Year Of Trastuzumab Research Articles

Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group. Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study. ClinicalTrials.gov Identifier: NCT00593697.

De-escalating treatment in the adjuvant setting in HER2-positive breast cancer.

The decision to offer adjuvant therapy to patients with early-stage cancer relies on factors related to the risk of disease recurrence, degree of benefit with the proposed therapy and the associated risk of toxicities. For patients with stages II and III HER2-positive breast cancer, administering 1year of trastuzumab plus comprehensive chemotherapy is the standard of care. However, the pivotal adjuvant trials had very few older patients and patients with small HER2-positive tumors. In this review, we will discuss the clinical data regarding strategies to de-escalate adjuvant systemic therapy in patients with early stage HER2-positive disease.

Abstract P1-13-01: Duration of adjuvant trastuzumab in HER-2 positive breast cancer: Pooled results of overall, and disease-free survivals from meta-analyses of randomized controlled trials

Abstract Background: The duration of one year of trastuzumab for treatment of HER-2 positive breast cancer was chosen arbitrarily. Randomized controlled trials (RCTs) have since explored efficacy of shorter durations of trastuzumab compared to 1 year, but the results from such RCTs are inconsistent, and are subject to different interpretations due mainly to varying definitions of non-inferiority. Methods: Systematic search of pubmed, embase, and major conference proceedings was performed to identify RCTs comparing outcomes of one year versus shorter trastuzumab in the adjuvant treatment of breast cancer. Efficacy outcomes [Hazard Ratios (HR) for Overall Survival (OS) and Disease Free Survival (DFS) with respective 95% Confidence Intervals (CI)] and toxicity outcome [Odds Ratios (OR) and 95% CI for cardiac events] from each study were weighted using generic inverse variance approach and pooled in a meta-analysis using RevMan 5.3 software. Heterogeneity among studies was assessed using tau2 and i2 statistics. Interactions on overall results by hormone receptor status, and nodal status were assessed using chi2 statistics. Results: Three RCTs involving 5,114 patients reported outcomes on both OS and DFS. Two studies evaluated 6 months and 1 study evaluated 9 weeks of adjuvant trastuzumab, compared to 1 year. Individual RCTs had failed to demonstrate non-inferiority of shorter duration compared to 1 year based on various pre-specified upper limits of CI (of <1.15, <1.29 and <1.59, respectively). Pooled analyses demonstrated statistically significant improvements in both OS (HR 0.78, 95% CI: 0.62-0.98), and DFS (HR 0.80, 95% CI 0.73-0.93) with the use of 1 year of trastuzumab compared to shorter durations suggesting superiority favoring 1 year of treatment, despite non-inferiority designs of individual trials. Sensitivity analyses based on duration of the experimental arm (9 weeks or 6 months) did not influence the direction, or size of overall effects. Pooled sub-group analyses demonstrated no interaction by hormone receptor status, or nodal status on overall results (p for sub-group difference = 0.73, and 0.52, respectively). Odds of cardiac events increased significantly with 1 year of treatment. (table 1) Conclusion: Pooled analyses of RCTs demonstrated a significant improvement in overall, and disease-free survivals with 1 year of adjuvant trastuzumab compared to shorter durations for adjuvant treatment of HER-2 positive breast cancer. One year of trastuzumab should remain as the standard of care. Cardiotoxicity increased significantly with the longer treatment. Hazard Ratios of Overall and Disease Free Survivals of 1 Year of Adjuvant Trastuzumab Compared to Shorter Durations in Treatment of HER2 positive Breast CancerOUTCOMESHAZARD RATIO95% CONFIDENCE INTERVALp (DIFFERENCE)INTERACTION TESTOVERALL SURVIVAL0.780.62 - 0.980.04DISEASE FREE SURVIVAL (DFS)0.800.70 - 0.930.004DFS - ESTROGEN RECEPTOR POSITIVE0.820.66 - 1.030.09CHI SQ. 0.12; p(SUBGROUP-DIFFERENCE)0.73DFS - ESTROGEN RECEPTOR NEGATIVE0.780.63 - 0.970.005DFS - NODE POSITIVE0.760.63 - 0.920.004CHI SQ. 0.42; p(SUBGROUP-DIFFERENCE)0.52DFS - NODE NEGATIVE0.870.60 - 1.260.46CARDIAC EVENTS2.65 (ODDS RATIO)2.00 - 3.50<0.001 . Citation Format: Niraula S, Gyawali B. Duration of adjuvant trastuzumab in HER-2 positive breast cancer: Pooled results of overall, and disease-free survivals from meta-analyses of randomized controlled trials [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 P1-13-01.

