Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Real-world Data on First-line Systemic Therapy for Hormone Receptor-positive HER2-negative Metastatic Breast Cancer: A Trend Shift in the Era of CDK 4/6 Inhibitors

Hormone receptor-positive (HR⁺) human epidermal growth factor receptor-2 negative (HER2^–) tumors represent the most common subtype of metastatic breast cancer (MBC). International guidelines clearly state that endocrine therapy (ET) should be considered the preferred first-line therapy for these patients in the absence of very symptomatic visceral disease or evidence of endocrine resistance. Nonetheless compliance with guidelines significantly vary worldwide for many different reasons. Historically, a substantial proportion of patients with HR⁺ HER2^– MBC have been treated with chemotherapy (CT) in first-line setting, jeopardizing patients’ quality of life without a significant benefit in outcome. In 17 observational studies, including more than 63,000 patients, ET was most frequently used in first-line treatment of HR⁺/HER2^– MBC (range, 42%-87%), nonetheless a high proportion of patients received CT (13%-66%) as initial therapy. More recently, results of clinical trials with CDK 4/6 inhibitors improved response, progression-free and overall survival in this population and are currently the standard of care. There was a trend toward increased use of ET in recent years. This review article aims to evaluate real-world data on patterns of first-line treatment of HR⁺ HER2^– MBC with a special focus on the use of CT in this setting and the potential implications and perceived preliminary changes after the introduction of CDK 4/6 inhibitors.     

First-Line Treatment of Metastatic Breast Cancer

For many years, tamoxifen was the mainstay of treatment for hormone receptor-positive metastatic breast cancer (MBC). However, in recent years, newer endocrine agents, particularly aromatase inhibitors, have consistently proved their superiority over tamoxifen by improving clinical outcomes. These agents have therefore been incorporated into first-line treatment strategies for endocrine-responsive disease. The chemother-apeutic armamentarium has also been enriched with new agents and combinations that have played a role in improving breast cancer survival in recent decades. However, few chemotherapy clinical trials have claimed a clear survival benefit of one regimen over another. More recently, the development of biologic agents has further widened the spectrum of available therapies. Among these, trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has significantly altered the lives of patients with HER2-positive MBC. The transfer of research findings to clinical practice is a delicate process that implies the ability to adequately tailor evidence obtained from well designed clinical trials to the individual patient. This article discusses landmark studies in the treatment of MBC, with emphasis on those treatments used as ‘first-line’ therapy following relapse.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.     

Updates in endocrine therapy for metastatic breast cancer

Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.     

HER2过表达乳腺癌曲妥珠单抗耐药后靶向治疗策略

 曲妥珠单抗与化疗药物联用后提高了人类表皮生长因子受体2（HER2）过表达乳腺癌的反应率,但在开始治疗后数月易出现治疗性耐药,限制了患者的总生存期。曲妥珠单抗耐药机制主要与HER家族以外的蛋白酪氨酸激酶受体信号通路活化、PI3K-AKT通路扩增等有关。酪氨酸激酶抑制剂、磷脂酰肌醇3-激酶抑制剂等分子靶向药物作为曲妥珠单抗耐药者的替代治疗手段,单药疗效均不甚满意。多个大型临床试验证实,新型分子靶向药物联合应用能明显限制,甚或最终消除曲妥珠单抗初始治疗耐药性问题。     

Clinical development of CDK4/6 inhibitor for breast cancer

Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2?) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation. Currently positive data of several clinical trials using three CDK4/6 inhibitors (palbocilcib, ribociclib, abemaciclib) were published and primary endpoint were met in all phase III studies. Therefore, practice change of endocrine therapy has been achieved in ER positive MBC. This review will present clinical trial data, including both the efficacy and safety of CDK4/6 inhibitors for MBC, and describe the designs of the mainly ongoing clinical trials examining CDK4/6 inhibitors for the treatment of MBC and EBC.     

CDK4/6 inhibitor plus endocrine therapy for hormone receptor‐positive,HER2‐negative metastatic breast cancer: The new standard of care

Patients presenting with hormone receptor‐positive (HR⁺), human epidermal growth factor receptor 2‐negative (HER2^–) metastatic breast cancer (MBC) are usually treated with endocrine therapy (ET), except if there is a concern about endocrine resistance or a need to achieve rapid disease control due to visceral crisis. The combination of CDK4/6 inhibitor + ET has now replaced single‐agent ET as the standard first‐line treatment; and it can also be considered a standard option in the second‐line setting. This review briefly summarizes recently reported efficacy findings from the key phase III clinical trials of CDK4/6 inhibitor + ET in patients with HR⁺/HER2^– MBC, including evidence that adding a CDK4/6 inhibitor to ET improves overall survival and does so without reducing patients’ quality of life. There is still much to learn regarding the use of CDK4/6 inhibitors and how they may be optimally integrated into clinical practice. In particular, there is a need for specific biomarkers that help predict the likelihood of response or resistance to CDK4/6 inhibitor therapy; and for data to guide treatment decisions when a patient's disease progresses on a CDK4/6 inhibitor.     

