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Case Vignettes in Metastatic Breast Cancer

Epidemiology and impact of metastatic breast cancer
Breast cancer is the most common malignancy in women in the United States. According to estimates from the American Cancer Society, up to 3.1 million women living in the United States have a history of invasive breast cancer, and 232,000 new breast cancer diagnoses were expected in 2014.1,2 About one-fifth of breast cancers are identified in women younger than 50 years, and the median age at breast cancer diagnosis is lower compared with that of other prevalent malignancies, such as lung or colorectal cancer (ages 61 years vs 70 years and 69 years, respectively).2 The incidence of cancer has remained relatively steady in the United States since 2003, and overall disease mortality has decreased, related to both early detection and more effective treatment options.3 This is reflected in an increase of 5-year relative survival rates for female patients from 74.8% in the late 1970s to above 90% from 2003 through 2009.1 However, with an estimated death toll of 40,000 for the year 2014, breast cancer remains the second most common cause of cancer mortality among women, and patients with advanced or metastatic breast cancer (MBC) represent a disproportionate number of these patients.1,2 

Breast cancer can be categorized into pure noninvasive carcinomas (stage 0); operable, locoregional invasive carcinoma with or without associated noninvasive carcinoma (clinical stage 1, stage 2, and some stage 3A tumors); inoperable locoregional invasive carcinoma with or without associated noninvasive carcinoma (clinical stage 3B, stage 3C, and some stage 3A tumors); and metastatic (stage 4) or recurrent carcinoma.4 

The prognosis for women with localized disease, approximately 61% of cases, has greatly improved. Current 5-year relative survival rates have reached 98.6%, and many patients experience long-term disease-free survival. However, outcomes for patients with distantstage breast cancer remain poor, with 5-year survival rates below 25%.1 Approximately 6% of patients present with metastatic disease at diagnosis; in addition, 30% to 40% of patients who receive treatment for early disease develop recurrence with distant metastases.5

 Over the past 30 years, overall survival (OS) of patients with MBC has improved with the addition of more effective chemotherapeutic and targeted treatments; however, progression-free survival (PFS) and time-to-progression (TTP) remain virtually unchanged, except for patients with human epidermal growth factor receptor–2 (HER2)-positive disease, in whom the addition of trastuzumab to chemotherapy (CT) has significantly increased PFS.5-8 Metastatic breast cancer is considered incurable, and treatment goals are focused on reducing or delaying disease progression, prolonging OS, and symptom palliation, while maximizing the patient’s quality of life (QOL). The choice of therapy is guided by multiple factors, including severity of symptoms and disease, sites of metastasis, duration of relapse-free interval, hormone receptor (HR) status, HER2 status, prior treatment, anticipated side effects, and patient preferences.5,9 

Breast cancer molecular subtypes 
Breast cancer is a heterogeneous disease encompassing different biological subtypes with distinct gene expression profiles that have been identified by DNA microarray gene expression analyses.4 In retrospective studies, specific subtypes have been associated with differing relapse-free survival and OS, such that prognostic information and treatment choices are based not only on patient age, tumor size, histological grade, and lymph node engagement, but also on the analysis of key biomarkers including the estrogen receptor (ER), the progesterone receptor (PR), and HER2.4 Clinically relevant subtypes include ER-positive/HER2-negative (luminal A and luminal B subtypes); ER-negative/HER2-negative (basal subtype); HER2-positive; and tumors that have characteristics similar to normal breast tissue.4 Assessment of ER and PR content and HER2 status by immunohistochemistry (IHC) and in situ hybridization is considered an essential component of the pathology assessment and in patients with metastatic disease should be performed on both primary tumor and metastases, due to frequent discordance of receptor status.4 

Approximately 72% to 80% of all breast cancers are HR positive (FIGURE 1), and the vast majority of patients with MBC have ERpositive/HER-negative disease.7,9,10 Estrogen receptors are intracellular ligand-induced transcription factors that, upon binding to estrogens such as estradiol, activate the expression of various genes involved in cell proliferation and differentiation; they also interact with signaling cascades outside of the nucleus.11

ER-positive breast cancer cells express predominantly the ER-alpha receptor, and transcriptional upregulation following estrogen exposure has been implied as a key mechanism that drives tumor growth, inva­sion, and angiogenesis.11 ER positivity renders cancers potentially sensitive to endocrine therapies, which target the ER by blocking receptor binding with an antagonist or by depriving the tumor of estrogen. Using additional markers of gene expression, including the proliferation marker Ki-67, and recurrence predictors that are based on multigene signatures, such as the 21-gene recurrence score (RS 21) or the 70-gene profiles, ER-positive tumors can be fur­ther subclassified according to their virulence, risk of recurrence, and likelihood of benefitting from adjuvant endocrine therapy or CT.12,13 Approximately half of ER-positive tumors are PR-positive, and downregulation of PR expression has been associated with the activation of pathways that contribute to the resistance to endocrine therapy.14 Tumors with high levels of ER and PR, negative for HER2, slowly proliferating (low Ki-67), of histologically lower grade, and with low-risk 21- or 70-gene profile scores are more likely to benefit from endocrine therapy and less likely to benefit from CT. These more indolent tumors largely overlap with the luminal A subtype of the current conceptual molecular classes (TABLE 1), associated with a more favorable prognosis and low recurrence risk.15,16 Pro­liferative ER-positive tumors with more aggressive morphology and less favorable genetic profiles correspond largely to luminal type B ER-positive/HER-negative tumors that are less likely to benefit from endocrine therapy; these tumors have a high risk for recurrence and poorer outcomes.17 HER-2–overexpressing tumors are highly proliferative with a poor prognosis; however, outcomes for patients have improved significantly with the emergence of targeted anti­HER2 agents, and HER2 tumor status is considered a main factor for choice of therapy.4,8 Triple-negative breast cancers (TNBC) are char­acterized by a high proliferative index, a high histological grade, and despite a high response to neoadjuvant CT, a higher risk for disease recurrence.

 Breast cancer recurrence and survival data 

Approximately 20% to 30% of patients with early breast cancers will experience relapse with distant metastatic disease, and de­spite responsiveness to anti-estrogen therapies and frequent use of hormonal adjuvant therapy, one-quarter of women with ER-pos­itive disease will experience relapse.18 Risk of recurrence is influ­enced by stage at initial presentation and the underlying biology of the tumor (TABLE 1); independent risk factors for relapse include tumor size, nodal involvement, grade, lymphovascular invasion, and ER and HER2 status.19-21 Different breast cancer molecular subtypes are further associated with distinct patterns of relapse, metastatic spread, and substantial differences in survival after relapse.22-24 Overall, HR-positive MBC is characterized by the low­est incidence of metastases, late development of metastases, and highest propensity for bone metastases among all breast cancer subtypes, with development of osseous metastases as late as 10 to 20 years after initial diagnosis.25

The correlation of tumor IHC profiles from women with nonmeta­static breast cancer and subsequent outcomes revealed that HR-pos­itive tumors with slow proliferation (luminal A-like) had the lowest risk of local and regional relapse at 5 and 10 years.26 HER2-enriched cancers and TNBCs had the highest rates of relapse (prior to the introduction of trastuzumab), and HR-positive, highly proliferative luminal B tumors were associated with high rates of locoregional re­lapse.26 Similar findings were reported from other studies, including earlier relapse of basal-like and HER2 tumors (within 5 years) com­pared with luminal subtypes (ER positive, HER negative; continuing between 5 and 15 years),27 and significantly higher rates of 10-year disease-free interval for patients with luminal A-like disease (defined as ER positive, HER negative, low Ki-67; 86% of patients) compared with luminal B-like (defined as ER positive, HER negative, high Ki-67; 76%), HER2-positive (73%), and triple-negative (TN) (71%; P <.001) breast cancer.22 Ten-year OS was higher for patients with ER-positive/ HER2-negative breast cancer (89%) compared with luminal B-like (83%), HER2 (77%), and TN disease (75%; P <.001).22

