Months Of Trastuzumab Research Articles

De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer.

Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.

Combination chemotherapy with trastuzumab in early-stage breast cancer: a meta-analysis and Bayesian decision analysis of different treatment regimens.

HER2-positive breast cancer is a high-risk malignant tumor, and trastuzumab is an effective targeted therapy drug, but its optimal duration remains uncertain. To compare the efficacy and cost-effectiveness of different durations (6 months, 9 months, 12 months, and 18 months) of trastuzumab combined with chemotherapy in patients with early breast cancer by meta-analysis and Bayesian decision analysis. Randomized controlled trials comparing the effectiveness of different durations of trastuzumab combination chemotherapy in early-stage breast cancer patients were collected by searching multiple databases. Data synthesis was performed using the R software, and a decision tree model was constructed to simulate the expected outcomes and anticipated costs associated with different treatment durations. This study included 9 randomized controlled trials involving 11,328 early-stage breast cancer patients. The meta-analysis results demonstrated that, compared to the control group, trastuzumab combination chemotherapy at different durations significantly improved disease-free survival and overall survival in early-stage breast cancer patients. Among the various treatment durations, it was observed that 12 months of trastuzumab combination chemotherapy, in comparison to other durations, significantly reduced the risk of recurrence and mortality in early-stage breast cancer patients while maintaining a favorable cost-effectiveness ratio. Bayesian decision analysis also confirmed that 12 months of trastuzumab combination chemotherapy is the optimal treatment duration. It is recommended to use 12 months of trastuzumab combination chemotherapy as the standard treatment for early-stage breast cancer patients.

Clinical outcomes of chemotherapy-induced subclinical left ventricular systolic dysfunction among breast cancer patients detected using echocardiographic global longitudinal strain

Abstract Background Echocardiographic global longitudinal strain (GLS) detects early subclinical left ventricular (LV) systolic dysfunction, before the occurrence of a decreased LV ejection fraction. However, our local data is lacking to determine its impact to clinical outcomes. Purpose The study aimed to determine the clinical outcomes of breast cancer patients who developed subclinical LV systolic dysfunction as determined by an abnormal GLS post-chemotherapy. Methods This retrospective cohort study included 99 breast cancer patients who underwent anthracycline and/or HER-2 receptor inhibitor chemotherapy from January 1, 2016 to December 31, 2018 in a single tertiary hospital. Clinical outcomes of all-cause mortality and overt heart failure were compared between those with normal and abnormal GLS post-chemotherapy. Results The prevalence of subclinical LV systolic dysfunction was 18%, wherein 28% of them had subsequent overt heart failure, and 33% expired. Abnormal GLS occurred at a mean 3.5 months (range 1–8 months) after initiation of chemotherapy and at 8 months (range 6–10 months) after the entire chemotherapy sessions. Development into heart failure was observed at a mean of 6.7 months (range 4–12 months) after occurrence of abnormal GLS. Hypertension and age >56 years were determined to be risk factors. Beta-blockers, ACE inhibitors and statins seemed to be non-protective in our cohort. Abnormalities in GLS were observed at a mean dose of 260 mg/m2 of epirubicin, lower than the dose described as high risk in the literature (600 mg/m2 for epirubicin). In trastuzumab, abnormal GLS occurred as early as 1 month after initiation. LVEF had no significant change within 2 months (p=0.56), but was significantly lower within 12 months post-chemotherapy (p=0.005). All-cause mortality was 3-fold higher (RR=3.00; p=0.02), and the risk to develop heart failure was 4 times higher (RR=4.74; p=0.008) in those with abnormal GLS. Conclusion The development of abnormal GLS post-chemotherapy was associated with subsequent development of overt heart failure and increased all-cause mortality. Abnormal GLS occurred at lower doses of epirubicin and as early as 1 month after initiating trastuzumab. We recommend echo surveillance with GLS monitoring beginning >250 mg/m2 with anthracycline (and after 1–2 months of Trastuzumab), and to repeat at 1–2 months and 9–12 months post-chemotherapy. Funding Acknowledgement Type of funding source: None

