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Case Vignettes in Metastatic Breast Cancer

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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).

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