aromatase inhibitor therapy was associated with an increased risk of CD. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-15.

OT1-02-13: Cardiac Biomarkers on Trastuzumab (Cabot Trial): Determining the Cardiac Biomarker Profile in Breast Cancer Patients Receiving Adjuvant Trastuzumab Therapy.

Abstract Background Trastuzumab is a humanized anti-HER2 monoclonal antibody that has demonstrated a 50% reduction in the risk of HER2+ breast cancer recurrence. This benefit is at the risk of possible cardiac dysfunction. Detecting trastuzumab-related cardiotoxicity based on physical examination and assessment of left ventricular ejection fraction (LVEF) by serial echocardiography or multi gated acquisition (MUGA) scan, has low diagnostic sensitivity and low predictive power in detecting subclinical myocardial injury. There is interest in developing simple, non-invasive, and cost-effective tools for early identification of trastuzumab-related cardiotoxicity. Use of easily detectible cardiac biomarkers in blood, such as cardiac troponins (cTnT and cTnI) and natriuretic peptides (NPs), are being evaluated. Kavsak et al. have studied a high-sensitivity cTn (hs-cTn) assay that is 10-fold more sensitive, and may be able to identify evolving injury earlier when compared to the conventional cTn assays. B-type natriuretic peptide (BNP) has been established as an indicator for heart failure. Pro-BNP is secreted from the cardiac ventricles in response to increased pressure and volume and is divided into NT-pro-BNP and BNP. The longer half-life of NT-proBNP may make it a more accurate predictor of ventricular stress. Trial design: This is a pilot single institution, prospective cohort study of 25 patients. Breast cancer patients will be seen at the Juravinski Cancer Centre, Hamilton, Canada. Biomarkers will be collected at baseline, then days 1 and 2 of every 21 day cycle for the first 3 months, then every 42 days for the next 3 months. LVEF will be measured at baseline and then every 3 months while on trastuzumab. Eligibility criteria: Patients with stage I-III, HER2 positive (3+ by immunohistochemistry or FISH+) breast cancer receiving adjuvant trastuzumab therapy. Patients who have received prior trastuzumab therapy or are unable to provide informed consent will be excluded. Specific aims: To determine the biological profile of cardiac biomarkers — cTnT, hs-cTn, and NT-proBNP — in patients on adjuvant trastuzumab; and, to determine if elevations in these biomarkers correlate with LVEF. Statistical methods: A convenient sample size of 25 patients will be entered into this pilot study. The minimum of 20 patients is a requirement by the Clinical Laboratory Standards Institute (CLSI) to formally accept existing reference ranges for the cardiac biomarkers to be used in the HER2 breast cancer population (National Committee for Clinical Laboratory Standards (NCCLS)). Present accrual and target accrual: 8 patients have enrolled to date. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-13.

P1-11-02: Racial/Ethnic Differences in Adjuvant Trastuzumab Receipt for Women with Breast Cancer within the National Comprehensive Cancer Network.

