Herceptin Adjuvant Trial Research Articles

Clinical relevance of clinical treatment score post 5 years (CTS5) in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial.

519 Background: The clinical treatment score post-5 years (CTS5) has proven valuable in assessing the necessity for extended endocrine therapy among patients with early-stage hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This study aimed to explore the potential of CTS5 as a predictive tool for long-term survival beyond five years in patients with specifically HR-positive, HER2-positive breast cancer. Methods: We collected patient-level data from the HERceptin Adjuvant (HERA) (BIG1-01; NCT00045032) trial. Our investigation focused on assessing the risk of late distant recurrence (DR) and overall survival (OS) according to the CTS5 risk score as continuous value and CTS5 stratification risk groups. Furthermore, we performed a Cox-regression analysis to determine the prognostic performance of CTS5, stratifying subgroups by age and administration of trastuzumab. Results: A total of 1,818 patients with HR-positive, HER2-positive breast cancer were included in this analysis. The CTS5 score, as a continuous variable, emerged as an independent prognostic factor for both late DR (adjusted HR, 2.04; 95% CI, 1.62-2.57; P < 0.001) and OS (adjusted HR, 2.02; 95% CI, 1.58-2.58; P < 0.001), respectively. In addition, multivariable analysis showed a significant association between the high-risk group and adverse outcomes in late DR (adjusted HR, 2.76; 95% CI, 1.84-4.15; P < 0.001) and OS (adjusted HR, 2.45; 95% CI, 1.60-3.74; P < 0.001) compared to low/intermediate group. Consistent results were observed, regardless of age or administration of HER2-targeted therapy. Conclusions: CTS5 is a useful prognostic tool for predicting late DR and OS in HR-positive, HER2-positive breast cancer patients. Extension of endocrine therapy should be actively considered in patients with CTS5 high-risk group.

Evaluation of Cardiotoxicity in HER-2-Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab

Trastuzumab is associated with cardiac dysfunction in patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer. The current study examines the effect of radiation therapy (RT) on cardiotoxicity in this patient population. The Herceptin Adjuvant (HERA) trial is a phase 3 prospective, randomized clinical trial that established the efficacy of trastuzumab in HER-2-positive breast cancer. The current study is a retrospective analysis of 3321 trial patients treated with trastuzumab, with or without RT. Cardiac function was closely monitored over a median follow-up period of 11 years. The primary endpoint of the current study was to determine the effect of RT on left ventricular ejection fraction (LVEF) and the occurrence of cardiovascular events. Patients were divided into 3 groups: 1270 patients received trastuzumab and left-sided RT (group 1); 1271 patients received trastuzumab and right-sided RT (group 2); and 780 patients received trastuzumab with no RT (group 3). The incidence of decline in LVEF documented by echocardiography was 9.18%, 8.99%, and 8.80%, respectively, with no significant differences among the 3 groups (P=.073). The incidence of cardiovascular events was low in all groups, with the lowest incidence noted in group 3 (0.62%) followed by group 2 (0.92%) and group 1 (1.08%) (P=.619). Univariate and multivariate competing-risks regression showed that left-sided and right-sided RT delivery did not significantly increase the risk of LVEF decline or cardiovascular events. Our analysis of the HERA trial suggests that RT does not significantly increase the risk of cardiotoxicity in HER-2-positive breast cancer patients treated with trastuzumab. Continued monitoring of patients is needed to investigate late effects of contemporary treatments for breast cancer patients.

De-intensifying Radiation Therapy in HER-2 Positive Breast Cancer: To Boost or Not to Boost?

