Adjuvant Treatment Of HER2 Research Articles

PCN110 Cost-Utility Analysis of Adjuvant Trastuzumab Emtansine Versus Trastuzumab in Patients with HER2+ EARLY Breast Cancer with Residual Invasive Disease after Neoadjuvant Therapy in Spain

Trastuzumab emtansine (T-DM1) in the adjuvant treatment of patients with HER2-positive early breast cancer (HER2+ eBC) with residual invasive disease (RD) after neoadjuvant taxane-based and HER2-targeted therapy demonstrated a clinically and statistically significant improvement in invasive disease-free survival (iDFS) compared to trastuzumab in the KATHERINE trial. The aim of this study is to determine the efficiency of T-DM1 versus trastuzumab as adjuvant treatment of HER2+ eBC with RD in Spain through a cost-utility analysis. A six-state Markov model (iDFS, local recurrence, iDFS after local recurrence, metastatic-relapse [1L], metastatic-relapse [2L], and death) was adapted over a lifetime horizon (specifically 38 years), considering the Spanish National Healthcare System (SNHS) perspective. KATHERINE iDFS data were fitted with a log-normal distribution to extrapolate iDFS beyond the trial follow-up. Transition probabilities and costs (list prices of medicines considered and, for the adjuvant treatment, trastuzumab biosimilar price assumed; €2019) were obtained from literature and national databases. Utilities were based mainly on the 5Q-5D outcomes from KATHERINE trial. Model inputs were validated by an expert panel. A 3% annual discount rate was applied to both effects and costs. Deterministic and probabilistic sensitivity analyses (SA) were performed to explore uncertainties. The incremental cost-utility ratio (ICUR) for T-DM1 versus trastuzumab was €6,748 per quality-adjusted life-year (QALY). Compared to trastuzumab, T-DM1 provided 1.702 additional QALYs at an additional cost of €11,485. SA confirmed the robustness of the model. In the probabilistic analysis, the probability of T-DM1 being cost-effective when considering a threshold of €30,000/QALY was >95%. T-DM1 is a more efficient therapeutic alternative than trastuzumab as adjuvant treatment of HER2+ eBC with residual invasive disease for the SNHS.

Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: a systematic review and meta-analysis

BackgroundAlthough the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients.MethodsA comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0.ResultsTwenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08–1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68–0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64–1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82–1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81–1.95; P = 0.309).ConclusionsOur study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia).Trial registrationA systematic review protocol was registered with PROSPERO (identification number: CRD42018110415).

Cardiotoxicity Alerts during Treatment with Trastuzumab in Breast Cancer at Four-year Follow-up

Background: Adjuvant treatment of HER2+ breast cancer includes adriamycin and trastuzumab, a monoclonal antibody that producescardiotoxicity. The actual epidemiologic impact of trastuzumab-related cardiotoxicity in unselected populations in Argentinaremains unknown.Objectives: The aim of this study was to evaluate the impact of trastuzumab-related cardiotoxicity during adjuvant treatment forbreast cancer in an unselected population after >12 months of completing therapy.Methods: Among 888 patients prospectively evaluated for breast cancer, 231 (38%) were HER2+ and received adjuvant therapy withadriamycin and trastuzumab. Left ventricular ejection fraction was evaluated before treatment, after completing adriamycin and thenevery 3 months during follow-up. Cardiotoxicity was defined as a decline in left ventricular ejection fraction >10%, according to the definitionof the American College of Cardiology and was compared with the definitions of the B-31 trial and the MD Anderson Cancer Center.Results: A decline in left ventricular ejection fraction >10% from baseline values occurred in 65% (n=150) of the patients during amean follow-up of 48±12 months. In the per group analysis, patients included in the B-31and MD Anderson Cancer Center vs. theAmerican College of Cardiology definitions presented greater percent fall in left ventricular ejection fraction during treatment: 20%vs. 20% vs. 16%, respectively (p <0.04) and ended treatment with left ventricular ejection fraction <50% in 42% vs. 41% vs. 33% ofcases, respectively (p=0.01).Conclusions: In the population treated with trastuzumab under cardio-oncology surveillance during 48±12 months:1- Left ventricular ejection fraction was significantly decreased in more than 60% of patients.2- Different guidelines show different cardiotoxicity risks which demands continuous cardio-oncological monitoring.