Abstract Background Racial/ethnic disparities in breast cancer care are well documented. Although adjuvant trastuzumab has been shown to improve disease outcomes for women with Human Epidermal Growth Factor Receptor 2 (HER2)-positive cancers, the ‘real world’ utilization and toxicity of adjuvant trastuzumab are unknown. Because therapy involves one year of treatment and the costs of treatment are high, a risk for treatment disparity exists. We examined differences in receipt and completion of adjuvant trastuzumab by race/ethnicity, education, employment, and insurance for women diagnosed with HER2−positive breast cancer. Methods Using the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database, we identified 1,146 women with stage I-III HER-2 positive breast cancer who presented to participating NCCN institutions during 2005–2008. In multivariable logistic analyses, we assessed the effect of race/ethnicity on the likelihood of trastuzumab therapy, and among women who initiated trastuzumab, the likelihood of completing ≥ 270 days of therapy, adjusting for center, diagnosis year, age, insurance, comorbidity, education, employment, and tumor characteristics. We also examined reasons for discontinuation of therapy among those who stopped treatment prematurely. Results Among patients eligible for this analysis, 75% women were Caucasian, 9% were African-American, and 9% were Hispanic. Most women had managed care insurance (71%) and were employed/student (52%). About one-third (36%) had a college degree and 39% had a high school education or less. Overall, most women (82%) received neo/adjuvant trastuzumab and there were no racial/ethnic differences in receipt of therapy (adjusted odds ratio [OR] 1.11, 95% confidence interval [CI] .72-1.71 for African-American and OR 1.39, 95% CI .76-2.54 for Hispanic, versus Caucasian women). Among the 769 women who initiated neo/adjuvant trastuzumab and had ≥ 365 days of follow-up, 84% completed ≥ 270 days of trastuzumab. Rates of completion were lower for African-American (72%) and Hispanic (82%) women than Caucasian women (85%). In adjusted analyses, African-American women but not Hispanic women had lower odds of completing therapy compared with Caucasian women (OR .45, 95% CI .29-.70, p=0.0003). Indemnity insurance (versus managed care) was associated with lower odds of trastuzumab completion, as was having a high school education or less (versus college education). Among the 123 women who did not complete trastuzumab, 26% stopped early for toxicity, and this occurred more frequently for African-American women than Caucasian women (50% vs. 21%), but small sample precluded a meaningful test for statistical significance. Conclusion: Compared with Caucasian women, African-American women had similar rates of initiation of adjuvant trastuzumab but much lower rates of completion that were not explained by differences in education, employment, or insurance. Because of the significant benefits conferred by adjuvant trastuzumab therapy for HER2−positive breast cancer, interventions to assure completion of therapy could lead to improved outcomes. Further exploration of racial differences in toxicity and tolerance of therapy are also warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-11-02.

Women prefer adjuvant endocrine therapy to chemotherapy for breast cancer treatment

We attempted to determine the preferences of women regarding the benefits they considered necessary to make adjuvant therapy worthwhile, and to compare preferences for adjuvant endocrine therapy, chemotherapy, and trastuzumab therapy. We also investigated the effect of information about cost on women's treatment preferences. Consecutive women who had a medical examination at the Breast Clinic, Ota General Hospital, were included in our study. We collected a questionnaire from a total of 365 women; 297 completed responses were included in the study. Among 297 women, 105 had breast cancer that had been treated and 192 did not have breast cancer; 38% of women judged that a 5% or less gain in the probability of survival was sufficient to make endocrine therapy worthwhile; 28% of participants judged that chemotherapy was worthwhile; 24% of participants judged that trastuzumab therapy was worthwhile. Women indicated that they were more likely to receive adjuvant endocrine therapy than chemotherapy or trastuzumab therapy, for the same gains in the probability of survival. Cost information about treatments did not affect women's treatment preferences. Younger women tended to judge improvements in survival sufficient to make adjuvant endocrine and chemotherapy worthwhile, as compared to older women. The comparisons were statistically significant in the 10 and 20% categories for endocrine therapy and chemotherapy. Women prefer endocrine therapy to chemotherapy or trastuzumab therapy, given the same projected treatment benefits. Younger women prefer both chemotherapy and endocrine therapy as compared with older woman.

High recurrence risk and use of adjuvant trastuzumab in patients with small, HER2-positive, node-negative breast cancers

