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`CURRENT ONCOLOGY, VOL 20, NO 1 (2013)
`
`Practice Guideline Series
`Endocrine therapy for postmenopausal women with hormone
`receptor–positive HER 2–negative advanced breast cancer after
`progression or recurrence on nonsteroidal aromatase inhibitor
`therapy: a Canadian consensus statement
`
`K.I. Pritchard , MD
`
`*
`
`†
`, K.A. Gelmon , MD
`
`||
`
`PhD
`
`, D. McLeod , BSc
`
`#
`
`, S. Verma , MD
`
`, D. Rayson , MD
`
`‡
`
`**
`
`, L. Provencher , MD
`
`, M. Webster , MD
`
`§
`
`*Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, ON.
`†BC Cancer Agency, Vancouver, BC.
`‡QEII Health Sciences Centre, Halifax, NS.
`§Centre des Maladies du Sein Deschênes–Fabia, CHU de Québec, Hôpital St-Sacrement, Québec City, QC.
`||Tom Baker Cancer Center, Calgary, AB.
`#Kaleidoscope Strategic, Toronto, ON.
`**Sunnybrook Odette Cancer Centre, Toronto, ON.
`doi: http://dx.doi.org/10.3747/co.20.1316
`
`ABSTRACT
`
`Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012.
`Despite improvements in screening and adjuvant treatment options, a substantial number of
`postmenopausal women with hormone receptor positive ( HR +) breast cancer will continue to
`develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of
`endocrine therapy for patients with HR + disease that is negative for the human epidermal growth
`factor receptor 2 ( HER 2–) and that has relapsed or progressed on earlier nonsteroidal aromatase
`inhibitor ( NSAI ) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen
`are approved therapeutic options in this context. Four phase III trials involving 2876 patients—
`EFECT , SoFEA , CONFIRM , and BOLERO -2—have assessed the efficacy of various treatment options in
`this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly)
`and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to
`500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to
`exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression,
`albeit with increased toxicity. Multiple treatment options are now available to women with HR + HER
`2– advanced breast cancer recurring or progressing on earlier NSAI therapy, although current clinical
`trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration
`should be given to the patient’s age, functional status, and comorbidities during selection of an
`endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.
`
`KEYWORDS: Advanced breast cancer , endocrine therapy , m TOR -inhibitor, nonsteroidal aromatase
`inhibitor , everolimus , fulvestrant , exemestane , endocrine resistance
`
`1. INTRODUCTION
`
`Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012, and 5100
`women were expected to die of their disease1. Between 70% and 75% of breast cancers are hormone receptor
`–positive ( HR +)2–4. Despite significant improvements in outcomes since the early 1990s, a substantial number
`of women with HR + breast cancer continue to develop metastatic disease. In the advanced breast cancer ( ABC )
`setting, sequential endocrine therapy ( ET ) is an optimal treatment strategy for women with reasonably limited
`and indolent disease; for rapidly progressive or symptomatic disease, chemotherapy is commonly considered
`optimal5,6. Aromatase inhibitors ( AI s) have improved ABC outcomes in postmenopausal women in the adjuvant
`and metastatic settings and have become important options in sequential ET 7–9.
`
`Despite the efficacy of ET for HR + ABC , approximately 30% of women with metastatic disease will have primary
`resistance to ET , which is commonly defined as recurrence within the first 2 years on adjuvant ET or as
`progressive disease within 6 months of treatment initiation for advanced disease10,11. Furthermore, many
`patients with initial response to ET will acquire secondary resistance, commonly defined as disease progression
`more than 6 months after ET initiation11,12. While there appears to be clinical benefit in combining therapies
`targeted to the human epidermal growth factor receptor 2 ( HER 2) with ET in HER 2-positive ( HER 2+) ABC 13,14,
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`attempts at combining other receptor tyrosine kinase inhibitors with ET in the HER 2-negative ( HER 2–) setting
`have met with limited success14–16, highlighting an unmet clinical need in this population.