Radiation therapy is fundamental in the management of breast cancer. After whole breast irradiation, an additional boost dose is often applied to the primary tumor bed. Here, we analyze the effect of radiation therapy boost on local control in patients with HER-2 positive breast cancer. We studied 1082 patients with HER-2 positive breast cancer who were originally enrolled in the Herceptin Adjuvant Trial and treated with breast-conserving surgery, radiation therapy, and adjuvant chemotherapy with trastuzumab. The primary endpoint of the study was to determine the effect of a radiation boost on local recurrence. Kaplan-Meier curves were generated, and hazard ratios were estimated using Cox regression. Our analysis included 441 patients (40.8%) who received radiation therapy boost and 641 patients (59.2%) who did not, after completion of whole breast radiation. Patients from both groups had similar baseline characteristics in terms of age, nodal involvement, and grade. At a median follow-up of 11 years, local control was 93% (confidence interval, 90%-95%) in the radiation boost group compared with 91% (confidence interval, 89%-93%) in the no-boost group (P = .33). When analyzing patients by age, patients <40 years of age had a higher risk for local recurrence; however, this was not significantly lowered by the addition of boost. Furthermore, no local control benefit for boost was noted in both hormone receptor (HR) subtypes (HR+: P = .11; HR-: P = .98). Patients with HER-2 positive breast cancer treated with breast-conserving surgery, whole breast radiation, and trastuzumab have excellent local control. Delivery of an additional radiation boost in this patient population was not shown to improve local control. Future studies are needed to identify subgroups of HER-2 positive patients who derive a clinically relevant benefit from radiation boost.

Post-Mastectomy Radiation Therapy in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer Patients: Analysis of the HERA Trial

Postmastectomy radiation therapy (PMRT) improves recurrence rates and overall survival in breast cancer patients. However, it remains unclear whether these findings can be applied to human epidermal growth factor receptor 2 (HER-2) positive patients treated with trastuzumab. The Herceptin Adjuvant (HERA) trial is a phase III randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The present study is a retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models, and LRR curves were generated by the Kaplan-Meier method. Our analysis included 940 patients (57.6%) who received PMRT and 693 patients (42.4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At a median follow-up of 11 years, no significant difference in LRR was noted after PMRT in node negative (N0) patients (P = .96). Patients with 1 to 3 positive lymph nodes had a LRR-free survival of 97% in the PMRT group compared with 90% in the no PMRT group (hazard ratio = 0.28, P = .004) and a nonsignificant improved overall survival after PMRT (hazard ratio = 0.63, P = .06). PMRT delivery in HER-2 positive breast cancer patients with 1 to 3 positive lymph nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historic studies, the present findings are in favor of PMRT for HER-2 positive breast cancer patients with 1 to 3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer patients benefit the most from PMRT.

Abstract P1-13-04: Impact of hormone receptor status in HER2-Positive early breast cancer in the trastuzumab era: Results of a National multi-institutional study