A study evaluating the predictive power of the graded prognostic assessment (GPA) for patients with breast cancer and brain metas­tasis found a profound effect of tumor subtype on brain metastasis and survival. Patients with ER-positive/HER2-negative MBC had a relatively long median interval from primary diagnosis to the devel­opment of brain metastasis (54.4 months), but their median survival following the diagnosis of brain metastases was relatively short (10 months) compared with TN (27.5 months and 7.3 months, respec­tively), HER2-positive disease (35.8 months and 17.9 months, respec­tively), and ER-positive/HER2-positive disease (47.4 months and 22.9 months, respectively).28 OS from primary diagnosis was 90.3 months. Similar observations in other studies show longer survival of patients with cerebral metastatic ER-positive/HER2-positive disease com­pared with metastatic ER-positive/HER2-negative and TN disease.29,30

Metastasis locations
The development of metastases may be detected by radiologic staging at initial diagnosis, by abnormalities in laboratory indices, or from the presence of focal symptoms such as abdominal or bone pain or from neurologic changes. Common sites for breast cancer metastases are bone, lung, and liver (TABLE 2).25,31 Brain metastases develop in approximately 10% to 30% of all patients with breast can­cer, and presence of brain metastases is associated with the shortest survival time compared with other sites of metastasis.27,32 The loca­tion of metastasis is associated with cancer subtype, with predomi­nance of brain metastases in HER2-enriched and TN subtypes, and of bone metastases in ER-positive/HER-negative and luminal HER2 subgroups.22,27,33 Recurrence patterns in patients with early disease revealed a higher 10-year cumulative incidence of bone recurrence (6.64%) in ER-positive/HER2-negative breast cancer compared with all other subtypes.22 The most common visceral metastasis site of ER-positive/HER2-negative disease was the liver.22

Case Vignette 1: First-line therapy for ER-positive/ HER2-negative MBC


Susan, a bank clerk and mother of 2 adult children, was diagnosed with stage T1bN0 ER-positive/HER2-negative ductal carcinoma at the age of 44 years, when she was premenopausal. She underwent a simple mastectomy followed by adjuvant treatment with tamoxifen but discontinued therapy after one year due to side effects, particularly hot flashes. She continued routine follow-up visits with regular breast imaging. Nine years after initial diagnosis, at the age of 53 years, local recurrence is detected, and sentinel node biopsy confirms lymph node involvement, with ER-positive/HER-negative disease. Susan is treated with anastrozole, which initially results in regression of disease, but there is evidence of tumor progression at 10 months, and spread to 10 axillary lymph nodes is confirmed after axillary node dissection. She is then treated with 500 mg fulvestrant and experiences stable disease for 6 months; however, at 9 months, pulmonary involvement is noted. Susan is still asymptomatic with an excellent QOL. She begins a combination regimen of exemestane and everolimus.

Current consensus guidelines released by the National Compre­hensive Cancer Network (NCCN) and recent recommendations by the American Society of Clinical Oncology (ASCO) regarding CT and targeted therapy for women with HER2-negative (or unknown) advanced breast cancer emphasize that for patients with advanced or metastatic HR-positive breast cancer, endocrine therapy is ef­fective and preferable to CT as first-line treatment unless improve­ment is medically necessary.4,7 First-line CT should be considered in patients with severe symptoms or immediately life-threatening disease; in these patients, a more rapid intervention is desired, and the likelihood of a response to CT is higher.7 Patients with lytic bone metastasis should be treated with bone resorption-inhibitory drugs (eg, bisphosphonates or denosumab).4

Estrogen promotes the growth of estrogen-sensitive breast can­cer through several mechanisms that involve both ER-receptor– mediated activation of transcription and indirect gene activation through interaction of the ER with other cell-signaling pathways. Three main classes of endocrine agents are available for the treat­ment of HR-positive MBC that target these mechanisms differ­ently: selective estrogen receptor modifiers (SERMs), such as tamoxifen, which directly bind to the ER and block its tran­scriptional activity; selective estrogen receptor downregulators (SERDs), such as fulvestrant, which bind to the ER and induce its degradation; and aromatase inhibitors (AIs), such as letrozole, an­astrozole, and exemestane, which reduce the production of estro­gen via inhibition of the aromatase enzyme in peripheral tissues and within the tumor itself (FIGURE 2). The choice of endocrine therapy depends on menopausal status and disease sensitivity to endocrine therapy in patients with prior exposure. In patients with MBC, response rates to endocrine therapies range between 20% and 40%, with median response durations between 8 and 14 months, although duration of response can last many years in some patients.35,36 Resistance to endocrine therapy is common and can be distinguished into de novo resistance (to first-line en­docrine treatment) and acquired resistance (developing after a patient has an initial response to endocrine therapy).37

First-line treatment options for premenopausal patients
First-line endocrine therapies recommended for premenopausal patients with ER-positive MBC include selective ER modulators, luteinizing hormone–releasing hormone (LHRH) agonists, and surgical oophorectomy (FIGURE 3A).Inhibition of aromatase, a key enzyme required for estrogen production in postmeno­pausal women, is not suitable in premenopausal women without concomitant ovarian suppression or ablation because aromatase inhibition in the setting of functional ovaries leads to ovarian hy­perstimulation and development of benign ovarian pathology; it also does not adequately suppress ovarian estrogen synthesis.4

In the absence of prior endocrine therapy within the preceding 12 months, treatment with a SERM such as tamoxifen or toremi­fene with or without an LHRH agonist is considered a suitable first-line option for premenopausal women with ER-positive MBC. For women with prior exposure to endocrine therapy, ovarian ablation or ovarian suppression is recommended to render these patients postmenopausal, permitting subsequent treatment with an AI (eg, anastrozole, letrozole, exemestane) as for postmenopausal women. This is also a treatment option for patients without prior exposure to endocrine therapy. Ovarian ablation can be accomplished by sur­gical oophorectomy or by ovarian irradiation; ovarian suppression utilizes LHRH agonists that result in suppression of luteinizing hormone (LH) and release of follicle-stimulating hormone (FSH) from the pituitary and reduction in ovarian estrogen production. Available LHRH agonists in the United States include goserelin and leuprolide, which are given as monthly injections. Older endocrine agents, such as progestins (megestrol acetate), ethinyl estradiol, and androgens (fluoxymesterone), for which mechanisms of ac­tion are not as well understood, are not recommended for first-line treatment.4

Tamoxifen is a selective modulator of ER activity; tamoxifen and its active metabolites competitively bind to the ER receptor, inhib­iting the activation of estrogen-activated genes implied in tumor growth.11 Tamoxifen has been considered a standard-of-care treat­ment of HR-positive MBC for more than 4 decades, based on equal or greater efficacy and a more favorable toxicity profile compared with first-generation anti-estrogenic drugs.4 A meta-analysis of 35 randomized controlled clinical trials (5160 patients) comparing tamoxifen with other endocrine therapies, such as megestrol, me­droxyprogesterone, androgens (fluoxymesterone), other SERMs, LHRH agonists (goserelin), and first-generation AIs, demonstrated similar overall response rate (ORR) for tamoxifen (30%) compared with other drugs (29%), and survival was similar (hazard ratio [HR], 1.02; 95% CI, 0.94-1.10).38

A randomized trial evaluating the combination of an LHRH ago­nist (buserelin) with tamoxifen in premenopausal women with HR-positive MBC demonstrated superiority of the combination over buserelin or tamoxifen alone in respect to ORR (48%, 34%, and 28%, respectively), median PFS (9.7, 6.3, and 5.6 months, respectively; P = .03), and OS (3.7, 2.5, and 2.9 years, respectively; P = .01).39 A subsequent meta-analysis of 4 randomized controlled trials found superior PFS and OS with combined tamoxifen/LHRH agonist regi­mens compared with LHRH agonists alone in the treatment of pre­menopausal women with HR-positive MBC.40