Single-cell RNA sequencing reveals novel gene expression signatures of trastuzumab treatment in HER2+ breast cancer: A pilot study.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ∼20% of invasive breast cancers and is associated with poor prognostics. The recent outcome of HER2+ breast cancer treatment has been vastly improved owing to the application of antibody-targeted therapies. Trastuzumab (Herceptin) is a monoclonal antibody designed to target HER2+ breast cancer cells. In addition to improved survival in the adjuvant treatment of HER2+ breast cancer, trastuzumab treatment has also been associated with cardiotoxicity side effect. However, the molecular mechanisms of trastuzumab action and trastuzumab-mediated cardiotoxicity are still not fully understood. Previous research utilized bulk transcriptomics analysis to study the underlining mechanisms, which relied on averaging molecular signals from bulk tumor samples and might have overlooked key expression features within breast cancer tumor. In contrast to previous research, we compared the single cancer cell level transcriptome profile between trastuzumab-treated and nontreated patients to reveal a more in-depth transcriptome profile. A total of 461 significantly differential expressed genes were identified, including previously defined and novel gene expression signatures. In addition, we found that trastuzumab-enhanced MGP gene expression could be used as prognostics marker for longer patient survival in breast invasive carcinoma patients, and validated our finding using TCGA (The Cancer Genome Atlas) breast cancer dataset. Moreover, our study revealed a 48-gene expression signature that is associated with cell death of cardiomyocytes, which could be used as early biomarkers for trastuzumab-mediated cardiotoxicity. This work is the first study to look at single cell level transcriptome profile of trastuzumab-treated patients, providing a new understanding of the molecular mechanism(s) of trastuzumab action and trastuzumab-induced cardiotoxicity side effects.

Abstract PD3-12: Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial

Abstract Introduction: Central Nervous System (CNS) metastases as first site of relapse is seen in 2-3% of patients with HER2+ early breast cancer (EBC) during or after treatment with adjuvant trastuzumab. Data about long-term follow-up outcomes in this population is scarce. Methodology: BCIRG-006 was designed to assess the efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of HER2+ EBC. 3,222 patients were randomized to standard AC-T or two trastuzumab-based regimens (AC-TH or TCH). Ten year follow-up outcomes were previously presented; we have used this data to assess the frequency and course of CNS relapses as first site of distant recurrence. DFS and OS in these patients were estimated and compared using the Kaplan-Meier method and Log-Rank test respectively. Univariate and multivariate analyses for DFS were conducted considering patient's age, nodal status, tumor size and estrogen receptor (ER) status in the primary tumor. Results: Of the 3,222 patients randomized, 575 (17.8%) experienced a distant relapse and in 17.5% of these (n=101) CNS was the first site of recurrence. With a median follow-up of 10.3 years, the frequency of CNS relapses did not differ when comparing the trastuzumab containing arms with the control arm (OR 0.86, 95% CI: 0.56-1.33; p= 0.519). No difference was observed either between AC-TH and TCH (OR 1.14, 95% CI: 0.67-1.94; p= 0.704). There were no differences in DFS (HR 1.21, 95% CI: 0.74-1.99; p= 0.621) nor in OS (HR 0.74, 95% CI: 0.43-1.27; p= 0.377) between AC-T, AC-TH and TCH arms. Positive axillary nodes (≥4 nodes) and ER negative status at baseline remained independent risk factors for CNS relapse after univariate and multivariate analysis (HR 0.60, 95% CI: 0.8-0.95; p= 0.007 for nodal status and HR 0.56, 95% CI: 0.37-0.85; p= 0.029 for ER status). Conclusion: Among the pivotal adjuvant trastuzumab trials, BCIRG-006 is the one with the longest median FUP in which data about CNS relapses has been presented. CNS relapse in patients in this trial was an infrequent event. Its frequency and outcomes were similar across the three treatment arms. Patients with ER negative and/or ≥ 4 positive nodes are at higher risk of CNS relapse irrespective of trastuzumab therapy and may be the patient population where research efforts should be focused. BC outcomes in patients with CNS metastases per treatment arm in the BCIRG-006 trial AC-T N=1073 n(%)AC-TH N=1074 n(%)TCH N=1075 n(%)p valueFrequency of CNS relapse37 (3.44%)30 (2.79%)34 (3.16%)0.519 ^Median DFS (months; 95% CI)23.8 (13.3-30.4)19.9 (16.6-25.1)19.9 (15.0-27.2)0.621 ⫲Median OS (months; 95% CI)42.5 (28.3-62.7)53.2 (31.2-103.6)30.3 (23.4-39.0)0.377 ⫲ ^ comparing control vs. trastuzumab-containing arm using Fisher's Exact test. ⫲ comparing control vs. trastuzumab-containing arms using Log Rank test. Citation Format: Chan A, Spera G, Machado A, Fung H, Bee V, Fresco R, Slamon DJ. Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-12.

