Prolonged Responses With Trastuzumab Emtasine Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer Refractory to Trastuzumab and Pertuzumab: Systematic Review of Evidence

Amplification of human epidermal growth factor receptor 2 (HER2) occurs in around 25% of breast cancers and has been associated with aggressive disease. Here, we summarize published evidence on efficacy and prolonged responses with trastuzumab emtansine (T-DM1) after first-line trastuzumab plus pertuzumab and provide possible factors related to prolonged responses to T-DM1. We conducted a literature search using PubMed, and articles that were published in English between July 1, 2012 and December 31, 2019 were included. A review of the bibliography included in the articles found was made. Nine articles were eligible; 2 were case reports, and the remaining 7 were nonexperimental studies, all retrospective. Five were multi-center works. The total number of patients was 796 (276 received pertuzumab). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for this systematic review. The population included was heterogeneous among studies according to hormone receptor status, de novo metastatic disease, number of metastatic sites, visceral involvement, brain metastasis, previous neoadjuvant or adjuvant trastuzumab, and line of therapy in which T-DM1 was administered. Less efficacy in terms of responses (overall response rate, 18%-33%) and progression-free survival (4-6 months) with second-line T-DM1, in patients pretreated with pertuzumab, was shown (if compared with the EMILIA trial). The results are more similar to those of the TH3RESA trial (very pretreated population). Prolonged treatments (6 months or more) were observed in at least 17% of cases. The efficacy of T-DM1 after a previous pertuzumab treatment is lower than if pertuzumab is not given, although prolonged responses are observed in this setting.     

Safety Profile of Pertuzumab With Trastuzumab and Docetaxel in Patients From Asia With Human Epidermal Growth Factor Receptor 2‐Positive Metastatic Breast Cancer: Results From the Phase III Trial CLEOPATRA

Introduction.

We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer.

Patients and Methods.

Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m². All study drugs were given intravenously, 3 times weekly.

Results.

Docetaxel dose reductions below 75 mg/m² were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m² were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66).

Conclusion.

Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.     

曲妥珠单抗和帕妥珠单抗联合化疗对HER2阳性乳腺癌新辅助治疗的真实世界研究

目的 分析曲妥珠单抗(H)和帕妥珠单抗(P)联合化疗对HER2阳性乳腺癌新辅助治疗的疗效和安全性.方法 回顾性分析行HP联合化疗新辅助治疗并完成手术的HER2阳性乳腺癌患者的临床资料,主要研究终点为总体病理完全缓解(tpCR)(ypT0/isypN0),次要研究终点为乳腺病理完全缓解(bpCR)(ypT0/is)和腋窝...     

Impact of Trastuzumab on Ipsilateral Breast Tumor Recurrence for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer after Breast-Conserving Surgery

PurposeTrastuzumab is effective in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, few studies have reported the effect of trastuzumab on ipsilateral breast tumor recurrence (IBTR), whose incidence is higher in the HER2-positive subtype than in other subtypes.MethodsWe retrospectively investigated 959 patients who underwent breast-conserving surgery (BCS), chemotherapy, and radiotherapy for HER2-positive breast cancer between 2000 and 2017. IBTR was compared between the patients who received neoadjuvant or adjuvant trastuzumab (Tmab group) for a total duration of 1 year and those who received no trastuzumab (N-Tmab group).ResultsPropensity score matching designated 426 and 142 patients in the Tmab and N-Tmab groups, respectively. The median follow-up period for all patients after matching was 73.79 months. The IBTR-free survival rate was significantly higher in the Tmab group than in the N-Tmab group (10-year IBTR-free survival rate, 92.9% vs. 87.3%; p = 0.002). The multivariate analysis showed a significant association between the N-Tmab and Tmab group (hazard ratio, 3.03; 95% confidence interval, 1.07–8.59) and IBTR in addition to close or positive resection margin and hormone receptor (HR) positivity. The subgroup analysis showed that adjuvant treatment with trastuzumab significantly reduced IBTR among the patients with HR-negative or lymph node-negative breast cancer.ConclusionSignificantly reduced IBTR after BCS was observed in the patients who received 1 year of adjuvant/neoadjuvant trastuzumab treatment for HER2-positive breast cancer.     