Five randomized trials of adjuvant trastuzumab have reported significant improvements in recurrence-free survival (RFS) and overall survival. However, patients with node-negative tumors 1 cm or smaller were excluded from these trials. We assessed the recurrence risk and benefit of adjuvant therapy in such patients with small tumors. We identified patients with node-negative breast tumors 1 cm or smaller between April 2003 and December 2007. Patients were categorized according to HER2 status and pathological tumor size (pT <5 mm vs. 5-10 mm), hormone receptor (HR) status and adjuvant chemotherapy. The primary endpoint was RFS. Of 267 patients included in the analysis, 42 had HER2-positive tumors. The median follow-up was 4.3 years. RFS was worse in patients with HER2-positive tumors than HER2-negative tumors (90.5 vs. 97.7% at 5 years; P = 0.031). In the group with HER2-positive tumors, there were no recurrences in patients with pT<5 mm, but 4 recurrences in those with pT 5-10 mm. RFS was worse in patients with pT 5-10 mm than pT <5 mm (79.0 vs. 100%, P = 0.025). Furthermore 3 recurrences occurred in patients without adjuvant trastuzumab, and 1 recurrence occurred as soon as adjuvant trastuzumab was finished. Our results appear to establish the efficacy of adjuvant trastuzumab therapy. HR status and use of adjuvant chemotherapy were not significantly associated with RFS. Patients with HER2-positive, node-negative breast tumors 1 cm or smaller (especially 0.5-1.0 cm) have a significant recurrence risk and the decision to employ adjuvant trastuzumab therapy should be discussed with patients based on our results and those of other studies.

Trastuzumab in the Adjuvant Treatment of HER2-Positive Early Breast Cancer Patients: A Meta-Analysis of Published Randomized Controlled Trials

BackgroundAdjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors.MethodsComputerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data.FindingsWith six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms.ConclusionThis analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

Clinical and health economic outcomes of alternative HER2 test strategies for guiding adjuvant trastuzumab therapy

Aim: To evaluate the clinical outcomes and cost–effectiveness of human epidermal growth factor receptor 2 (HER2) testing strategies to guide adjuvant trastuzumab (AT) therapy in women with HER2-positive breast cancer. Methods: A literature review produced 72 studies comparing HER2 test methods, and we computed concordance (assuming fluorescence in situ hybridization [FISH] as a reference assay) to assess performance relative to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. An economic analysis provided cost–effectiveness of alternative strategies, including a Monte Carlo simulation to vary key assumptions such as test price and performance. Results: Of 46 studies comparing immunohistochemistry (IHC) and FISH, only seven met the ASCO/CAP guideline of 95% or better concordance. A total of 14 out of 21 studies comparing chromogenic in situ hybridization and three out of five studies comparing silver-enhanced in situ hybridization met the guideline. Confirmation of IHC 2+ and 3+ and primary FISH strategies are likely to reduce costs and improve quality of life relative to confirmation of IHC 2+ only. Initial testing with a gene amplification-based assay is probably a cost-effective alternative to confirmation of IHC 2+ and 3+. The results are not sensitive to varying test price but are sensitive to test accuracy below 98%. Conclusion: Using a primary gene amplification-based assay to guide AT therapy for HER2-positive breast cancer probably results in lower US medical costs, increased life-years and increased quality of life compared with confirmation of IHC 2+ with a gene amplification-based assay. We recommend the ASCO/CAP guidelines reflect 98% or greater concordance relative to a reference assay. Additional research regarding therapy response is required to further differentiate between gene amplification-based assays.

Protection of adjuvant trastuzumab in sites of early relapses.

619 Background: About 50% of patients with HER2-positive breast tumors benefit from adjuvant trastuzumab therapy, but the highest benefit, as indicated by the HERA trial results, is restricted to the first 18 months from the start of treatment. Methods: The GHEA Italian multicentric observational study of 1021 patients treated with adjuvant trastuzumab according to HERA protocol between 2006 and 2008 registered 121 (11.8) events including distant, local, contralateral and second tumors according to anatomical sites in the first 18 months from the start of treatment (early relapses) and thereafter (late relapses). Based on an expected 50% reduction of early metastases at any site, the number of metastases per site was calculated and compared with the observed data to yield a percent trastuzumab protection value at each single site. Results: Early relapses comprised 49 (4.8%) events and late relapses represented 72 (7%) events. The frequency of late metastases in the different sites was similar to that observed for HER2-positive tumors before the trastuzumab era, while the frequency of early relapses followed a different pattern, i.e., liver, lung and lymph node relapses were less frequent in early than in late relapses (10.5% vs 18.6%, 10.5% vs 23.2% and 2.6% vs 9.3%, respectively), while bone and CNS metastatic disease was more frequent in early than in late relapses (36.9% vs 18.6% and 23.7% vs 14%, respectively). No changes in frequency of multiple metastases was observed (15.8% vs 16.3%). Trastuzumab did not protect against bone and CNS metastases (0% and 10% respectively), whereas a protection of 71.4% for liver, 75% for lung, 85.6% for lymph nodes was observed. Conclusions: In addition to the well-known CNS relapses due to the failure of the antibody to pass the blood-brain barrier, also bone relapses were found to be resistant. This may be due to a bone microenvironment inadequate for antibody activity or escape of bone metastases from HER2 targeting. Excluding the two “resistant” sites, the protection by trastuzumab was more than 70% in all other distant metastases. Supported by AIRC and Roche.

