Subsequent line systemic therapy for metastatic endometrial cancer

INTRODUCTION — Although most patients with endometrial cancer (EC) present with localized disease and are cured, a subset of patients present with metastatic disease or experience distant recurrence after treatment of their initial cancer. Treatment paradigms are evolving for patients with advanced EC, with immunotherapy options emerging for initial treatment options. As such, subsequent line options are also changing. In this topic, we will discuss the preferred treatment approaches for patients who have already experienced progression on an initial line of systemic therapy for metastatic cancer.

The approach to patients with newly diagnosed metastatic EC (either de novo metastatic disease or metastatic recurrence) is discussed elsewhere.

●(See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy'.)

GENERAL PRINCIPLES — For patients with metastatic EC who have already received a prior line of systemic therapy for metastatic disease, subsequent line therapy takes into account the type of therapy that was previously administered, the length of time since prior treatment, as well as molecular features of the tumor. If not performed at the initial diagnosis, molecular assessment should be performed upon diagnosis of metastatic disease. This includes assessment for human epidermal growth factor 2, estrogen receptor/progesterone receptor, tumor mutational burden, and mismatch repair deficiency. Some institutions also include testing for aberrations in POLE and p53, which may drive investigational strategies. (See "Initial treatment of metastatic endometrial cancer", section on 'Clinical presentation and evaluation'.)

An additional consideration is that with incorporation of immunotherapy or trastuzumab into initial lines of therapy, certain patients may experience progression while on maintenance with one of these agents. Present data are unclear regarding the optimal management in these situations, and we await further evidence to refine our treatment strategy. Recognizing the limitations in available data, our approach is outlined in the sections below.

PATIENTS TREATED WITH PRIOR CHEMOTHERAPY, WITHOUT IMMUNOTHERAPY — For patients who have not been treated with prior immunotherapy, our approach takes into account the platinum-free interval, as well as the molecular characteristics of the tumor.

Platinum-free interval >6 months — For patients who have relapsed with a treatment-free interval following carboplatin and paclitaxel of ≥6 months, we suggest retreatment with carboplatin/paclitaxel with the addition of an immune checkpoint inhibitor. Those with tumor mismatch repair deficiency (dMMR)/microsatellite instability (MSI) are more likely to derive benefit from the addition of immunotherapy. (See "Initial treatment of metastatic endometrial cancer", section on 'MMR deficient or MSI-H tumors'.)

Specific considerations for human epidermal growth factor 2-positive serous cancers are discussed below. (See 'HER2-positive serous carcinomas' below.)

However, endocrine therapy represents an acceptable alternative for select patients with a low burden of disease or are otherwise not symptomatic.

Other options include moving to next line therapy, depending on the molecular characteristics of the tumor. (See 'Tumors with dMMR (MSI-H) or high TMB' below.)

Although we have chosen an interval of six months as a cutoff, extrapolating from the definition of platinum sensitivity in ovarian cancer, high-quality data regarding platinum sensitivity between 6 and 12 months are lacking in EC. In reality, sensitivity is expected to be a continuum, and six months should not be considered an absolute condition for treatment decisions; other factors including patient preferences and tolerance of prior treatments should also be weighed.

Although there are no prospective data that a platinum-based combination improves outcomes compared with single-agent therapy in this context, the use of a platinum-based combination in second-line treatment in this population is extrapolated from the treatment of platinum-sensitive, recurrent ovarian cancer. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Relevance of the platinum-free interval'.)

Platinum-free interval <6 months — For patients with progressive disease within six months of or while on platinum chemotherapy, we move to next line therapy, with choice of treatment dependent on whether dMMR or high tumor mutational burden (TMB) is present.

Tumors with dMMR (MSI-H) or high TMB — Tumor mismatch repair deficiency (dMMR) may be determined by absent immunohistochemical staining for one or more MMR proteins, or polymerase chain reaction or next-generation sequencing demonstrating high levels of microsatellite instability (MSI-H), and is usually done upon diagnosis of metastatic disease. (See "Initial treatment of metastatic endometrial cancer", section on 'Clinical presentation and evaluation'.)

