Trastuzumab In Early Breast Cancer Research Articles

Do tumor infiltrating lymphocytes (TILs) predict benefits from trastuzumab therapy for HER2 positive breast cancer? Meta-analysis of individual patient data from 4097 women in 5 trials.

508 Background: High TIL counts are associated with a lower risk of breast cancer recurrence, especially in women with ER negative, HER2 negative tumors and, possibly, greater benefit from trastuzumab in women with HER2 positive cancer: the FinHER trial reported a differential effect of trastuzumab based upon TIL status. We performed a meta-analysis of randomized trials of trastuzumab in early breast cancer to attempt to validate this finding. Methods: TILs were quantified in 4097 women in 5 randomized controlled trials (NSABP B-31, FinHER, HERA, Intergroup N9831, PACS-04). All trials contributed to the Early Breast Cancer Trialists' Collaborative Group individual patient data meta-analysis of trastuzumab for women with HER2 positive tumors which found a significant benefit for trastuzumab therapy. TILs were assessed using established International Guidelines, with HERA using digital TIL-scores. The primary outcome was time to first recurrence. Cox regression analyses, adjusted for trial, treatment allocation, and nodal status, were used to quantify the prognostic value of TILs; and standard stratified logrank tests were used to assess the differential effect of trastuzumab therapy. Results: The median percentage TILs was 13% (Interquartile Range 5-30), with fewer than 10% of patients exhibiting TILs >50%. The prognostic value of TILs was confirmed, with patients with higher TILs being at lower risk for recurrence (adjusted hazard ratio per 10% increase in TILs 0.87 (95% CI 0.84-0.90), p<.0001) with similar effects in both treatment groups. Outcomes improved steadily with increasing TILs, and unadjusted 10-year recurrence rates fell from 30% in women with TILs <10% to 15% in those with TILs 70% or greater. Consequently, analyses of the predictive effect of TILs were stratified into 5 groups (0-9, 10-19, 20-39, 40-59, 60+). Overall, there was a highly significant benefit of trastuzumab on recurrence (HR 0.62 (0.54-0.70) p<.0001), but there was no evidence of any interaction between TILs and the proportional reduction in recurrence (p=0.8 for heterogeneity and trend). Conclusions: While higher TILs are associated with lower recurrence rates, there was no indication that the proportional reduction in recurrence with trastuzumab varied by TILs, although the number of patients with high levels was limited. Owing to a lower underlying recurrence rate, absolute benefits from trastuzumab were lower, but still substantial, in women with high TIL tumors. Clinical trial information: NCT00045032 , ISRCTN76560285 , NCT00005970 , NCT00004067 , NCT00054587 . [Table: see text]

A meta-analysis of cardiac toxicity of concurrent epirubicin and trastuzumab in early breast cancer.

e12583 Background: The concurrent use of doxorubicin and trastuzumab has been limited due to the increased risk of cardiac toxicity. Epirubicin is a less cardiotoxic alternative to doxorubicin, and the change in ejection fraction occurs until its cumulative dose doubles that with doxorubicin. This study aims to evaluate the cardiotoxicity and pathological complete response (pCR) rate associated with concurrent usage of epirubicin and trastuzumab in patients with HER2 positive early breast cancers (EBC). Methods: A literature search was conducted on NCBI/PubMed, and Cochrane database for phase II or III randomized controlled trials of concurrent use of epirubicin and trastuzumab in HER2 positive EBC between January 1, 2000 and February 28, 2021.The definition of adverse cardiac events varied among these trials, including changes in left ventricular systolic function and clinical heart failure. To compare the risk of cardiotoxicity and the odds of pCR rate between concurrent and non-concurrent regimens, a meta-regression analysis utilizing fixed-effects and mixed-effects linear models was conducted to investigate the relationship between various covariates. Results: Seven trials containing concurrent use of epirubicin and trastuzumab involving 1797 patients were analyzed. All of them are neoadjuvant studies. The median cumulative dose of epirubicin used was 300mg/m2 and there were a total of 96 reported cardiac adverse events. The concurrent use of epirubicin and trastuzumab did not result in a statistically significant increase in cardiotoxicity compared to non-concurrent regimens (risk ratio = 1.18, 95% CI: 0.68-2.05). Meanwhile, there was a significant increase in pCR rate with the concurrent regimens (odds ratio = 1.48, 95% CI: 1.04-2.12). Mixed-effects meta-regression analysis showed that in trials with higher proportion of hormone receptor-positive EBC patients, the risk ratio of cardiotoxicity significantly increased with concurrent regimens and pathological complete response rate became less significant. Conclusions: The concurrent use of a limited dose of epirubicin and trastuzumab demonstrated a positive impact on pCR rate without a significant increase in cardiotoxicity. Further research is necessary to fully comprehend the long-term safety profile in individuals with metastatic breast cancer. [Table: see text]