Trastuzumab use at relapse after adjuvant trastuzumab therapy in HER2-positive breast cancer.

575 Background: Trastuzumab (H) is the standard of care for patients with early and advanced HER2-positive breast cancer. It is therefore important to investigate the benefit of retreatment with H for patients who experienced a relapse after adjuvant H. The RHEA trial assessed the efficacy and safety of H plus a taxane, as first-line treatment for patients with metastatic breast cancer (MBC) who relapsed following adjuvant H for HER2-positive early breast cancer. Methods: RHEA was a two-cohort, non-randomized, multicenter, open-label, Phase II study. Patients (N=43) with HER2-positive MBC who had received prior adjuvant H for ≥10 months, with a relapse-free interval of ≥6 months after the last H dose, were recruited. Eligible patients (N=41) were assigned to receive H either weekly (loading dose 4 mg/kg, then 2 mg/kg) or 3-weekly (loading dose 8 mg/kg, then 6 mg/kg) in combination with docetaxel (100 mg/m2 q3w × 6) or paclitaxel (175 mg/m2 q3w × 6 or 75 mg/m2 qw × 18). H was given until progression, unacceptable toxicity, withdrawal or death. Taxanes were given for 18 weeks, with additional cycles at the investigator’s discretion. The primary endpoint was response rate (complete response or partial response) assessed according to RECIST criteria. Results: Patients had a median age of 54 years (range: 31–78) and a median ECOG status of 0 (range: 0–2). Thirty-seven patients received docetaxel, three received paclitaxel and one received nab-paclitaxel. Partial response was observed in 25/41 patients (61%), stable disease in seven patients (17.1%), and progressive disease in six patients (14.6%). Median progression-free survival was 8.0 months (95% CI: 6–11 months). The most common adverse events (AEs, all grades) were alopecia (32%), diarrhea (32%), fatigue (24%), peripheral edema (17%) and asthenia (15%). Six patients (14.6%) developed at least one serious AE. There were no reports of congestive heart failure or any unexpected toxicities. Conclusions: H, in combination with a taxane, is an effective and well tolerated first-line treatment for MBC in patients who relapsed following H-based adjuvant therapy. These data support the concept of retreatment with H in the metastatic setting in patients with HER2-positive BC.

The Utility of Cardiac Biomarkers, Tissue Velocity and Strain Imaging, and Cardiac Magnetic Resonance Imaging in Predicting Early Left Ventricular Dysfunction in Patients With Human Epidermal Growth Factor Receptor II–Positive Breast Cancer Treated With Adjuvant Trastuzumab Therapy