Nine weeks versus six months of adjuvant trastuzumab in HER2-positive breast cancer: 3-year disease-free survival results.

e12530 Background: A total of 12 months adjuvant trastuzumab is still the optimal choice for patients with HER2-positive early breast cancer. However, the shorter course of 9 weeks may be considered as a cost-effective and safe option in developing countries such as Syria. Purpose: We aimed at investigating whether short-course 9-week adjuvant Trastuzumab is non-inferior to 6-month treatment at Albairouni University Cancer Center. The primary endpoint was disease-free survival (DFS). The secondary objective was assessing toxicities, especially cardiotoxicity. Methods: Patients with HER2-positive stage I-IIIC breast cancer were assigned to receive either 9 weeks or 6 months of trastuzumab in combination with adjuvant chemotherapies (sequentially). The 9-week group; 90 patients received trastuzumab intravenously (loading dose 4 mg/kg; then 2mg/kg weekly), whereas in the 6-month group; 157 patients, trastuzumab was delivered every 3 weeks intravenously (loading dose 8 mg/kg then 6 mg/kg). The LVEF was measured pretreatment and every 3 months afterwards. Results: 3-year DFS was 71.87% in the 9-week group versus 76.43% in the 6-month group, (Non-significant). No obvious side effects have been noticed during the follow-up period in the 9-week group. Congestive heart failure was reported in 2.55% of patients in the 6-month group. Conclusions: Short-course 9-week adjuvant trastuzumab is less effective than 6 months of treatment, with less cardiotoxicity. The short course could be considered in patients with heart disease and low risk of recurrence.

Anti-Her2neu directed therapy in advanced gall bladder cancer: A prospective, multicenter experience from India.

e16682 Background: Prognosis of Gallbladder cancer (GBC) remains unchanged over the last 20 years. Her2neu amplification is present in 17% of cases of advanced GBC. We present our experience of anti Her2 targeted therapy. Methods: This is a multicenter, prospective, observational study conducted in northern India from Sept2017-Sept2019. All consecutive patients were tested for Her2neu by standard techniques or next-generation sequencing (NGS). Trastuzumab or Lapatinib was used as the anti Her2 therapy along with chemotherapy. Outcome measures were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and compared to historical controls. Data were censored on 31Dec2019. Results: A total of 181 patients were screened; 38 (20.9%) patients were positive for Her2neu or Her3neu. Demographic details are depicted in the table. Her2 was detected by IHC 18 (47%), FISH 6(15.7%) or NGS 14(36.8%). Five patients were positive for Her3 mutation and/or amplification. Twenty-one patients received anti Her2 therapy upfront with chemotherapy. At a median follow-up of 6.8 months, median PFS was 4.1 months for chemotherapy only (n = 85) and 9.7 months for trastuzumab with chemotherapy (n = 21) (HR 0.22; P < 0.05). The median OS was 14 and 6 months in patients with or without trastuzumab-based therapy (HR 0.08 P = 0.001), respectively. Trastuzumab with chemotherapy was well tolerated. Conclusions: Her2neu directed therapy significantly improve ORR, PFS, and OS in GBC with no added toxicities in the first line. It must be evaluated in a randomized phase 3 clinical trials. [Table: see text]

Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials

BackgroundTreatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question.Materials and methodsA meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting.ResultsClinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I2=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I2=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I2=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I2=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I2=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias.ConclusionsCompared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.