THE CHARACTERISTICS AND PROGNOSIS OF HEART FAILURE ASSOCIATED WITH CHEMOTHERAPY FOR EARLY BREAST CANCER: A POPULATION-BASED MATCHED COHORT STUDY

THE CHARACTERISTICS AND PROGNOSIS OF HEART FAILURE ASSOCIATED WITH CHEMOTHERAPY FOR EARLY BREAST CANCER: A POPULATION-BASED MATCHED COHORT STUDY

Cost-effectiveness analysis of trastuzumab for early breast cancer in Brazil

ABSTRACT Background: Adjuvant chemotherapy with trastuzumab for HER2 positive breast cancers has brought considerable benefits to disease-free survival and overall survival. Objective: To conduct a cost-effectiveness analysis of the treatment of patients with early and locally advanced HER2 positive breast cancer, within the scope of the Brazilian public health system, comparing adjuvant chemotherapy with and without trastuzumab, for 1 year of treatment. Methods: A 4-state Markov model was developed to estimate strategy costs and outcomes. Results: Based on the proposed model, we verified an incremental benefit of trastuzumab therapy compared to treatment without trastuzumab with 0.84 quality-adjusted life years (QALY) and 1.16 life years gained (LYG). The use of adjuvant chemotherapy with trastuzumab has an ICER of US$19,599.26 for each quality-adjusted life year and US$14,180.68 for each life year gained in relation to chemotherapy without trastuzumab. Conclusion: In Brazil, adjuvant chemotherapy with trastuzumab may be considered cost-effective only if a cost-effectiveness threshold is stipulated with the value starting at three times the Brazilian GDP per capita for QALY or two times the Brazilian GDP per capita for LYG, from health system perspective.

Cardiovascular Risk After Adjuvant Trastuzumab in Early Breast Cancer: An Italian Population-Based Cohort Study.

BackgroundAlthough trastuzumab (T) represents the standard of care for the adjuvant treatment of HER2‐positive early‐stage breast cancer, contrasting results are available about the cardiac toxicity associated to its use. We conducted a multiregional population‐based cohort investigation aimed to assess both the short‐ and long‐term cardiovascular (CV) outcomes in women with early breast cancer treated with T‐based or standard adjuvant chemotherapy (CT).Materials and MethodsWe used health care use databases of six Italian regions, overall accounting for 42% of the Italian population. The study cohort was made by all women surgically treated for breast cancer who started a first‐line adjuvant T‐based or CT treatment. Patients treated with T were 1:2 matched to those treated with CT based on date of treatment start, age, and presence of CV risk factors. Short‐ and long‐term CV outcomes (heart failure and cardiomyopathy) were measured, respectively, after 1 year and at the end of follow‐up.ResultsAmong 28,599 women who met the inclusion criteria, 6,208 T users were matched to 12,416 CT users. After a mean follow‐up of 5.88 years, short‐ and long‐term cumulative CV risk were 0.8% and 2.6% in patients treated with T and 0.2% and 2.8% in those treated with CT, respectively. Adjusted hazard ratios were 4.6 (95% confidence interval [CI], 2.6–8.0) for short‐term and 1.2 (95% CI, 0.9–1.6) for long‐term CV risk.DiscussionIn our large real‐world investigation, T‐associated cardiotoxicity was limited to the treatment period. The addition of T to adjuvant CT did not result in long‐term worsening of CV events.Implications for PracticeAdjuvant trastuzumab‐based chemotherapy represents the backbone therapy in patients with HER2‐positive early breast cancer. Although well tolerated, cardiovascular events can manifest during or after therapy because of treatment‐related toxicities. In this wide multicenter and unselected cohort, long‐term symptomatic cardiotoxicity was low and limited to the treatment period. The findings suggest that developing tools that would be adequately able to predict cardiac toxicity at an early stage remains an important area in which additional research efforts are needed.