Abstract Background: Recent updated analysis of the HERA (HERceptin Adjuvant) trial indicate that tumor hormone receptor status (HR)remains a major determinant of outcome in HER2-positive (HER2+) early breast cancer (BC) patients, with higher rates of recurrence and death in women with HR-negative (HR-) disease, even after 11 years' median follow-up. Furthermore, data reported from the HERA trial suggest that the timing of recurrences is different, with an initial higher frequency of disease-free survival (DFS) events in patients with HR- disease than those with HR-positive disease (HR+). No evidence of a different trastuzumab efficacy according to the HR of the primary tumor was found. In this study, we examined the impact of HR on outcome in a large, multicenter, “real-world”, retrospective cohort of HER2+ early breast cancer patients Methods: HER2+ BC were retrospectively identified from a large cohort of 23,375 consecutive patients who underwent primary surgery at 17 French centers between Dec 1987 and Jan 2014. A multivariate Cox model was built including age, tumor size, SBR grade, lymphovascular invasion, lymph node involvement, hormonal receptors status, adjuvant chemotherapy, adjuvant hormone therapy, trastuzumab, radiotherapy and type of surgery. Results: A total of 1308 cases were identified, including 829 (63%) HR+ and 479 (47%) HR- patients. Median follow-up was 52 months (range 0 to 201). Compared with HR+, HR- patients had significantly smaller tumors (37 vs. 31% ≤ 10mm, p=0.027; information for multifocal tumors was not available), with higher SBR grade (58 vs. 40% grade 3, p&amp;lt;0.001) and had more lymph nodes involvement (41 vs. 32% pN+, p=0.001). HR- patients were more frequently treated by mastectomy (41 vs. 31%, p&amp;lt;0.001), received more trastuzumab (63 vs. 53%, p&amp;lt;0.001) and less radiotherapy (85 vs. 89%, p=0.020). Endocrine therapy was administered in 90% (744) of HR+ patients. No other significant difference in patient, tumor or treatment characteristics was found. HR status impacted DFS, metastasis free-survival (MFS) and BC-Specific survival (BC-SS) (hazard ratios: 0.46 [0.32-0.66]; p&amp;lt;0.001, 0.52 [0.33-0.82]; p=0.004 and 0.56 [0.34-0.90]; p=0.017, respectively), log-rank test) in overall population with higher rates of recurrence and death in women with HR- disease. In multivariate analysis, lymph node involvement and use of trastuzumab but not HR status impacted significantly DFS, MFS and BC-SS. Considering patients by treatment groups (with or without trastuzumab), HR status was not predictive of survival outcomes in the trastuzumab group, as opposed to the group without trastuzumab. Regarding the timing of recurrences, we observed an increased tendency for later relapse in patients with HR+ disease compared with HR- disease, for both DFS and MFS events. Conclusions: Our results suggest that HR status remains a major determinant of outcome in HER2+ BC, including the timing of recurrence. Yet, this prognostic impact appears to be mitigated by trastuzumab-based adjuvant treatment. Citation Format: de Nonneville A, Gonçalves A, Cohen M, Reyal F, Classe JM, Giard S, Colombo PE, Muracciole X, Chopin N, Lambaudie E, Houvenaeghel G. Impact of hormone receptor status in HER2-Positive early breast cancer in the trastuzumab era: Results of a National multi-institutional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-04.

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial

Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. F Hoffmann-La Roche (Roche).

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. clinicaltrials.gov Identifier: NCT00045032.

Impact of updated HER2 testing guidelines in breast cancer—re-evaluation of HERA trial fluorescence in situ hybridization data

Recently the American Society of Clinical Oncology and the College of American Pathologists have updated their clinical practice guidelines for HER2 testing in breast cancer. In order to evaluate these new recommendations, we have re-assessed the HER2 status of 6018 breast cancer cases of the screening population for the HERceptin adjuvant (HERA) trial that were originally centrally tested by fluorescence in situ hybridization based on the FDA-released test guidelines. According to the most recent 2013 ASCO/CAP recommendations, 3380 (56.2%) cases were classified as HER2 positive compared with 3359 (55.8%) applying the HERA/FDA scheme and 3339 (55.5%) applying the 2007 ASCO/CAP guidelines. Twenty-one cases switched from negative (HERA/FDA scheme) to positive (2013 ASCO/CAP guidelines). This group is characterized by a mean HER2 gene copy number of ≥6.0, polysomy or co-amplification of CEP17 with an average CEP17 count of 5, and with HER2 receptor overexpression in 75% of cases. On the basis of the HER2 gene copy number alone, we observe 494 cases (8.2%) that are in the equivocal range. Most of these cases (>80%) were also nondecisive by immunohistochemistry (score 2+) irrespective of whether ratio was <2.0>. The number of equivocal cases that would require HER2 reflex testing decreases to 113 (1.9%) if in addition to the HER2 gene copy number also the ratio of HER2 and CEP17 copy numbers is considered via dual-color in situ hybridization. The combination of applying the HER2 mean gene copy number as well as the HER2/CEP17 ratio to define equivocal test decisions by fluorescence in situ hybridization as proposed by the current ASCO/CAP guidelines appears to be a more optimum approach to adopt in order to avoid or minimize reporting of false negative results. Using the mean HER2 gene copy number alone for decision making results in a significant increase of equivocal cases.