State of the art therapy for HER2-negative metastatic breast cancer

Metastatic breast cancer (MBC) remains a challenging disease to treat with only a small minority of patients achieving long-term survival. Although great strides have been made in the fight against breast cancer, international consensus to the approach to treat the disease is lacking. Over the past few decades, the introduction of several new agents, including biologically-targeted agents, have impacted disease control as well as survival, albeit modestly. Despite these advances, treatment for the majority of breast cancer remains empirically based, especially in the approach to HER2-negative, endocrine non-sensitive disease. Taxane- and anthracycline-containing regimens continue to be a mainstay of MBC therapy; however, increasing use of these agents in the adjuvant and neoadjuvant settings provides a challenge for the treating oncologist. As such, this review will focus on state of the art therapy for patients with endocrine non-sensitive, HER2-negative MBC, highlighting recent advances offering new treatment paradigms.     

Evolving nonendocrine therapeutic options for metastatic breast cancer: how adjuvant chemotherapy influences treatment

Patients with metastatic breast cancer (MBC) represent a very heterogeneous population and several factors are important for therapeutic decision: patients' characteristics including age, comorbidities, performance status, tumor biological profile, site and extension of metastatic spread, previous adjuvant therapies, and disease-free interval. New cytotoxic agents, new endocrine agents, and targeted therapies are becoming the new mainstay of adjuvant treatment. The growing understanding of the biology of breast cancer cells has led to the identification of key molecular points that represent possible targets for target-specific agents. Trastuzumab, the monoclonal antibody against the HER2 receptor, represents the standard treatment of high-risk early-stage breast cancer overexpressing HER2. With increasing use of very active drugs in the adjuvant setting, there is a greater need for effective therapy at the time of relapse. In endocrine resistant disease, a treatment-free interval > 12 months after adjuvant chemotherapy has been shown to be an important factor for drug sensitivity. If the tumor has been exposed to an anthracycline and a taxane in adjuvant setting and the treatment-free interval is > 12 months, the rechallenge with the same agents might be an option. If the treatment-free interval is < 12 months, it is preferable to use a different agent. Capecitabine, gemcitabine, and vinorelbine have demonstrated substantial activity in MBC. Novel cytotoxic agents including epothilones and vinflunine are currently in clinical development for taxane-resistant disease. Lapatinib, a new target agent that simultaneously inhibits both HER2 and epidermal growth factor receptor tyrosine kinases has been shown to be active in trastuzumab-resistant MBC. Moreover, several new agents targeting HER2 are currently under clinical development. There are no data on rechallenge with trastuzumab in patients who had received this agent as adjuvant treatment and relapsed after a long treatment-free interval, and this issue is a new area of research.     

Human epidermal growth factor receptor-2 and hormonal therapies: clinical implications

Estrogen-targeted therapies such as administration of tamoxifen or aromatase inhibitors are among the most important treatment strategies in the modern management of breast cancer. Despite initial responses in the metastatic setting and prolonged disease-free intervals in the adjuvant setting, many patients subsequently become resistant to these agents. Human epidermal growth factor receptor-2 (HER2) is a transmembrane glycoprotein receptor that is overexpressed in 13%-30% of human breast cancers. There are experimental data suggesting an important role for HER2 in de novo and acquired resistance to endocrine therapies. These experimental data are discussed in this article, as are clinical data addressing the role of HER2 in resistance to endocrine therapy in the adjuvant, neoadjuvant, and metastatic settings. Responses and benefit from tamoxifen appear to be impaired in patients in whom HER2 is overexpressed. In contrast, early data from the neoadjuvant setting suggest that responses to aromatase inhibitors may be maintained in patients with HER2 overexpression.     