`
`Sequential ET with selective estrogen receptor modulators, steroidal AI s, and estrogen receptor downregulators
`remains the current standard of care for postmenopausal women with HR + HER 2– ABC . Considering the
`increased use of nonsteroidal AI ( NSAI ) therapy in both the adjuvant and the first-line metastatic setting, the
`question of which ET to use upon recurrence or progression during prior NSAI therapy is of increasing clinical
`interest. Historically, high-dose estrogen and megestrol acetate—and the more established selective estrogen
`receptor modulator tamoxifen—have demonstrated clinical benefit while being reasonably well-tolerated among
`patients with HR + ABC 17–24. However, megestrol acetate and tamoxifen have not been investigated in large
`phase III trials for HR + ABC disease progressing or recurring on NSAI therapy and are therefore not considered in
`this consensus statement. Exemestane ( EXE ), a steroidal AI , acts by binding irreversibly to the substrate binding
`site of aromatase, a mechanism that contrasts with the reversible binding of NSAI s25. Exemestane has
`demonstrated activity comparable to that of tamoxifen as initial therapy for HR + metastatic disease in
`postmenopausal women9, is not fully cross-resistant with NSAI s26, and is commonly recommended as the next
`line of therapy after disease progression on a NSAI . Unlike tamoxifen, the estrogen receptor downregulator
`fulvestrant is devoid of any agonist activity27. On binding to the estrogen receptor, fulvestrant induces rapid
`degradation of the estrogen and progesterone receptors28,29. Fulvestrant has demonstrated activity similar to
`that of tamoxifen when used as initial therapy for metastatic HR + ABC progressing on prior ET 17,30–33.
`
`Researchers studying resistance to ET in HR + ABC have sought to identify new therapeutic strategies that
`enhance the efficacy of ET s34. A recently identified mechanism of endocrine resistance is aberrant signalling
`through the phosphatidylinositol 3 kinase–Akt–mammalian target of rapamycin (m TOR ) signalling pathway35
`–37. Targeted inhibition of this pathway using m TOR inhibitors has therefore become a key clinical research
`strategy in the attempt to reverse resistance to ET . Three m TOR inhibitors— temsirolimus, sirolimus, and
`everolimus ( EVE )—have been tested in combination with ET in the treatment of HR + ABC 10,38–41. Temsirolimus
`was not found to improve outcomes when combined with letrozole as initial therapy for women with HR + ABC
`38,40; however, sirolimus and EVE have both demonstrated activity when combined with ET in HR + HER 2–
`patients recurring or progressing on prior ET 10,39.
`
`Postmenopausal women with HR + HER 2– ABC recurring or progressing on NSAI s have an unmet clinical need. The
`present consensus statement weighs available phase III evidence and clinical issues to formulate evidence-based
`recommendations for ET in this patient population.
`
`2. FORMULATION OF PANEL DISCUSSIONS AND RECOMMENDATIONS
`
`The discussions and author recommendations that follow were developed in a two-step consensus development
`process. Authors first participated in a Web-based consensus panel discussion on September 10, 2012, to review
`and discuss available evidence and to formulate treatment recommendations. The second phase of the
`development process involved the refinement both of the consensus discussions and of the recommendations
`with the active involvement of all participants in the iterative manuscript development process.
`
`3. OVERVIEW OF KEY TRIALS OF ET FOR HR+ HER2– ABC PATIENTS
`RESISTANT TO NSAI THERAPY
`
`Results from four large phase III trials evaluating ET for postmenopausal patients with HR + ABC that relapsed or
`progressed on prior NSAI therapy have been reported to date (Figure 1)31–33,41.
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`FIGURE 1
` Trial design summary. HR + = hormone receptor–positive; ABC = advanced breast cancer; NSAI = nonsteroidal aromatase
`inhibitor; R = randomization; ER + = estrogen receptor–positive; ET = endocrine therapy; HER 2– = human epidermal growth factor
`receptor 2–negative.
`
`The EFECT trial evaluated the safety and efficacy of fulvestrant compared with EXE in patients with advanced
`disease31. This placebo-controlled trial enrolled 693 patients and compared
`fulvestrant delivered
`intramuscularly [beginning with a loading dose of 500 mg on day 1, followed by 250 mg on days 14 and 28, and
`monthly thereafter (F250)] with once-daily oral EXE at 25 mg (Figure 1). The primary endpoint was time to
`progression ( TTP ), and baseline patient and disease characteristics were balanced between the treatment arms.
`The two regimens demonstrated comparable objective response rates ( ORR : 7.4% and 6.7%; p = 0.74) and TTP
`(3.7 months in both arms, p = 0.653, Table I). Survival data have yet to be reported31.
