Baseline characteristics and first-line treatment patterns in patients with HER2-positive metastatic breast cancer in the SystHERs registry

Breast Cancer Research and Treatment - Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs, NCT01615068) was a prospective, observational disease registry designed to...     

Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer

Background: Although trastuzumab therapy improves survival inpatients with human epidermal growth factor receptor 2 (HER2)-positivemetastatic breast cancer, 40% of patients develop brain metastasis(BM) even when extracranial disease is under control. We studiedwhether trastuzumab therapy beyond or after BM was beneficialto patients with BM. Patients and methods: The effect of trastuzumab on survivalafter BM was analyzed in 78 HER2-positive breast cancer patients.Patients were grouped according to trastuzumab therapy; no treatmentand treatment before and after BM were diagnosed. Results: Overall survival after the diagnosis of BM as wellas time to progression (TTP) of intracranial tumors was prolongedin patients who received trastuzumab after BM was diagnosed.Conversely, BM occurred much later in patients who receivedtrastuzumab before BM. In the multivariate Cox regression model,age at BM <50 years, disease-free interval     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

Quantitative assessment of HER2 amplification in HER2-positive breast cancer: its association with clinical outcomes

Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast cancer. However, not all patients benefit from trastuzumab-based therapy. We aimed to investigate whether patients with different levels of HER2 amplification would experience different clinical outcomes with trastuzumab-based chemotherapy. We quantified the HER2 gene copy number (GCN) and HER2/centromere chromosome probe 17 (CEP17) ratio in 291 breast cancer patients with HER2 amplification confirmed by immunohistochemistry and fluorescence in situ hybridization. The optimal cutoff points for HER2 GCN and the HER2/CEP17 ratios for distinguishing positive results were determined by receiver operating characteristic (ROC) curve analyses. ROC analysis identified optimal cutoff points for HER2 GCN and HER2/CEP17 ratios as 11.5 and 6.5 (P = 0.039 and P = 0.012), respectively. The DFS in patients with HER2 GCN <11.5 was significantly longer than in HER2 GCN ≥11.5 patients (P = 0.015) according to Kaplan–Meier survival curves analysis. Similarly, patients with HER2/CEP17 ratios <6.5 had a significantly longer DFS than those with HER2/CEP17 ratios ≥6.5 (P = 0.013). Moreover, patients with HER2 cluster amplification showed a worse survival than those with HER2 non-cluster amplification (P = 0.041). This study demonstrated a significant association between the level of HER2 amplification and survival time in a relatively large cohort of HER2-positive breast cancer patients undergoing trastuzumab-based chemotherapy. Further investigations of more precise quantitative measurements and larger cohorts are required to define this threshold.     

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0–81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6–13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03–2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47–1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07–2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse. Presented in part in oral form at the 2007 European Cancer Conference, Barcelona, Spain.     

Prognostic value of HER2-positive circulating tumor cells in patients with metastatic breast cancer

Backgrounds  

The presence of ≥5 circulating tumor cells (CTCs) in 7.5 ml blood is a poor prognostic marker in metastatic breast cancer (MBC). However, the role of human epidermal growth factor receptor 2 (HER2) status in CTCs is not known.     

Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab

Background

Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane.

Patients and methods

Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated.

Results

Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29–23.70) for a change from 1st quartile (Q1) to Q1–Q3 and HR of 15.54 (95% CI 3.70–65.24) for a change from Q1 to Q4.

Conclusion

In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2–3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2–3 years and who remain disease-free after 2–3 years.

     

Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab

Gastric Cancer - The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity...     

Blockade of the HER family of receptors in the treatment of HER2-positive metastatic breast cancer

Breast cancer is the most common type of cancer among women and the second leading cause of cancer death in the United States. Metastatic breast cancer is considered incurable, and treatment is aimed at palliating symptoms, achieving remission, and prolonging survival. Treatment options for metastatic disease vary based on tumor surface markers and clinical factors in an individual patient and include cytotoxic chemotherapy, hormonal therapy, biological therapy, or some combination of these. An important molecular determinant of therapy is the human epidermal growth factor receptor 2 (HER2) positivity of the tumor, which affects response to HER2-targeted treatment. HER2 is a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, also known as the HER family, which activates signaling that promotes tumorigenic cellular processes such as proliferation and evasion of apoptosis. Several targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors that inhibit one or more HER family receptors have been developed that affect signaling through this pathway. Some of these, such as trastuzumab and lapatinib, have been approved for breast cancer treatment. Resistance to therapy is a challenge that limits the duration of benefit achieved with these agents. Therefore, combinations of HER family-targeted agents with other therapies such as cytotoxic agents, hormonal therapy, or inhibitors of other cellular pathways, are being developed to exploit synergy and overcome resistance mechanisms. Here we review the HER family-targeted agents currently approved or in development for HER2-positive metastatic breast cancer with a focus on strategies to overcome tumor resistance.     