Immune checkpoint inhibitors — After progression on platinum-based chemotherapy, for patients with high TMB (≥10 mutations/megabase), we suggest the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab. For those with dMMR or MSI-H EC who have progressed on platinum-based chemotherapy, either pembrolizumab or dostarlimab (another anti-PD-1 antibody) are appropriate options [1,2].

In the absence of direct comparisons, a choice between pembrolizumab and dostarlimab for such tumors should be based on factors such as availability and cost. We typically continue treatment until progression or unacceptable toxicity.

For patients who are not candidates for immune checkpoint inhibitors, endocrine therapy is an alternative option, particularly if they have little or no symptoms of disease. Side-effect profile should also be taken into account when choosing between these options. Immunotherapy is typically tolerated but is associated with toxicities including dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Endocrine therapy is also typically tolerated but is associated with menopausal symptoms, weight gain, and myalgias, depending on the class of endocrine therapy used. (See "Managing the side effects of tamoxifen and aromatase inhibitors".)

●Supporting data according to biomarker

•High TMB – In a study including 15 patients with EC with TMB ≥10 mutations/megabase, pembrolizumab was associated with a response rate of 47 percent [3]. These data are discussed elsewhere.

•dMMR/MSI-H – In a phase II study of pembrolizumab including nine patients with progressive noncolorectal dMMR metastatic carcinomas, these patients experienced an immune-related objective response rate (ORR) of 71 percent and a 20-week immune-related progression-free survival (PFS) rate of 67 percent [4]. In a separate phase II trial including 79 patients with MSI-H/dMMR, treatment-refractory EC, the ORR was 48 percent, and median PFS was 13 months [5].

Separately, in a single-arm study including 71 patients with advanced dMMR EC, the ORR to dostarlimab was 42 percent, with 13 percent experiencing a complete response [6]. Anemia (3 percent), colitis (2 percent), and diarrhea (2 percent) were the most common grade 3 or higher treatment-related adverse events.

Further attempts are being made at identifying an appropriate biomarker for patient selection. In the phase IB KEYNOTE-028 study, among 24 patients with locally advanced or metastatic, pretreated EC with at least 1 percent of tumor cells staining for programmed cell death ligand 1, 13 percent achieved a partial response and 13 percent had stable disease, with a median duration of 25 weeks [7]. Grade 3 treatment-related toxicities occurred in 17 percent.

Tumors without dMMR or high TMB

Pembrolizumab plus lenvatinib — For patients with tumors that are neither dMMR nor have high TMB, who have relapsed with a treatment-free interval following carboplatin and paclitaxel of <6 months, we suggest pembrolizumab and lenvatinib, provided that immunotherapy has not yet been administered. However, as discussed above, the cutoff of six months is somewhat arbitrary and should not be used as an absolute condition for treatment decisions. Alternatively, endocrine therapy or single-agent chemotherapy are appropriate in select patients. (See 'ALTERNATIVES OR LATER-LINE OPTIONS' below.)

The combination of pembrolizumab plus the vascular endothelial growth factor receptor inhibitor lenvatinib is US Food and Drug Administration approved for advanced EC that is not MSI-H or dMMR, is progressive on prior systemic therapy, and is not amenable to curative surgery or radiation [8]. A randomized trial evaluating pembrolizumab and lenvatinib versus treatment of physician's choice (TPC; between doxorubicin and paclitaxel) was conducted in 827 patients with advanced EC progressive on prior platinum-based chemotherapy (697 of whom had proficient MMR tumors and 130 of whom had dMMR tumors) [9,10].

●Overall, pembrolizumab and lenvatinib resulted in statistically significant improvements in median PFS over TPC (7.2 versus 3.8 months; hazard ratio [HR] 0.56) as well as overall survival (OS; 18.3 versus 11.4 months; HR 0.62, respectively). ORR was also higher (32 versus 15 percent).

●Similarly, among the subset of patients with proficient MMR tumors, pembrolizumab and lenvatinib also resulted in improvements in PFS (median PFS, 6.6 versus 3.8 months; HR 0.60), OS (median OS, 17.4 versus 12.0 months; HR 0.68), and ORR (30 versus 15 percent) relative to TPC.

●Grade ≥3 treatment-related adverse events occurred in 89 percent receiving pembrolizumab and lenvatinib and 73 percent receiving TPC, with the most common being hypertension (64 percent), hypothyroidism (57 percent), diarrhea (54 percent), and nausea (50 percent).