Abstract PD3-12: PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial

Abstract Background: Neratinib is a pan-HER tyrosine kinase inhibitor that blocks the PI3K/Akt and MAPK signaling pathways downstream from HER2. The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.0091) [Chan et al. Lancet Oncol 2016]. Furthermore, the effects of neratinib on iDFS were shown to be durable at 5 years' follow-up (HR 0.73; 95% CI 0.57–0.92; p=0.008) [Martin et al. ESMO 2017]. PIK3CA alterations are common in HER2+ breast cancers, and in general are associated with a worse prognosis. We sought to assess the prognostic and predictive significance of PIK3CA alterations in an exploratory substudy of the ExteNET trial. Methods: ExteNET is an international, multi-center, randomized, double-blind, placebo-controlled phase III trial (Clinicaltrials.gov: NCT00878709). Patients received oral neratinib 240 mg/day or placebo for 1 year. Of the intent-to-treat (ITT) population (n=2840), primary formalin-fixed paraffin-embedded (FFPE) tumor specimens were available from 991 patients for PIK3CA mutation testing by RT-PCR for two hot-spot mutations in exon 9 (E542K, E545K/D) and one hot-spot mutation in exon 20 (H1047R). 702 FFPE tumor slides underwent FISH analysis for PIK3CA amplification with a ratio of ≥2.2 considered as amplified. Primary endpoint: iDFS. iDFS events were tested by 2-sided log-rank tests, and HR (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Results: Baseline demographics and disease characteristics between treatment arms of the correlative cohort (n=1201) were balanced. Overall, 21.2% (n=210) of primary tumors harbored one of the specified PIK3CA mutations, and 8.7% (n=61) were PIK3CA FISH-amplified. Patients with PIK3CA-altered tumors (i.e. PIK3CA mutations or FISH-amplified) had fewer iDFS events with neratinib compared with placebo (HR 0.41; 95% CI 0.17-0.90, p=0.028). The interaction test was not significant (p=0.1842). Results of the various correlative analyses within treatment arms are shown in the table. NeratinibPlacebo iDFS iDFS 2-sidedPopulationnevents, nnevents, nHR (95% CI)P valueaITT142011614201630.73 (0.57–0.92)b0.008bCorrelative cohort59345608700.67 (0.45–0.96)0.0317PIK3CA-mutation positive1047106170.43 (0.17–1.01)0.056PIK3CA-mutation negative38527396420.66 (0.40-1.06)0.089PIK3CA-amplified3312840.20 (0.01-1.33)0.106PIK3CA-non-amplified31629325360.85 (0.52-1.39)0.521PIK3CA-altered1308132200.41 (0.17-0.90)0.028a. Log-rank test; b. Stratified analysis Conclusions: One year of neratinib treatment after trastuzumab-based adjuvant therapy significantly improves iDFS after 5 years in patients with early-stage HER2+ breast cancer. From this modest-sized exploratory cohort, it appears that PIK3CA may be a biomarker for differential sensitivity to neratinib after 1 year of trastuzumab in the adjuvant setting.These exploratory results should be validated in a larger subset. Citation Format: Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Kim S-B, Hugger Jakobsen E, Harvey V, Robert N, Smith II J, Harker G, Lalani AS, Zhang B, Eli LD, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial [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 PD3-12.