First-line treatment options for postmenopausal patients
Recommended first-line regimens for postmenopausal women with ER-positive MBC are nonsteroidal AIs (anastrozole and le­trozole) and steroidal AIs (exemestane), SERMs (tamoxifen or to­remifene), and the SERD fulvestrant (FIGURE 3A).Postmenopausal women with prior exposure to endocrine therapy may be treated with an alternate endocrine therapy on disease progression. Stud­ies evaluating single-agent first-line regimens found a modest but higher efficacy of AIs compared with tamoxifen (TABLE 3), and a meta-analysis reported a small survival benefit with AIs compared with other endocrine therapies.41 The third-generation AIs anastro­zole and letrozole are currently considered superior to tamoxifen for the treatment of advanced disease based on the longer TTP ob­served in multiple trials (TABLE 3).42-45 Outcomes from a phase II trial suggest that a high-dose (500 mg) fulvestrant regimen is supe­rior to anastrozole in respect to TTP (23.4 months vs 13.1 months; HR, 0.63; 95% CI, 0.39-1.00; P = .0496)46,47 and OS (median, 54.1 months vs 48.4 months; HR, 0.70; 95% CI, 0.50-0.98; P = .041).48

Combination therapy with hormonal agents that have different mechanisms of action may provide clinical benefit beyond that of single hormonal agents. Two trials in the first-line setting have assessed potential benefits of adding fulvestrant, which downreg­ulates ER activity by inhibiting dimerization and promoting deg­radation, to inhibition of estrogen synthesis via AI (TABLE 3). The Southwest Oncology Group (SWOG) study S0226 reported supe-rior PFS (HR, 0.80; 95% CI, 0.68-0.94; stratified log-rank P = .007) and OS (HR, 0.81; 95% CI, 0.65-1.00; stratified P = .049) with the combination regimen over single-agent anastrozole, particularly among patients without prior exposure to tamoxifen.49 Contrasting with these findings, the Fulvestrant and Anastrozole Combination Therapy (FACT)50,51 study did not find superiority of combination endocrine therapy to single-agent anastrozole in patients, most of whom had received prior endocrine therapy; median TTP, OS, ORR, or clinical benefit rate (CBR) were similar between arms. The reason for the divergent outcomes in these 2 studies may include differences in patient characteristics, particularly prior exposure to endocrine therapy versus no exposure.

Mechanisms of endocrine resistance
Endocrine therapy is the most effective treatment for ER-positive metastatic breast cancer, but its effectiveness is limited by frequent failure to respond to initial therapy (de novo or intrinsic resistance) and high rates of acquired resistance (resistance that develops dur­ing a given therapy after an initial period of response). Only about one-third of patients with metastatic disease will have objective re­gression of tumor with initial endocrine treatment, and prolonged stable disease is experienced by only 20%.52

Intrinsic resistance to endocrine treatment can derive from loss of ERα expression and ER gene mutations, such as amplification or point mutations.

Multiple mechanisms have been identified for acquired resis­tance to endocrine interventions; these include changes in the tu­mor microenvironment and in the tumor itself that can be broadly categorized into deregulation of classic estrogen signaling, activa­tion of growth factor receptor pathways, changes in cell cycle sig­naling and apoptosis, epigenetic modifications, and changes in mi­croRNA (miRNA) expression.

Deregulation of classic estrogen signaling
In its classic nuclear function, ligand-bound ER can activate gene expression through direct binding of dimeric ER to specific DNA response elements in complexes with other factors, or it can in­teract with other transcription factors to influence gene activity (FIGURE 4A). This activity of ER can be deregulated in tumor cells through multiple mechanisms that include loss of expression of ERα; expression of splice variants, including truncated versions of ER; overexpression of ER co-activators; downregulation of ER co-repressors; increased levels of transcription factors involved in ER-regulated gene expression; and various posttranslational mod­ifications that influence ER activity, such as phosphorylation.52,53 Any such changes in ER presence or activity can result in an en­docrine-insensitive phenotype.

Activation of growth factor receptor pathways
Increased nonnuclear activity of the ER, that is, ligand-indepen­dent activation through crosstalk between the ER and growth factor receptor signaling pathways, can cause endocrine resis­tance (FIGURE 4B,4C). Multiple signaling pathways controlling cell growth and proliferation have been implied; these include the HER2 pathway,54 the epidermal growth factor receptor (EGFR) pathway,55 the mitogen-activated kinase pathway (MAPK),52 the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway,56 hedgehog signaling,57 fibroblast growth factor (FGF) signaling,58 and the insulin-like growth factor receptor (IGFR) pathway.59 Therapeutic approaches disrupting these pathways with specific inhibitors may therefore restore endocrine sensitivity. Combined therapy with the mTOR inhibitor everolimus and exemestane has entered clinical practice, and combination therapy of endocrine regimens with panPI3K inhibitors (BKM120, XL147, GDC-0032), dual PI3K-mTOR inhibitors (BEZ235, XL765, GDC-0941/GDC-9080), AKT inhibitors (MK2206, AZD5363), dual IGF-1R/insulin receptor kinase inhibitors (BMS-754807), and in­hibitors of multiple tyrosine kinases (TKI258) are being evaluated for the treatment of endocrine-resistant ER-positive MBC in clini­cal trials.37

Changes in cell cycle signaling and apoptosis
Escape from the antiproliferative effects of endocrine treatment can occur through upregulation of positive regulators of the cell cycle and changes in the expression of factors modulating apop­tosis. Increased expression of anti-apoptotic molecules, such as BCl-2 and BCl-Xl, and decreased expression of pro-apoptotic mol­ecules, such as BAK, BiK, and caspase 9, is one mechanism of re­sistance.60 The upregulation of positive cell cycle regulators, such as cyclins E1 and D1, can lead to loss of proliferative control by activation of downstream cyclin-dependent kinases (CDKs).61,62 In­creased expression of cyclin D1, which is normally subject to tran­scriptional regulation through the ER, appears to be a common event in breast cancers, particularly of the luminal type, leading to the activation of CDKs 4 and 6, which are key regulators of the cell cycle that trigger cellular progression from the growth phase into the S-phase.63,64 The oral CDK4/6 inhibitor palbociclib was re­cently approved for the treatment of advanced breast cancer,65 and 2 oral CDK4/6 inhibitors (abemaciclib, and ribociclib [LEE011]) are in advanced clinical development.37

Epigenetic changes
Epigenetic changes that cause silence of the ER gene and of ER target genes can contribute to ER-independent tumor growth and thus endocrine resistance. Different breast cancer subtypes have distinct methylation patterns that correlate with different expres­sion patterns. Epigenetic modulators, such as inhibitors of histone deacetylases (HDAC), are therefore being evaluated in endocrine-resistant breast cancer, including regimens of vorinostat with tamoxifen, exemestane with entinostat, and triple combinations of letrozole, panobinostat, and everolimus.37

Micro RNA
Small noncoding miRNA are conserved regulators of almost all cellular processes, and changes in the expression of miRNAs that control expression of ER or cell cycle regulators have been corre­lated with endocrine resistance in preclinical models.37

Second-line endocrine strategies: sequencing and combination approaches
Because of the underlying differential mechanisms of endocrine resistance, many patients with hormone-responsive breast cancer benefit from sequential use of endocrine therapies at disease pro­gression. For instance, tamoxifen-resistant tumors may still be es­trogen dependent but have become resistant to ER-targeted ther­apy; such tumors may respond to an AI or fulvestrant.52 Current guidelines therefore recommend that women experiencing clinical benefit from first-line endocrine therapy should receive additional endocrine therapy at disease progression. In premenopausal wom­en with previous anti-estrogen therapy who are within 1 year of anti-estrogen exposure, the preferred second-line therapy is ovar­ian ablation or suppression followed by endocrine therapy, as it is for postmenopausal women. Subsequent endocrine therapy op­tions recommended by the NCCN to be used after progression on first-line endocrine treatment are listed in FIGURE 3B. An optimal sequence of these therapeutic options is not established, but for as­ymptomatic patients with slowly progressive disease and response to prior lines of endocrine therapy, continued sequencing of other endocrine therapies is considered the preferred approach. Continu­ation of endocrine therapy is recommended until disease progres­sion or intolerable toxicity, and switching to CT is recommended if there is no benefit after 3 sequential endocrine regimens.4