The aim of this study was to evaluate whether cardiac biomarkers, tissue velocity (TVI) and strain imaging, and cardiac magnetic resonance imaging can predict early left ventricular (LV) dysfunction in human epidermal growth factor receptor II-positive breast cancer patients treated with trastuzumab in the adjuvant setting. Early indexes of LV systolic dysfunction with noninvasive cardiac imaging would be useful for addressing the cardiac safety profile of trastuzumab, potentially avoiding the detrimental effects of heart failure. We used cardiac biomarkers, TVI and strain imaging, and cardiac magnetic resonance imaging to detect pre-clinical changes in LV systolic function, before conventional changes in left ventricular ejection fraction (LVEF) in human epidermal growth factor receptor II-positive breast cancer patients treated with trastuzumab in the adjuvant setting. Of 42 patients (mean age 47 ± 9 years) prospectively followed between 2007 and 2009, 10 (25%) developed trastuzumab-mediated cardiomyopathy (CM). Troponin T, C-reactive protein, and brain natriuretic peptide did not change over time. Within 3 months of adjuvant therapy with trastuzumab, there was a significant difference in the lateral S' between the normal cohort and the CM group (9.1 ± 1.6 cm/s and 6.4 ± 0.6 cm/s, respectively, p < 0.05). Similarly, the peak global longitudinal and radial strain decreased as early as 3 months in the trastuzumab-mediated cardiotoxicity group. As compared with both global longitudinal and radial strain, only S' was able to identify all 10 patients who developed trastuzumab-mediated CM. The LVEF subsequently decreased at 6 months of follow-up in all 10 patients, necessitating discontinuation of the drug. All 10 patients demonstrated delayed enhancement of the lateral wall of the LV within the mid-myocardial portion, consistent with trastuzumab-induced CM. Both TVI and strain imaging were able to detect pre-clinical changes in LV systolic function, before conventional changes in LVEF, in patients receiving trastuzumab in the adjuvant setting.

Evaluation of HER2 Protein Expression in Gastric Carcinomas: Comparative Analysis of 1414 Cases of Whole-Tissue Sections and 595 Cases of Tissue Microarrays

Recent advances in molecular targeted therapy have identified HER2 as an important target for anti-cancer therapy in gastric cancer (GC). Although the clinical relevance and prognostic significance of HER2 in breast cancer has been well acknowledged, it remains controversial in GC. HER2 expression was investigated in two independent series of GC by immunohistochemical staining. One series corresponded to 1,414 cases of whole-tissue sections and the other corresponded to 595 cases of tissue microarrays (TMAs). Results were compared and correlated with clinicopathologic parameters. HER2-positivity was detected in 12.3% of whole-tissue sections and 17% of TMAs. Among samples scored 3+, 90.1% stained ≥50% of the tumor area, but only 40.9% in score 2+ cases stained ≥50% of the tumor area. In whole-tissue sections, HER2-positivity was correlated with age (P = 0.002), histological type (differentiated or intestinal, P < 0.001), lymphovascular invasion (P = 0.005), and lymph node metastasis (P = 0.009). In TMAs, HER2-positivity was correlated only with age (P = 0.003) and histological type (P < 0.001). Multivariate analyses of the differentiated GC subgroup revealed that HER2-positivity was an independent poor prognostic factor (P = 0.042). The cases with HER2-positive in ≥50% of the tumor area showed worse prognosis than those of <50% (P = 0.021). Despite discrepancies in the results from whole-tissue sections and TMAs, HER2 overexpression was positively correlated with aggressive biological behavior and was an independent poor prognostic factor for recurrence in differentiated GCs. Therefore, HER2-positive GCs should be considered for adjuvant trastuzumab therapy.

Benefit shown from continued adjuvant trastuzumab tHERApy

In 15 to 25% of patients with breast cancer, HER2 is overexpressed and/or amplified resulting in a very aggressive disease course. The humanized monoclonal antibody trastuzumab that targets HER2 has an established clinical benefit in women with HER2-positive, early-stage and metastatic breast cancer. The Herceptin Adjuvant (HERA) trial coordinated by the Breast International Group is one of the pivotal studies on the adjuvant use of trastuzumab, with collaboration from many academic cooperative groups and industry. The HERA trial showed that disease-free survival (DFS) was significantly improved in women who received trastuzumab following adjuvant chemotherapy compared with those who received chemotherapy alone.

Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: Cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer Trial

Background. Trastuzumab is a standard treatment of HER2-positive early breast cancer in many countries, and it is usually given as a one year adjuvant treatment. However, its cost-effectiveness has not been assessed in Finland. The Finland Herceptin (FinHer) trial has compared a shorter 9-week treatment protocol against no trastuzumab with promising results. The aim of this study was to assess the potential cost-effectiveness of the 9-week treatment based on the recently published five-year follow-up results of the FinHer trial. Methods. An evaluation model of breast cancer treatment was constructed using fitted survival estimates and a long-term Markov model. The cost-effectiveness of 9-week adjuvant treatment was assessed in a Finnish setting, compared to treatment without trastuzumab. The analysis was performed from a societal perspective, and a 3% discount rate was applied for future costs and outcomes. Value of information analysis was performed to estimate the potential value of further research. Results. According to the probabilistic analysis, the incremental cost-effectiveness ratio was €12 000 per quality adjusted life year (QALY), and €9300 per life year gained (LYG), when comparing adjuvant trastuzumab therapy to standard treatment without trastuzumab. The modelled incremental outcomes for trastuzumab treatment were 0.66 QALY and 0.85 LYG for a lifetime perspective. Value of information analysis showed that additional research on treatment effects would be most valuable for reducing uncertainty in the adoption decision. Conclusions. Adjuvant 9-week trastuzumab is likely to be a cost-effective treatment in the Finnish setting. Results from an ongoing trial comparing adjuvant 9-week treatment with the 12-month treatment will play a key role in addressing the uncertainty related to the treatment effect and potential cost-effectiveness of these two treatment protocols.

HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies

HER2 amplification is seen in up to 20% of breast cancers and is associated with an aggressive phenotype. Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment. Given the increased recognition of de novo and acquired resistance to therapy, considerable research has been dedicated to understanding the molecular mechanisms of trastuzumab resistance. Here, we highlight putative models of resistance, including activation of the downstream PI3K-signaling pathway, accumulation of a constitutively active form of HER2, and crosstalk of HER2 with other growth factor receptors. The identification of these specific mechanisms of trastuzumab resistance has provided a rationale for the development of several novel HER2-targeted agents as the mechanisms have largely suggested a continued tumor dependence on HER2 signaling. We explore the emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinib, pertuzumab, trastuzumab-DM1, HSP90 and PI3K pathway inhibitors, and the future potential for these inhibitors which, if combined with reliable biomarkers of resistance, may ultimately usher in a new era of personalized medicine for this disease.

Abstract P3-14-12: High Risk of Recurrence in Japanese Patients with HER2-Positive T1N0 Breast Cancer

Abstract Background: The necessity of adjuvant trastuzumab therapy for patients with T1N0M0 tumors remains controversial. The objective of this study is to determine the risk of recurrence in Japanese women with T1N0 HER2- positive tumors compared with HER2-negative tumors. Methods: Among 1,180 patients with breast cancers diagnosed at our institution between 2001 and 2007, we reviewed 464 T1N0M0 diseases in which HER2 status was evaluated by IHC or gene amplification, who had not received trastuzumab in the adjuvant setting. Recurrence free survival (RFS) was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were used to determine the association of each group with the risk of recurrence. Results: Seventy-nine (17%) of 464 patients had HER2-positive tumors and remaining 385 (83%) were HER2-negative diseases. Patients who had HER2-positive tumors tended to be younger (P=0.015), have more hormone receptor-negative tumors (P&amp;lt;0.001), and have higher histological grade (P&amp;lt;0.001). At a median follow-up of 46 months, 18 patients had experienced recurrences. The 5-year recurrence-free survival (RFS) rates were 88.2% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P&amp;lt;0.001). In patients with T1bN0 tumors and T1cN0 tumors, HER2-positive group had worse RFS than HER2-negative group (P=0.004 and P=0.002, respectively), while there were no differences in the RFS between patients with T1aN0 HER2-positive and HER2-negative tumors (P=0.835). In a multivariate analysis, HER2 status was identified as one of the independent risk factors to predict RFS in patients with T1N0M0 breast cancers (hazard ratio 5.23; 95% CI, 2.07 to 13.21; P&amp;lt;0.001). Conclusion: Japanese women with T1bcN0M0 HER2-positive breast cancer have a significant high risk of recurrence, and adjuvant trastuzmab therapy should be considered for those patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-12.