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Background/aim This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant trastuzumab-based therapy. Patients and methods HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated. Results A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival). Conclusion No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.

This retrospective analysis conducted using data from patients enrolled onto the Herceptin Adjuvant has two objectives: The first is to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI) upon overall survival (OS). The second is to describe the duration of trastuzumab-based regimens in the metastatic setting for patients previously treated with adjuvant trastuzumab. The first objective included 187 patients treated with adjuvant trastuzumab and diagnosed with distant recurrence at 4-year median follow-up. The second objective included data from questionnaires sent to investigators retreating patients with trastuzumab upon distant recurrence: 144 of 156 questionnaires were returned (93 %), and 90 patients were selected based on available clinical information and consent for subsequent studies. There was no statistically significant relationship between TDRI following 1 year of adjuvant trastuzumab and OS from distant recurrence: hazard ratio 0.991, p = 0.46. The median OS from distant recurrence was numerically longer among patients with a TDRI of ≥12 months (n = 103) than

Background: Trastuzumab (T) forms the backbone of the current first-line treatment of advanced HER2+ breast cancer. In the present study we sought to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI), upon a) overall survival (OS), b) the duration of trastuzumab-based regimens (T) in the advanced setting. Patients & Methods: a) The first hypothesis involved 187 pts on HERA treated with adjuvant T and diagnosed with distant recurrence after the scheduled treatment period of 1 year at 4 years median follow-up. The impact of TDRI on OS from distant recurrence was evaluated in a Cox model adjusted for tumor size, nodal and hormone receptor status at time of enrollment into the HERA trial. b) The second hypothesis involved 90 patients retreated with T in the metastatic setting. A questionnaire was sent to investigators retreating pts with T upon distant recurrence; 144 of 156 questionnaires were returned (93%), and 90 pts were selected based on available clinical information and consent for subsequent studies (14 pts were randomized to observation and received adjuvant trastuzumab after crossover). Results: a) There was no statistically significant relationship between TDRI following 1yT and OS from distant recurrence: HR 0.99, p = 0.46; HR 0.99, p = 0.27 from the stratified and unadjusted Cox proportional hazard models, respectively. The median OS from distant recurrence was numerically longer among pts with a TDRI of ≥ 12 months (n = 103) than < 12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). b) The median duration of T-based regimens for metastatic disease was 8.8 months (n = 88), 9.4 months in the ER+ cohort (n = 36) and 8.8 months in the ER- cohort (n = 52); (n = 2, missing). Sites of first distant recurrence and subsequent disease progression for the 90 pts were hierarchically distributed as below. First distant recurrence n (%)Subsequent progression n (%)CNS6 (6.7%)22 (24.4%)Visceral45 (50.0%)39 (43.3%)Skeletal25 (27.8%)9 (10.0%)Soft Tissue14 (15.6%)9 (10.0%)No event-11 (12.2%) Conclusions: In the HERA trial, TDRI following 1yT did not impact on OS from distant recurrence in pts experiencing distant disease recurrence. This may be due to the benefit of anti-HER2 regimens in subsequent lines of therapy. Although our sample size is limited, the present analysis suggests that pts experiencing a shorter interval (≤ 12 months) from the end of adjuvant trastuzumab to distant recurrence derive similar benefit from trastuzumab-containing regimens in the metastatic setting when compared to the cohort with an interval > 12 months. CNS relapse in HER2-postive breast cancer remains a clinical problem. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-04.

Purpose 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. Patients and Methods 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. Results 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). Conclusion 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.

Background: Retrospective studies of HER2−positive metastatic breast cancer (BC) showed an incidence of CNS metastases of 21% to 34%. We investigated the incidence and clinical aspects of CNS relapse (CNS-R) in patients (pts) enrolled in the HERA trial, a prospectively randomized adjuvant trial in node + or high-risk node - HER2−positive early BC pts. Methods: 3401 pts were randomized into the 1-year trastuzumab (1yT) or the observation (obs) arms of HERA (Piccart-Gebhart et al, 2005, Gianni et al, 2011). The cumulative incidences of first disease-free survival (DFS) events in the CNS vs other sites were estimated using competing risk analysis. The database of the main study had a clinical cut-off date of 9th June 2008. To obtain additional information regarding CNS-R (including occurrence of CNS-R after first DFS event), a specific CNS-directed questionnaire was sent to investigators of pts who were deceased as of July 2009. Information collected included the date of CNS-R, whether it was symptomatic, the type of CNS-R (brain metastases (BM) or meningeal carcinomatosis (MC)), methods of diagnosis, and treatments at the time of CNS-R. Results: 1yT significantly reduced the risk of other DFS events (p=0.000017, Gray's test), but not of CNS-R (p=0.55) as first event (see table). During the first year of follow up, CNS-R accounted for 15 (14.9%) of the 101 first DFS events in the 1yT arm and 15 (7.7%) of the 194 first DFS events in the obs arm. The analysis of baseline patient and tumor characteristics associated with CNS-R as first event confirmed known risk factors such as young age ( 413 of the 481 questionnaires (85.9%) were returned. 217 of the 413 deceased pts had a CNS-R diagnosed prior to death (52.5%), with more events occurring in the 1yT arm (see table). By contrast, the incidence of CNS-R as first DFS event was balanced across the arms. Based on the survey data, CNS-R was symptomatic in 189 pts (87.1%) with no differences between arms. BM were present in 211 pts (97.2%), absent in 5 (2.3%), and missing information in 1 (0.5%). MC was diagnosed in 25 pts (11.5%), absent in 187 (86.2%), missing information in 5 (2.3%). Frequencies for BM and MC were very similar in both arms. Conclusion: This retrospective analysis of a prospective large study shows more than 50% incidence of clinically diagnosed CNS-R in HER2−positive BC pts who have died. CNS-R was symptomatic in most pts. CNS-R at any time was less frequent in the 1yT arm (88 vs 129). There is no evidence that adjuvant trastuzumab increases the incidence of CNS-R. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-01.