PRM162 - A PIECEWISE APPROACH TO THE EXTRAPOLATION OF INVASIVE DISEASE-FREE SURVIVAL (IDFS) IN THE ADJUVANT TREATMENT OF HER2+ BREAST CANCER

Cost-effectiveness analyses often necessitate the extrapolation of survival data beyond the observation period of a trial. In adjuvant breast cancer, risk of recurrence is high immediately following surgery but decreases over time. An extrapolation reliant solely on observed trial data may lead to estimated survival outcomes that are not reflective of survival rates observed at later timepoints. This study outlines a piecewise approach to survival extrapolation. Outcomes from this piecewise approach are then compared to standard extrapolation and observed values in the long-term follow-up of trials evaluating trastuzumab + chemotherapy (TC) in the adjuvant treatment of HER2+ breast cancer. The adjusted extrapolation was segmented into three separate “phases”. During phase one (time zero to year 4), a log-logistic extrapolation is fitted to invasive disease-free survival (IDFS) data from a Phase III randomised controlled trial, APHINITY. From years four to 10 (time period 2), the initial parametric extrapolation is augmented using a “cure” model. Implementation of the ‘cure’ model assumes that the proportion of patients being “cured” (no longer at risk of recurrence and only subject to background mortality) linearly increases with time from 0% at 48 months to 95% at 120 months. In phase three (year 10 onwards), 95% of event-free patients are assumed to be no longer at risk of recurrence and are susceptible to background mortality only. The unadjusted extrapolation, vastly underestimates expected DFS at later timepoints. The piecewise approach produced similar hazard rates to those observed in the long-term follow-up of older adjuvant trials. IDFS/EFS values at 10 years are 75.23% and 70.00% for the adjusted extrapolation and the BCIRG-006 trial, respectively. The adjustment appears to be beneficial and serves to improve the real-world accuracy of the extrapolation.

Adjuvant HER2-Targeted Therapy Update in Breast Cancer: Escalation and De-escalation of Therapy in 2018

Purpose of Review The introduction of trastuzumab for the adjuvant treatment of tumors with amplification of HER2/neu has been one of the most exciting advances in systemic treatment in the history of breast cancer and has transformed the natural history of HER2/neu-positive (HER2+) breast cancer (BC). There have been several recent advances in the adjuvant treatment of HER2+ BC and herein we review recently reported clinical trials focusing on the impact of expanding therapeutic options with attention to optimal sequence of the available treatment options and clinical aspects of escalating or de-escalating therapy for patients based on their level of risk.

Abstract P1-13-10: Adjuvant treatment of HER2+ breast cancer: Should trastuzumab be given sequentially or concurrently with chemotherapy?