Similar results were observed in a prior single-arm, open-label trial including 94 patients with metastatic, pretreated EC that was neither MSI-H nor dMMR, in which the ORR to pembrolizumab with lenvatinib was 36 percent, with a complete response rate of 2 percent [11,12]. For those responding, the probability of having a response duration ≥6 months was 85 percent. Fatal adverse reactions occurred in four patients, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage, and intracranial hemorrhage.

PATIENTS WITH PRIOR CHEMOTHERAPY AND IMMUNOTHERAPY — There are no data to inform the approach to subsequent line therapy in patients whose initial treatment regimen included immunotherapy, and expert consensus does not exist. All such patients should be offered participation in a clinical trial.

If a clinical trial is not available, a possible treatment approach is represented below:

●For patients with a long treatment-free interval (ie, ≥6 to 12 months off of any therapy), it is reasonable to resume immunotherapy and with carboplatin and paclitaxel.

●For patients with a long platinum-free interval (ie, ≥6 months off of any therapy) but who relapse while on immunotherapy, it is reasonable to resume platinum-based chemotherapy. In such instances, we would discontinue immunotherapy. There are no data to inform use of an alternative immunotherapy after progression on one agent.

●For patients who have a short platinum-free interval (ie, <6 months) or who relapse while on chemotherapy, options include moving to next line single-agent chemotherapy, endocrine therapy (for estrogen receptor-positive cancers), or bevacizumab.

However, in the absence of data, other treatment strategies may also be reasonable. We await further data to refine our approach to treatment following progression on immunotherapy.

PATIENTS TREATED WITH INITIAL ENDOCRINE THERAPY — Select patients with estrogen receptor-positive carcinomas are treated with initial endocrine therapy. Upon progression, these patients should be treated with platinum-based chemotherapy (with or without immunotherapy) as for other chemotherapy-naïve patients. (See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy'.)

SPECIAL CONSIDERATIONS

HER2-positive serous carcinomas — Patients with human epidermal growth factor 2 (HER2)-positive serous carcinomas are typically treated with initial chemotherapy and trastuzumab, with trastuzumab continuing until progression.

●For those who experience progression more than six months from completion of chemotherapy, while on trastuzumab, we continue trastuzumab and resume chemotherapy, as for other cancers. (See 'Platinum-free interval >6 months' above.)

However, for such cancers, we do not use immunotherapy with trastuzumab, instead reserving immunotherapy for the next line setting.

●For patients who experience progression while on chemotherapy or within six months of completion, we discontinue chemotherapy and trastuzumab and offer next line treatment according to MMR and tumor mutational burden status, as discussed above. (See 'Platinum-free interval <6 months' above.)

ALTERNATIVES OR LATER-LINE OPTIONS

Endocrine therapy, for ER-positive cancers — For patients with estrogen receptor (ER)-positive cancers, endocrine therapy represents an acceptable alternative to first- or second-line therapy, particularly for those who wish to avoid the toxicities associated with other treatments, or for those with minimally symptomatic or more indolent disease. It may also be used in ER-positive cancers as a later-line option, for those who have progressed on chemotherapy- or immunotherapy-based options. ER-positivity is, however, less of a biomarker in EC than it is for breast cancer. Endocrine therapy may be used for ER-negative cancers, although the response rate may be less than that for ER-positive cancers.

When endocrine therapy is administered, it is typically continued until progression or unacceptable toxicity. Endocrine therapy is well tolerated and lacks the usual toxicities associated with cytotoxic chemotherapy. Approximately 15 to 30 percent of patients respond to endocrine therapy, with responses most frequent in low-grade tumors [13]. While most remissions are partial and relatively brief in duration, some patients may remain progression free for extended periods of time (>2 years) [14].

●Preference for megestrol acetate alternating with tamoxifen – If endocrine therapy is administered, we typically use megestrol acetate alternating in sequence with tamoxifen. The benefit of sequential therapy was demonstrated in a phase II study conducted by the GOG that enrolled 56 patients assigned to treatment with megestrol acetate (160 mg orally daily for three weeks), alternating with tamoxifen (40 mg daily for three weeks) [15]. Treatment resulted in an objective response rate (ORR) of 27 percent, with a median progression-free survival (PFS) of 2.7 months and median overall survival (OS) of 14 months [15]. Interestingly, the response rate among patients with grade 3 tumors was 22 percent, presumably due to tamoxifen induction of progesterone receptors.