Impact of Stopping Trastuzumab in Early Breast Cancer: APopulation-Based Study in Ontario, Canada.

Adjuvant trastuzumab for early-stage (I-III) HER2-positive breast cancer (BC) has led to statistically significant improvement in cancer outcomes but carries a risk of cardiotoxicity. Trastuzumab is discontinued early in many patients for asymptomatic changes in left ventricular ejection fraction. We evaluated the impact of early discontinuation of trastuzumab on cancer outcomes. We conducted a retrospective population-based cohort study of early BC patients treated with adjuvant trastuzumab in Ontario, Canada, 2007-2016. Four groups were analyzed: group A was full treatment, 17-18 cycles trastuzumab; group B was cardiac event (CE) within treatment period; group C was ≤16 cycles, no CEs, stopped within 30 days from last cardiac imaging; and group D was ≤16 cycles, no CEs, stopped more than 30 days from cardiac imaging. Primary outcome was disease-free survival (DFS); secondary outcomes were: overall survival, cancer-specific mortality, and cardiovascular mortality. Sensitivity analyses were performed 14 months after cycle 1 trastuzumab to control for early relapse. A total of 5547 patients met the inclusion criteria: group A = 3921, group B = 309, group C = 362, and group D = 955. The 5-year DFS was 94.1% in group A, 80.1% in group B, 81.4% in group C, and 82.4% in group D. Using a Cox model, the hazard ratio for 5-year DFS was 3.15 (95% confidence interval [CI] = 2.13 to 4.65) for group B, 1.94 (95% CI = 1.30 to 2.89) for group C, and 1.92 (95% CI = 1.46 to 2.53) for group D. Overall, 26 patients (0.5%) died of cardiac causes. BC patients in Ontario who did not complete adjuvant trastuzumab had a statistically significantly higher risk of BC relapse and death and low incidence of cardiac death. These findings support 1 year of adjuvant trastuzumab in early-stage BC.

Association of body mass index and cardiotoxicity related to anthracyclines and trastuzumab in early breast cancer: French CANTO cohort study

BackgroundIn patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity.Methods and findingsUsing prospective data collected from 2012–2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction [LVEF] > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I–III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio [OR] 3.02; 95% CI 1.10–8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6–40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort.ConclusionsIn BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498).Trial registrationClinicalTrials.gov NCT01993498.

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.

PMU26 - BUDGET IMPACT ANALYSIS OF INTRAVENOUS BIOSIMILARS COMPARED WITH INTRAVENOUS ORIGINATORS AND SUBCUTANEOUS PRODUCTS

In the UK, biosimilar rituximab and trastuzumab have lower prices than originators but are available only in intravenous (IV) formulations. We assessed the budget impact of adopting IV biosimilar rituximab and IV biosimilar trastuzumab compared with subcutaneous (SC) and IV originators from the perspective of the UK National Health Service (NHS). Patients were included if they had received rituximab for rheumatoid arthritis, chronic lymphocytic leukaemia, Non-Hodgkin’s lymphoma (NHL), granulomatosis with polyangiitis and microscopic polyangiitis (MPA), and trastuzumab for early breast cancer, metastatic breast cancer and metastatic gastric cancer. Drug acquisition and administration costs were obtained from national tariffs. Projected biosimilar uptake ranged from 19–90% over five years. Compared with sc originators, administration costs for IV biosimilars were higher but drug costs were reduced, leading to lower total cost for IV biosimilars. Per-patient savings with IV biosimilar rituximab ranged from £328 (MPA) to £774 (NHL). Per-patient savings with IV biosimilar trastuzumab ranged from £4,623 (gastric) to £4,824 (breast). At maximum uptake, 76% of patients switched to biosimilar rituximab, resulting in annual savings of £8.2m. If 67% of patients switched to biosimilar trastuzumab, the annual saving was £49.2m. The larger saving with trastuzumab was due to higher originator price and greater cost difference between originator and biosimilar. Scenario analysis found cost savings to be sensitive to IV biosimilar price but not sensitive to plausible variation in administration costs. Further scenario analysis estimated a positive budget impact for a hospital provider, with increased reimbursement revenue outweighing additional IV administration costs. Increasing biosimilar rituximab and trastuzumab uptake can deliver substantial cost savings for the NHS. Increased administration cost should not act as a barrier to IV biosimilar uptake. The ability to realise these benefits will depend on price agreed and capacity to deliver larger numbers of IV infusions.