Abstract GS1-02: NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low

Abstract Background: Adjuvant trastuzumab (H) reduces cancer recurrence and improves survival in patients (pts) with HER2-amplified or overexpressing (IHC 3+ staining intensity) IBC. Two of the landmark trials that demonstrated the efficacy of H-based eligibility on HER2 testing performed at local site laboratories were found to contain a cohort of pts without amplification or IHC overexpression on tissue submitted for central testing. These HER2-low cohorts appeared to benefit from the addition of H, and efforts at external HER2 testing validation and laboratory explorations did not negate these findings. NSABP B-47 was performed to determine if these findings would be confirmed in a large prospective randomized trial. The primary aim was to determine whether the addition of H to chemotherapy (CT) regimens of AC→WP or TC (choice per investigator discretion) would improve invasive disease-free survival (IDFS). Methods: From 2/8/2011 to 2/10/2015, 3270 women were enrolled with 1630 pts randomly assigned to Arm 1 [TC: docetaxel 75mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks x 6 cycles; or AC→WP: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks x 4 cycles followed by paclitaxel 80 mg/m2 every week x 12], and 1640 pts to Arm 2 [same CT regimens + 12 months of H]. Pts were stratified by IHC score (1+ vs 2+), number of positive nodes (0-3, 4-9, ≥10), hormone receptor status (ER or PgR positive vs both negative), and CT (TC vs AC→WP). Overall 58.5% were ≥50 years, 57% had tumors with IHC 1+, 17.3% were ER- and PgR-, 19.9% were node negative, and 27.4% had ≥4 positive nodes. TC was the intended CT regimen for 44.2%. Results: As of 7/31/2017, the median follow-up time was 46.1 months. We observed 264 IDFS events, which triggered the definitive analysis for the primary endpoint. The addition of H to CT showed a 5-year IDFS of 89.6% compared to 89.2% for CT alone (HR 0.98; 95%CI 0.77-1.26; P=0.90). The findings did not differ by level of HER2 IHC expression, level of lymph node involvement, or hormone receptor status. 5-year point estimates for RFI were 92.0% for CT+H compared to 92.2% for CT alone (HR 0.995; 95%CI 0.75-1.32; P=0.97). 5-year estimates for DRFI were 92.7% for CT+H and 93.5% for CT alone (HR 1.10; 95%CI 0.81-1.49; P=0.55). The addition of H did not change OS significantly with 5-year point estimates of 94.8% in CT+H vs 96.2% in CT alone (HR 1.33; 95%CI 0.91-1.94; P=0.14). 4.3% of women in the CT arm experienced Grade 4 or 5 toxicities compared to 5.0% in CT+H. Conclusion: The addition of H to CT did not demonstrate a reduction in IDFS, RFI, or DRFI in women with non-overexpressing but IHC measurable HER2 IBC. This prospective study did not confirm the retrospective findings in NSABP B-31 or N9831. The threshold of HER2 expression or genetic amplification for H benefit remains unchanged. Support: NCI U10-180868, -180822, -44066, UG1-189867, and Genentech, Inc. Citation Format: Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, Polikoff J, Boileau J-F, Provencher L, Stokoe C, Moore TD, Robidoux A, Borges V, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC) [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 GS1-02.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER.

501 Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting. Clinical trial information: NCT00629278.

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

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

Cardioprotective Effect of Dexrazoxane in Patients with HER2-Positive Breast Cancer Who Receive Anthracycline Based Adjuvant Chemotherapy Followed by Trastuzumab

PurposeWe intended to determine whether dexrazoxane (DZR) is cardioprotective during administration of adjuvant anthracycline-based chemotherapy followed by a 1-year trastuzumab treatment.MethodsThe medical records of 228 patients who underwent surgical resection and received adjuvant chemotherapy with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer between January 2010 and December 2014 were reviewed. Approximately 25% of patients received DZR prior to each administration of doxorubicin during doxorubicin with cyclophosphamide (AC) chemotherapy. DZR was not administered during the 1-year trastuzumab maintenance period. Rates of cardiac events (reduction in left ventricular ejection fraction [LVEF] by 10% or more; reduction in absolute LVEF to <45%) and cardiac event-free duration (CFD) were examined. The trastuzumab interruption rate was also assessed.ResultsTwelve percent of patients experienced a cardiac event. Repeated-measures analysis of variance for ejection fraction revealed a significant main effect of time, and a significant group (DZR)×time interaction. The group treated with adjuvant chemotherapy and DZR experienced significantly lower frequencies of cardiac events than the adjuvant chemotherapy only group. In multivariate analysis, DZR administration was associated with significantly fewer cardiac events. Moreover, DZR administration was an independent good prognostic factor for CFD. Only one patient (2.3%) experienced early interruption of trastuzumab in the adjuvant chemotherapy with DZR group due to cardiac toxicity, whereas 10 patients (7.6%) experienced a trastuzumab stop event in the adjuvant chemotherapy only group.ConclusionDZR is cardioprotective in HER2-positive breast cancer patients who received adjuvant chemotherapy with trastuzumab. A large cohort randomized trial is needed to determine if DZR has an effect on trastuzumab interruption and completion of 12-month trastuzumab. Because cardiac toxicity has a significant negative effect on trastuzumab maintenance and quality of life, DZR administration could be considered concomitantly with anthracycline-based adjuvant chemotherapy with trastuzumab.