Treatment patterns and survival in HER2-positive early breast cancer: a whole-of-population Australian cohort study (2007\u20132016)

BackgroundRandomised clinical trials (RCTs) demonstrate that trastuzumab improves survival in patients with human epidermal growth factor 2-positive early breast cancer (HER2 + EBC), but real-world patients and clinical practice often differ from RCTs. We examine real-world treatment patterns and outcomes associated with trastuzumab for HER2 + EBC.MethodsWe identified all Australians dispensed trastuzumab for HER2 + EBC between 1/1/2007 and 30/6/2016. We estimated the proportion of patients completing 12 months of treatment (defined as ≥350 days of exposure within 540 days of initiation). We estimated overall survival (OS) and recurrence-free survival (RFS) by using trastuzumab dispensing for metastatic breast cancer as a surrogate for recurrence.ResultsOur study included 14,644 patients. Among patients with ≥540 days of follow-up (n = 11,903), 67.4% completed 12 months of trastuzumab. OS rates at 5 and 9 years were 92.7 and 87.9%, and RFS rates at 5 and 9 years were 86.8 and 81.4%, respectively. Patients who completed 12 months of trastuzumab had a 9-year OS rate of 90.2% compared with 86.2% among patients receiving <12 months of therapy (adjusted HR 0.71, 95% CI 0.62–0.81).ConclusionsReal-world HER2 + EBC patients are less likely to complete 12 months of trastuzumab than some clinical trial counterparts but have survival outcomes comparable to those reported in landmark RCTs.

253P - Meta-analysis in HER2+ early breast cancer therapies and cost-effectiveness in a Brazilian perspective

BackgroundHER2-targeted therapy was a paradigm shift for breast cancer. However, the optimal duration of adjuvant trastuzumab remain unknown. This issue is important in lower and middle-income countries such as Brazil where financial resources are scarce. The aim of this study is to determine which patients will benefit most with the addition of Pertuzumab to trastuzumab [T+P], trastuzumab for 12 months [T12] or trastuzumab for 6 months [T6]. MethodsIndividual data meta-analysis was performed using 5 studies (Persephone, Phare, Horg, Aphinity and Katherine) for the intention to treat (ITT) population. Through pooled analyzes of the Persephone, Phare and Horg studies, we compared 12 months and 6 months of trastuzumab. The comparison between T+P and T6 was performed through an indirect comparison using Bayesian methodology. For cost-effectiveness analysis, we compared the treatment lining up in pairs exclusively considering the data from the Aphinity (T+P vs T12), Persephone (T12 vs T6) and Katherine (T12 vs T-DM1), setting a 30 years period of time and costs of adjuvant treatments and after progression in the Brazilian perspective. ResultsIndividual data were analyzed from 12,753 patients. Patients who progressed in a 4-year period were 7.1% for T + P, 10.2% for T12 (HR 1.37, 95% CI 1.16-1.63) and 12.9% for T6 (HR 1.73, 95% CI 1.45-2.06). Regarding DFS in the N+ subgroup, T+P showed HR 0.77 (95% CI 0.62-0.96) and 0.74 (95% CI 0.49-1.11) compared to T12 and T6, respectively. Among patients N-, T+P compared to T12 showed a HR 1.13 (95%CI 0.68-1.86) and compared to T6HR 0.83 (95%CI 0.45-1.52). ER+ patients, T+P showed HR 0.86 (95%CI 0.66-1.13) compared to T12 and HR 0.74 (95%CI 0.49-1.11) to T6. Among ER-, the values were HR 0.76 (95%CI 0.56-1.04) and HR 0.59 (95%CI 0.41-0.85), respectively. In the cost-effectiveness analysis, T+P demonstrated an ICER of $ 332,903 compared to T12, while T12 set side by side of T6 resulted in $ 42,774. In the subgroup N+, T+P presented $ 308,019 when compared to T12. T-DM1 was considered a cost-effective treatment with $ 3,031 compared to T12. ConclusionsThe combination T+P presented an benefit in the subgroup N+, but it was not considered cost-effective. T6 may be considered a therapeutic option in low budget scenarios for patients HR+/N-. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity

ObjectivesThe aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BackgroundCardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. MethodsA total of 222 patients with early-stage human epidermal growth factor receptor 2–positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. ResultsTRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a “low-risk TRC score” to identify patients with low TRC incidence. ConclusionsLow baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039)

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial

In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. The French National Cancer Institute.