Abstract Background Human Epidermal growth factor Receptor 2 positive (HER2+) breast cancers have a high risk of recurrence in the absence of systemic treatment. The monoclonal antibody trastuzumab in combination with chemotherapy has significantly improved survival. Randomized trials have given trastuzumab both concurrently and sequentially with chemotherapy. To date, only one study reported a comparison between concurrent and sequential trastuzumab, with a numerically but not statistically significant benefit for concurrent use. Our aim is to evaluate whether there is a difference in survival between patients who received trastuzumab sequentially to chemotherapy compared to concurrently with chemotherapy using data from the population-based, Netherlands Cancer Registry (NCR). Methods All women diagnosed in the Netherlands with a HER2+, TanyNanyM0 breast tumor between 2005 and 2007 who received both chemotherapy and trastuzumab were identified from the NCR. Kaplan Meier survival estimates and Cox regression were used to compare recurrence free survival (RFS) and overall survival (OS) by trastuzumab sequence. Hazard ratios (HR) were adjusted for grade, pathological T-stage, pathological N-stage, estrogen receptor (ER), progesterone receptor, radiotherapy, hormonal therapy and ovarian ablation. Results A total of 1,849 patients were identified, with a mean follow-up of 7.8 years. Of these, 1,260 received concurrent trastuzumab and 589 sequential trastuzumab. Most tumors were grade 3, node positive and ER+. During follow-up 358 RFS events occurred, 231 in the concurrently treated patients compared to 127 in sequentially treated patients. Regarding OS, 290 deaths were observed, 188 deaths in concurrently treated patients compared to 102 deaths in sequentially treated patients, respectively. OS and RFS were similar among sequentially versus concurrently treated patients (adjusted HR 1.11; 95% CI 0.87-1.42; P=0.420 and adjusted HR 1.15; 95% CI 0.92-1.44; P=0.209, respectively). Conclusion We observed no significant difference in OS and RFS between patients who received sequential trastuzumab compared to patients treated concurrently. Based on our results no recommendation can be made favoring either of the two treatment sequences for the adjuvant treatment of HER2+ breast cancer patients. Citation Format: Dackus GMHE, Jóźwiak K, Van der Wall E, Van Diest PJ, Hauptmann M, Siesling S, Sonke GS, Linn SC. Adjuvant treatment of HER2+ breast cancer: Should trastuzumab be given sequentially or concurrently with chemotherapy? [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 P1-13-10.

Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer

Abstract Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material &amp; Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p&amp;lt;0.001)) and TCH (HR=0.76, 95% CI [0.65, 0.90]; p&amp;lt;0.001). At this final analysis, the DFS HRs for AC-TH and TCH are closer than those observed in any prior protocol-directed study analyses (at 5 years follow-up the HRs were 0.64 and 0.75 for AC-TH and TCH respectively). Also, an OS benefit was observed in both AC-TH (HR=0.64, 95% CI [0.52, 0.79]; p&amp;lt;0.001)) and TCH (HR=0.76, 95% CI [0.62, 0.93]; p=0.0081). Importantly, TCH has significantly lower symptomatic CHF events by five-fold compared to AC-TH; 21 (2.0%) for AC-TH vs. 4 (0.4%) for TCH; p=0.0005. The AC-T control arm had 8 (0.8%) symptomatic CHF events. The incidence of patients with a relative LVEF decline &amp;gt;10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p&amp;lt;0.0001). Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bée-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-04.

P5-18-12: Perception, Practice and Toxicity of Adjuvant Treatment of HER2+ Breast Cancer in Wisconsin.