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

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

The real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu-positive early breast cancer in Taiwan

Background: Trastuzumab was considered a cost-effective adjuvant treatment for HER 2-positive early breast cancer. Since 2010, the Taiwanese National Health Insurance (NHI) has started to reimburse for 1-year adjuvant treatment. This study aims to provide an updated cost-effectiveness analysis from the NHI perspective, which explores assumptions about long-term cardiac toxicity and treatment benefit of 1-year adjuvant treatment sequentially after chemotherapy.Methods: A Markov model was used to evaluate the cost-effectiveness of 1-year adjuvant trastuzumab for HER-2/neu positive early breast cancer over a 20-year life-time horizon. A probability sensitivity analysis using Monte Carlo simulation was performed to characterize uncertainties in the expected outcomes, which are expressed as an incremental costs effectiveness ratio (ICER, cost/QALY). A willingness-to-pay threshold of 3-times the per capita gross domestic product was adopted according to the WHO definition. The Taiwan per capita gross domestic product in 2015 was US$22,355; thus, a threshold was considered as NT$2,011,950 (US$67 065, 1USD =30 NTD in 2015).Results: The model showed that adjuvant trastuzumab treatment in HER-2/neu positive early breast cancer yielded 1.631 quality-adjusted life-years (QALY) compared with no trastuzumab treatment. The ICER was US $51,863 per QALY gained in the base-case scenario. The Monte Carlo simulation by varying all variables simultaneously demonstrated that the probability of cost-effectiveness at the willingness-to-pay threshold of US$67,065 was 50% for 1-year adjuvant trastuzumab.Conclusions: From this real-world study, 1-year adjuvant trastuzumab treatment is likely to be a cost-effective therapy for patients with HER-2 positive breast cancer at the willingness-to-pay threshold of 3-times GDP per capita in Taiwan.

Abstract P4-14-07: Outcome with use of 12 weeks of adjuvant or neoadjuvant trastuzumab in a resource constrained setting

Abstract Background: Adjuvant trastuzumab has improved overall survival in women with HER2 receptor positive breast cancer. However, only a small fraction (4%) of eligible patients in resource constrained settings have access to this drug. A patient assistance program of 12 weeks of adjuvant or neoadjuvant trastuzumab was thus started for those who did not have any access to trastuzumab due to financial constraints. We undertook a retrospective analysis of outcomes in women who were enrolled between January 2011 to December 2012 in this patient assistance program. Methods: Patients received four cycles of anthracycline based chemotherapy (AC/CAF/ EC/CEF) and 12 doses of weekly paclitaxel (80mg/m2) with trastuzumab (4mg/kg loading followed by 2mg/kg) in the neoadjuvant or adjuvant setting in either sequence (anthracycline followed by taxane trastuzumab or taxane trastuzumab followed by anthracycline). Patients received adjuvant hormonal therapy depending on the hormone receptor status. The primary endpoint of this analysis was disease free survival (DFS). Results: A total of 103 patients with HER2 receptor positive breast cancer were analysed. The median age was 46 (24-65) years, 50% were premenopausal, 60.7% had stage III disease (86.8% had node positive disease) and 37% patients had ER and or PR positive disease. Forty patients (38.8%) had breast conserving surgery while the rest had modified radical mastectomy. At a median follow-up of 34 (7-46) months the 3-year DFS and overall survival was 77.2% and 82.7% respectively. Among patients who developed recurrence one had only local recurrence, 4 had both local and distant recurrence and 11 had distant metastasis alone. Of the 15 patients who developed distant metastasis 7 had brain involvement . Symptomatic cardiac dysfunction developed in four patients, two of whom died while in the other 2 ejection fraction recovered. The results are summarised in the table. Patient Characteristic and outcome with 12 weks of adjuvant or neoadjuvant TrastuzumabNumber of PatientsNode Positive (%)Hormone Positive (%)DFS at 3 yearsOS at 3 yearsBrain Mets(%)Grade 3/4 Cardiac Toxicity(%)10386.83777.282.76.83.9 Conclusions: These results suggest that 12 weeks of neoadjuvant or adjuvant trastuzumab is an acceptable alternative in patients who lack access to full 1 year of trastuzumab. Citation Format: Ghosh J, Joy Phillip DS, Ghosh J, Gupta S, Bajpai J, Gulia S, Parmar V, Nair N, Budrukkar AN, Jalali R, Desai SB, Sawant S, Dhir AA, Kembhavi S, Hawaldar R, Banavali SD, Badwe RA. Outcome with use of 12 weeks of adjuvant or neoadjuvant trastuzumab in a resource constrained setting. [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 P4-14-07.