`
`TABLE I Efficacy outcomes: phase III clinical trials of endocrine therapy for advanced breast cancer failing prior
`nonsteroidal aromatase inhibitors
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`The SoFEA trial compared both fulvestrant alone and fulvestrant plus anastrozole with EXE . This threearm trial
`accrued 750 HR + patients and compared an intramuscular injection of fulvestrant [beginning with a loading dose
`of 500 mg, followed by 250 mg on day 15, and monthly thereafter (F250)] plus an oral daily dose of anastrozole 1
`mg with F250 plus placebo and with an oral daily dose of EXE 25 mg (Figure 1)32. Baseline patient and disease
`characteristics were balanced between the treatment arms, and the primary endpoint was progression-free
`survival ( PFS ). Compared with EXE , neither F250 alone nor F250 combined with anastrozole resulted in a
`significantly improved ORR (6.9% vs. 7.4% vs. 3.6%), PFS (4.8 months vs. 4.4 months vs. 3.4 months), or overall
`survival ( OS : 19.4 months vs. 20.2 months vs. 21.6 months; Table I).
`
`In both the foregoing trials, F250 and EXE were well tolerated, with low rates of treatment discontinuation
`because of toxicity and low rates of serious adverse events. The most common adverse events of any grade for
`the SoFEA trial were nausea (43.5% F250 vs. 37.2% EXE ), arthralgia (42.6% vs. 46.6%), and lethargy (62.6% vs.
`54.3%, Table II).
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`TABLE II Summary of adverse events of any grade reported at 40% or more frequentlya in phase III endocrine
`therapy trials
`
`The phase III double-blind placebo-controlled CONFIRM trial evaluated the safety and efficacy of doubling the
`dose of fulvestrant for patients with prior exposure to ET 33. A total of 736 patients with recurrent or progressive
`disease on either prior AI therapy (42.5%) or prior anti-estrogen therapy (57.5%) were enrolled in the trial.
`Patients were randomized to receive an intramuscular dose of fulvestrant either 500 mg or 250 mg monthly
`(F500 vs. F250, Figure 1). The primary endpoint was PFS . Baseline patient and disease characteristics were
`balanced between the treatment arms. Doubling the dose of fulvestrant did not improve the ORR (9.1% F500 vs.
`10.2% F250, p = 0.795) or OS (25.1 months vs. 22.8 months, p = 0.91, Table I). Patients receiving the higher dose of
`fulvestrant experienced a statistically significant improvement in median PFS [6.5 months vs. 5.5 months; hazard
`ratio ( HR ): 0.80; 95% confidence interval ( CI ): 0.68 to 0.94; p = 0.006], which trended toward significance in
`patients recurring or progressing on prior AI s (estimated HR : 0.85; 95% CI : 0.67 to 1.08). No substantial
`differences in the incidence or severity of adverse events were observed in the two arms. With F500, no adverse
`events with an overall incidence of 40% or greater were observed (Table II). Although F500 is clearly superior to
`F250, the optimal dose and schedule of fulvestrant remains unclear43,44.
`
`The placebo-controlled phase III BOLERO -2 trial evaluated the safety and efficacy of adding EVE to EXE in this
`patient population41. A total of 724 patients were randomized 2:1 to either a daily oral dose of EVE 10 mg and EXE
`25 mg or to placebo and EXE (Figure 1). The primary endpoint was investigator-assessed PFS . Baseline patient and
`disease characteristics were balanced between the treatment arms. Results of the primary analysis
`demonstrated statistically significant improvements in ORR and in both the investigator-assessed and the
`centrally-reviewed PFS favouring the experimental arm (Table I). Updated outcomes reported at a median follow-
`up of 18 months confirmed significant improvements in ORR (12.6% vs. 1.7%, p < 0.0001) and investigator-
`assessed median PFS (7.8 months vs. 3.2 months; HR : 0.45; 95% CI : 0.38 to 0.54; p < 0.0001) favouring the
`addition of EVE to EXE 45. Fewer deaths were reported in the EVE plus EXE arm ( OS events: 25.4% vs. 32.2%)45,
`although OS results remain immature at the time of writing. Adverse events observed in the EVE plus EXE arm
`were consistent with those reported in other studies, with increased toxicity observed for the addition of EVE to
`EXE 41. Stomatitis and infection were the most common adverse events associated with EVE plus EXE (grade 3 or
`4: 8% EVE + EXE vs. 1% placebo+ EXE , and 6% vs. 2%; any grade: 56% vs. 11%, and 50% vs. 25%; Table II).