Summary Background Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray's test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray's test]). Most CNS relapses were symptomatic (189 [87%] of 217). Conclusion Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding None.

About 30% of the randomized clinical trials are stopped early because of appearance of clear clinical benefit. Though interim analyses protect patients in case of significant imbalance between two treatment arms, conclusions drawn from truncated studies can be premature and should be viewed with caution. We report the lesson learnt from the Herceptin adjuvant (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 > 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]

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.

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 t...

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.

672 Background: GHEA (Group Herceptin in Adiuvant Treatment), an Italian multicentric observational study, was designed with the aim to investigate on adjuvant trastuzumab therapy of HER2-positive breast carcinomas in conventional clinical setting. Methods: Eligible patients should have been treated with trastuzumab in adjuvant setting and were collected among 35 oncologic Italian centers. Results: The 516 patients registered in the GHEA database had a median age of 52 years and 50% were in post-menopause at the time of trastuzumab therapy, similarly to the patients enrolled in HERA (median age of 49 years and postmenopause status in 46%). Primary breast tumors in GHEA were mainly of ductal type (93%) of high grade (53% were GIII) and small in size (50% T1); moreover, 7% of the samples were classified as N- negative and T1micro, T1a and T1b, and around 4% were T4, four categories not included in HERA. ER-PgR-positive tumors were 42%, thus higher than in HERA (31%). Negative lymph nodes were present in 42%...

1136 Background: Trastuzumab received in 2006 the European Medicines Agency approval for the adjuvant treatment of patients affected by HER2-overexpressing early breast cancer after the results of ...

582 Background: Guidelines for cardiac scanning in adjuvant Trastuzumab (T) trials were developed due to clinical concerns regarding cardiotoxicity, and these same guidelines are now used in clinical practice. This was a retrospective audit to assess adherence to these guidelines and characterise the nature and timescale of problems experienced with adjuvant T in clinical practice. Methods: A retrospective review of MUGA/ECHO results was conducted in patients who received adjuvant T for breast cancer. Data was compiled from five UK cancer centres: Glasgow, Manchester, Cardiff, The Royal Free hospital and Newcastle. Results: A total of 424 patients received at least one dose of adjuvant T between September 2005 and January 2008, using a HERA trial schedule. There were 262 with detailed information regarding treatment delays/withdrawals for cardiac reasons. 12% (32/262 pts) were withdrawn from adjuvant trastuzumab treatment for cardiac reasons, with another 11% (29/262 pts) experiencing at least 1 delay in treatment. Analysis of cardiac scan results for the remaining 162 pts suggested a total cardiac delay/withdrawal percentage of 14.4% (61/424 pts). There was no age effect with 15% (50/338) of [Table: see text]

trastuzumab in this trial were similar to those seen in the NSABP and NCCTG trials. All patients in the HERA trial will continue to be followed up for longterm safety and patients in the observation-only arm will be offered trastuzumab. Results regarding optimal trastuzumab duration (2 years vs 1 year) should be available in 2008. Sledge reiterated the importance of investigating trastuzumab’s cardiotoxicity, including whether the adverse effects are completely or partially reversible. “We know virtually nothing about the long-term effects of [trastuzumab] on the heart,” he stressed. Nonetheless, he added, with NSABP/NCCTG and HERA results clearly indicating that adjuvant trastuzumab improves diseasefree survival for women with HER2positive breast cancer, the drug’s benefits far outweigh its risks. “There’s no question in my mind about this— biology has spoken, and we should listen,” he said. “But the price [of potential cardiotoxicity] is real and has to be discussed with patients.” MORE TO BE DONE The promising data from these monoclonal antibody trials have created a buzz among oncologists and cancer researchers, but they also caution that for most of the women participating in the studies, the new drugs provide a prolongation of survival, not a cure. Combining targeted therapies—a strategy similar to that used for treating patients with HIV—may someday prove to be the way to go, but life-saving drug cocktails for cancer have not yet been discovered.

Background: The efficacy of sequential adjuvant trastuzumab (aTZ) after chemotherapy in women with early-stage human epidermal growth factor-2 (HER2/neu)-positive breast cancer reported by the updated Herceptin Adjuvant (HERA) trial appears less favorable than originally reported. Based on these updated results, we estimated the cost-utility (CU) of sequential aTZ relative to chemotherapy alone in terms of incremental cost per quality-adjusted life-year (QALY) gained. Methods: A Markov model estimated incremental costs and outcomes of 12 months of aTZ after adjuvant chemotherapy in women with HER2/ neu-positive breast cancer over a 25-year horizon. The model incorporated four broad health states (disease-free, local recurrence [LCR], distant recurrence [DCR], death), stratified with or without symptomatic cardiotoxicity. Baseline event rates and 3-year relative risk (RR = 0.75) were derived from the HERA trial. As the duration of the benefit remains uncertain, the analysis considered 5-year and 3-year duration of benefit in two scenarios. Costs and utility weights were from the literature. The analysis took a direct payer perspective, with costs reported in 2007 Canadian dollars. Costs and QALYs were discounted by 3% annually. Results: The mean CU of sequential aTZ at a 25-year horizon was $72,292 per QALY gained in the 5-year scenario and $127,862 per QALY gained in the 3-year scenario. Results were particularly sensitive to the magnitude and duration of carryover benefit. Conclusions: The CU of sequential aTZ is primarily dependent on the magnitude and duration of benefit. Further clinical research is required to establish the optimum sequence and duration of aTZ therapy and clarify the magnitude and duration of treatment benefit.