Quality of Life in Hormone Receptor–Positive HER‐2+ Metastatic Breast Cancer Patients During Treatment with Letrozole Alone or in Combination with Lapatinib

Background.

A phase III trial compared lapatinib plus letrozole (L + Let) with letrozole plus placebo (Let) as first-line therapy for hormone receptor (HR)⁺ metastatic breast cancer (MBC) patients. The primary endpoint of progression-free survival (PFS) in patients whose tumors were human epidermal growth factor receptor (HER)-2⁺ was significantly longer for L + Let than for Let (8.2 months versus 3 months; p = .019). This analysis focuses on quality of life (QOL) in the HER-2⁺ population.

Methods.

QOL was assessed at screening, every 12 weeks, and at withdrawal using the Functional Assessment of Cancer Therapy–Breast (FACT–B). Changes from baseline were analyzed and the proportions of patients achieving minimally important differences in QOL scores were compared. Additional exploratory analyses evaluated how QOL changes reflected tumor progression status.

Results.

Among the 1,286 patients randomized, 219 had HER-2⁺ tumors. Baseline QOL scores were comparable in the two arms. Mean changes in QOL scores were generally stable over time for patients who stayed on study. The average change from baseline on the FACT-B total score in both arms was positive at all scheduled visits through week 48. There was no significant difference between the two treatment arms in the percentage of QOL responders.

Conclusion.

The addition of lapatinib to letrozole led to a significantly longer PFS interval while maintaining QOL during treatment, when compared with letrozole alone, thus confirming the clinical benefit of the combination therapy in the HR⁺ HER-2⁺ MBC patient population. This all oral regimen provides an effective option in this patient population, delaying the need for chemotherapy and its accompanying side effects.     

PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

BackgroundPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.Patients and methodsPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.ResultsA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]).ConclusionCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.Trial registration IDNCT01589861.     

拉帕替尼在乳腺癌中的应用及其耐药机制研究现状

随着分子肿瘤学的发展,乳腺癌进入了分子分型时代。基于患者不同生物标志物表达的个体化医疗已经成为目前乳腺癌治疗的模式。HER2阳性乳腺癌侵袭性高、预后差,占所有乳腺癌患者的20%~30%。曲妥珠单抗作为第一个人源化单克隆抗体,以HER2为靶点,改善了这部分患者的预后,因此乳腺癌相关各大临床实践指南和专家共识明确推荐HER2阳性乳腺癌患者不同阶段均可以使用曲妥珠单抗进行抗HER2治疗。但是曲妥珠单抗的心脏毒性及原发、继发耐药等问题迫使临床医生对二线抗HER2治疗进行探索。拉帕替尼作为第一个被批准用于临床作用于HER1和HER2双靶点的酪氨酸激酶抑制剂,是曲妥珠单抗失败后的不错选择。本文对拉帕替尼在乳腺癌中的应用、相关临床研究及其耐药机制研究进行简要综述。     

The HERBA Study: A Retrospective Multi-Institutional Italian Study on Patients With Brain Metastases From HER2-Positive Breast Cancer

BackgroundThere is no sufficient evidence to establish a standard of care for patients with brain metastases (BM) from HER2⁺ breast cancer (BC). The aim of this study was to assess the impact of local and systemic treatments on the outcome of patients diagnosed with BM from HER2⁺ BC over a period of 10 years, from 2005 to 2014.Patients and MethodsData of 154 patients were retrospectively collected at 14 Italian institutions through a specifically designed database.ResultsMedian overall survival (OS) was 24.5 months. Patients receiving surgery/stereotactic radiosurgery experienced longer OS compared to those receiving whole-brain radiotherapy or no treatment (33.5 vs. 11.4 months; hazard ratio = 0.34; 95% confidence interval, 0.22-0.52; P < .001). Interestingly, whole-brain radiotherapy did not improve OS compared to no treatment (11.4 vs. 9.8 months; hazard ratio = 0.99; 95% confidence interval, 0.62-1.62; P = .99). HER2-targeted therapy was associated with better OS compared to systemic therapy without HER2-targeted therapy or no systemic therapy (27.5 vs. 5.4 months; hazard ratio = 0.26; 95% confidence interval, 0.17-0.41; P < .001). At multivariate analysis stratified by local treatments, systemic therapy, Karnofsky performance status, and neurologic symptoms significantly affected OS. Age, number of BM, steroid therapy, number of previous lines of systemic therapy, status of extracranial disease, and period of diagnosis had no significant impact on OS.ConclusionPatients with BM from HER2⁺ BC treated with surgery/stereotactic radiosurgery as local treatment and HER2-targeted therapy as systemic treatment experienced the best outcomes. Patients with low Karnofsky performance status and neurologic symptoms had poor survival.     