365 (PB-160) - Clinical comparison of the biosimilar ABP 980 and trastuzumab in early breast cancer: Results of the phase 3 LILAC study and justification for extrapolation across approved trastuzumab indications

365 (PB-160) - Clinical comparison of the biosimilar ABP 980 and trastuzumab in early breast cancer: Results of the phase 3 LILAC study and justification for extrapolation across approved trastuzumab indications

Abstract P2-12-01: Real-world use and outcomes of trastuzumab for HER2+ metastatic breast cancer in Australia: Analysis of the herceptin program, 2001-2015

Abstract Aims Between December 2001 and July 2015 Australian women with HER2-positive metastatic breast cancer (MBC) accessed trastuzumab in combination with taxane chemotherapy or as monotherapy via the government funded Herceptin Program (HP); we characterise their treatment patterns and survival outcomes. Methods This retrospective, whole-of-population cohort study used linked dispensing, medical services, and death records. We stratified patients into three year-of-trastuzumab-initiation groups: 1. 2001-2002 (may include patients accessing trastuzumab in later lines); 2. 2003 - October 2006 (likely first-line treated but prior to trastuzumab availability for early breast cancer (EBC)); and 3: October 2006–June 30 2015 (most representative of contemporary practice). Patients were observed until death or censored at June 30 2016. We estimated duration of trastuzumab therapy from the initial dispensing date for MBC until 30 days after the last dispensing. We considered a gap of ≥90 days between trastuzumab dispensings a separate course of treatment. We estimated overall survival (OS) as the time from first trastuzumab dispensing until death from any cause. We used Kaplan-Meier methods to estimate the total duration of trastuzumab therapy and OS. We used dispensing dates of cancer medicines to determine concomitant treatments and used claims for echocardiography and MUGA scans to determine the timing of cardiac monitoring. Results 5,895 patients accessed trastuzumab for MBC. Median age at trastuzumab initiation was 57 years (IQR: 48 – 66). 800 patients (22%) from Group 3 also received trastuzumab for EBC. Treatment details and OS are tabulated: Overall (n = 5,895)Group 1 (n = 495)Group 2 (n = 1,709)Group 3 (n = 3,691)Median time on trastuzumab for MBC, first course, months (IQR)13.2 (5.7 – 26.6)9.2 (3.8 – 22.5)12.3 (5.4 – 23.3)14.0 (6.1 – 29.8)Median OS from first trastuzumab dispensing for MBC, months (IQR)30.3 (13.4 – 68.7)19.8 (8.9 – 38.8)27.5 (12.5 – 58.9)34.6 (15.1 – 82.8)Patients initiating trastuzumab, n (%): monotherapy1,571 (27)226 (46)625 (37)720 (20)+ taxane3,150 (53)157 (32)800 (47)2,193 (59)+ hormonal therapy763 (13)47 (9)169 (10)561 (15)+ non-taxane chemotherapy376 (6)65 (13)115 (7)217 (6)Cardiac assessment: at baseline (60 days prior to 30 days following trastuzumab initiation)3,721 (63%)189 (38%)831 (49%)2,701 (73%)during treatment3,324 (56%)150 (30%)778 (46%)2,396 (65%) Conclusions Our real-world estimates of OS for each patient group are both similar to and shorter than those from clinical trials published during similar time periods. Group 3 median OS is 6 months shorter than the control arm of the CLEOPATRA study (34.6 v 40.8 months) while median duration of first trastuzumab course was 4 months longer (14.0 v 10.4 months), suggesting patients continue trastuzumab beyond progression. In Group 3, 25% of patients died within 15 months of starting trastuzumab, 50% survived beyond 3 years and 25% survived beyond 7 years. These estimates will be useful for clinicians discussing expected survival time with patients in routine practice. Although the cardiotoxicity of trastuzumab is well recognised, baseline cardiac assessment was not universal, even in the most recent cohort. Citation Format: Daniels B, Kiely BE, Lord SJ, Houssami N, Pearson S-A. Real-world use and outcomes of trastuzumab for HER2+ metastatic breast cancer in Australia: Analysis of the herceptin program, 2001-2015 [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 P2-12-01.