Abstract GS2-07: PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer

Abstract Since 2005, 12 months of trastuzumab added to chemotherapy alone is the standard of care in patients with HER2-positive breast cancer. PHARE ('Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure') is the first trial comparing a reduction of adjuvant trastuzumab versus the standard 12 months. In 2012, the first analysis failed to prove that 6-months was non-inferior to 12-months of adjuvant trastuzumab (NCT00381901). The current presentation reports the final analysis. Methods: The trial was sponsored by the French National Cancer Institute (INCa) (www.e-cancer.fr), and approved by central Ethical Committee on May 15th 2006. Patients with HER2-positive early breast cancer were randomly assigned between 12 and 6 months of adjuvant trastuzumab duration. The randomization was stratified by concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status and center. The primary objective was non-inferiority of 6- versus 12-months arms in the intent to treat population, in terms of disease-free survival (DFS) with a pre-specified hazard margin of 1.15. Overall Survival (OS) and metastasis free survival (MFS) were secondary endpoints. Results: A total of 3380 patients were randomized, their median age was 54 years (21-86). Patients and disease characteristics were well balanced between the two arms. No involved axillary node was observed in 54.5% of cases, 41.7% of tumors were ER negative. At a median follow-up of 7.5 years, 704 events counting for DFS were observed. Between the 12- and 6-months arms, the adjusted Hazard Ratio (HR) for DFS rates was 1.08 (95%CI: 0.93-1.25; p=0.39) favoring the longer exposure. The 1.15 margin of non-inferiority was included in the 95%CI. No heterogeneity in terms of treatment effect was observed, no significant difference for trastuzumab duration effects was found in any subgroups.For OS and MFS, the adjusted HR were 1.13 (95%CI 0.92-1.39) and 1.15 (95%CI 0.96-1.37), respectively. Conclusion: The choice of the non-inferiority margin will remain inherently a subject of controversy especially in the context of oncology trials where the primary outcome is survival and the least additional death could be considered unacceptable questioning the very feasibility of such trials. Nevertheless, PHARE failed to show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. The standard of care should remain 12 months of adjuvant trastuzumab. Citation Format: Pivot X, Romieu G, Debled M, Pierga J-Y, Kerbrat P, Bachelot T, Espie M, Lortholary A, Fumoleau P, Serin D, Jacquin J-P, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure Mercier C, Paget-Bailly S, Henriques J, Grouin J-M. PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer [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 GS2-07.

Trastuzumab as An Adjuvant Therapy for Early Breast Cancer

Background: In Malaysia, breast cancer is the most common cancer in females and also the first most common cancer among population regardless of gender. Trastuzumab is used for the treatment of early-stage breast cancer that is HER2 positive. Although this treatment has been routinely used, there are still controversial on the duration of the addition of trastuzumab to the chemotherapy regimen. Aim: To assess the safety and effectiveness of trastuzumab as an adjuvant in early breast cancer patients through a systematic review. Methods: Electronic databases were searched through the Ovid interface. The titles and abstracts were screened against the inclusion and exclusion criteria and then evaluated the selected full-text articles. Results: There was high level of evidence to suggest that the risk of congestive heart failure (CHF) was significantly higher in patients treated with trastuzumab compared with nontrastuzumab control group (RR 5.11; 90% CI: 3.00-8.72, P &lt; 0.00001) in one Cochrane review, (RR 3.19; 95% CI: 2.03-5.02, P &lt; 0.00001) in one systematic review and meta-analysis. Evidence also suggested that the risk was significantly higher with longer duration of treatment (&gt; 6 months) RR 5.39; 90% CI: 3.56-8.17, P &lt; 0.00001. The overall survival (OS) significantly favored trastuzumab-containing regimen over nontrastuzumab control group, (HR 0.66; 95% CI: 0.55-0.77, P &lt; 0.00001). In terms of duration, subgroup analysis reported that the overall survival (OS) significantly favored trastuzumab-containing regimen over nontrastuzumab control group trials where trastuzumab was given longer (&gt; 6 months), HR 0.67; 95% CI: 0.57-0.80, P &lt; 0.00001. In the trials that gave trastuzumab and chemotherapy concurrently, HR significantly favored trastuzumab-containing regimens (HR 0.64; 95% CI: 0.57-0.80, P &lt; 0.00001). The evidence from Cochrane systematic review suggests that disease-free survival (DFS) favored trastuzumab-containing regimen over the nontrastuzumab control group (HR 0.60; 95% CI: 0.50-0.71, P &lt; 0.00001). In terms of duration of treatment, there was no significant difference in DFS when trastuzumab was used for less than six months or more than six months. The DFS significantly favored trastuzumab-containing regimen over nontrastuzumab control group when used either concurrently or sequentially. Limited evidence to suggest that two years duration of adjuvant trastuzumab was not more effective that one year of treatment. However, six months treatment with trastuzumab failed to show that it was noninferior to twelve months of trastuzumab. There was limited retrievable evidence to suggest that there is no significant difference in OS and DFS between the twelve months regimen and 9-week regimen for trastuzumab. Conclusion: Despite the higher rates of cardiac events, twelve months of adjuvant trastuzumab was suggested as the standard of care. However, other issues including cost and cost-effectiveness should be considered.

Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab

BackgroundCardiac toxicity with a decrease of the left ventricular ejection fraction (LVEF) is the main side effect induced by trastuzumab. This study reports the fluctuation of LVEF over the 12 months of adjuvant trastuzumab in PHARE trial (NCT00381901). MethodsLVEF assessment was performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and then every 6 months afterwards. The fluctuations of LVEF over time were described and a logistic regression model was performed investigating associated factors to LVEF perfect recovery at baseline value. ResultsA total of 1631 patients who received 12 months of trastuzumab from PHARE trial, were considered in the analysis. A total of 13 881 LVEF measurements were assessed. Baseline mean LVEF was 66.08% (standard error (SE): 0.15) and the mean relative LVEF decrease observed at 12-month was 3.61% (SE: 0.31). No clinical characteristic was significantly associated to LVEF fluctuation. After completion of trastuzumab, the relative difference progressively disappeared with beyond 30 months a relative difference value of 0.08% (SE: 0.42). Nevertheless, at 30 months, 48.53% of patients with available measures (379/781) did not fully recover their baseline LVEF value. ConclusionThe LVEF decreased during treatment with trastuzumab and rose up after the completion of treatment without coming back to the initial values for a substantial subset. These results would suggest investigating some strategies aimed to improve the ability to achieve a full recovery.

Patient’s perspective of living with and beyond the treatment of trastuzumab: Results from the PERSEPHONE early breast cancer trial.

e22101Background: PERSEPHONE is a randomised controlled non-inferiority trial comparing 6 months of trastuzumab to the standard 12 months in patients with HER2 positive early breast cancer. An impo...

Abstract P6-16-03: Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC)

Abstract Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer. Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death. Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction. Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340. Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-03.