 In patients with progression on tamoxifen, clinical trial evidence indicates that fulvestrant appears to be at least as effective as anas­trozole and can provide significantly longer duration of response (16.7 months vs 13.7 months).66 In postmenopausal women with MBC disease progression following aromatase inhibitor therapy, treatment with fulvestrant produced a CBR of 35%, including partial response rate of 14.3% and 20.8% in patients achieving stable disease for at least 6 months.67 Outcomes from the EFFECT trial suggest that for patients with progression of HR-positive advanced breast cancer on prior nonsteroidal AI therapy, fulvestrant (loading dose regimen of 500 mg intramuscularly (IM) on day 0, 250 mg on days 14 and 28, and 250 mg every 28 days thereafter) and exemestane (25 mg daily) yielded similar CBR (32.2% vs 31.5%; P = .853) and median TTP (3.7 months in both groups).68 Similar outcomes were reported from the SoFea (Study of Faslodex, Exemestane, and Arimidex) trial evaluating fulvestrant (250-mg loading schedule) with or without anastrozole to exemestane in patients with advanced, nonsteroidal AI-resistant disease. Median PFS did not differ between groups (combination, 4.4 months; fulvestrant, 4.8 months; exemestane, 3.4 months).69 Thus, adding an aromatase inhibitor to fulvestrant in patients with nonsteroidal AI-resistant disease does not appear to improve the results achieved with fulvestrant alone. The CONFIRM study demonstrated that a high-dose 500-mg fulvestrant regimen was associated with a significant increase in PFS (HR, 0.80; 95% CI, 0.68-0.94; P = .006) but not increased toxicity compared with a 250­mg dosing regimen.70 The high-dose regimen also increased median OS by 4.1 months (26.4 months vs 22.3 months; HR, 0.81; 95% CI, 0.69-0.96; P = .016) and reduced risk of death (19%).4

Subsequent responses to serial endocrine therapy tend to be­come increasingly shorter, which is often associated with decreases in ER level, implying less dependence on ER and increasing usage of alternative growth-promoting pathways. Progression on second-line and subsequent endocrine therapies can be expected between 3 and 6 months after previous aromatase inhibitor therapy. A regi­men of the mTOR inhibitor everolimus in combination with the AI exemestane can be considered for patients who progressed within 12 months on letrozole or anastrozole, or any time on tamoxifen.4 Results from the BOLERO-2 trial demonstrated that this regimen produced significantly longer PFS (7.8 months vs 3.2 months; P <.0001), ORR (12.6% vs 1.7%), and a 4.4-month improvement in OS compared with exemestane alone.71,72

In the MBC setting, close monitoring for potential early pro­gression is recommended, with assessment of symptoms, physical examination, routine laboratory tests, imaging studies, and, if suit-able, serum tumor markers, every 2 to 3 months (TABLE 4).Deter­mining whether or not the current regimen is continuing to control the disease may be complicated by contradictory outcomes in these assessments. Disease progression is defined as evidence of growth or worsening of disease at previously known sites of disease and/or of the occurrence of new sites of metastatic disease. Findings indica­tive of progression of disease include worsening symptoms such as pain or dyspnea; evidence of worsening or new disease on physi­cal examination; declining performance status; unexplained weight loss; increasing alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin; hypercalcemia; new radiographic abnormality or increase in the size of preexisting ra­diographic abnormality; new areas of abnormality on functional im­aging; or consistently rising tumor markers.4

Emerging first- and second-line endocrine strategies
Palbociclib is an oral targeted agent that selectively inhibits CDKs 4 and 6; dual inhibition of CDK 4/6 and ER signaling was found to be synergistic in preclinical studies.73 Outcomes from the phase II PALOMA-1 trial (NCT00721409; n = 165) have shown a significant improvement in PFS for patients with ER-positive/HER2-negative ad­vanced inoperable breast cancer who received palbociclib in combi­nation with letrozole compared with those receiving letrozole mono-therapy (20.2 months vs 10.2 months; 1-sided P = .0004).73 Based on these results, palbociclib received accelerated FDA approval for the treatment of MBC in postmenopausal women in combination with letrozole.65 The most common adverse events (AEs) with the combination regimen were neutropenia, leukopenia, fatigue, and anemia. Multiple phase III trials with palbociclib are ongoing both in the first-line setting (NCT01740427 [PALOMA-2], in combination with letrozole, postmenopausal patients) and second- and later-line settings (NCT01942135 [PALOMA-3], in combination with fulves­trant; NCT02028507, plus exemestane vs capecitabine in AI refrac­tory disease). Abemaciclib (LY2835219) is a dual CDK 4/6 inhibitor in advanced clinical development in the first-line (NCT02246621 in combination with nonsteroidal AI) and second-/later-line settings (NCT02107703, in combination with fulvestrant). Phase Ib trial data suggest that a combination regimen of the dual CDK4/6 inhibitor ribociclib (LEE011) and letrozole is feasible and has clinical activ­ity in patients with HR-positive/HER2-advanced breast cancer who had received prior endocrine therapy and up to one prior cytotoxic regimen.74 Two ongoing phase III studies are evaluating combina­tion regimens with LEE011 as first-line therapy in patients with HR-positive/HER2-negative disease (NCT01958021 [MONALEESA-2], in combination with letrozole, postmenopausal patients; NCT02278120 [MONALEESA-7], in combination with tamoxifen and goserelin or a nonsteroidal AI and goserelin, premenopausal patients).

Case Vignette 2: Later-line therapy for ER-positive/HER2-negative MBC

Martha, a 52-year-old bank clerk and mother of 2 adult children, is newly postmenopausal. During a routine self-exam, she discov­ers a lump in her right breast, and a subsequent mammogram reveals multiple tumors in both breasts. Based on biopsy findings, stage IIIA ER-positive/HER2-negative breast cancer without nodal involvement is diagnosed. After discussing her treatment options with her gynecologist and a surgical oncologist, Martha under­goes a bilateral mastectomy followed by adjuvant therapy with anastrozole. At her 5-year checkup, a computed tomography (CT) scan reveals bone lesions. Martha then starts a course of letrozole therapy and is additionally prescribed a bisphosphonate. However, progression of disease occurs within 7 months. An alternative regimen of exemestane and everolimus results in initial tumor regression; however, Martha needs to interrupt treatment twice because of stomatitis, and disease progression is detected after 4 months. After discussion with her oncologist, she agrees to re­ceive a CT scan and begins treatment with paclitaxel monotherapy, then switches to capecitabine when her disease again progresses. Martha’s medical oncologist orders another biopsy in order to determine if her metastatic disease continues to be ER-positive/ HER2-negative. Tumor IHC reveals this to be the case, and the physician discusses alternative treatment options with her. Martha agrees to begin treatment with eribulin.

Later-line therapy for ER-positive/HER2-negative MBC
In the absence of curative approaches for MBC, the main treatment goals are to prolong survival, palliate symptoms, and optimize QOL. Later-line treatment regimens that may yield tumor response or stability in advanced MBC include combination regimens of en­docrine therapies with targeted therapies (such as mTOR inhibi­tors), cytotoxic CT, and targeted therapies. Potentially severe AEs associated with later-line treatment regimens in MBC require care­ful balance of potential treatment effectiveness over QOL. While clinical trials have shown differences in response rate and TTP between different treatment regimens, few studies demonstrated an OS benefit with later-line regimens. The heterogeneity of the disease and prior exposure and the need for tumor subtype clas­sification complicate such analyses. Current guidelines strongly encourage participation in clinical guidelines, including phase I trials for targeted agents, even before all available treatment op­tions are exhausted.4,7

Cytotoxic CT options
According to both NCCN and ASCO guidelines, CT should be con­sidered for patients with MBC refractory to endocrine therapy and for those in whom MBC is associated with symptomatic visceral me­tastasis, such that the need for a more rapidly efficacious therapy prohibits the use of endocrine therapy.4,7 There is currently no evi­dence-based consensus on an optimal CT regimen in HR-positive/ HER-negative disease. Although combination therapy can increase response rates and TTP, this does not appear to translate into an OS benefit compared with single-agent regimens and is associated with increased toxicity and more severe AEs.58,75,76 Clinical trial evidence suggests that overall outcomes with single-agent sequential therapy are likely no different from those obtained with combination regi­mens.Sequential single-agent CT is therefore the current preferred choice of treatment in the absence of rapid clinical progression, life-threatening visceral metastases, or a need for rapid symptom and/or disease control; in these cases, combination regimens may be considered.Sequential administration decreases the likelihood that dose reductions will be needed.