Abstract INTRODUCTION: Multiple trastuzumab-containing (neo)adjuvant regimens are used for HER2+ BrCa, but the experience with these regimens in routine practice is not reported. Some oncologists select TCH based on BCIRG 006, whereas others prefer anthracycline-based therapy. We evaluated whether oncologists’ perceptions of these regimens match clinical experience. METHODS: We surveyed 151 Wisconsin (WI) oncologists regarding factors impacting selection of TCH versus AC-TH; 65 (42%) responded. At the same time, we reviewed 200 cases of HER2+ BrCa treated with adjuvant trastuzumab from 2003 to 2010 at the University of Wisconsin Carbone Cancer Center (UW) and the Marshfield Clinic. We collected baseline patient and tumor characteristics, regimen administered, and toxicities as assessed by lab values, cardiac ejection fraction (EF), hospitalizations, dose reductions/delays, and ability to complete therapy. RESULTS: Two-thirds of surveyed oncologists prefer anthracycline-based therapy over TCH. Of oncologists preferring TCH, 20 of 23 had been in practice for &amp;gt;10 years. Oncologists perceived that AC-TH and TCH were equally likely to be completed. The majority of physicians select therapy based on patient age and stage, with a preference for AC-TH for node-positive disease and TCH for early stage (T1a-bN0) tumors. Despite BCIRG 006 remaining unpublished at the time of the survey, peer-review publication was cited as the most important factor in selecting this regimen. Although use of granulocyte colony stimulating factor (GCSF) in BCIRG 006 has not reported, 50% of oncologists indicated routine use with cycle 1 of TCH. Of the 200 cases reviewed, 114 women received AC-TH, 48 women received TCH, and 38 had other regimens. The median age was 53 years old, 52% had node positive disease. Acute toxicity trended higher with TCH. For example, there were fewer dose modifications/delays for AC-TH than TCH (31% vs. 46%, p=0.07). This may have been due to common use of GCSF with AC-TH (77% vs. 33% use with TCH). Neutropenic fever (NF) was higher with TCH, reaching 25% incidence when administered without GCSF. However, NF did not occur in the 8 TCH patients who received cycle 1 GCSF. There was no correlation between NF and patient age. The incidence of left ventricular EF decline leading to cessation of trastuzumab was similar for both regimens (19.4% AC-TH vs. 14.6% TCH; p = 0.64). Trastuzumab was completed as planned in 70% of patients. Although EF decline was most common explanation, 13% of early trastuzumab discontinuations occurred for other reasons. CONCLUSION: TCH and AC-TH are the most commonly administered adjuvant regimens for WI women with HER2+ BrCa. Amongst WI oncologists, TCH is perceived as safer, but is less likely to be recommended for node-positive BrCa. This retrospective analysis suggests that acute myelosuppression is greater for TCH, with a significant rate of NF. Per ASCO guidelines, these data suggest GCSF should be used routinely with TCH due to high rate of FN. We were intrigued that oncologists who have been in practice longer are more likely to choose TCH. The reasons for this are unclear, but are perhaps related to prior experience with long-term cardiotoxicity with AC-TH. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-12.

P5-18-08: A Comparative Effectiveness Analysis of Trastuzumab Persistence between Two Adjuvant Breast Cancer Treatment Regimens among US Health Plan Enrollees.