Trastuzumab Retreatment after Relapse on Adjuvant Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Final Results of the Retreatment after Herceptin Adjuvant Trial

AimsTrastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer.Materials and methodsIn total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for ≥10 months, with a relapse-free interval of ≥6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression.ResultsAt the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7–80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression-free survival (PFS) was 8.0 months (95% confidence interval: 6–11 months) and the median overall survival was 25.0 months (16–33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported.ConclusionTrastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy.     

Safety and Tolerability of Docetaxel,Cyclophosphamide, and Trastuzumab Compared to Standard Trastuzumab-Based Chemotherapy Regimens for Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Purpose

We evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH).

Methods

We retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated.

Results

One hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two-thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade ≥3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen.

Conclusion

TCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary to support the wider use of TCyH as an adjuvant regimen.     

Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Neoadjuvant Docetaxel,Carboplatin, Trastuzumab,and Pertuzumab

PurposeThe tumor-infiltrating lymphocytes (TILs) expression in breast cancer is a positive prognostic marker for certain breast cancer subtypes. We evaluated the efficacy of dual anti-human epidermal growth factor receptor 2 (HER2) blockade in HER2-positive breast cancer and hypothesized that high TILs tumors are associated with better outcomes.MethodsA total of 176 patients who were treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) between December 2015 and December 2018 were reviewed. They were grouped based on a cut-off value of the stromal TILs grade (≤ 20% TILs, > 20% TILs).ResultsIn total, 107 patients (60.8%) achieved pathological complete response (pCR). Hormone receptor (HR)-negativity (p = 0.001) and a high TILs grade (p = 0.022) were independent predictors of pCR. Among the HR-negative patients, high TILs tumors were significantly associated with pCR (p = 0.035).ConclusionHR status and the TILs grade are significantly correlated with pCR in dual anti-HER2 neoadjuvant therapy. The evaluation of the TILs at baseline may be beneficial for predicting pCR in HER2-positive breast cancer.     

MicroRNA-130a Increases and Predicts Cardiotoxicity during Adjuvant Chemotherapy in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer

PurposeThis study aimed to investigate the changes in microRNA-130a (miR-130a) and its correlation with cardiotoxicity during epirubicin/cyclophosphamide followed by docetaxel plus trastuzumab (EC-D+T) adjuvant chemotherapy in human epidermal growth factor receptor-2-positive (HER2⁺) breast cancer patients.MethodsA total of 72 HER2⁺ breast cancer patients who underwent resection and were scheduled to receive EC-D+T adjuvant therapy were consecutively enrolled. The expression of miR-130a and cardiotoxicity (defined as any of the following situations: 1) absolute decline of left ventricular ejection fraction (LVEF) ≥ 10% and LVEF < 53%; 2) heart failure; 3) acute coronary artery syndromes; and 4) fatal arrhythmia) were assessed every 3 months throughout the 15-month EC-D+T treatment.ResultsThe accumulating cardiotoxicity rate was 12 (16.7%), of which the incidence of heart failure, acute coronary syndrome, life-threatening arrhythmias, ΔLVEF ≥ 10%, and LVEF < 53% was 0 (0.0%), 1 (1.4%), 0 (0.0%), and 12 (16.7%), respectively. Baseline miR-130a expression was negatively correlated with LVEF (%) and positively correlated with cardiac troponin I. The expression of miR-130a gradually increased in both cardiotoxicity and non-cardiotoxicity patients during EC-D+T treatment, while the increment of miR-130a was more obvious in cardiotoxicity patients compared with non-cardiotoxicity patients. Further logistic regression and receiver operating characteristic curve analysis indicated that miR-130a was an independent predictive factor for increased cardiotoxicity risk.ConclusionMiR-130a increases constantly and predicts high cardiotoxicity risk during EC-D+T adjuvant chemotherapy in HER2⁺ breast cancer patients.     

Patients with HER2-positive Early Breast Cancer Receiving Adjuvant Trastuzumab: Clinicopathological Features,Efficacy, and Factors Affecting Survival