Trastuzumab-Associated Cardiac Events at 8 Years of Median Follow-Up in the Herceptin Adjuvant Trial (BIG 1-01)

To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy. The Herceptin Adjuvant (HERA) trial is a three-arm, randomized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2) -positive early-stage breast cancer. Cardiac function was closely monitored. Eligible patients had left ventricular ejection fraction (LVEF) ≥ 55% at study entry following neoadjuvant chemotherapy with or without radiotherapy. This 8-year median follow-up analysis considered patients randomly assigned to 2 years or 1 year of trastuzumab or observation. The as-treated safety population for 2 years of trastuzumab (n = 1,673), 1 year of trastuzumab (n = 1,682), and observation (n = 1,744) is reported. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of patients in the 2-year arm and 5.2% of patients in the 1-year arm. Cardiac death, severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. The incidence of severe CHF (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant LVEF decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe CHF was the same for 2-year and 1-year trastuzumab. Of patients with confirmed LVEF decrease receiving 2-year trastuzumab, 87.5% reached acute recovery. Of patients with confirmed LVEF decrease receiving 1-year trastuzumab, 81.2% reached acute recovery. Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy, and cardiac events were reversible in the vast majority of patients.

The 41st David A. Karnofsky Memorial Award Lecture: Academic research worldwide--quo vadis?

Academiaplaysavitalrole inrandomizedclinical trials; by counterbalancing commercial interests, it can act as a guardian to protect patients’ needs. Moreover, the relationship between investigators and patients enrolling onto clinical trials can be viewed as one based on an implicit ethical contract. Its premise is that the primary objective of randomized clinical trials is to improve patient outcome, free from bias, whether commercial or academic. Indeed, more than 50 years of sustained commitment to randomized clinical trials in early breastcancerhavecontributedtothedecliningmortality from the disease in the Western world and would not have been possible without this understanding. The Breast International Group (BIG), created in 1996, is an umbrella organization harnessing the efforts and supporting the activities of its almost 50 national and international cooperative group members worldwide. It has become a major actor in the conduct of early breast cancer trials, particularly those run in partnership with the pharmaceutical industry for the global registration of new anticancer drugs in the adjuvant setting. The HERA (Herceptin Adjuvant) trial (NCT00045032) is one such example, contributing to the registration of adjuvant trastuzumab in 39 countries in fewer than 4 years. BIG also supports clinical trials sponsored by its academic member groups and facilitates collaboration between international researchers and US cooperative groups. The International Breast Cancer Study Group (IBCSG) –led SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) trials (NCT00066690 and NCT00963417, respectively) evaluating endocrine therapies for 5,738 premenopausal women are cases in point. BIG is therefore uniquely positioned to examine how academic research in oncology has evolved over the last two decades, to alert the oncology community about the dangerous shift toward commercially oriented research, and to propose some new routes for empowering academics at a critical time when the remarkable progress in elucidating cancer complexity, stemming from The Cancer Genome Atlas (TCGA) project, needs to be translated into new and effective clinical applications.

HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab

BackgroundTrastuzumab treatment improves survival of HER2-positive primary breast cancer. HER2 staining intensity varies widely in HER2-positive tumours. Patients and methodsWe investigated whether differences in immunohistochemical (IHC) staining intensity for HER2 in HER2-positive tumors (IHC 3+ or FISH ratio ≥2.0) was associated with prognosis or benefit from trastuzumab treatment in patients randomized to 1 year or no trastuzumab in the HERceptin Adjuvant (HERA) trial. Median follow-up was 2 years. The nested case–control analysis, included 425 patients (cases) with a disease-free survival (DFS) event and two matched controls (no DFS event) per case. Tissue sections stained for HER2 were assessed for HER2 staining intensity by image analysis. ResultsHER2 staining intensity varied widely and correlated with HER2 gene copy number (Spearman, r = 0.498, P < 0.001) or less closely with HER2/CEP17 FISH ratio (r = 0.396, P < 0.001). We found no significant difference in DFS in the observation arm according to staining intensity (odds ratio [OR] change per 10 unit change in intensity: 1.015, 95% confidence interval [CI] 0.930–1.108) and no impact of staining intensity on benefit derived from 1-year trastuzumab (OR: 1.017, 95% CI 0.925–1.120). ConclusionsVariability in HER2 staining in HER2-positive tumours has no role in clinical management with adjuvant trastuzumab. HERA trial noNCT00045032.