Abstract Background Approved US indications for trastuzumab include adjuvant treatment of HER2−overexpressing breast cancer in anthracycline-based (ACTH) or non-anthracycline-based (TCH) regimens. The objective of this study was to compare trastuzumab persistence across adjuvant breast cancer treatment regimens for US health plan enrollees. Materials and Methods: This retrospective cohort study using the IMS LifeLink™ Health Plan Claims Database included adjuvant breast cancer patients, defined as those with a mastectomy or lumpectomy and a primary breast cancer diagnosis (index diagnosis) from 1/1/2006 to 12/31/2008. Additional inclusion criteria were: aged ≥18 years; a second primary breast cancer diagnosis ≤90 days of the first; no other primary or secondary neoplasms ≤180 days before or ≤90 days after the index diagnosis; a first trastuzumab claim (index claim) and ≥1 carboplatin, cyclophosphamide, taxane, or anthracycline claim ≤210 days of the index diagnosis; and no trastuzumab claim before the index diagnosis. Regimens were classified as ACTH (doxorubicin, cyclophosphamide, a taxane, trastuzumab) or TCH (docetaxel, carboplatin, trastuzumab) from therapies observed after the index claim. Trastuzumab persistence (days from the index claim to earliest of trastuzumab discontinuation, a new malignant neoplasm, end of plan enrollment, 360 days after the index claim, or end of available data) was reported for patients with ≥2 trastuzumab claims and compared across regimens using the Kaplan-Meier estimator and Cox proportional hazards models. Results: 550 breast cancer patients met all study criteria (291 ACTH, 259 TCH, 46 unassigned); patients receiving TCH were older (median 52 vs. 50 years; P=0.018). For years 2006–2008, the annual share of the cohort initiating ACTH decreased from 69.3% to 35.2%; patients initiating TCH increased from 26.7% to 56.5%. Patients receiving ACTH were treated with trastuzumab for fewer days (mean=256, median=334) versus patients on TCH (mean=282, median 344, P=0.018). Fewer patients on ACTH remained on trastuzumab at day 90 (83% vs. 91%), day 180 (71% vs. 79%), day 270 (61% vs. 72%), and day 360 (20% vs. 26%). Compared to patients on TCH, patients on ACTH continued to be treated with trastuzumab for a shorter duration post-index after adjusting for age, region, plan type, prescriber specialty, and comorbidities (HR=0.77, 95% CI [0.63, 0.95]; P=0.016). Discussion: The share of adjuvant breast cancer patients initiating TCH increased from 2006 to 2008, while use of ACTH decreased over the same time period, and patients treated with TCH remained on trastuzumab for a longer period of time. From a clinical standpoint, patients derive maximum benefit from their medications when they are persistent long-term, which can lead to economic benefits with regards to lower overall healthcare costs. Further analyses will evaluate whether adjuvant breast cancer regimens differ in weight-adjusted cumulative trastuzumab doses received during therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-08.

Adjuvant therapy of HER2+ breast cancer

Adjuvant therapy of HER2+ breast cancer has evolved dramatically over the past 4 years. It is now widely appreciated that treatment with trastuzumab, when administered concurrently or sequentially with chemotherapy, will decrease the risk of disease recurrence by approximately 50%. Clinical trials have also demonstrated a modest improvement in overall survival, and it is anticipated that this survival advantage will increase with further follow-up. Nevertheless, there are patients who will experience disease recurrence in spite of optimal trastuzumab-based therapy, and new treatment approaches are needed for these individuals. The results of the initial randomized trials have also given rise to a number of difficult questions that clinicians and patients face on a daily basis. The presentation will focus on controversial topics in the adjuvant treatment of HER2+ disease, including: the treatment of small, node-negative tumors; the uncertainty surrounding intermediate HER2+ test results; and the concerns about cardiac toxicity. New treatment approaches for HER2+ breast cancer that hold promise for the adjuvant setting will also be discussed.

HER-2/neu positive breast cancer: how to prescribe adjuvant trastuzumab (Herceptin)?

One of the most recent advances in the management of Her-2/neu positive breast cancer is the validation of a targeted therapy from bench to the clinic, particularly towards the adjuvant setting. The recommended dose of trastuzumab (Herceptin), a humanized monoclonal antibody targeting the HER-2 antigen, has been determined in phase I studies. In the metastatic patients two randomised trials have demonstrated its efficacy when associated to taxanes. In less than 10 years, trastuzumab became the standard of care in the adjuvant treatment of HER-2/neu positive breast cancer. In this setting, two combinations regimen with chemotherapy (concomitant or sequential) have been recently published. The concomitant schedule has been used in three studies (North American Group, BCIRG, FinHer), whereas in the Hera trial trastuzumab was started after the end of neo-adjuvant and adjuvant chemotherapy. In this article, the advantages and uncertainties on efficacy and toxicities of the trastuzumab administration modalities, associated or not to chemotherapy and radiation therapy, are discussed.