The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to ...approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.
Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity ...of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers.
Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20-25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, ...including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.
Purpose
Chemotherapy has been the historical mainstay of treatment for patients with breast cancer, with immunohistochemical markers and tumor characteristics driving treatment decisions. The ...discovery of different intrinsic subtypes of breast cancer has advanced the understanding of breast cancer, with gene‐based assays shedding further light on tumor behavior and response to treatment.
Design
This review focuses on the landscape of the luminal A subtype, its definition based on immunohistochemistry (IHC) and gene assays, the prognostic and predictive value of these assays, guideline recommendations, and treatment implications.
Results
Clinical studies of the prognostic value of gene‐based and IHC‐based assays in patients with luminal A‐subtype breast cancers suggest a better prognosis for these patients compared with those with breast cancers of other subtypes.
Conclusion
In today's era of precision medicine, the best treatment regimen for patients with luminal A‐subtype tumors is still undetermined, but available data raise the question whether chemotherapy can be omitted and endocrine therapy alone is sufficient for this patient population.
Implications for Practice
Immunohistochemical markers have traditionally guided treatment decisions in breast cancer. However, advances in gene‐expression profiling and availability of gene‐based assays have launched these newer tests into everyday clinical practice. Luminal A‐subtype tumors are a unique subset that may have favorable tumor biology. Properly defining this tumor subtype is important and may identify a subset of patients for whom endocrine therapy alone is sufficient.
摘要
目的.化疗一直是乳腺癌患者治疗历史中的主要疗法, 其免疫组化标志物和肿瘤特征决定了治疗决策。对不同亚型乳腺癌的探索促进了对乳腺癌的了解, 基于基因的检测方法进一步阐明了肿瘤行为和治疗反应。
设计.本综述侧重于Luminal A亚型、基于免疫组织化学（IHC）和基因检测得出的定义、这些检测的预后和预测价值、指南建议以及治疗影响等领域。
结果.基于基因和基于IHC的检测在Luminal A亚型乳腺癌患者中的预后价值的临床研究表明, 与其他亚型的乳腺癌患者相比, 这些患者的预后更好。
结论.在当今的精准医疗时代, 仍未确定Luminal A亚型肿瘤患者的最佳治疗方案, 但现有的数据可以提出的问题是, 化疗是否可以省略, 仅采用内分泌治疗是否足以满足该患者人群的需求。
对临床实践的提示：传统上, 免疫组织化学标志物指导乳腺癌治疗决策。然而, 基因表达谱的进展和基于基因的检测的可用性已将这些较新的检测投入到日常临床实践中。Luminal A亚型肿瘤是可能具有良好肿瘤生物学特征的独特亚型。正确定义这种肿瘤亚型很重要, 并且可能确定仅采用内分泌疗法即可满足其需求的患者亚组。
This review focuses on the luminal A subtype in breast cancer: how it is defined by immunohistochemical‐based and gene‐based assays, the prognostic and predictive value of these assays and treatment implications. With population studies projecting that half of all new breast cancer diagnoses will be of the luminal A subtype, the question of how to best determine whether a tumor is luminal A and how to best approach treatment is clinically important.
Summary Background CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive ...first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up. Methods The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov , number NCT00567190. Findings In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3–NE not estimable) in the placebo group but had not been reached (95% CI 42·4–NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52–0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4–13·5) in the placebo group and 18·7 months (16·6–21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58–0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity. Interpretation Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients. Funding F Hoffmann-La Roche, Genentech.
Summary Background High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to ...investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. Methods CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov , number NCT00567190. Findings Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41–54) for progression-free survival and 51 months (IQR 46–57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5–30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10·00% 95% CI 5·00–20·00 vs 15·00% 5·00–35·00; p=0·00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0·95, 95% CI 0·90–1·00, p=0·063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0·89, 95% CI 0·83–0·96, p=0·0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction =0·23) or overall survival (pinteraction =0·21). Interpretation In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival. Funding F Hoffmann-La Roche–Genentech and the Breast Cancer Research Foundation.
Dysregulation of the cyclin dependent kinase pathway in luminal breast cancer creates a new therapeutic opportunity for estrogen receptor positive breast cancer. Initial pan-CDK inhibitors were ...associated with extensive toxicities but in recent years, the development of potent specific CDK inhibitors with favorable tolerability has driven renewed interests in this class of targeted therapies. Palbociclib, ribociclib and abemaciclib are specific CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration for use in combination with endocrine therapy for women with advanced hormone receptor positive breast cancer. These three anticancer therapeutics were approved based on progression free survival benefit seen on phase III trials with the most common grade 3 treatment-related side effects being neutropenia, fatigue, nausea and diarrhea. Except for estrogen receptor positivity, no biomarkers predictive of response to CDK4/6 inhibitors have been identified to date. Based on mechanistic insights here described, CDK4/6 inhibitors are currently being explored in combination with other agents, including targeted therapies, immunotherapy and chemotherapy.
Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were ...first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point.
In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed.
Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio HR, 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent.
The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus ...docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.
Mandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival PFS benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled).
Pertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor-negative and -positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-type PIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CA showed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months).
Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.
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