Monitoring the circulating levels of the HER2/neu oncoprotein in breast cancer

The HER2/neu oncoprotein is a major target for the development of new cancer therapies and is similar to the estrogen receptor, which guides hormone therapy. The HER2/neu status is used to guide therapy decisions in patients with HER2/neu-overexpressing breast cancer tumors. The HER2/neu oncogene, or c-erbB-2, encodes a transmembrane receptor protein that is expressed on normal epithelial cells and can be overexpressed in breast cancer cells. Studies have shown that the extracellular domain (ECD) of the HER2/neu oncoprotein is released from the cell and can be measured in the circulation of women with breast cancer. Enzyme-linked immunosorbent assay methods used to measure the circulating HER2/neu ECD have shown that the prevalence of elevated ECD levels is approximately 18.1% in women with primary breast cancer and approximately 45.6% in women with metastatic breast cancer (MBC). Many studies have monitored the circulating ECD levels after surgery and indicate that increasing ECD levels can indicate recurrence of breast cancer earlier than clinical diagnosis. Studies in women with MBC showed that serial changes in circulating HER2/neu ECD levels paralleled the clinical course of disease, regardless of the treatment regimen. Several studies identified a subgroup of patients with MBC who had HER2/neu-negative disease by tissue testing but developed elevated ECD levels with MBC. In contrast to tissue testing, which is a one-time event, monitoring the circulating levels of the HER2/neu ECD in patients with breast cancer provides a real-time assessment of the HER2/neu status and provides important information for managing the therapy of patients with MBC.     

Long-term management of patients with hormone receptor-positive metastatic breast cancer: Concepts for sequential and combination endocrine-based therapies

Treatment options for hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) continue to increase in parallel with expanding knowledge about the complex biology of breast cancer subtypes and resistance mechanisms to endocrine therapy. For patients with HR-positive MBC, there are now an unprecedented number of endocrine-based treatment options that can improve long-term outcomes, while preserving or optimizing quality of life, and that can be used before selecting more cytotoxic chemotherapeutic regimens. In addition to antiestrogens, steroidal and nonsteroidal aromatase inhibitors, the selective estrogen-receptor degrader, fulvestrant, and new endocrine-based combinations provide significant and clinically meaningful improvements in outcomes in the first line setting and beyond. Also, new clinical scenarios and indications for monotherapy endocrine and targeted therapies continue to be explored. Patients have several therapeutic options when their disease progresses or becomes resistant, although the optimal sequencing of these therapies remains unclear. Ongoing research in the resistant/refractory setting is anticipated to continue improving the outlook for these patients. This review will discuss current and investigational approaches to sequential single-agent endocrine and endocrine-based combination therapy for the long-term management of patients with HR-positive, human epidermal growth factor receptor 2-negative MBC.     

Extending the Clinical Benefit of Endocrine Therapy for Women With Hormone Receptor–Positive Metastatic Breast Cancer: Differentiating Mechanisms of Action

Principal goals of therapy for women with hormone receptor (HR)–positive metastatic breast cancer (MBC) are to maintain a good quality of life and to prolong survival; another important goal is to delay initiation of chemotherapy. Most women with tumors that are estrogen receptor (ER)–positive, progesterone receptor (PR)–positive, or both are treated initially with endocrine therapy because of its effectiveness and relatively low toxicity. Several classes of single-agent endocrine therapies are available for postmenopausal women, including the nonsteroidal aromatase inhibitors (AIs), steroidal AIs, selective ER modulators, selective ER downregulators, progestins, androgens, and high-dose estrogen. In addition, combination therapy, either with 2 different endocrine agents or with endocrine therapy plus newer targeted therapies, provides some relatively new strategies for the treatment of these patients. Nevertheless, disease resistance ultimately develops with each endocrine regimen, and many questions remain regarding the optimal timing and sequencing of these treatments. This article reviews the efficacy and safety of endocrine therapy regimens in women with HR–positive MBC, and it addresses the effect of prior endocrine therapies and the mechanisms of action of the different endocrine regimens within the context of overall treatment goals.     

Treatment of metastatic breast cancer: second line and beyond

Increasing use of standard chemotherapy, especially anthracycline- and taxane-based therapies, in early-stage breast cancer has led to a corresponding increase in heavily pretreated and/or treatment-resistant cases of metastatic breast cancer (MBC). Thus, second and later lines of MBC therapy frequently involve the clinically challenging picture of progressive disease and limited treatment options. While several prognostic factors have been identified to aid treatment selection in MBC patients, treatment is palliative and aimed at prolonging survival, controlling symptoms, and maximizing patients' quality of life. No globally accepted standard exists for meeting these goals, and treatment patterns vary according to region. The list of available agents for the treatment of MBC is increasing with newer chemotherapeutic agents and molecular-targeted therapies. Within recent years, several single-agent and combination chemotherapy regimens have been shown to improve progression-free survival and reduce symptoms of disease in clinical studies in patients with resistant and/or heavily pretreated MBC. However, at present, the demonstrated benefits of these medical interventions have usually not included extension of overall survival times. It is hoped that in the near future, ongoing refinements to treatment approaches used in second-line settings and beyond will allow meaningful improvements in symptom control and survival in MBC.     