`
`4. PANEL DISCUSSION AND RECOMMENDATIONS
`
` MANAGEMENT OF POSTMENOPAUSAL PATIENTS WITH HR+
`4.1
`HER2– ABC RECURRING OR PROGRESSING ON PRIOR NSAI
`THERAPY
`
`4.1.1
`
` Discussion
`
`In first- and second-line treatment of ABC , PFS and OS are both important measures of clinical benefit. However,
`clinical trials are often underpowered to effectively evaluate OS as a primary endpoint in the endocrine-sensitive
`ABC patient population because of sequential treatment options and the protracted post-progression survival
`interval, which often confound detection of ET -related OS benefits46. Determining whether, in this clinical
`setting, nonsignificant OS differences are a result of limitations in trial design or a true measure of lack of OS
`benefit is therefore difficult. As a result, PFS as a primary endpoint is gaining importance in first- and second-line
`settings. However, PFS is often considered a less reliable measure, being more complex and possibly more
`susceptible to bias and error. Results from trials that control for investigator bias through the use of a double-
`blind trial design and independent review assessment are therefore considered more reliable46.
`
`Four clinical trials have assessed the benefit of ET therapy in postmenopausal women with HR + disease recurring
`or progressing on prior NSAI therapy. In all four trials, investigator-assessed PFS was the primary endpoint, and
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`two of them—the CONFIRM and BOLERO -2 trials—reported statistically significant improvements in PFS . Both
`trials used a double-blind design to control for investigator bias, and the BOLERO -2 results were also
`independently assessed.
`
`In the CONFIRM trial, patients receiving a higher dose of fulvestrant (F500 compared with F250) experienced a
`20% reduction in the risk of progression ( HR : 0.80; 95% CI : 0.68 to 0.94) and an incremental gain in median PFS of
`1.0 month (6.5 months vs. 5.5 months, p = 0.006). In the BOLERO -2 trial, patients receiving EVE plus EXE
`experienced a reduction in the risk of progression of between 57% and 64% (locally assessed HR : 0.43; 95% CI :
`0.35 to 0.54; centrally assessed HR : 0.36; 95% CI : 0.27 to 0.47) and a net gain in median PFS of between 4.1 and
`6.5 months (locally assessed: 6.9 months vs. 2.8 months, p < 0.001; centrally assessed: 10.6 months vs. 4.1
`months, p < 0.001)41. At a median follow-up of 18 months, the OS data remained immature45.
`
`Subgroup analyses are used to identify treatment effects i n s pecific p opulations, b ut t hey a re o ften limited in
`statistical power and may be susceptible to bias related to imbalances in patient or disease characteristics
`between treatment arms. Investigators conducting the CONFIRM and BOLERO -2 trials carried out preplanned
`subgroup analyses based on endocrine sensitivity, burden of disease, and age. Patients in the CONFIRM trial were
`stratified based on institutional affiliation, and patients in the BOLERO -2 trial were stratified according to the
`presence or absence of visceral disease and endocrine sensitivity. In CONFIRM , a statistically significant PFS
`benefit favouring F500 was observed in patients demonstrating resistance to prior ET therapy and in those
`without visceral disease. Robust statistically significant effects were seen in all subgroups in the BOLERO -2 trial,
`regardless of burden of disease, endocrine sensitivity, and age.
`
`In both the CONFIRM and BOLERO -2 trials, most patients were described as having endocrine-sensitive disease
`(63%–67% and 84% respectively), defined as disease recurrence lasting at least 2 years after initiation of
`adjuvant ET or progression after more than 6 months on ET for advanced disease33,41. Subgroup analyses were
`conducted for endocrine-sensitive patients in both trials. Overall benefits for EVE plus EXE were confirmed in the
`subpopulation of 610 endocrine-sensitive patients (estimated HR : 0.43; 95% CI : 0.34 to 0.54; Table III). The
`overall benefits of F500 were not statistically significant in the endocrine-sensitive population (estimated HR :
`0.86; 95% CI : 0.72 to 1.05), but the results are likely similar to those observed in the overall population.