Trastuzumab Retreatment after Relapse on Adjuvant Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Final Results of the Retreatment after Herceptin Adjuvant Trial

AimsTrastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer. Materials and methodsIn total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for ≥10 months, with a relapse-free interval of ≥6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression. ResultsAt the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7–80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression-free survival (PFS) was 8.0 months (95% confidence interval: 6–11 months) and the median overall survival was 25.0 months (16–33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported. ConclusionTrastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy.

Effect of Age on Breast Cancer Outcomes in Women With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From a Herceptin Adjuvant Trial

Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. No prior studies have adequately controlled for human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. We sought to evaluate whether age was a prognostic or predictive factor in the HERA trial. We used 2-year median follow-up data and dichotomized age at 40 years to evaluate its prognostic effect on outcomes for women assigned to trastuzumab for 1 year or observation. Of the 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 to observation, 722 (21%) were age ≤ 40 years at study entry. In separate Cox models, controlling for relevant prognostic and predictive factors, disease-free (DFS) and overall survival (OS) hazard ratios (HRs) were consistent for women age ≤ 40 versus > 40 years, regardless of treatment assignment (observation group: DFS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.90 to 1.54; OS HR age ≤ 40 v > 40 years, 1.01; 95% CI, 0.60 to 1.69; trastuzumab group: DFS HR age ≤ 40 v > 40 years, 1.11; 95% CI, 0.81 to 1.51; OS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.66 to 2.09). Interaction between age group and treatment effect was not statistically significant (DFS P = .89; OS P = .55). In a retrospective analysis of a large randomized controlled trial of women with early-stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes.

Long-term (8 years) assessment of trastuzumab-related cardiac events in the HERA trial.

525 Background: Trastuzumab-related cardiac dysfunction may occur in patients (pts) treated with adjuvant therapy and it is mostly reversible. We report the long-term outcome of pts with cardiac dysfunction treated with adjuvant trastuzumab (T) in the Herceptin Adjuvant (HERA) trial. Methods: HERA is a three-arm, randomized trial that compared 1 year or 2 years of T with observation (Obs) in women with HER2-positive early breast cancer (EBC). Eligible pts had a left ventricular ejection fraction (LVEF) ≥ 55% at study entry (i.e. after completion of (neo)adjuvant chemotherapy with or without radiotherapy). Cardiac function was closely monitored throughout the trial. This analysis at 8-year median follow-up considers pts randomly assigned to 1 year or 2 years of T therapy or observation. Results: 5102 pts were randomized to HERA. The “as treated” safety population is considered: 2 years T (N=1,673), 1 year T (N=1,682) and Obs (N=1,744). Cardiac events leading to T discontinuation in the 1-year and 2-year arms were observed in 5.2% and 9.4% of pts, respectively. Cardiac death, severe congestive heart failure (CHF) and confirmed significant LVEF drop remained low in all three arms (Table). In the 1 year T arm, 71.4% of pts with severe CHF, and 81.2% of pts with confirmed LVEF drop recovered cardiac function (at least 2 sequential LVEF assessments &gt; 50%). The median time to recovery was 9.7 months and 6.3 months, respectively. In the 2 years T arm, 87.5% of pts with confirmed LVEF drop recovered cardiac function and median time to recovery was 8.3 months. Conclusions: At 8-year median follow-up the incidence of cardiac events during adjuvant T remains low and these events are mostly reversible. These results confirm low cardiac events when T is given as part of the adjuvant therapy for pts with HER2-positive EBC. Clinical trial information: NCT00045032. [Table: see text]