In addition to the preferred single agents provided by the NCCN guidelines (TABLE 5), ASCO recommendations also include plat­inum-based compounds and ixabepilone as agents with clinical evidence supporting activity in both first- and subsequent-line set­tings. No evidence for superiority of a single agent exists; however, a comprehensive literature review supporting the current ASCO guidelines concluded that clinical evidence for efficacy in the first-line setting was strongest for taxanes and anthracyclines.Among second- and later-line regimens, evidence was strongest for a sur­vival benefit with the microtubule-targeting agent eribulin.7

The number of available combination regimens is exten­sive; NCCN-recommended options include cyclophosphamide/ doxorubicin/5-fluorouracil-based regimens (FAC/CAF); cyclophos­phamide/epirubicin/5-fluorouracil (FEC); doxorubicin/cyclophosphamide (AC); epirubicin/cyclophos­phamide (EC); cyclophosphamide/methotrexate/5­fluorouracil (CMF); docetaxel/capecitabine; gem­citabine/paclitaxel (GT); gemcitabine/carboplatin; and paclitaxel plus bevacizumab.

The addition of bevacizumab to CT has been shown to increase PFS (HR, 0.70; 95% CI 0.60-0.82; P = 9.3 × 10-6) and ORR (RR, 1.26; 95% CI, 1.17­1.37; P = 9.96 × 10-9),77 compared with CT alone, but it did not affect OS.77,78 The combination of beva­cizumab with paclitaxel is currently not indicated for breast cancer and should be considered only for immediately life-threatening disease or severe symptoms.7

Chemotherapy-associated adverse events
Chemotherapy-related AEs are common, with vary­ing toxicity profiles across agents. Because of their negative impact on QOL and on treatment efficacy if interruptions or dose reductions are required, poten­tial AEs need to be considered and treated proactive­ly. Generally, frequency and severity of AEs increase with the number of drugs included in the regimen.7

For example, taxane and capecitabine each given as monotherapy were found to cause significantly fewer AEs, particularly grade 3 and higher stomatitis and diarrhea, and lower myelosuppression, respectively, compared with combination regimens.7,79-80 Signifi­cant superiority of one treatment arm over the other in respect to AEs was also found for paclitaxel or docetaxel plus bevacizumab over triple regimens with additional capecitabine and docetaxel plus epirubicin over docetaxel plus capecitabine in first-line regimens, and for docetaxel plus gemcitabine over docetaxel plus capecitabine.7

Anthracyclines cause cumulative and dose-related cardiotoxicity, leading to progressive myocardial damage that can manifest with a range of symptoms from asymptomatic reduction in left ven­tricular ejection fraction to life-threatening chronic heart failure.81 Chronic and late-onset doxorubicin cardiotoxicity causes irrevers­ible cardiac dysfunction.82 Apart from the cumulative anthracycline dose, risk factors include dosing schedules, previous anthracycline therapy, radiation therapy, co-administration of additional poten­tially cardiotoxic agents, and patient-related factors including age, preexisting cardiovascular disease, or cardiac risk factors (hyper­tension, diabetes, obesity, smoking). The risk for anthracycline cardiotoxicity can be reduced by limiting the lifetime cumulative dose (<550 mg/m2 for doxorubicin), longer infusion duration, and weekly administration.4,82 Liposomal anthracycline formulations (nonpegylated and pegylated) reduce the toxicity for healthy tis­sues while increasing the concentration within the neoplastic tis­sue. According to a meta-analysis, liposomal-encapsulated doxo­rubicin was associated with a lower rate of clinical and subclinical heart failure compared with the conventional form (RR, 0.20; 95% CI, 0.05-0.75 and RR, 0.38; 95% CI, 0.24-0.59, respectively).83 Both pegylated and nonpegylated formulations of doxorubicin have sim­ilar efficacy with less cardiac toxicity when compared with free doxorubicin.84,85

Peripheral neuropathy can occur with microtubule-targeted agents, including taxanes and nontaxane microtubule inhibi­tors, such as ixabepilone and eribulin. Taxane-induced peripheral neuropathy manifests predominantly with paresthesia, sensation loss, and dysesthetic pain in feet and hands.86 This neurotoxic­ity is dose- and infusion-duration related and is associated with both the single and cumulative dose. Lower doses of paclitaxel (135-200 mg/m2) or weekly regimens can reduce the incidence and severity of neuropathy.87 Eribulin caused less neuropathy in animal models compared with paclitaxel88 and did not exacerbate preexisting neuropathy in patients pretreated with taxanes.89 In phase II clinical trials in patients with MBC who received prior treatment, the overall incidence of peripheral neuropathy (up to 32.6%) was lower than that observed in similar studies with other microtubule-targeting agents (above 60%); peripheral neuropathy led to discontinuation of eribulin in 5% of patients.90,91

 Hand-foot syndrome is the dose-limiting toxicity associated with capecitabine, with up to 20% of patients experiencing grade 3 to 4 toxicity.7 Early symptoms include erythema, skin peeling, numbness, tingling, or burning on the palms of the hands or soles of the feet, and treatment should be interrupted if grade 2 or high­er hand-foot syndrome occurs.

Myelosuppression is a common AE with cytotoxic CT. Che­motherapy-induced neutropenia is one of the most common tox­icities associated with anthracycline/taxane- or docetaxel-based regimens, eribulin, and vinorelbine, requiring dose reductions in the event of grade 4 neutropenia lasting 7 or more days or febrile neutropenia. Secondary prophylaxis with granulocyte colony-stimulating factor can be considered when treatment outcome is compromised.89,90 Combination regimens such as CMF are associ­ated with significantly higher neutropenia compared with inter­mittent or concurrent capecitabine (26% vs 1% vs 1%, respectively; P <.05).7

For taxane agents, alternative formulations have been suc­cessful at reducing certain treatment-associated AEs. Traditional formulations of taxanes in polyethoxylated castor oil have been associated with risk for potentially life-threatening hypersensitiv­ity reactions, requiring premedication and alteration of infusion schedules.86,87 A solvent-free albumin-stabilized nanoparticle for­mulation of paclitaxel (nab-paclitaxel) has been shown to be more effective than the conventional formulation (21.5% vs 11.1%; P = .003), while causing less neutropenia (9% vs 22%).92 Nab-paclitaxel is approved for the treatment of MBC after failure of combination CT (to include an anthracycline) for metastatic disease or relapse within 6 months of adjuvant CT. Due to lack of solvent, the dura­tion of nab-paclitaxel administration is shorter than that of other taxanes (30 minutes). Recent outcomes from a phase II study sug­gest a survival benefit with nab-paclitaxel at a 150-mg/m2 dose over lower (100-mg) or higher (300-mg) doses or docetaxel alone (median survival, 33.8 months vs 27.2 months, 22.2 months, and 26.6 months, respectively; P = .05).93 However, the 150-mg/weekly regimen has been associated with a higher incidence of grade 3 neuropathy compared with other dosing schedules and is there­fore generally not recommended.94

Targeted therapies in advanced HR-positive MBC
Insight into molecular mechanisms conferring resistance to en­docrine regimens has identified multiple pathways as potential targets for interventional therapies that may either restore sensi­tivity to endocrine regimens or that may be antineoplastic in the setting of endocrine resistance. Among these, mTOR and nontax­ane microtubule targeting strategies have advanced into clinical practice, and combination regimens of endocrine regimens with other targeted agents are in advanced clinical development. Stud­ies with EGFR-targeted agents such as erlotinib or gefitinib have so far failed to show significant clinical efficacy.95

Targeting mTOR
Activation of the PI3K–Akt–mTOR signal transduction pathway is one key mechanism by which tumors become resistant to endo­crine therapy. Clinical effectiveness of everolimus, a rapamycin derivative that inhibits mTOR signaling through allosteric binding to the mTORC1 protein complex, was first indicated by outcomes from the phase II TAMRAD study reporting that addition of evero­limus to tamoxifen resulted in improvements in CBR (61% vs 42%) and TTP (8.6 months vs 4.5 months; HR, 0.54).96 Based on out­comes of the phase III BOLERO-2 trial,97 everolimus received FDA approval in 2012 for the treatment of ER/PR-positive/HER2-neg­ative advanced breast cancer in combination with the aromatase inhibitor exemestane. BOLERO-2 demonstrated a significant PFS advantage for patients treated with everolimus/exemestane com­pared with exemestane monotherapy (7.8 months vs 3.2 months; P <.0001) and ORR (12.6% vs 1.7%).72 Recently reported OS data showed a 4.4-month improvement in OS compared with exemes­tane alone.71 While this difference was not statistically significant, it represents the longest median OS reported in a phase III clinical study of ER-positive/HER2-negative MBC to date.