Cardiotoxicity Assessment After Different Adjuvant Hypofractionated Radiotherapy Concurrently Associated with Trastuzumab in Early Breast Cancer.

To evaluate cardiotoxicity in patients with human epidermal growth factor receptor 2+ (HER2+) breast cancer (29 left-sided, 23 right-sided) treated with adjuvant whole-breast hypofractionated radiotherapy (HRT) concurrently administered with the humanized monoclonal antibody to HER2, trastuzumab. From February 2008 to June 2017, 52 patients received three-dimensional conformal RT, with different HRT schemes. Echocardiogram monitoring was used to evaluate the decrease in left ventricular ejection fraction (LVEF). At a median follow-up of 5 years, cardiotoxicity was as follows: among the 15 patients treated with 46 Gy: grade (G) 2 in two (13%), G1 in three (20%), and G0 in 10 (67%);in those treated with 39 Gy (16 patients): G1 in five (31%), and G0 in 11 (69%);among the 21 patients treated with 35 Gy: G2 in one (5%), G1 in five (24%), and G0 in 15 (71%). Trastuzumab was shown to be a safe adjuvant treatment when administered with concomitant HRT since it did not increase cardiotoxicity in those with left-sided breast cancer. No differences in LVEF were observed between the HRT schemes.

Abstract P1-09-08: Predictive effect of cytotoxic tumor infiltrating lymphocytes in HER2-positive metastatic breast cancer: A correlative study with CCTG MA.31