ASCO 2015: Highlights in breast cancer

Several important studies were presented at the 2015 ASCO Annual Meeting in the field of breast cancer. Austrian Breast and Colorectal Study Group trial 18 again indicated the importance of bone health in postmenopausal women receiving endocrine therapy and showed that denosumab, a monoclonal antibody targeting the RANK ligand, was highly active in the reduction of fracture rates in this population. In the metastatic setting, addition of palbociclib to fulvestrant nearly tripled progression-free survival in pretreated women with luminal breast cancer as shown in the randomized phase III PALOMA-3 trial. In HER2-positive breast cancer, results from a randomized phase II study suggested that T-DM1 with or without endocrine therapy may be a valuable option as neoadjuvant treatment. In this trial, pathologic complete remission rates of > 40 % were observed after only four cycles of T-DM1. The phase III ExteNET study evaluated the role of neratinib, a tyrosine-kinase inhibitor targeting HER2 and epidermal growth factor receptor, as extended adjuvant therapy after 1 year of trastuzumab; while the future role of neratinib remains still undefined, this was the first study to show an improvement in terms of disease-free survival over the current treatment standard. Finally, the MARIANNE trial showed that T-DM1 was as effective as trastuzumab plus docetaxel as first-line therapy, while dual HER2-inhibition with T-DM1 plus pertuzumab yielded no further benefit.

Long-term outcome of HER2 positive metastatic breast cancer patients treated with first-line trastuzumab

BackgroundTrastuzumab has changed the natural history of metastatic HER2 positive breast cancer. Some patients remain well and in remission for many years. There is currently no established duration after which trastuzumab in the advanced setting can be safely discontinued. This study aims to evaluate long-term efficacy and cardiac safety of trastuzumab when used as first-line treatment for patients with metastatic HER2 positive breast cancer. Patient and methodsWe retrospectively identified 215 patients with HER2 positive, locally advanced or metastatic breast cancer who commenced first line trastuzumab-containing therapy for metastatic disease between 2001 and 2010 at The Royal Marsden Hospital. ResultsThe median progression free survival for all patients was 12 months (95%CI: 10.3–14.6 months); 103 (48%) patients remained in remission beyond one year, 59 (27%) beyond two years and 25 (12%) beyond five years. The median overall survival was 2.6 years (95% confidence interval (CI): 2.2–3.3). The objective response rate (ORR) was 65% with 17 (8%) complete responses and 120 (57%) partial responses. Trastuzumab was well tolerated. Twenty eight (13%) patients recorded any grade of left ventricular dysfunction. There was no significant difference in cardiac toxicity between those patients on less than or more than one year of trastuzumab. ConclusionTrastuzumab is associated with long-term remissions in a significant proportion of patients with metastatic HER2 positive disease when used in the first-line advanced setting.

Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab.

Although intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been associated with a poor prognosis for primary HER2-positive breast cancer and metastatic HER2-positive breast cancer treated with trastuzumab, the clinicopathologic significance in a setting involving trastuzumab treatment as an adjuvant treatment has not been studied in patients. We retrospectively investigated 443 patients with HER2-positive breast cancer treated with surgery, adjuvant chemotherapy, and 1 year of trastuzumab. Three areas that showed different levels of HER2 protein expression were chosen, and silver in situ hybridization was performed. HER2 regional and genetic heterogeneity was found in 6.2% and 6.8% of tumors, respectively. Both types of heterogeneity were significantly associated with hormone receptor positivity, HER2 immunohistochemistry score of 2+, a low level of HER2 gene amplification, and absence of an extensive intraductal component. Genetic heterogeneity also showed strong correlation with a lower histologic grade. In the hormone receptor-positive group, the regional heterogeneity affected disease-free survival of patients (hazard ratio, 4.869; 95% confidence interval, 1.424-16.646; P = .005), whereas genetic heterogeneity did not. Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.

Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015

The introduction of trastuzumab as adjuvant treatment for patients with HER2-positive breast cancer changed the natural course of early-stage disease. Currently, one year of trastuzumab given concurrently with a taxane and following an anthracycline regimen is the preferred standard of care in Europe. The first attempt to escalate this approach, though the implementation of dual HER2 blockade with lapatinib added to trastuzumab, as assessed by the ALTTO trial, failed to improve further clinical outcomes; clinical assessment of the adjuvant trastuzumab/pertuzumab regimen is still ongoing in the APHINITY trial. Negative results were also reported for the addition of bevacizumab to adjuvant trastuzumab treatment within the context of the BETH study. Similarly, efforts to de-escalate through shortening the duration of adjuvant trastuzumab treatment failed (the PHARE trial), whereas others are still ongoing. Of note, evidence supports the use of lighter chemotherapy regimens with one year of adjuvant trastuzumab as backbone, for women with small HER2-positive breast tumors, where the omission of anthracyclines did not compromise the clinical outcome. Despite the successes achieved so far, a proportion of women with early-stage HER2-positive breast cancer, will still experience disease recurrence. The identification of these women is urgently needed, as well as the identification of predictive biomarkers to dictate the optimal treatment strategy. So far, HER2 expression status has been the only validated predictive biomarker for this patient population. Despite the clear association of pCR achieved through neoadjuvant trastuzumab-based chemotherapy with clinical outcome, results from neoadjuvant trials have not been always consistent with what was seen in the adjuvant setting. Similarly, inconsistent results have been reported for the predictive ability of alterations affecting the PI3K signaling pathway or the quantification of tumor infiltrating lymphocytes. In the era of personalized oncology, rigorous translational and clinical collaborative efforts are needed to further advance the field of treatment of patients with HER2-positive breast cancer.

Prognostic Significance of Tumor-Infiltrating Lymphocytes and the Tertiary Lymphoid Structures in HER2-Positive Breast Cancer Treated With Adjuvant Trastuzumab.

Tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The tertiary lymphoid structure (TLS) is related to the influx of TILs, and expression of major histocompatibility complex (MHC) I in tumor cells is necessary for the effective action of TILs. We retrospectively evaluated the relationship of TILs and TLS and the expression of MHC I in 447 HER2-positive breast cancers treated with chemotherapy and 1 year of trastuzumab. TILs were more abundant in hormone receptor (HR)-/HER2+ tumors than in HR+/HER2+ tumors. HR-/HER2+ breast cancers with abundant TILs showed a higher histologic grade, the absence of lymphovascular invasion, the presence of peritumoral lymphocytic infiltration, moderate to abundant TLSs in adjacent tissue, and stronger HLA-ABC and HLA-A expression. Abundant TILs and the absence of lymphovascular invasion were found to be good, independent prognostic factors for disease-free survival in patients with HR-/HER2+ breast cancer. The level of TILs was not associated with the patients' prognosis in HR+ tumors. Abundant TILs are an independent prognostic factor in HR-/HER2+ breast cancers. Evaluation of TILs in HR-/HER2+ breast cancers may provide valuable information regarding the prognosis of patients treated using adjuvant chemotherapy and trastuzumab.

Abstract P3-06-22: Identification of ERBB2 gene variants in HER2 positive disease associated with trastuzumab response in an adjuvant trastuzumab chemotherapy trial