A phase II trial evaluating the combination of everolimus with cisplatin and paclitaxel in patients with HER2-negative pretreated MBC (range: 0-4 prior chemotherapies and 0-7 prior endocrine therapies and/or investigational agents) found a median TTP of 5 months; ORR and CBR were 23.4% and 31%, respectively.98 The most frequently reported grade 3/4 AEs were neutropenia (28%) and anemia (16%); dose reductions due to myelosuppression were common from cycle 2 of treatment onward.98 Multiple combination clinical trials of everolimus in patients with HER2-negative/HR­positive breast cancer are ongoing.98

Oral ulceration is the most frequent AE in patients treated with everolimus, with a reported incidence in 44% to 86% of patients treated with everolimus across clinical trials.56 Suggested man­agement recommendations for grade 1 stomatitis include nonal­coholic or saltwater (0.9%) mouthwash several times daily without dose reduction, whereas for grade 2 and 3 stomatitis temporary dose interruptions are recommended, along with management with topical analgesic mouth treatments with or without topical corticosteroids; everolimus should be discontinued if grade 4 sto­matitis occurs.99 Clinical trials are currently evaluating steroid mouth rinses to prevent and treat everolimus-related stomatitis (NCT02229136, NCT02069093).

Targeting microtubules
Microtubules are essential to cellular function and are required for intracellular trafficking, cellular motility, and mitosis, repre­senting a target for antineoplastic drugs.90 Eribulin mesylate (er­ibulin) is a nontaxane microtubule dynamics inhibitor that binds to a unique site on tubulin and causes sequestration of tubulin into nonfunctional aggregates, which results in irreversible mitot­ic block and inhibition of cancer cell growth (FIGURE 5).89 Clinical activity of eribulin was shown in 3 phase II trials in patients with advanced breast cancer or MBC, yielding ORRs of 11.5%100 and 14.1%101 in heavily pretreated patients, and 21.3%102 among pa­tients who had previously received an anthracycline and a taxane; median duration of response ranged from 3.9 to 5.7 months.100-102 Based on results from the phase III EMBRACE trial (NCT00388726) that demonstrated a survival benefit with eribulin monotherapy over treatment of physician’s choice (TPC),103 eribulin received approval for third-line therapy in patients with MBC who have previously received treatment with both an anthracycline and a taxane. Patients (N = 762) with locally recurrent disease or MBC previously treated with 2 to 5 prior CT regimens (including an an­thracycline and a taxane) were randomly allocated to eribulin (1.4 mg/m2 as a 2-5 min IV infusion on days 1 and 8 of a 21-day cycle) or TPC.103 Patients treated with eribulin had a significantly longer median OS compared with patients in the TPC arm (13.1 months vs 10.7 months; HR, 0.81; 95% CI, 0.66-0.99; P = .04) and a signifi­cantly higher ORR (12.2% vs 4.7% treated with eribulin; P = .002). The median PFS was 3.7 months and 2.2 months with eribulin and TPC, respectively. The toxicity pro­file for eribulin monotherapy was manageable; grade 3/4 AEs were asthenia/fatigue (8.2% grade 3; 0.6% grade 4), neutropenia (21.1% grade 3; 24.1% grade 4), and pe­ripheral neuropathy (7.8% grade 3; 0.4% grade 4).102

A second phase III study (Study 301) compared eribulin with capecitabine in women with local­ly advanced or metastatic disease who had previously been treated with anthracyclines and taxanes but were in an earlier stage of their disease treatment.104 No difference in PFS or OS was observed between arms, but patients receiving eribu­lin had a significant improvement in QOL.104,105 A pooled analysis of both trials confirmed superior OS with eribulin over control (15.2 months vs 12.8 months; HR, 0.85; 95% CI, 0.77-0.95; P = .003), with significant benefit particularly among patients with HER2-negative disease.106 A nonrandomized phase II study evaluated eribulin in the first-line setting. Among patients with HER2-negative, locally recurrent disease or MBC (n = 56; 73% ER-positive disease, 21% TN MBC), the ORR was 29% after a median of 7 treatment cycles, with a median duration of response of 5.8 months and median PFS of 6.8 months. The most common grade 3/4 AEs included neutropenia (50%), leukopenia (21%), and peripheral neuropathy (21%).107 Multiple advanced clinical studies with eribulin in MBC are ongoing, including com­parative phase III trials versus vinorelbine (NCT02225470) and standard weekly paclitaxel (NCT02037529).

Targeting histone deacetylases
Promising activity of adding the oral HDAC inhibitor entinostat to endocrine therapy with exemestane was found in a randomized phase II study.108 Postmenopausal patients with ER-positive ad­vanced disease or MBC that had progressed on prior aromatase inhibitor therapy had a significantly longer median PFS when receiving exemestane plus entinostat compared with exemestane plus placebo (4.3 months vs 2.3 months; HR, 0.73; 95% CI, 0.49­1.09; P = .06). Median OS, an exploratory endpoint, was signifi­cantly prolonged in the entinostat compared with the placebo arm (28.1 months vs 19.8 months; HR, 0.59; 95% CI, 0.36-0.97; P = .036). ORRs and CBRs were similar between entinostat and pla­cebo groups (6.3% vs 4.6% and 28.1% vs 25.8%, respectively). The addition of entinostat was well tolerated, with a low incidence of added graded 3/4 AEs over placebo.108

Proteasome inhibitors
Recently reported outcomes from a phase II study suggest that adding the proteasome inhibitor bortezomib, which blocks NF-kB signaling, to endocrine therapy may benefit patients with ER-pos­itive advanced MBC resistant to AI therapy. The addition of bort­ezomib to fulvestrant reduced the rate of disease progression (HR, 0.73; P = .6) and significantly improved 12-month PFS from 13.4% to 28% (P = .03); however, 6-month and median PFS (2.72 months vs 2.69 months) were similar for the combined regimen and ful­vestrant monotherapy.109

Case Vignette 3: Factors to consider when selecting treatments

Elizabeth is a 76-year-old widow who lives by herself. She was di­agnosed with ER- and PR-positive/HER-negative MBC 3 years ago and has experienced disease progression with 3 successive endo­crine therapies, including tamoxifen, letrozole, and fulvestrant. As bone metastases were discovered after progression on letrozole, she has additionally received treatment with denosumab. At the most recent progression, liver metastases were detected. Eliza­beth suffers from hypertension and metabolic syndrome and has been treated with an angiotensin-converting enzyme (ACE) inhibi­tor for 8 years. After failure of endocrine therapy, Elizabeth moves in with her daughter’s family. Her daughter, a nurse, has investi­gated options for hospice care but currently considers home care feasible, which is much preferred by Elizabeth, who enjoys the company of her grandchildren. Elizabeth is willing to try CT and is placed on a weekly paclitaxel regimen, during which she needs to delay 2 cycles due to peripheral neuropathy; she also suffers from ongoing fatigue. She experiences stable disease for 7 months. A subsequent regimen with liposomal doxorubicin is interrupted after 3 cycles because Elizabeth experiences hand-foot skin reac­tions. She is unwilling to resume CT because she feels that therapy is starting to affect her cognition and functional status. She and her daughter discuss options with her oncologist, and Elizabeth decides to begin treatment with eribulin.

Personalizing goals of CT in MBC
At present, MBC remains incurable, and the general goals of ther­apy are to prolong survival, palliate symptoms, and optimize QOL. Treatment selection should therefore not be solely based on effi­cacy data but should also include toxicity profile, the patient’s per­formance status and comorbid conditions, prior therapy received, disease pace (indolent, rapidly progressive), and the patient’s pref­erences regarding additional therapy and anticipated AEs, as well as schedule and dosing mode.Endocrine therapy is preferable to CT as first-line treatment for patients with ER-positive MBC unless very rapid clinical improvement is medically necessary or endocrine resistance is present. Optimal first- or later-line therapy can therefore vary substantially between individual patients and can be influenced also by estimated survival and expected gain from treatment.