Abstract Background and Objectives: The presence of tumor infiltrating lymphocytes (TILs), particularly CD8+ cytotoxic T-cells, has been associated with improved prognosis in patients with HER2+ breast cancer. Increasing levels of TILs also appear to predict response to adjuvant trastuzumab in early breast cancer, although they did not predict benefit of combined trastuzumab-lapatinib neoadjuvant dual therapy over monotherapy in NeoALLTO. CCTG MA.31 randomized 652 women with HER2+ metastatic breast cancer to treatment with trastuzumab (T) vs. lapatinib (L), in combination with taxane (Tax) chemotherapy for 24 weeks, followed by the same HER2-targeted monotherapy. Final results from MA.31 found trastuzumab was superior to lapatinib for the primary endpoint of progression free survival (PFS): the hazard ratio (HR) for lapatinib to trastuzumab was 1.37 (95% CI, 1.13-1.65). Although both agents block HER2 signaling, trastuzumab has additional mechanisms of action via the immune system. We hypothesized that TIL levels may predict response to HER2-targeted therapy (trastuzumab vs. lapatinib). Methods: MA.31 included HER2+ metastatic breast cancer patients, median age 55 years, and median follow-up 21.5 months. Overall TILs were counted per published guidelines on the original H&amp;E stained sections used for pathology review at study entry. Immunohistochemistry (IHC) was performed on unstained sections from tissue microarrays or individual formalin-fixed paraffin-embedded blocks to test expression of lymphocyte biomarkers CD8, FOXP3, CD56 and PD-1 on stromal and intra-tumoral TILs (sTILs, iTILs). Statistical analysis was conducted by CCTG for a total of 9 prespecified biomarker tests. Associations of TILs with PFS were evaluated by univariate stratified log-rank test with graphical Kaplan-Meier curves, and by stratified multivariate Cox proportional hazards regression analysis. Predictive effect was examined with a test of interaction between treatment allocation and biomarker classification (high vs. low, using pre-established cutpoints). Results: Of the 652 cases, 614 had slides for overall TIL assessment and 427 for IHC biomarker assessments. In this correlative study set, superiority of trastuzumab over lapatinib for PFS was confirmed in multivariate analysis (LTax/T vs. TTax/L: HR = 2.55, 95% CI = 1.43-4.55, p = 0.001). TIL counts by H&amp;E were neither prognostic nor predictive in this set of metastatic HER2+ breast cancers. Lymphocyte IHC markers were not prognostic. However, prespecified stratified univariate analysis detected a significantly higher risk for lapatinib over trastuzumab (HR = 2.94, 95% CI = 1.40-6.17, p = 0.003) in patients with low CD8+ sTIL (&amp;lt; 3) than was observed among those with high CD8+ sTIL (HR = 1.36, 95% CI = 1.05-1.75, p = 0.019). This differential effect was confirmed in multivariate analysis (interaction test p = 0.042). The other tested biomarkers did not demonstrate significant predictive effects. Conclusions: In this correlative study of metastatic HER2+ breast cancer, a low level of pre-existing stromal cytotoxic T cell infiltration predicts women who benefit most from trastuzumab over lapatinib. Overall TIL counts were neither prognostic nor predictive. Citation Format: Liu S, Chen B, Burugu S, Leung S, Gao D, Virk S, Kos Z, Parulekar WR, Shepherd L, Gelmon K, Nielsen TO. Predictive effect of cytotoxic tumor infiltrating lymphocytes in HER2-positive metastatic breast cancer: A correlative study with CCTG MA.31 [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 P1-09-08.

Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer.

The addition of adjuvant trastuzumab therapy for 1 year to standard chemotherapy significantly improved disease-free survival and overall survival versus chemotherapy alone in a number of pivotal early breast cancer studies. Here we review long-term follow-up data on the efficacy, cardiac safety, and general safety of trastuzumab in these pivotal studies. We also evaluate ongoing phase II/III adjuvant trials with newer HER2-targeted agents and the efficacy and safety of the recently developed subcutaneous (SC) formulation of trastuzumab in early breast cancer. Long-term follow-up data confirm the significant survival benefit afforded by the addition of trastuzumab to chemotherapy in patients with HER2-positive disease, with an acceptable safety profile. Long-term cardiac safety data suggest that the incidence of cardiac adverse events is maintained at a relatively low level with continued follow-up. At this present time, 1 year of trastuzumab treatment remains the standard of care in HER2-positive early breast cancer. Future adjuvant trastuzumab treatment strategies should focus on reducing cardiotoxicity, particularly in elderly patients, by identifying potential predictive biomarkers of cardiac dysfunction. Clinicians must also decide whether to omit trastuzumab in women who would achieve little benefit from treatment to avoid cardiotoxicity.

P201 Subcutaneous versus intravenous trastuzumab in early breast cancer: 2-year follow-up of HannaH

P201 Subcutaneous versus intravenous trastuzumab in early breast cancer: 2-year follow-up of HannaH C. Jackisch *, R. Hegg, D. Stroyakovskiy, J. Ahn, B. Melichar, S.C. Chen, A. Crepelle-Flechais, D. Heinzmann, M. Shing, X. Pivot. Department of Obstetrics and Gynecology & Breast Cancer and Gynecology Cancer Center, Sana Klinikum Offenbach GmbH, Offenbach, Germany, Department of Gynecology and Obstetrics, Hospital Perola Byington, Sao Paulo, Brazil, Chemotherapeutic Department, City Clinical Oncology Hospital 62, Moscow, Russian Federation, Department of Medicine, Samsung Medical Center, Seoul, Korea, Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic, Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan, Global Pharma Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Global Pharma Development, Genentech, Inc., South San Francisco, United States of America, Chemotherapy–Oncology, CHU Jean Minjoz, Besancon, France

