Endocrine Therapy for Stage IV or Recurrent Metastatic Disease
Women with recurrent or metastatic disease characterized by tumors that are ER- and/or PR-positive are appropriate candidates for initial endocrine therapy.
In premenopausal women, endocrine therapies include selective ER modulators (tamoxifen or toremifene); LHRH agonists (goserelin and leuprolide); surgical or radiotherapeutic oophorectomy; progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol).
For most premenopausal patients the use of ovarian suppression or ablation in combination with endocrine therapy for postmenopausal women is appropriate.
In premenopausal women without previous exposure to an antiestrogen, initial treatment is with selective ER modulator alone or ovarian suppression/ablation plus endocrine therapy as for postmenopausal women.
In premenopausal women with previous antiestrogen therapy who are within one year of antiestrogen exposure, the preferred second-line therapy is ovarian ablation or suppression followed by endocrine therapy as for postmenopausal women.
Endocrine therapies in postmenopausal women include nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum ER modulators (tamoxifen or toremifene); ER down-regulators (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol) and recently several new combination therapies with novel agents have become available.
According to some studies, aromatase inhibitors appear to have superior outcome compared with tamoxifen, although the differences are modest.
A Cochrane review has also suggested a survival benefit favoring the aromatase inhibitors over other endocrine therapies, although the advantage is small.
A randomized phase III trial comparing tamoxifen with exemestane as first-line endocrine therapy for postmenopausal women with metastatic breast cancer showed no significant differences in progression-free survival (PFS) or OS between the two arms.
Fulvestrant appears to be at least as effective as anastrozole in patients whose disease progressed on previous tamoxifen.
A randomized phase II study compared anastrozole versus fulvestrant in over 200 patients with advanced breast cancer.
In the initial analysis, fulvestrant was as effective as anastrozole in terms of overall response (36.0% vs. 35.5%; odds ratio, 1.02; 95% CI, 0.56 -1.87; P = .947) in 461 evaluable patients (n = 89 for fulvestrant and n = 93 for anastrozole).
在初步分析中，461例可评价的患者中（氟维司群n= 89，阿那曲唑n = 93）总有效率氟维司群与阿那曲唑一样（36%对35.5%；优势比，1.02；95% CI，0.56-1.87；P= .947）。
An improved time to progression was seen with fulvestrant compared to anastrazole (median time to progression was 23.4 months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39- 1.00; P =.0496).
与阿那曲唑相比氟维司群改善至进展时间（中位至疾病进展时间氟维司群是23.4个月而阿那曲唑是13.1个月；风险比，0.63；95% CI，0.39-1.0；P= .0496）。
This study used a higher 500 mg loading dose every 2 weeks for 3 doses and then 500 mg monthly.
The median OS was longer in the fulvestrant group than in the anastrozole group (54.1 463 months vs. 48.4 months; HR, 0.70; P = .041).
氟维司群组比阿那曲唑组中位OS更长（54.1个月对48.4个月；HR，0.70；P = .041）。
A phase II study of fulvestrant in postmenopausal women with advanced breast cancer and disease progression following aromatase inhibitor therapy documented a partial response rate of 14.3% with an additional 20.8% of patients achieving stable disease for at least 6 months.
The clinical benefit rates of exemestane and fulvestrant observed in a phase III trial of postmenopausal women with hormone receptor-positive advanced breast cancer who experienced disease progression on prior nonsteroidal aromatase inhibitor therapy were comparable (32.2% vs. 31.5%; P = .853).
In that study, fulvestrant was administered as a 500 mg loading dose followed by doses of 250 mg on day 14, day 28, and then monthly.
A separate phase III randomized study in postmenopausal women with metastatic ER-positive breast cancer compared fulvestrant 500 mg every 2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 mg monthly.
The PFS was superior with the fulvestrant 500 mg regimen (HR 0.80; 95% CI, 0.68-0.94; P = .006), indicating an increased duration of response with the higher dose of fulvestrant.
氟维司群500mg方案PFS占优势（HR 0.80；95% CI，0.68-0.94；P = .006），说明较高剂量的氟维司群应答持续时间增加。
The final analyses demonstrated an increase in median OS (4.1 months) and reduced risk of death (19%) with a dose of 500 mg compared with 250 mg.