复方苦参注射液联合拉帕替尼治疗Her-2阳性晚期乳腺癌疗效及对肿瘤标志物的影响

目的:观察复方苦参注射液联合拉帕替尼治疗Her-2阳性晚期乳腺癌疗效及对肿瘤标志物的影响。方法:选取2013年5月至2017年6月辽宁中医药大学附属第二医院门诊及住院部就诊的Her-2阳性Ⅳ期的乳腺癌患者65例,按随机编号随机分为观察组和对照组,对照组使用拉帕替尼片口服治疗,观察组加以复方苦参注射液静脉滴注治疗,分别在治疗前及治疗18周后,对2组的临床疗效、生命质量、不良反应发生率、广谱肿瘤标志物、乳腺癌特异性肿瘤标志物进行比较分析。结果:在治疗18周后,对照组患者的总有效率为69.70%,观察组患者的总有效率为87.50%,观察组的优于对照组(P0.05);治疗后,2组患者的KPS评分均明显升高,ECOG评分明显降低(P0.05),且观察组优于对照组(P0.05);2组患者CEA、CA153、CA125治疗后均较治疗前下降(P0.05),TK1和IGF-1表达均下调(P0.05);其中观察组优于对照组(P0.05);治疗后观察组外周血CD3~+、CD4~+、CD4~+/CD8~+、CD69表达高于对照组,CD8~+低于对照组,差异均有统计学意义(P0.05)。观察组心脏、肝胆、感染、皮肤、疼痛和肺部的不良反应率均较对照组低(P0.05)。结论:复方苦参注射液联合拉帕替尼对Her-2阳性晚期乳腺癌患者具有较佳的临床疗效,可降低广谱肿瘤标志物及乳腺癌特异性肿瘤标志物的表达,从而提高患者的生命质量,其作用机制可能与改善机体细胞免疫有关。     

The HER‐2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER‐2 Therapy and Personalized Medicine

The human epidermal growth factor receptor (HER‐2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER‐2 gene amplification and protein overexpression in the absence of anti–HER‐2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER‐2–positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER‐2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER‐2–positive disease. The major marketed slide‐based HER‐2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology–College of American Pathologists guidelines for HER‐2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER‐2 testing, are also discussed. Emerging novel HER‐2 testing techniques, including mRNA‐based testing by real‐time polymerase chain reaction and DNA microarray methods, HER‐2 receptor dimerization, phosphorylated HER‐2 receptors, and HER‐2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin‐like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER‐1/HER‐2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti–HER‐2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER‐2–targeting agents is also presented, including pertuzumab, ertumaxomab, HER‐2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER‐2 targeted therapy toxicity are included, and the review concludes with a consideration of HER‐2 status in the prediction of response to non–HER‐2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.     

Dual targeting of EGFR and HER-2 in colon cancer cell lines

Purpose  A number of studies have revealed that coexpression of EGFR and HER-2 has been found in a subset of colon cancers and may cooperatively promote tumor cell growth and survival. In the present work, two tyrosine kinase inhibitors, gefitinib and lapatinib, together with trastuzumab, raised a monoclonal antibody against HER-2 were evaluated in two colon cancer cell lines, DLD-1 and Caco-2. The aim of the study was to investigate their effect on tumor cell proliferation and apoptosis. Methods  Cell proliferation was assessed using the MTT assay and apoptosis was evaluated by DNA fragmentation and the Annexin V binding assay. EGFR and HER-2 protein and mRNA levels were evaluated by immunoblotting and quantitative RT-PCR, respectively. Results  Treatment of cells with each agent alone resulted in inhibition of cell proliferation after 48 h in a dose-dependent manner except for trastuzumab, which did not alter cell proliferation of DLD-1. Apoptosis increased in DLD-1 cells, after 24 h treatment with gefitinib. None of the tested agents altered apoptosis in Caco-2 cells. HER-2 and EGFR protein levels did not follow the changes of mRNA levels after treatment with the tested agents. Conclusions  Τhe inhibitory effect of these agents on cell proliferation and the induction of apoptosis differ for the two colon cancer cell lines under consideration. Further studies are necessary to investigate the way they exert their antitumor effect.     

Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf > MEK > ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK

Background and purpose

We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer.

Materials and methods

Response of EGFR downstream signaling pathways was assessed by Western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5 Gy), lapatinib, CI-1040, or combined treatment.

Results

In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation.

Conclusions

These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.     

Intermediate to highly suspicious calcification in breast lesions: a radio-pathologic correlation

Targeted therapies against the human epidermal growth factor receptor HER2, have led to revolutionary strides in breast cancer research and treatment. Clinical therapeutic decisions in the treatment of patients with HER2 positive metastatic breast cancer are based on appropriate patient selection, the clinical situation, and data related to the available therapeutic agents trastuzumab and lapatinib. Trastuzumab was the first agent tested and approved in 1996 as single agent for patients with chemotherapy-refractory disease, and in combination with paclitaxel as first-line treatment. This intravenous humanized monoclonal antibody is directed against the extracellular domain of the HER2 protein. Lapatinib, an oral small molecule tyrosine kinase inhibitor has more recently become available (in 2007), approved for used in combination with capecitabine for patients with HER2 positive metastatic disease that has progressed on trastuzumab. Important questions and controversies still remain and are reviewed, including patient selection for anti-HER2 treatment of metastatic disease based on HER2 testing, dose scheduling of trastuzumab, duration of therapy, tolerability, role of lapatinib and clinical significance of trastuzumab resistance and efficacy. Ongoing trials designed to maximize the therapeutic ratio of these agents, are also discussed.