Abstract Background Among 493 patients with early stage, lower risk (70% node negative), HER2 positive breast cancer, the 2-year DFS was 97% with adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab (TCH) in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). The objective of this work was to investigate the presence of ERBB2 specific DNA biomarkers in HER2 amplified tumors associated with relapse compared to those which did not recur during 3 years of followup. Methods The 26 coding exons of the ERBB2 gene were analyzed by next generation sequencing (NGS) on the HiSeq-2500 (Illumina) platform using DNA samples from the primary tumors of 13 of the 493 patients who progressed. Treatment refractory cases were analyzed in parallel with a clinically and pathologically matched group of 11 patients from the same trial with 2-year relapse free survival (RFS). Results ERBB2 gene variants were detected in all 11 relapse-free patients and 10/13 patients with relapse. Heterogeneity for sub-clonal ERBB2 variants at &amp;lt;1% tumor variant frequency (TVF) was pronounced. There were 126 total distinct ERBB2 SNVs across the 24 tumors. Only 4 occurrences of SNVs known to us to be activating (G309A, D769H, D769Y, V777L, V842I, R896C, S310Y, S310F, T798M, 611M, 678M) were found: 3 times V842I and a single case with R896C. Of the investigated tumors, 5 exhibited sub-clonal hyper-mutability with &amp;gt;30 ERBB2 SNVs. These sub-clonal ERBB2 SNVs were not detected in a comparison set of non-HER2 positive solid tumors. We did find variants that seem to be associated with later relapse, of which one is statistically significant (I655V; p=1.2%, Fisher exact test, no compensation for multiple testing), and further 5 have p&amp;lt;10%. Conclusions We find no evidence for known activating HER2 mutations to confer increased (nor decreased) risk of relapse after TCH therapy (p=30.0%). Remarkably, I655V is found significantly less often in the relapse group. This variant is known to increase BC risk by activating HER2 dimerization; an effect that may be muted by trastuzumab, in contrast to some other causes of BC. Moreover, I655V mutations with high TVF (&amp;gt;75%, hence suggesting homozygous germline presence) are exclusively found in the no-relapse group (p=3.1%). These biomarkers in combination with other molecular studies including immune function gene status may help define the subset of patients at risk for relapse during TCH therapy. The hyper-mutability genotype does not seem to correlate with later relapse, so it may be hypothized that the low TVF mutations are passengers rather than drivers. Further studies are needed to verify and precisely define the role of these ERBB2 biomarkers in HER2 positive breast cancer. Citation Format: Shelly Gunn, Alexander Zien, Markus Hartenfeller, Francesca Diella, Stephan Brock, Martin Stein, Sasha Badbanchi, Anja Doerks, David Jackson, Lina Asmar, Yunfei Wang, Steve Jones. Identification of ERBB2 gene variants in HER2 positive disease associated with trastuzumab response in an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-22.

Abstract P4-15-01: Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial

Abstract Background: HER2+, hormone receptor-positive (HR+) breast cancer is a distinct subtype associated with good prognosis but poor response to standard chemotherapy + anti-HER2 (single or dual blockade). Substantial overtreatment by poly-chemotherapy combined with anti-HER2 therapy is suspected in this subtype. Yet, the efficacy of combining endocrine therapy (ET) with anti-HER2 therapy or novel antibody drug conjugates like T DM1 without systemic chemotherapy remains unclear. Methods: ADAPT HER2+/HR+ is a phase II, randomized, neoadjuvant, 3-arm trial (12 weeks) in patients with cT1c-cT3, cN0/+ HER2+, ER+ and/or PR+ early BC. Arm A: T-DM1 (3.6 mg/kg) alone; Arm B: T DM1 + ET (premenopausal: tamoxifen, postmenopausal: AI); Arm C: trastuzumab + ET. Postoperative chemotherapy is recommended together with completion of one year of trastuzumab. Initial and serial core biopsies were obtained prior to therapy and after 3 weeks. First translational analysis of the trial run-in phase (n=130) focuses on dynamics of HER2, Ki67, ER and PR. Results: 162 tumors, HR+ and HER2+ by local pathology, were screened; n=130 were HR+ and HER2+ by central pathology and randomized at 40 trial sites in Germany between 11/2012 and 03/2014 (Arm A/B/C: 37/49/44). Median age was 49 years; 60% were cT2-3, 32% cN+, 75% central G3; median baseline Ki67 was 30%; 49 patients were treated by TAM and 44 postmenopausal patients by AI in ET containing arms. Three-week core biopsies were available in 117 patients (arm A/B/C: n=33/43/41), n=99 with invasive tumor tissue (61/76 (80%) in T-DM1 containing arms and 38/41(93%) in trastuzumab + ET arm). Three-week Ki67 could only be analyzed in n=73 (53% of patients in T-DM1-containing arms, 81% in the T+ET arm) due to a lacking amount of cells for counting (&amp;lt;500). Median fractional decrease in proliferation (Ki67) after 3 weeks of therapy was 40% in the T-DM1 + ET arm (B) as compared to 14% and 25% in the T-DM1 (A) and T+ET (C) arms, respectively. Among postmenopausal patients, the contrast (52% (B) vs. 0% (A) and 28% (B)) was significant. Mean PR expression change (absolute, measured in %) was -15 in the B Arm vs. 7 and -7 in the A and C arms, respectively (p=0.04) – particularly in postmenopausal women ( 25 vs. +13 and -10, respectively, p=0.04). Baseline ER expression was positively associated with early proliferation response (fractional Ki67 decrease), e.g., by logistic regression using 30% decrease as response criterion. Data on the impact of gene mutations and further molecular markers on proliferation response will be available for presentation at the meeting. Conclusions: In the unique neoadjuvant ADAPT HER2+/HR+ trial, the combination of T-DM1 with ET (particularly AI) seems to be associated with a strong early proliferation response and PR expression drop in anti-HER2 antibody (drug conjugate) +/- ET, without systemic pre-operative chemotherapy. Interim analysis is scheduled after 130 completely treated patients. The high percentage of non-invasive tissue biopsied after 3 weeks in the T-DM1 arms is intriguing, as it would be consistent with higher pathological complete response rates. Citation Format: Oleg Gluz, Ulrike Nitz, Kuemmel Sherko, Kraemer Stefan, Michael Braun, Claudia Schumacher, Bahriye Aktas, Helmut Forstbauer, Toralf Reimer, Peter Fasching, Jochem Potenberg, Daniel Hofmann, Ronald E Kates, Rachel Wuerstlein, Matthias Christgen, Hans H Kreipe, Nadia Harbeck. Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-01.