Our Takeaways from the San Antonio Breast Cancer Symposium

Our Takeaways from the San Antonio Breast Cancer Symposium

Magnitude of Trastuzumab Benefit in Patients With HER2-Positive, Invasive Lobular Breast Carcinoma: Results From the HERA Trial

To evaluate the benefit of adjuvant trastuzumab in patients diagnosed with human epidermal growth factor receptor 2 (HER2) -positive invasive lobular carcinoma (ILC) enrolled onto the Herceptin Adjuvant (HERA) trial. Patients randomly assigned to receive one year of trastuzumab and one year of observation in the HERA trial were included (n = 3,401). Centrally reviewed estrogen receptor (ER), progesterone receptor (PgR), and HER2 copy numbers were used. First site-specific relapse pattern was evaluated for ILC and invasive ductal carcinoma (IDC). The magnitude of trastuzumab benefit was assessed using the Cox proportional hazards model for disease-free survival (DFS) and overall survival (OS). Median follow-up time was 4 years. A total of 187 ILC and 3,213 IDC patients were included. High Allred scores (6 to 8) were more common in patients with ILC than IDC for both ER (36.9% v 22.7%) and PgR (44.1% v 28.5%). A trend toward decreased HER2 copy number was observed in the ILC group. The ILC and IDC subgroups had similar patterns of first site of disease relapse. DFS hazard ratios (HRs) comparing 1 year of trastuzumab versus observation were 0.63 for ILC (95% CI, 0.34 to 1.15) and 0.77 for IDC (95% CI, 0.67 to 0.89; P for interaction = .49). The OS HRs comparing 1 year of trastuzumab versus observation were 0.60 for ILC (95% CI, 0.27 to 1.31) and 0.86 for IDC (95% CI, 0.71 to 1.06; P for interaction = .29). In this retrospective analysis, there was no suggestion that patients in the ILC cohort experienced a different magnitude of benefit from adjuvant trastuzumab than those in the IDC cohort.

HERA TRIAL: 2 Years versus 1 Year of Trastuzumab after Adjuvant Chemotherapy in Women with HER2-Positive Early Breast Cancer at 8 Years of Median Follow-Up

In 2005, data from 3 large randomized trials demonstrated that 1 year of trastuzumab treatment provided a statistically significant disease-free survival benefit compared with no trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer [Piccart-Gebhart MJ et al. N Engl J Med 2005]. One of these studies, the Trastuzumab in Treating Women with Primary Breast Cancer [HERceptin Adjuvant (HERA); NCT00045032] trial, continued trastuzumab therapy to assess whether 2 years of treatment was superior to 1 year. This article provides an update of the HERA trial after 8 years of median follow-up.

Abstract P5-18-02: Selective Crossover in Randomized Trials of Adjuvant Trastuzumab for Breast Cancer: Coping with Success