Based on a comprehensive literature review, the ASCO guidelines provide a listing of multiple randomized clinical trials in which supe­riority of one CT treatment arm over the other was found both in re­spect to efficacy outcomes such as median survival, ORR, PFS, or TTP and in respect to QOL, AEs, functioning, and specific AE.This listing can provide guidance in treatment selection, incorporating patient goals and preferences, and will likely be expanded with increasing incorporation of QOL assessments as an outcome measure in breast cancer clinical trials.105 A survey of 181 patients with MBC reported that effectiveness (OS) was of primary importance to patients, fol­lowed by AEs specifically alopecia, fatigue, neutropenia, neuropathy, and nausea/vomiting, and lastly, dosing regimen schedule.110 Ap­proximately 33% of patients reported nonadherence to regimens, with forgetfulness and AEs as main reasons.110 Outcomes from a study of 226 patients with limited life expectancy for various medical reasons emphasize the importance of QOL. Almost all patients indicated that they would accept a low-burden treatment, but 74% and 89% would decline a treatment that resulted in severe functional impairment or cognitive impairment, respectively.111

Although long-term survival is possible for a small subgroup of patients with MBC, approximately 1% to 3%, usually young patients with good performance status and limited metastatic disease,112 the majority of patients face a limited life expectancy, which ren­ders communication about disease state and possible and expect­ed benefits from therapy of high importance. Most patients prefer to obtain information regarding survival, side effects, symptoms, and treatment options.113 Shared decision making between physi­cians and patients will be different for newly diagnosed patients and those whose disease has progressed on multiple previous treatment regimens. A recent study revealed that patients with breast cancer expected much greater benefits from therapy than did physicians; about 50% of patients responding to a question­naire outlining therapy options for MBC in specific case settings expected more than a 12-month increase in OS for all therapies.114Previous experience of side effects and having young children in the family were the strongest influencing factors.114

Discussions with patients regarding treatment goals should therefore include the rationales for evidence-based therapies and provide guidance to patient resources such as Cancer.Net. Addition­ally, patients should be referred to psychosocial support and intro­duced to concepts of concurrent palliative and antitumor therapy.7 Defining the disease context with patients and families includes the consideration of specific psychosocial needs, such as job flexibility, rehabilitation, body image (including sexuality), home and child care in younger patients, and incorporating family members in consultations and decision making for older patients.115,116 Specific domains to be evaluated in geriatric assessment include functional status (such as ability to live independently), comorbidities, psy­chological state, social support, nutritional status, cognition, and medications and possible drug interactions.34 Particularly in older patients, a tendency exists for undertreatment because of fear of toxicity or concern about comorbidities; however, age alone should not affect treatment selection, and management needs to be cus­tomized individually.34

Tolerance of adverse effects
Adverse effects may require dose reduction and cessation of CT prior to disease progression. Both the ASCO and NCCN guidelines recognize the difficulty of balancing the benefits of CT (ie, modest improvement of OS but substantial improvement of PFS), particu­larly with continuous CT versus shorter-course CT, against toxicity and QOL.4,7 The ASCO guidelines suggest that short breaks, flexibil­ity in scheduling, or a switch to endocrine therapy may be offered to selected patients; this decision will be influenced by many factors including drug used (eg, long-term use of capecitabine is generally feasible whereas docetaxel is limited by cumulative toxicity) and re­quires a continuing dialogue between doctor and patient.

An important consideration is to determine which, if any, comorbid condition may have an impact on treatment toxicity. Common comor­bidities differ between younger and older patients (TABLE 6) and may be disproportionately present in patients of racial/ethnic minorities.7 Predicting toxicity in older patients is complex, as age-related changes in physiology, such as impaired renal clearance, decreased hepatic mass, and alterations in gastric function, can affect drug metabolism and clearance, and thus toxicity.34

TABLE 7 lists therapies in MBC and specific geriatric considerations. Out­comes from a recent phase III trial comparing pegylated liposomal doxorubicin (PLD) with capecitabine as first-line CT in older patients revealed similar effectiveness (median PFS, 5.6 months vs 7.7 months; median OS, 13.8 months vs16.8 months) and feasibility, with grade 3 toxicities consist­ing of fatigue (both arms: 13%), hand-foot syndrome (PLD: 10%; capecitabine: 16%), stomatitis (PLD: 10%; capecitabine: 3%), exanthema (PLD: 5%), and di­arrhea (PLD: 3%; capecitabine: 5%).116

Among microtubule-target­ing agents, clinical trial evi­dence suggest a more favorable toxicity profile of eribulin compared with other agents, with a lower incidence of peripheral neuropathy, at rates of 31% to 32.6% in phase II trials, which are lower than those observed in similar trials with paclitaxel, nab-paclitaxel, and ixabep­ilone (70%, 71%, and 63%, respectively).90 A recent phase III study found that QOL and cognitive functioning improved more signifi­cantly in pretreated patients with MBC who received eribulin com­pared with capecitabine, whereas emotional functioning improved significantly for patients receiving capecitabine. Patient-reported signs/symptoms in favor of eribulin included nausea and vomiting and diarrhea; systemic side effects and upset by hair loss favored capecitabine.105

An important consideration is to encourage accurate communi­cation of AEs, as frequency and severity of many symptoms that impact upon an individual patient’s QOL are often not sufficiently recognized and treated.117 Instruments and measures of patient-reported outcomes that can be used to more accurately monitor the harms and benefits of patient experience include the EORTC QLQ­C3 (http://groups.eortc.be/qol/eortc-qlq-c30) and the FACT (http:// www.facit.org/FACITOrg/Questionnaires).115

Sequencing of therapies in the metastatic setting and QOL considerations
According to the ASCO guidelines, second- and later-line therapy may be of clinical benefit and should be offered as determined by previous treatments, toxicity, co-existing medical conditions and patient choice. As with first-line treatment, no clear evidence ex­ists for the superiority of one specific drug or regimen; for later-line treatment, outcomes from the EMBRACE trial demonstrated survival superiority with eribulin over best standard treatment. Evidence suggests that response to second and subsequent lines of CT is strongly influenced by response to earlier treatment; pa­tients whose disease has not responded to up to 2 initial lines of treatment are less likely to respond to a third or subsequent line.7

Palliative care should be incorporated into treatment early on and be offered throughout. This need is underlined by multiple studies documenting poor QOL among patients with MBC, caused by pain and poor symptom control but also psychological distress, with de­pression, anxiety, and loss of self-image.112,118,119 Psychological dis­tress also represents a challenge for family members. Incorporating distress screening and psychosocial interventions such as nurse-delivered interventions can improve QOL.120,121

With diminishing effectiveness of later lines of CT, clinicians should also offer best supportive care without further CT as an op­tion.The NCCN considers not obtaining a tumor response with any of 3 sequential CT regimens or ECOG performance status of 3 or greater an indication for supportive therapy only.Lack of response to a CT regimen is defined as the absence of even a marginal re­sponse to the use of a given CT regimen.Hospice and palliative-care interventions can substantially improve QOL, and possibly sur­vival, in cancer patients.122 Outcomes from a trial evaluating early addition of a structured palliative-care program to CT in patients with metastatic NSCLC showed significant improvement in QOL and mood compared with standard care, as well as extended me­dian survival.123 The importance of early referral to palliative care and hospice is underlined by findings that patients with referral are more likely to have an advanced directive and die at home; however, in many cases, hospice services are delayed.124,125 Consultations on end-of-life planning can increase the use of hospice care and reduce potentially unnecessary interventions.126

Conclusions

MBC remains an incurable disease, such that the main goals of treatment focus on prolongation of survival while maintaining or improving QOL. For women with HR-positive MBC, who constitute the vast majority of patients with MBC, current guideline recom­mendations strongly advocate endocrine therapies as first-line intervention unless the disease is immediately life threatening.4,7 Main benefits of endocrine therapy are lower toxicity and better QOL. It is also recommended to extend the duration of hormonal therapy before advancing to cytotoxic CT, with sequential use of endocrine agents.Resistance to endocrine agents is common; however, because of multiple mechanisms that may cause resis­tance, patients may still benefit from other endocrine therapies with different mechanisms of action.37 The optimal sequence for use of the available single-agent therapies—including tamoxifen, nonsteroidal AI (anastrozole, letrozole), the steroidal AI exemes­tane, and fulvestrant—is not established. Fulvestrant and exemes­tane represent equivalent therapies for patients with recurrence during treatment with AI, a frequent scenario due to the extensive use of AI in earlier stages of the disease.Among potential ap­proaches to restore endocrine resistance by blocking complemen­tary pathways, mTOR inhibition has entered clinical practice, and everolimus can be offered in combination with exemestane follow­ing treatment with a nonsteroidal AI.56 The oral CDK 4/6 inhibi­tor palbociclib has recently become available for the treatment of MBC in postmenopausal patients, in combination with letrozole,65 and 2 inhibitors of CDK kinases are in advanced clinical evalua­tion in combination with an AI or fulvestrant as first- and second-line therapy. 

