Case Vignettes in Metastatic Breast Cancer
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.7 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.7 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.7 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
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).
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
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