Abstract BACKGROUND: Disease-free survival (DFS) is often a primary endpoint of randomized trials of adjuvant therapies for breast cancer, but long-term follow-up of DFS and especially overall survival (OS) remain important. When the primary DFS results favor the experimental arm, patients (pts) assigned to the control group may select the option to crossover to receive the experimental treatment via protocol amendment. Such “selective crossover” disturbs the integrity of the randomized comparison for any efficacy endpoints that rely on further follow-up. Selective crossover, which is motivated by positive results having been observed in the current trial, is distinct from so-called “unplanned crossover,” which refers to non-adherence to protocol. In this abstract, we discuss the consequences of selective crossover for trials evaluating adjuvant trastuzumab, using the HERA (HERceptin Adjuvant) trial as an example, and present a variety of alternative analysis approaches. METHODS: HERA enrolled 5102 women with HER2-positive early breast cancer who had completed all surgery and (neo)adjuvant chemotherapy to compare 1 or 2 years of trastuzumab treatment vs observation. After a positive first interim analysis at 1y median follow-up (MFU) showed that 1 year of trastuzumab significantly improved DFS vs observation [MJ Piccart-Gebhart et al; NEJM 2005], event-free patients in the observation group were offered crossover to receive trastuzumab. 885 (52%) of the 1698 pts in the observation group selectively crossed over to trastuzumab. RESULTS: Previously reported intention-to-treat (ITT) analysis of HERA at 4y MFU showed a decreasing effectiveness of trastuzumab with respect to DFS compared with those at 2y MFU [L Gianni et al, Lancet Oncol 2011; I Smith et al, Lancet 2007]. In addition, the ITT analysis of OS at 4y MFU showed little effect of trastuzumab, while the analysis artificially censoring follow-up in the observation group at the time of selective crossover showed a substantial OS advantage for trastuzumab. The dependent censored analysis of OS is clearly biased in favor of trastuzumab because data for pts who remain event-free can be censored at the time of crossover, while data for the sicker pts in the observation group (those who relapsed) cannot be censored due to crossover. The issues related to the ITT and dependent censored analyses will be reviewed and discussed. Alternative analytic approaches designed to estimate the treatment effect that would have been observed had there been no selective crossover will be presented. The methods include the inverse probability of censoring weighted (IPCW) approach, and randomization-based estimators under the accelerated failure time model. HERA data to about 8y MFU (available fall 2012) will be used to illustrate approaches. CONCLUSION: Alternative methods addressing selective crossover are required to estimate the trastuzumab effect for updated analyses of DFS and OS for HERA, and for any other large randomized trial with positive interim results. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-02.

19P Her2 Extracellular Domain Levels in Patients With Her2-Positive Early Breast Cancer Experiencing Disease Progression: Case-Control Comparison of Samples from the Hera Study

ABSTRACT Background Levels of serum-soluble human epidermal growth factor receptor 2 (HER2) extracellular domain (ECD) are elevated in some patients with HER2-positive breast cancer. Serum ECD levels have been proposed as a potential biomarker of response to given therapies or an indication of disease progression. Serum ECD elevations >20% from baseline have been associated with disease progression. We performed a nested case-control study to test this hypothesis in patients with HER2-positive early breast cancer (EBC). Methods Serum for the measurement of ECD was collected from 992 patients in the Herceptin Adjuvant (HERA) trial (N Engl J Med 2005; 353: 1659-72). Samples were taken at baseline, weeks 25 and 52, and months 18, 24, 36, 48 and 60, from patients in any of the three HERA trial arms. Serum was stored until assayed using the Siemens Serum HER-2/neu Test. Cases were identified as the last sample before the date of first local, regional or distant recurrence. Two control samples without recurrence prior to that of the case were selected to form case-control triplets, matched on time from randomisation to ECD sample, nodal and neoadjuvant chemotherapy status, histological grade, and ER/PgR status. Statistical analyses included conditional logistic regression (CLR) and the Wilcoxon signed-ranked test. Results A total of 160 case-control triplets were considered. The median ECD level in case samples was 2.4% higher than in control samples. CLR indicated that ECD samples with a higher ECD level had a higher probability of being a case sample than a control sample (p 20% in 44 (27.5%) and ≤20% in 116 (72.5%) case-control triplets. The Wilcoxon test did not indicate that the difference in mean ECD level between cases and controls was >20%. Conclusions Higher ECD levels were indicative of case samples rather than control samples. However, the mean difference between ECD levels in case samples and control samples was not >20%. These data were therefore insufficient to support the use of the specified ECD level as a predictive biomarker in patients with EBC. Disclosure M. Dowsett: I serve on Advisory Boards for Roche and receive grant income form them. M. Procter: Marion Procter's institution received funding from Roche in relation to the HERA trial. E. de Azambuja: Honoraria as Roche speaker; travel grant from Roche (ASCO 2011). M.J. Scullion: Roche employee. All other authors have declared no conflicts of interest.

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.