`
`TABLE III Phase III subgroup outcomes by degree of sensitivity to prior endocrine therapy
`
`A substantial proportion of patients in both the CONFIRM and BOLERO -2 trials lacked visceral involvement
`(approximately 45%)33,41. Patients without visceral disease receiving F500 in the CONFIRM trial experienced a
`25% reduction in the risk of progression compared with patients receiving F250 (estimated HR : 0.75; 95% CI :
`0.57 to 0.95); patients without visceral involvement receiving EVE plus EXE in the BOLERO -2 trial experienced a
`59% reduction in the risk of progressive disease (9.9 months vs. 4.2 months; HR : 0.41; estimated 95% CI : 0.30 to
`0.56; Table IV )45. The benefit of EVE plus EXE was pronounced in patients with bone-only disease; those patients
`experienced a 67% reduction in the risk of progression and a net median PFS gain of 7.6 months (12.9 months vs.
`5.3 months; HR : 0.33; estimated 95% CI : 0.20 to 0.55) compared with those receiving placebo plus EXE 45. It is
`notable that EXE alone increased bone turnover and that the addition of EVE reversed the EXE -induced increase in
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`bone resorption and appears to have contributed to a significant reduction in the cumulative incidence of disease
`progression from bone metastases in patients receiving EVE plus EXE compared with those receiving placebo plus
`EXE ( p = 0.036)47.
`
`TABLE IV Phase III subgroup outcomes by burden of disease
`
`No significant differences in the incidence or severity of adverse events were observed between F500 and F250
`in the CONFIRM trial. However, higher rates of trial discontinuation for toxicity were observed when EVE was
`added to EXE (19% vs. 4%), with increased rates of serious adverse events attributable to treatment (11% EVE +
`EXE vs. 1% placebo+ EXE ) and a slightly higher proportion of deaths attributable to adverse events (1% vs. <1%)
`41. However, despite those differences, quality of life was not compromised for patients receiving EVE plus EXE
`compared with those receiving placebo plus EXE (European Organisation for Research and Treatment of Cancer
`QLQ –C30 Global Health Status—Time to Definitive Deterioration minimally important difference: 5% change
`from baseline, 8.3 months vs. 5.8 months, p = 0.0084; 10% change from baseline, 11.7 months vs. 8.4 months, p =
`0.1017)48.
`
`4.1.2 Recommendation
`
`Multiple treatment options are available to women with HR + HER 2– ABC recurring or progressing on prior NSAI
`therapy, including EXE , F250, F500, and EVE plus EXE 31–33,41. When considering ET , thought should be given to
`disease extent, degree of symptomatology, and duration of clinical benefit on prior ET . For patients with
`relatively indolent progression and endocrine-sensitive disease for whom ET is indicated, the available evidence
`supports the use of EVE plus EXE , which may be of particular benefit for patients with bone-only disease. But this
`combination may not be ideal for all patients; when selecting ET , consideration should be given to patient age,
`functional status, and extent of comorbidities. Other ET options should be considered in the event that a patient is
`unable to tolerate EVE .
`
`Because of the increased risk of serious adverse events with the addition of EVE to EXE , together with the
`potential for early onset of select adverse events, careful proactive safety monitoring and toxicity management is
`strongly recommended for patients on EVE plus EXE , so as to maximize clinical benefit and treatment
`adherence49. For appropriate patients, EVE should begin at the prescribed dose of 10 mg, with a first follow-up
`appointment within 2 weeks to ensure early detection of hematologic or pulmonary adverse events, oral
`mucositis, or fatigue. Patients should undergo regular monthly clinical monitoring, including functional inquiry
`and symptom-directed physical examination, complete blood count and glucose level, and disease imaging every
`3 months. For grade 3 adverse events, treatment may be interrupted until resolution and then resumed at the
`same or a lower dose. In the event of symptomatic pneumonitis, infection should be ruled out, treatment
`interrupted, and oral corticosteroids administered until symptoms resolve. Resolution may take between 7–10
`days, at which point EVE may be reinitiated at a lower dose. Treatment should be discontinued in the event of
`grade 4 adverse events. If a patient is unable to tolerate EVE plus EXE , treatment with F500 or EXE is also an
`option.