Background: The aim of the present study was to evaluate clinicopathological characteristics of our early stagebreast cancer patients who are epidermal growth factor receptor 2 (HER2) overexpressed/ amplified (HER2+),the efficacy of trastuzumab treatment and survival results. Materials and Methods: Patients with HER2- positiveearly stage breast cancer receiving adjuvant trastuzumab were investigated retrospectively. Clinicopathologicalfeatures of 210 patients and treatment outcome were analysed. To evaluate survival rates, the Kaplan-Meiermethod was used. Univariate and multivariate analyses were conducted with the Cox regression model. Results:Mean age of the patients was 51.8, 71.9% being postmenopausal. Some 37.6% of patients were node negative,and 31% had T1 tumor size and 52.4% were positive for estrogen receptor. Of 210 patients, 89.5% completedplanned 52 weeks adjuvant trastuzumab treatment. The median follow up was 27.5 months (6.0-86.0 ). Relapsefree survival (RFS) was 68.0 months (95% CI: 62.1-74.0) and overall survival (OS) was 74.8 months (95%CI: 69.5-80.1). The 3 year OS for all patients was 92.0% and RFS was 79.6%. During follow up, relapse wasdetected at the rate of 14.3%. Trastuzumab associated cardiotoxicity was found at the rate of 3.3%. In univariateanalyses, larger tumor size and grade III were significantly associated (p<0.05) with RFS. Multivariate analysesof covariates displaying p<0.05 identified grade III as an independent prognostic factor. Conclusions: In thepresent study, it was established that trastuzumab had a satisfactory safety profile and treatment efficacy as inother clinical studies and that among clinicopathological factors evaluated, only being grade 3 had a significanteffect on RFS. The occurrence of relapse with adjuvant trastuzumab makes it necessary to identify molecularpredictors, which will define this group better and help explain resistance to anti HER2 based therapies.     

Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus Docetaxel in Patients With HER2‐Positive Metastatic Breast Cancer in CLEOPATRA: A Randomized,Double‐Blind,Placebo‐Controlled Phase III Study

Introduction.

We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC).

Patients and Methods.

Left ventricular ejection fraction (LVEF) ≥50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m² q3w.

Results.

The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff.

Conclusion.

The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.     

Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction

Background.

Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatment-induced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment. We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF.

Methods.

We retrospectively evaluated patients with HER2-positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of ≥10% to below 55% or an absolute decrease of ≥16%. Logistic regression was used to determine the association between candidate risk factors and treatment-induced cardiotoxicity.

Results.

Among 573 patients, 92 (16%) developed treatment-induced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity—all were asymptomatic with LVEF of ≥50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%–63%), and none developed heart failure during follow-up. Risk factors associated with treatment-induced cardiotoxicity included age (p = .011), anthracycline chemotherapy (p = .002), and lower pretrastuzumab LVEF (p < .001).

Conclusion.

Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of ≥50%, continuous trastuzumab therapy appears to be safe.

Implications for Practice:

Cardiotoxicity is the most common reason for patients with HER2-positive breast cancer to receive an incomplete course of life-saving trastuzumab therapy. Data from this study suggest that continuous trastuzumab may be safe in patients with asymptomatic cardiotoxicity and left ventricular ejection fraction of ≥50%. Given the substantial oncologic benefit of trastuzumab, increasing efforts are needed to ensure that patients complete the full course of treatment without interruption. Current recommendations for trastuzumab interruption in patients who develop cardiotoxicity should be re-evaluated.     

The Global Need for a Trastuzumab Biosimilar for Patients With HER2-Positive Breast Cancer

Trastuzumab improves survival outcomes for patients with HER2-positive (HER2⁺) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2⁺ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2⁺ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2⁺ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2⁺ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2⁺/hormone receptor-positive disease, and women with small and/or node-negative HER2⁺ tumors, were less likely to receive anti-HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2⁺ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes.     

曲妥珠单抗治疗1 8 5例HER2阳性乳腺癌患者的心脏安全性评价

 目的 探讨HER2阳性乳腺癌患者应用曲妥珠单抗治疗的心脏安全性。方法 185例HER2阳性乳腺癌患者接受每3周一次的曲妥珠单抗治疗,首次以负荷剂量8 mg/kg给药,此后每3周给予6 mg/kg静脉滴注,接受治疗4~36周期,观察其心脏安全性。结果 接受曲妥珠单抗治疗的HER2阳性乳腺癌患者中位治疗周期数为17个（4~36个）,88例（47.6%）出现LVEF下降、74例（40.0%）出现瓣膜反流（新增+加重）、16例（8.0%）出现左室舒张功能下降。发生心脏毒性88例（47.6%）,其中Ⅰ级心脏毒性83例、Ⅱ级心脏毒性5例,未见Ⅲ级心脏毒性发生。结论 曲妥珠单抗对HER2阳性乳腺癌患者心脏功能有一定影响,总体安全性良好。但是,在治疗中仍需注意评估与监测。