Long term survival of HER2-positive early breast cancer treated with trastuzumab-based adjuvant regimen: A large cohort study from clinical practice

Trastuzumab-based regimens for the adjuvant treatment of HER2-positive early breast cancer significantly prolonged overall survival (OS) and disease free survival (DFS) in large randomized trials, with sustained benefits at four-year follow-up. We assessed long-term survival estimates and predictors in a large cohort of Italian women with early breast cancer treated with trastuzumab in clinical practice. Through a record linkage between five regional healthcare databases, we identified women treated with trastuzumab for early breast cancer in Lombardy (2006–2009). DFS and OS were estimated using the Kaplan–Meier method, and independent predictors were assessed using proportional hazard models. 2046 women received trastuzumab in early breast cancer adjuvant setting. Overall, the proportion of patients surviving free of disease was 93.9% at one year, 85.8% at 2 years, 79.4% at 3 years, and 75.0% at 4 years. OS estimates were 98.7%, 95.4%, 91.5% and 89.4% at 1, 2, 3 and 4 years, respectively. Significant independent predictors of worse survival outcomes were age <40 or ≥70 years compared to age 40–69 years, positive nodal status, radical breast surgery, combination therapy with paclitaxel, having at least one comorbidity (i.e. diabetes, cardiovascular disease), and a trastuzumab-based regimen lasting less than six months. Long term survival rates of women treated with trastuzumab for early breast cancer in clinical practice were consistent with estimates from clinical trials testing the drug in the adjuvant setting.

Cardiotoxicity of concomitant radiotherapy and trastuzumab for early breast cancer.

BackgroundTrastuzumab therapy given in combination with one of several chemotherapy regimens is currently considered the standard of care for the treatment of early-stage, human epidermal growth factor receptor-2 (HER2) -positive breast cancer. The treatment with trastuzumab is due to a significant impact on the survival part of the standard adjuvant treatment of patients with HER2-positive breast cancer. Patients treated with postoperative breast or chest wall irradiation receive trastuzumab concomitant with radiotherapy. In a small proportion of patients trastuzumab causes cardiotoxicity. Preclinical findings indicate a radiosensibilizing effect of trastuzumab in breast cancer cells, but it is not yet clear whether it radiosensibilizes cells of healthy tissues too.ConclusionsSpecial attention is required when left breast or left thoracic wall is irradiated in patient receiving trastuzumab, because long-term effects of the concurrent treatment with trastuzumab and radiotherapy are not yet known. In an era where more patients are surviving a diagnosis of breast cancer, better understanding and earlier detection of therapy-induced cardiac toxicity will be of paramount importance.

Nine weeks versus 1 year adjuvant trastuzumab in patients with early breast cancer: an observational study by the Turkish Oncology Group (TOG)

Optimal duration of adjuvant trastuzumab in early breast cancer is an unresolved issue. In this observational study, we compared the outcome of 9weeks and 1year adjuvant trastuzumab in early breast cancer patients in Turkey. Records of 680 patients with HER2-positive early breast cancer who received adjuvant trastuzumab plus chemotherapy were obtained and patients were followed up to compare the disease-free survival (DFS) outcome of 9weeks versus 1year trastuzumab. Nine weeks and 1year trastuzumab was given to 202 (29.7%) and 478 (70.3%) patients, respectively. There was a significantly lower rate of patients with negative lymph nodes in the 9-week trastuzumab group. At median 3years of follow-up from the date of starting trastuzumab, the DFS rates were 88.6 and 85.6%, respectively (p=0.670). When adjusted for all the prognostic factors that were significant on univariate analysis, again there was no significant difference in DFS between the groups (HR 0.675; 95% CI 0.370-1.231; p=0.200). Cardiac toxicity defined as a ≥15% decrease in LVEF was significantly higher in the 1-year trastuzumab group (1.88% versus none for 1-year and 9-week trastuzumab groups, respectively; p=0.050). The results of this observational study suggest that DFS outcome of 9weeks of adjuvant trastuzumab may be comparable to 1year adjuvant trastuzumab: this needs confirmation by randomized trials.