HER2 mutation status in Japanese HER2-positive breast cancer patients

Background

Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs.

Methods

Here, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309–310 and the kinase domain between 755 and 781.

Results

Two patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively.

Conclusions

Our data show that HER2 mutations are rare in HER2-positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future.

     

Progression and treatment of HER2-positive breast cancer

Purpose

Approximately 20–30% of breast cancer tumors overexpress or amplify human epidermal growth factor receptor 2 (HER2). The role of this receptor in the progression of HER2+ breast cancer and resistance to certain anticancer monotherapies was investigated. The results of several pre-clinical and clinical trials, with the aim of determining the most safe and effective course of treatment for HER2+ breast cancer, were also thoroughly examined.

Methods

A thorough search of databases including Pubmed, Springer, and The American Society of Clinical Oncology was performed, and pertinent studies were identified. The most relevant studies were preclinical, phase II, and III clinical trials identifying the function of the HER2 receptor in HER2+ breast cancer progression, as well as studies assessing the efficacy of monotherapy and combination therapy in the treatment of this aggressive form of cancer.

Results

The HER2 receptor belongs to a family of receptors that consists of four cell-surface receptors (HER1-4) that share strong homology with the epidermal growth factor receptor (EGFR). All HER receptors interact with specific types of ligands to induce receptor activation, except for HER2, for which no known ligand has yet been identified. HER2 is activated by forming dimers with other HER receptors, and this results in a stronger and more prolonged signal transduction event. When expressed at normal levels, HER2 regulates cell growth, differentiation, and survival. However, under pathological conditions of HER2 overexpression, numerous HER2 heterodimers are formed resulting in aggressive tumor growth. Therefore, the prognosis associated with HER2-positive breast cancer is usually poor. A specific cohort of patients with breast cancer whose tumors test both hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 positive have been found to be resistant to targeted hormone therapy. Studies investigating the etiology of this resistance have found that the cell membrane estrogen receptor communicates with HER2 in promoting the release of ER coactivators that cause the endocrine drug and selective estrogen receptor modulator, tamoxifen, to act as an agonist rather than an antagonist of the hormone estrogen. Thus, research has directed its inquiry toward the development of therapies specifically targeting HER2. The development of trastuzumab, a recombinant monoclonal antibody against HER2, initially proved to be a well-tolerated first line of treatment. However, in the long-term patients, trastuzumab was shown to develop resistance to this monotherapy. Therefore, research on HER2 positive breast cancer has focused on the study of different anti-HER2 combination therapies over the past decade.

Conclusions

While the development and approval of the HER2-targeted recombinant monoclonal antibody trastuzumab (Herceptin) has been efficacious in slowing HER2 cancer progression, combining this and other anti-HER2 therapy with either chemotherapy or endocrine therapy has proven more effective in improving overall and progression free survival.     

HER2-positive advanced breast cancer treatment in 2020

HER2-positive breast cancer is an aggressive subtype identified in the 1980s. The development of therapies targeting the HER2 has improved outcomes. The current standard of care, established in 2012 is dual blockade with trastuzumab + pertuzumab as first-line followed by TDM-1 as second-line. Several suboptimal choices are available in third-line or more. In 2019 the presentation of several trials evaluating new drugs and regimens in third-line has re-opened questions about sequencing, treatment of triple positive disease and treatment choice after exposure to TDM-1. These include tucatinib, neratinib and trastuzumab-deruxtecan. Other agents – including other antibody drug conjugates and bispecific antibodies as well as combinations - will lead to further changes in coming years. Additionally, should the numerous putative biomarkers thus identified ever come into use at the clinic, choice of treatment and response evaluation may be substantially changed.     

Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.     

HR +/HER2+转移性乳腺癌的MDT诊断策略

本文介绍1例改良根治术后复发转移的乳腺癌病例的多学科诊治过程.患者术后8年复查发现双肺、颈淋巴结转移,经过多学科讨论后患者接受靶向药物联合化疗控制病情,后续联合内分泌治疗维持.随访近2年后再次发现颈淋巴结转移,经多学科讨论后治疗再次获得缓解.19月后复查发现肝转移灶,经多学科讨论,于部分肝切除术成功的基础上行全身化疗,使用创新性联合抑制雌激素受体(estrogen receptor,ER)、人表皮生长因子受体2(human epidermal growth receptor-2,HER2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)方案,患者获益显著,无进展生存期＞27月.该病例的诊治过程说明,分析病例需要把握病情发展中的主要问题,需要多学科交流以避免出现认识上的误区和局限.应当普及多学科讨论以进一步保证治疗方案的合理性和优化.