Abstract P4-21-38: Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer

Abstract Background: Trastuzumab and pertuzumab are approved for the treatment of HER2-postiive breast cancer in the neoadjuvant setting. However, limited cardiac safety data is available when used in combination with doxorubicin-based chemotherapy. At a single center we retrospectively report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. Methods: Patients treated with neoadjuvant dose dense AC followed by THP from September 1, 2014 to March 1, 2015 were retrospectively identified. Patients then had breast surgery and completion of anti-HER2 therapy for 1 year. The primary outcome was cardiac event rate, defined by New York Heart Association (NYHA) class III/IV or cardiac death. The secondary outcome was significant asymptomatic decline in left ventricular ejection fraction (LVEF) of 10%-15% from baseline to below the lower limit of normal, or &amp;gt; 16% from baseline. Patients underwent LVEF monitoring at baseline prior to AC, prior to initiation of THP, and serially during 1 year of anti-HER2 therapy (neoadjuvant to adjuvant phases). Results: Fifty-seven patients were included in the study. The median age was 46 years (range 26-68 years). The median number of cycles of trastuzumab and pertuzumab in the neoadjvuvant setting was 6 (range 3-8) and 6 (range 2-8), respectively. In the adjuvant setting, 56 (98%) patients received trastuzumab with pertuzumab with a median cycle number of 12 (range 1-13). Two of 57 (3.5%) patients developed NYHA class III/IV heart failure after 5 and 9 months of trastuzumab, leading to permanent discontinuation of anti-HER2 treatment. Additionally, 7 (12.3%) patients developed a significant LVEF decline (without severe HF symptoms). The median LVEF was 65% (range 55-75%) at baseline and 64% (range 53-72%) after AC. There was a reduction in median LVEF to 60% (range 35-70%), 60% (range 23- 73%), 61% (range 25-73%), and 58% (range 28-66%) at 3, 6, 9, and 12 months (+/- 6 weeks) of trastuzumab-based therapy. Conclusion: In patients with HER2-positive breast cancer treated with neoadjuvant dose-dense AC and THP followed by completion of anti-HER2 therapy in adjuvant setting, the overall rate of NYHA Class III/IV heart failure was comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity when pertuzumab is added to trastuzumab following a doxorubicin-based regimen. Citation Format: Yu AF, Wang R, Singh J, Liu JE, Eaton A, Jones L, Oeffinger K, Steingart RM, Hudis CA, Dang CT. Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-38.

1031P - Cost-effectiveness analysis (CEA) of adjuvant trastuzumab therapy use in HER2-positive early-stage breast cancer (EBC)

Adjuvant treatment options for HER2-positive early-stage breast cancer (EBC) have expanded in recent years. Trastuzumab has been shown in several randomized controlled trials (RCTs) to offer significant survival advantage in patients with high-risk HER2-positive EBC. This study aimed to estimate cost-effectiveness of adjuvant trastuzumab therapy compared to standard chemotherapy alone in patients with HER2-positive EBC in Ireland. A CEA was performed using a decision-tree model using estimate outcomes and costs over a 10-year period using a cohort of women with HER2-positive EBC, treated with or without 12 months of trastuzumab after adjuvant chemotherapy. These patients received ambulatory care in the Department of Medical Oncology (DoMO), University Hospital Limerick (UHL). Transition probabilities were derived from the cohort. Costs were estimated from the perspective of the Irish healthcare system. Both costs and outcomes were discounted by 5%. One-way sensitivity analysis was undertaken to assess the associated uncertainties in the expected output measures. In this study group, our model showed that adjuvant trastuzumab treatment in HER2-positive EBC, yield 8.54 quality-adjusted life-years (QALY) compared to adjuvant chemotherapy alone. Adjuvant trastuzumab treatment yielded an incremental cost-effectiveness ratio (ICER) of &euro;42,801.62 per QALY. It has been shown that for a 10-year time horizon, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk EBC (i.e. less that &euro;45,000.00 threshold set in Republic of Ireland).

A multicenter randomized study comparing 6 versus 12 months of trastuzumab in combination with dose-dense docetaxel following FEC as adjuvant treatment of women with axillary node–positive or high-risk, node-negative breast cancer overexpressing HER2.

623 Background: Adjuvant trastuzumab in combination with chemotherapy improves outcome of women with HER2 positive early breast cancer. However, the optimal duration of treatment remains unknown. I...

PERSEPHONE: Duration of trastuzumab with chemotherapy in patients with HER2-positive early breast cancer—Six versus twelve months.

TPS656 Background: PERSEPHONE is a randomised controlled trial comparing six months of trastuzumab to the standard 12 months in patients with HER2 positive early breast cancer. Methods: 4,000 patie...

Cardiology monitoring substudy in the PERSEPHONE trial: 6 versus 12 months of trastuzumab.

552 Background: PERSEPHONE is a randomised trial comparing 6month (6m) to 12month (12m) of trastuzumab in patients (pts) with HER2-positive early breast cancer. The trial has recruited 3,166 of 4,0...