Chemotherapy should be considered for patients with rapidly progressing or life-threatening disease, and for those with resis­tance to multiple endocrine therapies.4,7 Multiple CT agents with proven activity in HR-positive MBC are available, and the se­quential use of single agents is recommended over combination regimens unless the disease is immediately life threatening, such that the need for a response outweighs the disadvantages of in­creased toxicity.Although combination regimens increase ORR and PFS compared with sequential single-agent therapies, they do not provide benefits in duration of response and OS.Agent selection should be based on previous exposure, differential toxicity, comorbid conditions, and patient preferences. First-line recommendations include taxanes and anthracyclines, for which efficacy data are strongest, as well as capecitabine, gemcitabine, platinum compounds, vinorelbine, and ixabepilone.7 As long as it is tolerated, CT should be continued until progression of dis­ease; however, interruptions and scheduling changes need to be considered to maintain QOL, and palliative strategies should be incorporated into treatment early on. Second- and later-line CT treatments are recommended because they can provide clinical benefit. Again, the choice of agent depends on previous treatment, toxicity, comorbidities, and patient choice; efficacy data suggest a survival benefit with eribulin.92 Participation in clinical trials, in­cluding earlier stages such as targeted phase I and II, is strongly encouraged. With intense research into treatment modalities for MBC, clinical trial data are evolving rapidly, and continuing incor­poration of novel strategies into clinical practice is essential to al­low for best patient care. The palliation of symptoms, both medical and psychosocial, remains a major aspect of the management of patients with MBC.

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Community Oncologist’s Perspective

Hussein Ali-Ahmad, MD, is a clinical assis­tant professor of oncology at Rosewell Park Cancer Institute in Jamestown, NY. He is board certified in oncology. He completed an internship and residency in internal medicine at the Bronx-Lebanon Hospital, and a fellowship in hematology/oncology at Okla­homa University Health Sciences Center.

In cases where I suspect metastatic disease based on laboratory results, physical examination, or radiographs, I always recommend that the metastatic site be biopsied to confirm that the lesion is con­sistent with breast cancer rather than another primary malignancy or some other benign process. Repeat biopsy when metastatic dis­ease is diagnosed is also important in order to reassess receptor status prior to the initiation of therapy.

Before I initiate therapy for metastatic breast cancer (MBC), I assess the extent of the disease with imaging studies, specifically, a computed tomography (CT) scan of the chest and abdomen and a bone scan. A positron emission tomography (PET) scan coupled with a CT scan is another option, but it is costlier and does not provide any more information than a CT scan and bone scan may provide. Brain magnetic resonance imaging (MRI) should also be performed in any patient with focal neurologic signs that suggest central nervous system involvement, such as headaches, seizures, cognitive changes, or focal neurologic weakness.

Laboratory studies are also necessary. These include a complete blood count to assess the bone marrow reserve, blood chemistry tests to assess renal and hepatic function and electrolyte levels, and testing for tumor markers, such as CA 15-3 and CA 27-29. El­evations in tumor marker levels at the time of MBC diagnosis yield helpful information for monitoring the response to treatment.

To control pain, I recommend local therapy for metastatic breast lesions. In the event of cord compression or unstable bone lesions, I recommend palliative surgery of the primary tumor, although this will not impact the clinical outcome.

For patients with bone metastasis, I add bisphosphonates (pami­dronate and zoledronic acid) or denosumab in combination with calcium and vitamin D. Due to the risk of osteonecrosis of the jaw, I recommend dental clearance before starting bisphosphonate treat­ment. When possible, dental procedures should be avoided.

When choosing therapy for MBC, I take many factors into con­sideration. My goal is to select the treatment regimen that is most likely to yield clinical response with the least amount of toxicity and side effects. It is critical to assess the hormonal status from the original breast biopsy or from a metastatic site. It is also very important to assess HER2 status early on in order to determine whether or not HER2-targeted therapy is a viable option.

In patients with hormone receptor-positive tumors, I recommend endocrine therapy as a first-line treatment if there is no evidence of visceral metastatic disease or rapid disease progression. I choose the type of endocrine therapy based on the patient’s menopausal status and comorbidities, as well as what agents she has received in the adjuvant setting.

For premenopausal women with no prior adjuvant tamoxifen therapy or who discontinued it more than 12 months prior to di­agnosis, I treat with tamoxifen and ovarian suppression. I always inform patients about the different options of ovarian suppression that are available, namely, medical suppression with a luteinizing hormone-releasing hormone analogue, surgery, or ovarian irradia­tion. Most patients prefer medical suppression. Further treatment in patients with ovarian ablation or suppression does not differ from that in postmenopausal women. 

 In postmenopausal women with no prior adjuvant hormonal therapy, or if it was discontinued more than 12 months prior to di­agnosis, I recommend an aromatase inhibitor, such as anastrozole, letrozole, or exemestane. To lower the risk of accelerated bone loss, I add calcium and vitamin D supplements. Patients whose disease displays resistance to upfront endocrine therapy should proceed to chemotherapy.

Patients with hormone-refractory or triple-negative disease should receive chemotherapy. I select the first-line chemotherapy regimen based on the patient’s performance status, comorbidities, and the presence or absence of visceral metastasis. I recommend taxane-based regimens as first-line therapy for patients progress­ing after adjuvant anthracycline-based, non-taxane-containing chemotherapy regimens. There are many single agents from which to choose; these include anthracyclines (doxorubicin, epirubicin, and doxil); taxanes (paclitaxel, docetaxel, and albumin-bound pa­clitaxel); antimetabolites (capecitabine and gemcitabine), and mi­crotubule inhibitors (eribulin and vinorelbine).  I usually select eribulin in the third-line setting after 2 failed chemotherapy regi­mens, one of them including an anthracycline.

I treat patients with triple-negative breast cancer with cytotoxic agents.  Combination therapy is more often required in triple-neg­ative breast cancer because of its aggressive course and frequent visceral involvement. However, triple-negative histology alone is not sufficient reason to give combination chemotherapy.

I reserve combination chemotherapy for highly symptomatic pa­tients or for those with high tumor burden. There are several com­bination chemotherapy regimens from which to choose. The most common regimens that I use are doxorubicin and cyclophospha­mide, gemcitabine and paclitaxel, or docetaxel and capecitabine. Ixabepilone and capecitabine are used in the third-line setting.

In patients with HER2-positive MBC, I generally recommend pertuzumab plus trastuzumab in combination with a taxane as the first-line treatment. Other possible regimens include trastuzumab in combination with any of the following agents: paclitaxel with or without carboplatin, docetaxel, vinorelbine, or capecitabine. Lapa­tinib and capecitabine are options for treatment in patients with HER2-positive disease following progression on a trastuzumab­containing regimen.

Finally, I monitor patients with MBC with examination and labo­ratory studies every 2 to 3 months for those on endocrine therapy and prior to each cycle in those on chemotherapy. I order a CT scan and bone scan every 3 to 6 months in patients on endocrine thera­py, and every 3 to 4 cycles in patients on chemotherapy.

Begin the post-test (Free activity)