●Alternative endocrine regimens – In light of the limited evidence to support the use of sequential megestrol acetate plus tamoxifen, other options for endocrine treatment are also acceptable. These include:

•Single-agent progestins – Progesterone was first shown to be an effective anticancer agent for patients with advanced disease in 1951, and contemporary trials report an ORR between 15 and 20 percent [16-22]. There is no evidence of a dose-response relationship with progestins. This was shown in a 2010 meta-analysis where medroxyprogesterone acetate at 1000 mg/day was associated with a higher risk of disease progression (hazard ratio [HR] 1.35, 95% CI 1.07-1.71) and death (HR 1.31, 95% CI 1.04-1.66) compared with a lower dose (200 mg/day).

•Single-agent tamoxifen – Tamoxifen is the only selective ER modulator that has demonstrated activity in this population. When used for patients with hormone receptor-positive tumors, response rates ranging from 10 to 46 percent have been reported [23-27].

•Letrozole plus targeted agents – The aromatase inhibitor letrozole appears to have activity in ER-positive disease when combined with cyclin-dependent kinase (CDK) 4/6 inhibitors or the mammalian (mechanistic) target of rapamycin (mTOR) inhibitor everolimus. In one phase II study in 30 patients with recurrent ER-positive EC (28 with endometrioid histology), letrozole/abemaciclib was associated with an objective response rate of 30 percent, with all responses occurring in cancers of endometrioid histology [28]. The median PFS was 9.1 months. Additionally, in a study in 73 patients with recurrent ER-positive endometrioid histology the addition of the CDK 4/6 inhibitor palbociclib to letrozole improved PFS (8.3 versus 3 months, respectively; HR 0.56, 95% CI 0.32-0.98) [29]. Separately, in a randomized trial in 74 patients with advanced/persistent/recurrent EC, everolimus/letrozole (EL) resulted in a response rate of 22 versus 25 percent in those assigned to medroxyprogesterone acetate/tamoxifen (MT) [30]. Median PFS was six months with EL and four months with MT. Chemotherapy-naïve patients experienced a median PFS of 28 months on EL and 5 months on MT; those with prior treatment with chemotherapy experienced a median PFS of four months on EL and three months on MT.

However, the aromatase inhibitors have little activity in EC as single agents. Both letrozole and anastrozole were tested in phase II clinical trials of patients with advanced, recurrent, or persistent EC and had response rates of less than 10 percent [31,32], although evidence suggests that patients may have a response rate as high as 32 percent when combined with the mTOR inhibitor everolimus [33]. In addition, limited data suggest that hormone receptor expression does not appear to predict treatment outcomes from these agents. This was demonstrated in a trial of letrozole conducted by the National Cancer Institute of Canada [31]. Among 22 patients with available tissue, the majority were positive for progesterone receptor (86 percent) and ER (86 percent), but the ORR was only 9 percent.

Single-agent chemotherapy — There are limited data to inform the benefits of subsequent treatment for patients who progress despite two prior regimens. However, patients who relapse following first- and/or second-line chemotherapy have a poor prognosis. The median OS in clinical trials after first- or second-line agents is generally 12 months or less. We individualize our approach and take into account the patient's clinical status, including her ability to tolerate subsequent treatment; any prior toxicity experienced or persisting; their individual goals of treatment; and prior therapies. Given the poor prognosis of these patients, palliative care should be offered regardless of whether subsequent treatment is administered. For patients who desire further treatment, the choice of agents is similar to those listed above. However, for patients who maintain a good performance status, we encourage participation in clinical trials.

●Doxorubicin – There are no published, prospective data to inform the benefit of doxorubicin (60 mg/m² every three weeks) as a later-line therapy. However, we extrapolate its administration in this setting given its activity when given as a first-line treatment, where it produces an ORR ranging from 19 to 37 percent [34]. In addition to treatment every three weeks, weekly doxorubicin (20 mg fixed dose) is sometimes administered based on low-quality data in the treatment of advanced breast cancer showing it resulted in an ORR of 19 percent and lacked serious side effects [35].