Median OS was 26.4 versus 22.3 months (HR, 0.81; 95% CI, 0.69-0.96; P = .02).
中位OS为26.4个月对22.3个月（HR，0.81；95% CI，0.69-0.96；P = .02）。
Combination endocrine therapy in postmenopausal women with hormone receptor-positive, previously untreated metastatic breast cancer has been reported from two studies comparing single-agent anastrozole versus anastrozole plus fulvestrant.
In one study (FACT), combination endocrine therapy was not superior to single-agent anastrozole (time to progression HR, 0.99; 95% CI, 0.81-1.20; P = .91).
在一项研究（FACT）中，联合内分泌治疗并不优于单药阿那曲唑（疾病进展时间HR，0.99；95% CI，0.81-1.20；P = .91）。
In the second study (S0226), 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) were superior with combination anastrozole plus fulvestrant.
在第二项研究（S0226）中，联合阿那曲唑加氟维司群PFS（HR，0.80；95% CI，0.68-0.94；分层秩和检验P = .007）和OS（HR，0.81；95% CI，0.65-1.00；分层P = .049）均占优。
An unplanned subset analysis in this trial suggested that patients without prior adjuvant tamoxifen experienced the greatest benefit.
The reason for the divergent outcomes in these two studies is not known.
A phase III trial studied the effect of fulvestrant alone or in combination with anastrozole or exemestane in patients with advanced breast cancer and an acquired non-steroidal aromatase inhibitor-resistant disease.
An aromatase inhibitor had been given as adjuvant treatment to 18% of patients for a median of 27.9 months, and to 82% of patients for locally advanced/metastatic disease for a median of 19.3 months.
Median PFS was 4.8 months, 4.4 months, and 3.4 months for patients treated with fulvestrant alone, anastrazole plus fulvestrant, and fulvestrant plus exemestane, respectively.
No differences were observed for overall response rate, clinical benefit rate, and OS.
This trial provides no evidence that adding an aromatase inhibitor to fulvestrant in patients with non-steroidal aromatase inhibitor-resistant disease improves the results achieved with fulvestrant alone.
In postmenopausal women who have received previous antiestrogen therapy and are within one year of antiestrogen exposure, there is evidence supporting the use of a selective aromatase inhibitor as the preferred first-line therapy for their recurrent disease.
New agents, such as palbociclib, a highly selective inhibitor of CDK 4/6 kinase activity, now have a role in treating women with ER-positive metastatic breast cancer in combination with endocrine therapy.
A phase 2, open-label, randomized, multicenter trial evaluated the safety and efficacy of palbociclib in combination with letrozole versus letrozole alone as first-line treatment for patients with advanced ER-positive, HER2- breast cancer.
Median PFS reported was double with the combination regimen compared to letrozole alone (20.2 months for the palbociclib plus letrozole group and 10.2 months for the letrozole alone group; HR, 0.488; 95% CI, 0.319-0.748).
The grade 3/4 adverse reactions reported at a higher incidence in the palbociclib plus letrozole versus letrozole alone included neutropenia (54% vs. 1%) and leukopenia (19% vs. 0%).
Based on this study, the FDA approved palbociclib in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.
The NCCN Panel has included the combination of palbociclib with letrozole as a first-line endocrine therapy option for postmenopausal patients with ER-positive, HER-negative metastatic breast cancer.
Limited studies document a PFS advantage of adding trastuzumab or lapatinib to aromatase inhibition in postmenopausal women with hormone receptor-positive metastatic breast cancer that is HER2- positive.
Resistance to endocrine therapy in women with hormone receptor-positive disease is frequent.
One mechanism of resistance to endocrine therapy is activation of the mammalian target of rapamycin (mTOR) signal transduction pathway.
Several randomized studies have investigated the use of aromatase inhibition in combination with inhibitors of the mTOR pathway.
A randomized phase II study estimated the efficacy of tamoxifen alone versus tamoxifen combined with everolimus, an oral inhibitor of mTOR, in women with hormone receptor-positive, HER2-negative metastatic breast cancer previously treated with an aromatase inhibitor.