`
`4.2 MANAGEMENT OF ET-RESISTANT DISEASE
`
`4.2.1
`
` Discussion
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`Although fewer in number, endocrine-resistant patients were represented in both the CONFIRM (33%–37%) and
`the BOLERO -2 (16%) trials33,41. Compared with endocrine-resistant patients receiving F250 in the CONFIRM
`trial, those receiving F500 experienced a 28% reduction in the risk of progression (estimated HR : 0.72; 95% CI :
`0.57 to 0.93), and in the BOLERO -2 trial, compared with patients receiving placebo plus EXE , those receiving EVE
`plus EXE experienced a 51% reduction in the risk of progression (estimated HR : 0.49; 95% CI : 0.30 to 0.81; Table
`III). The benefits of EVE plus EXE extended to patients receiving 3 or more lines of prior systemic therapy. These
`heavily pretreated patients experienced a 59% reduction in the risk of progression ( HR : 0.41; estimated 95% CI :
`0.32 to 0.53) and incremental median PFS gains of 5.2 months (8.2 months vs. 3.0 months)45.
`
`4.2.2 Recommendation
`
`Treatment options in women with HR + HER 2– ABC recurring or progressing on prior NSAI therapy who have
`relatively indolent progression and resistant disease are limited to F500, EVE plus EXE , chemotherapy, and EXE 31
`–33,41. For those patients, the magnitude of the clinical benefit, balanced with tolerability and convenience
`relative to chemotherapy, support the use of EVE plus EXE regardless of prior therapies. Chemotherapy remains
`the recommended treatment choice for patients with symptomatic visceral disease. Because EVE plus EXE may not
`be ideal for all patients, consideration should be given to the patient’s age, functional status, and comorbidities,
`and alternative ET options should be considered if a patient is unable to tolerate EVE . A proactive EVE safety
`management strategy is recommended, and for patients for whom EVE plus EXE is not well tolerated, treatment
`with F500, EXE alone, or chemotherapy should be considered.
`
`4.3
`
` TREATMENT OF PATIENTS WITH HIGH BURDEN OF DISEASE
`
`4.3.1
`
` Discussion
`
`Endocrine therapy is the preferred option for HR + ABC , even in the presence of visceral disease6, and
`chemotherapy is recommended for patients with rapidly progressive or symptomatic visceral disease5,6. More
`than half the patients in both the CONFIRM and the BOLERO -2 trials had visceral disease (55%–56%). Among
`patients with visceral disease in the CONFIRM trial, those receiving F500 (compared with those receiving F250)
`experienced a 20% reduction in the risk of progression (estimated HR : 0.80; 95% CI : 0.65 to 1.00)33, and in the
`BOLERO -2 trial, compared to those receiving placebo plus EXE , those receiving EVE plus EXE experienced a 53%
`reduction in the risk of progression ( PFS : 6.8 months vs. 2.8 months; HR : 0.47; estimated 95% CI : 0.38 to 0.60)45
`and a significantly improved ORR (9.5% vs. 0.4%, p < 0.001) overall41. Additionally, at a median follow-up of 18
`months, patients with extensive visceral involvement and those who had received prior chemotherapy both
`experienced a 59% reduction in the risk of progression (>3 organs involved: 6.9 months vs. 2.6 months; HR : 0.41;
`estimated 95% CI : 0.30 to 0.55; prior chemotherapy: 8.2 months vs. 3.2 months; HR : 0.41; estimated 95% CI : 0.33
`to 0.52)45.
`
`4.3.2 Recommendation
`
`Chemotherapy is recommended for women with HR + HER 2– ABC with symptomatic or rapidly progressive
`disease5,6. For patients with more indolent visceral disease or those declining chemotherapy, a number of
`treatment options, including EXE , F250, F500, and EVE plus EXE are available31–33,41. The strength of the
`evidence and the magnitude of clinical benefit observed in BOLERO -2 supports the use of EVE plus EXE in patients
`with asymptomatic or minimally symptomatic visceral disease, regardless of disease extent and receipt of prior
`chemotherapy. A proactive EVE safety management strategy is recommended, and for those in whom EVE plus EXE
`is not well-tolerated, treatment with F500, EXE , or chemotherapy should be considered.