Abstract P5-10-18: The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial

Abstract Background Early stage HER2 amplified breast cancer has a generally favorable prognosis with over 95% of patients showing 2-year disease free survival (DFS) when treated with adjuvant trastuzumab. However, a subset of these tumors are refractory to treatment and present a challenge for the oncologist, particularly when clinical and histologic parameters, including the patient’s nodal and hormonal status, are indicative of lower-risk HER2 positive disease. In this study we describe the genomic landscape of three clinically lower-risk patients with HER2 amplified tumors who relapsed on adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). All patients’ tumors showed high-level HER2 amplification ratios by FISH (8.51-14.46) and were analyzed in parallel with a fourth clinically matched 2-year DFS patient’s tumor from the same trial with high HER2 gene amplification (FISH ratio 11.38). Methods Primary tumor genomic DNA analysis was performed from archival tissue by next generation sequencing (NGS) on the Illumina HiSeq 2500 platform in a CLIA certified laboratory. Tumors were screened for point mutations and copy number alterations (CNAs) by NGS using a targeted-whole exome 613 gene panel. CNAs detected by NGS were confirmed on a DNA microarray featuring high-density probe coverage of the same 613 genes on the targeted panel. CGH chromosome ratio plots were overlaid with algorithmically derived NGS copy number data to generate a map of the chromosomal genomic landscape for each patient’s tumor. Results High-level HER2 gene amplification status was confirmed, and co-amplified chromosome 17 genomic regions were detected in all three relapsed patients’ tumors. High-level HER2 amplification was also confirmed in the non-relapsed patient’s tumor but co-amplified regions were not detected on chromosome 17 or elsewhere in this patient’s tumor genome. Two of the relapsed ER negative tumors shared focal high-level CCNE1 gene amplifications on chromosome 19. High-level MAP3K3 gene amplification on chromosome 17 was detected in the one ER positive tumor from a relapsed patient. Focal PIK3CA gene amplifications were not identified in any of these tumors, but two tumors (one from the relapse group and one non-relapse) were positive for activating H1047R mutations. Conclusions Combined NGS and CGH analysis of HER2 positive early stage breast cancer can be performed in the clinical laboratory to reveal the tumor’s chromosomal genomic landscape. Combined with other test results, this tumor map can help identify patients at high-risk for relapse and reveal alternative predictive biomarkers of therapeutic response. Citation Format: Shelly Gunn, Chris McCaskill, Linda Daley, Agnes Puskas, Lina Asmar, Yunfei Wang, Stephen Jones. The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-18.