After a median follow-up of 13 months, an intent-to-treat analysis showed that the clinical benefit was 42.1% (95% CI, 29.1-55.9) with tamoxifen alone and 61.1% (95% CI, 46.9-74.1) with tamoxifen plus everolimus.
在中位随访13个月后，意向治疗分析显示，临床受益率单独他莫昔芬为42.1%（95% CI，29.1-55.9）而他莫昔芬联合依维莫司为61.1%（95% CI，46.9-74.1）。
An improvement in median time to progression was seen when everolimus was combined with tamoxifen compared with tamoxifen alone.
Median time to progression was 4.5 months (95% CI, 3.7-8.7) with tamoxifen alone versus 8.5 months (95% CI, 6.01-13.9) with everolimus and tamoxifen.
中位疾病进展时间单独他莫昔芬为4.5个月（95% CI，3.7-8.7）而依维莫司加他莫昔芬是8.5个月（95% CI，6.01-13.9）。
A phase III trial in postmenopausal women with advanced, hormone receptor-positive breast cancer with no prior endocrine therapy for advanced disease, randomized subjects to letrozole with or without the mTOR inhibitor temsirolimus has been reported.
In this study, PFS was not different between the treatment arms (HR, 0.89; 95% CI, 0.75- 1.05; long-rank P = .18).
在这项研究中，治疗组间PFS没有差异（HR，0.89；95% CI，0.75 - 1.05；对数秩和检验P = 18）。
The results of this trial differ from that of the BOLERO-2 trial (described below).
The reasons for the differences in the outcomes of these two randomized phase III studies is uncertain, but may be related to the issues of patient selection and extent of prior endocrine therapy.
A phase III study (BOLERO-2) randomized postmenopausal women with hormone receptor-positive advanced breast cancer that had progressed or recurred during treatment with a nonsteroidal aromatase inhibitor to exemestane with or without the mTOR inhibitor everolimus.
Final results reported after median 18-month follow-up show that median PFS (by central review) remained significantly longer with everolimus plus exemestane versus placebo plus exemestane at 11.0 versus 4.1 months, respectively; (HR, 0.38; 95% CI, 0.31-0.48; P < 0.001).
在中位随访18个月后报告的最终结果表明，中位PFS（由中心审查）依维莫司加依西美坦仍然比安慰剂加依西美坦明显更长，分别为11个月和4.1个月；（HR，0.38；95% CI，0.31-0.48；P<0.001）。< p="">
The adverse events (all grades) that occurred more frequently in those receiving everolimus included stomatitis, infections, rash, pneumonitis, and hyperglycemia.
Analysis of safety and efficacy in the elderly patients enrolled in this trial showed that elderly patients treated with an everolimus-containing regimen had similar incidences of these adverse events, but the younger patients had more on-treatment deaths.
The NCCN Panel agrees that the evidence from the BOLERO-2 trial is compelling enough to consider the addition of everolimus to exemestane in women who fulfill the entry criteria for BOLERO-2.
Many premenopausal and postmenopausal women with hormone-responsive breast cancer benefit from sequential use of endocrine therapies at disease progression.
Therefore, women with breast cancers who respond to an endocrine maneuver with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should receive additional endocrine therapy at disease progression.
After second-line endocrine therapy, little high-level evidence exists to assist in selecting the optimal sequence of endocrine therapy.
Additional endocrine therapies for second-line and subsequent therapy are listed in the algorithms.
Endocrine therapy may be active in patients with negative ER and PR determinations, especially on the primary tumor and in soft tissue disease and/or bone-dominant disease.
Endocrine therapy is associated with relatively low toxicity.
Further false-negative determinations of ER and PR tumor status are not unusual and the hormone receptor status of primary and metastatic sites of disease may differ.
Therefore, the NCCN Breast Cancer Panel recommends consideration of a trial of endocrine therapy for patients with disease characterized as hormone receptor-negative with disease localized to the bone or soft tissue only or with asymptomatic visceral disease, irrespective of HER2 tumor status.