`
` TREATMENT OF ELDERLY PATIENTS WITH HR+ DISEASE
`4.4
`REFRACTORY TO NSAIS
`
`4.4.1
`
` Discussion
`
`Elderly patients are more likely to have multiple comorbidities that may limit life expectancy or tolerance of
`therapies50. A comprehensive geriatric assessment is an important component in the decision to pursue systemic
`therapies. A substantial proportion of patients in both the CONFIRM and BOLERO -2 trials were 65 years of age or
`older (median: 61 years and 61–62 years respectively), and preplanned subgroup analyses in elderly populations
`were conducted for both trials. In the CONFIRM trial, elderly patients receiving F500 (compared with those
`receiving F250) experienced a 14% reduction in the risk of progression ( HR : 0.86; 95% CI : 0.67 to 1.09) and no
`observed increase in the rate of adverse events. At 18 months’ follow-up, patients receiving EVE plus EXE in the
`BOLERO -2 trial experienced a 41% (for those 65 years of age or older) and a 55% reduction in the risk of
`progression (for those 70 years of age or older)51. The most common adverse events in elderly patients were
`stomatitis, fatigue, decreased appetite, and diarrhea. Treatment with EVE was also associated with a greater
`incidence of on-treatment death in elderly women than in younger patients (Pritchard K. Unpublished data,
`November 2012). Most of the deaths were reported in very elderly patients (70 years of age and older) and might
`have been associated with comorbidities and overall health status at study entry.
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`4.4.2 Recommendation
`
`Many treatment options are available to elderly post-menopausal HR + HER 2– patients who have recurrent or
`progressive disease on prior NSAI therapy, including EXE , F250, F500, and EVE plus EXE 31–33,41. Clinical
`judgment should be used when selecting an ET , and elderly patients should be well informed about the need for
`early toxicity reporting. Current evidence supports use of EVE plus EXE in conjunction with thorough and
`proactive adverse event management. In very elderly patients or in those with comorbidities or compromised
`health status, a dose escalation strategy should be considered, beginning with a starting dose of 5 mg and slowly
`increasing to a dose of 10 mg with demonstrated tolerance. In the event that an elderly patient is unable to
`tolerate EVE plus EXE , the use of F500 or another ET regimen is encouraged.
`
`5. RE-BIOPSY
`
`5.1
`
` DISCUSSION
`
`There is evidence that receptor status may change over time and over the course of treatment. Guidelines from
`the Advanced Breast Cancer First International Consensus Conference therefore recommend biopsy of a
`metastatic lesion, if easily accessible, to confirm diagnosis and to evaluate hormone receptor and HER 2
`expression52,53. In the context of HR + HER 2– disease, a previously HER 2– tumour may be found to be HER 2+
`upon re-biopsy, which would increase the number of treatment options by adding HER 2-targeted therapies. In
`contrast, discovery of a change from HR + to HR – potentially suggests resistance to ET and a need to try
`alternative therapies. Regardless of findings, re-biopsy results should be interpreted with caution and within the
`context of the patient’s unique disease and treatment history, because variations in tissue processing and
`sampling can produce erroneous results.
`
`5.2 RECOMMENDATION
`
`The re-biopsy of a tumour once over the course of treatment for advanced disease is a reasonable practice if
`sample collection is straightforward and does not pose undue risk to the patient. Re-biopsy is strongly
`encouraged in women whose disease is not following the expected pattern of progression based on tumour
`receptor profile or in the case of an isolated lesion. Caution should be used when interpreting re-biopsy results,
`especially in instances in which loss of receptor status expression might result in the withholding of targeted
`therapy.
`
`6. SUMMARY
`
`With the increased use of NSAI therapy in both the adjuvant and first-line settings, there is a need to identify the
`optimal sequencing of ET in women with HR + HER 2– ABC who have recurrent or progressive disease on NSAI
`therapy. Sequential ET remains the goal of treatment for these patients5. Four large phase III trials— EFECT ,
`SoFEA , CONFIRM , and BOLERO -2—assessed the benefits of particular ET regimens in this patient population31
`–33,41. Those studies demonstrated that F250 and EXE are of comparable efficacy and that, compared with
`fulvestrant alone, the addition of anastrozole to fulvestrant does not improve outcomes. Data also demonstrate
`that F500 and EVE plus EXE result in statistically significant improvements in PFS compared with control regimens,
`with associated reductions of 20% and 57% respectively in the risk of progression. Increasing the dose of
`fulvestrant from F250 to F500 did not increase toxicity, but an increase in toxicity was seen with the addition of
`EVE to EXE . Of the many available ET options for patients with HR + HER 2– disease who have experienced disease
`recurrence or progression on prior NSAI therapy, the rigour of the evidence and the magnitude of the clinical
`benefit support the use of EVE plus EXE in most clinical cohorts (Figure 2). Consideration should be given to the
`patient’s