Assessment of single-institution HER2 testing patterns, rate of HER2+ disease, and utilization of trastuzumab in early breast cancer.

124 Background: Improved outcomes with HER2-directed therapies highlight the importance of standardized testing for HER2 positivity. This study aimed to assess HER2 testing practices, rate of HER2+ disease, and trastuzumab use in early breast cancer (EBC) at the Huntsman Cancer Institute (HCI) a National Cancer Institute-Designated Center and member of the National Comprehensive Cancer Network. Methods: Included patients’ records from the HCI electronic data warehouse (EDW) and the HCI tumor registry were female, age ≥ 18 years, ≥ 2 visits in the EDW and a stage I to IIIa EBC diagnosis from 2005 to 2012. HER2 testing patterns were identified through chart review of pathology and clinical notes in the EDW. HER2+ was defined as either FISH+ or IHC3+. Patient characteristics, HER2+ rate, and trastuzumab use were evaluated descriptively. Discordance rate associated with reflex testing (IHC 2+ retested by FISH) was also evaluated. Results: A total of 1,459 women were included with stage I (49%, n=720), IIa (26%, n=374), IIb (14%, n=197), and IIIa (12%, n=168) EBC. Mean age was 57 years. HER2+ disease was identified in 243 (17%) tumors. Of HER2+ tumors, 104 (43%) were ER+/PR+, 33 (14%) ER+/PR-, 1 (&lt;1%) ER-/PR+, 79 (32%) ER-/PR-, and 26 (11%) unknown. Tumors were first tested for HER2 using: 1,192 (82%) IHC, 36 (3%) FISH, 227 (15%) unknown and 4 (&lt;1%) other tests. First IHC results were scored 0 (23%), 1+ (33%), 2+ (26%), 3+ (17%), and unknown (&lt;1%). Reflex testing within one month was performed in 301/308 (98%) of IHC 2+ tumors. The discordance rate of IHC/FISH was 10%. Trastuzumab was prescribed for 184/243 (76%) women whose tumors were considered HER2+ based on final interpretation and in 1 HER2 equivocal tumor. Documented reasons for lack of trastuzumab use in HER2+ patients (n=59) included low risk of recurrence based on stage or other treatments (n=18), loss to follow-up (n=13), unknown (n=11), not clinically appropriate due to age or comorbidity (n=10), and patient declined (n=7). Conclusions: This is one of few cancer registries assessing the rate of HER2+ disease in EBC. Reflex testing identified additional HER2+ tumors. The HER2+ rate was within range of previously published studies.

PCN149 Transferability of Pharmacoeconomic Evaluations: Case Study of Trastuzumab for Early Breast Cancer

Using a simple method we determined the potential transferability of a previous economic evaluation on the cost effectiveness of adjuvant trastuzumab therapy for the treatment of HER2/Neu-positive breast cancer in Canada (Skedgel et al, 2009) to five other countries (UK, US, Australia, Japan and Germany). Based on data from a literature review, we firstly identified all possible transferability factors. From this we selected key transferability factors – those with values that differed across the countries or were factors that were shown to influence the cost-effectiveness ratio in sensitivity analysis in the Canadian reference study. We then considered the ease of transferability (ranging from very low to very high) for each of these potential factors from the Canadian study to the other countries. We identified seven potential key factors for transferability: cost discount rate, health outcomes discount rate, unit costs (particularly drug acquisition cost), resources used, treatment effectiveness, (including duration of benefit) and measures used to determine utility values. Overall, potential transferability was highest for the UK, where treatment practice is similar to that in Canada and data on unit costs, resource use and discount rates are readily available. Because the authors of the reference study did not report unit costs and resource use separately, however, transferability of the analysis was hindered. Transferability to Australia, Germany and the United States was of an intermediate level, while transferability to the Japanese setting was the lowest because treatment practice is likely to be different, and little cost of illness and utility data exist for that country. Several key factors need to be considered when evaluating whether a study is transferable to another setting. To enable the transferability of economic evaluations from one country to another, authors need to ensure that they report their economic data clearly and in sufficient detail.