●Paclitaxel – Paclitaxel (175 mg/m² every three weeks) is an option in the subsequent line setting, particularly in patients who were not previously treated with this agent. In one study, paclitaxel resulted in a 25 percent ORR among 48 paclitaxel-naϊve patients [36]. However, weekly administration (80 mg/m²) is also a reasonable option, particularly in patients who were previously treated with paclitaxel. This is based on data showing activity with weekly treatment in patients with platinum- and paclitaxel-resistant ovarian cancer [37].

●Pegylated liposomal doxorubicin – Pegylated liposomal doxorubicin has limited activity in this setting, but is a well-tolerated agent in this population. In one study involving 46 patients treated at a dose of 50 mg/m² on a four-week schedule, the ORR was 9.5 percent [38]. However, it was generally well tolerated with limited myelotoxicity. The only grade 4 toxicities reported were esophagitis, hematuria, and vomiting, which occurred in one patient each. For patients with recurrent EC, a dose of 40 mg/m² is generally administered to reduce the treatment-related toxicities, particularly in those patients previously treated with a platinum agent.

Bevacizumab — The anti-vascular endothelial growth factor monoclonal antibody bevacizumab (15 mg/kg intravenous [IV] every three weeks) appears to be an active agent in EC, both as a single agent and when combined with chemotherapy. Although it is not our standard first- or second-line therapy and there is no US Food and Drug Administration approval in the United States for this indication, we consider it a reasonable later-line option for those without contraindications (eg, poorly controlled hypertension).

●First-line treatment – The benefit of bevacizumab with chemotherapy as first-line treatment for advanced, metastatic, or recurrent EC was evaluated in the three-arm randomized phase II NRG Oncology/GOG 86P trial, which randomly assigned 349 patients (over 80 percent of whom had received prior radiation therapy) to treatment on one of three arms using: carboplatin and paclitaxel plus bevacizumab, carboplatin, and paclitaxel plus temsirolimus (an mTOR inhibitor), or carboplatin and ixabepilone plus bevacizumab. The main results were compared with a historic reference using the data from GOG 209, which are discussed above.

There was no statistically significant difference in PFS compared with historic reference for any of the arms, but median OS was improved with the addition of bevacizumab to chemotherapy (34 versus 23 months) [39]. Further discussion of mTOR inhibition is covered below.

●Treatment-refractory disease – Other studies suggest bevacizumab may have activity as a second-line treatment, but further data are needed. In the MITO Group END-2 trial, 108 patients who had received ≤1 prior platinum-based regimen and progressed >6 months after completion of first-line therapy were treated with carboplatin plus paclitaxel and randomly assigned to treatment with or without bevacizumab [40]. Compared with carboplatin plus paclitaxel, the addition of bevacizumab resulted in numerically higher ORR rates (74 versus 53 percent), median PFS (13.7 versus 10.5 months), and OS (40 versus 29.7 months), although these differences were not statistically significant. These results suggest bevacizumab may have activity for patients with recurrent or metastatic EC. Other data suggest that bevacizumab may have greater activity in TP53 mutated uterine cancers. However, definitive data from phase III randomized trials are needed before adopting it as a standard treatment option. (See "Initial treatment of metastatic endometrial cancer".)

INVESTIGATIONAL STRATEGIES

●P13K/PTEN/AKT/mTOR pathway inhibitors – The phosphoinositide-3 kinase (PI3K), phosphatase and tensin homolog (PTEN), protein kinase AKT, and mTOR (formerly mammalian target of rapamycin) are all involved in a key pathway that regulates metabolism, cellular growth, and survival [41]. Multiple agents have been evaluated and show promise for patients with EC, including temsirolimus and everolimus [33,42-44]. As an example:

•Temsirolimus – Temsirolimus (25 mg IV weekly) is an mTOR inhibitor that shows some promise in this population. In one trial, 27 patients with previously treated, recurrent, or metastatic EC were treated with this agent in a single-arm phase II trial [42]. The ORR was 7 percent, but 44 percent had stable disease. Eight patients experienced serious (grade 3/4) toxicities (pneumonitis, mucositis, fatigue, gastrointestinal, and pain). When combined with bevacizumab (10 mg/kg every other week), a response rate of 25 percent was seen in a separate trial that included 49 patients with previously treated disease [43]. This combination resulted in serious gastrointestinal toxicities, including fistula formation (n = 2) and intestinal perforations (n = 2).