Predictive markers for efficacy of everolimus plus exemestane in patients with luminal HER2-negative metastatic breast cancer

Metastatic breast cancer (MBC) is essentially incurable despite recent improvements in systemic therapies. We often encounter difficulties in choosing the most appropriate treatments, with optimal timing, for individual patients. Everolimus, one of the mTOR inhibitors, is usually used with endocrine therapy for MBC. Identification of predictive markers for everolimus-based treatment remains a major issue, but to date, no predictive markers have been established. We retrospectively investigated predictive markers for treatments with everolimus plus exemestane in patients with ER-positive and HER2-negative breast cancer. Clinicopathological features of 18 patients, with locally advanced disease or MBC given everolimus plus exemestane treatments, were examined in relation to treatment effects. Also, primary breast cancer specimens, all ER positive and HER2 negative, were immunohistochemically investigated for phospho-S6 (pS6) and PTEN, to evaluate the mTOR and PIK3CA/Akt pathways. Those showing a good clinical response had a significantly lower Ki67 labeling index than the poor responders. A similar trend was observed in pS6 level but without statistical significance. Interestingly, there was no correlation between the Ki67 labeling index and pS6, and when both indexes were low, the good clinical response rate was high. The median progression-free survival was longer in the group showing a low Ki67 labeling index (109 weeks) than in that with high Ki67 (19 weeks). There was no trend between PTEN expression and treatment effects. Our results suggest that the primary tumor in luminal HER2-negative breast cancer patients with a low Ki67 labeling index and pS6 level has the potential to respond well to everolimus plus exemestane.     

Everolimus Plus Exemestane for the Treatment of Advanced Breast Cancer: A Review of Subanalyses from BOLERO-2

Hormone receptor–positive breast cancer is typically managed with endocrine therapies. However, resistance to endocrine therapy results in disease progression in a large proportion of breast cancers. Through the understanding of the mechanisms of endocrine resistance, identification of implicated pathways and targets has led to the development of novel agents targeting these pathways. Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway aberrations are common in breast cancer, with increased PI3K/AKT/mTOR signaling associated with resistance to endocrine and human epidermal growth factor receptor 2 (HER2)–targeted therapies. The mTOR inhibitor everolimus, in combination with exemestane, has been approved for patients with advanced hormone receptor–positive/HER2-negative breast cancer who progress on prior nonsteroidal aromatase inhibitor therapy based on results reported in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study. This review will summarize the overall findings from BOLERO-2 and will consider available subanalyses by age, Asian origin, visceral or bone metastases, and prior therapy, with the aim of identifying populations most likely to benefit from everolimus therapy. The review will also summarize safety findings and their management and the effects of everolimus on quality of life.Abbreviations: AE, adverse event; BSAP, bone-specific alkaline phosphatase; CBR, clinical benefit rate; CR, complete response; CTX, C-terminal cross-linking telopeptide of type 1 collagen; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; NIP, noninfectious pneumonitis; ORR, objective response rate; PI3K/AKT/mTOR, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PFS, progression-free survival; P1NP, amino-terminal propeptide of type 1 collagen; PR, partial response; QoL, quality of life; TDD, time to definitive deterioration     

Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies

Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.     

Serum soluble epidermal growth factor receptor concentrations decrease in postmenopausal metastatic breast cancer patients treated with letrozole

Previous studies have implicated estrogen as a regulator of epidermal growth factor receptor (EGFR) expression in breast tumors. We therefore speculated that estrogen might modulate serologic soluble EGFR (sEGFR) concentrations in breast cancer patients. Accordingly, we measured serum sEGFR concentrations in postmenopausal women with metastatic breast cancer (MBC) treated with letrozole, an aromatase inhibitor that blocks estrogen synthesis. Serum specimens were obtained prior to and following 1 and 3 months of letrozole therapy. We report that sEGFR concentrations do not differ between MBC patients prior to letrozole treatment and age- and postmenopause-matched healthy women (P = 0.468). In contrast, however, sEGFR concentrations decreased significantly in 76% of MBC patients after both 1 month (P = 0.006) and 3 months (P = 0.003) of letrozole therapy versus pretreatment concentrations. Within the limitations of this study, we found no evidence for an association between pretreatment sEGFR concentrations or decreased treatment sEGFR concentrations and either progression-free or overall survival. Nonetheless, we conclude that future prospective studies are warranted to determine if baseline and/or longitudinal serum sEGFR concentrations may be useful for predicting disease progression and survival, and/or for monitoring responsiveness to aromatase inhibitors or other endocrine therapies in breast cancer patients.