As discussed earlier, GOG 86P incorporated the mTOR inhibitor temsirolimus in one of the three treatment arms for patients with advanced, recurrent, or metastatic EC not previously treated with chemotherapy. However, compared with historic reference, the addition of temsirolimus was not associated with an improvement in PFS or OS [44].

The combination of the mTOR inhibitor everolimus with the aromatase inhibitor letrozole has shown a response rate of 32 percent in a phase II study of 38 patients with recurrent, incurable EC, though further study is needed prior to routine clinical use [33].

●Selinexor – Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53. In an analysis of a prespecified exploratory subgroup of patients with advanced or recurrent wildtype TP53 endometrial cancer, maintenance therapy with selinexor improved median PFS (13.7 and 3.7 months with selinexor and placebo) [45]. Further data are necessary. The most frequent grade 3 treatment-related adverse events were nausea (9 percent), neutropenia (9 percent), and thrombocytopenia (7 percent).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – For patients with metastatic endometrial cancer (EC) who have already received a prior line of systemic therapy for metastatic disease, subsequent line therapy takes into account the type of therapy that was previously administered, the length of time since prior treatment, as well as molecular features of the tumor. (See 'General principles' above.)

Although we use six months as a cutoff extrapolating from the ovarian cancer setting, high-quality data regarding platinum sensitivity are lacking in EC. Sensitivity is expected to be a continuum, and six months is not an absolute condition for treatment decisions; other factors including patient preferences and tolerance of prior treatments should also be weighed.

●No prior immunotherapy

•Platinum-free interval >6 months – For patients who are immunotherapy naïve who have relapsed with a treatment-free interval following carboplatin and paclitaxel of ≥6 months, we suggest retreatment with carboplatin/paclitaxel plus immunotherapy (Grade 2C), rather than other regimens. Patients with tumor mismatch repair deficiency (dMMR) cancers may derive the most benefit from the addition of immunotherapy. (See 'Platinum-free interval >6 months' above and "Initial treatment of metastatic endometrial cancer", section on 'MMR deficient or MSI-H tumors'.)

For those with serous HER2-positive cancers, we suggest trastuzumab with chemotherapy (Grade 2C). (See 'HER2-positive serous carcinomas' above.)

•Platinum-free interval <6 months – For patients with a short platinum-free interval (<6 months) and no prior immunotherapy, our approach takes into account molecular features, as follows:

-For those with dMMR (microsatellite instable-high) tumors, or with tumors that have high tumor mutational burden (TMB), who experience progression on chemotherapy, we suggest pembrolizumab or dostarlimab (Grade 2C).

-For those with tumors that are neither dMMR nor have high TMB, we suggest pembrolizumab and lenvatinib rather than further chemotherapy (Grade 2B). (See 'Pembrolizumab plus lenvatinib' above.)

●Prior immunotherapy – There is no consensus regarding subsequent line therapy in patients previously treated with immunotherapy, given a lack of data.

A reasonable strategy would be to consider when relapse occurred in relation to prior treatment. For example, if the interval from prior treatment is long (ie, >6 months), reinitiation of prior therapy may be attempted. (See 'Patients with prior chemotherapy and immunotherapy' above.)

However, it is also reasonable to proceed with the next line of treatment (eg, single-agent chemotherapy, bevacizumab, or endocrine therapy for estrogen receptor [ER]-positive tumors), irrespective of treatment-free interval. We await further data to refine our approach.

●Alternatives or later line options – For select patients, particularly those with ER-positive cancers, endocrine therapy represents an acceptable alternative, particularly for those who wish to avoid the toxicities associated with these agents, or for those with minimally symptomatic or indolent disease.

●Endocrine therapy and single-agent chemotherapy are appropriate later line options. (See 'Endocrine therapy, for ER-positive cancers' above and 'Single-agent chemotherapy' above.)