Neoadjuvant management of newly diagnosed hormone-positive breast cancer

INTRODUCTION — Hormone receptor (HR)-positive breast cancer is the most common subtype of breast cancer, comprising 70 to 80 percent of all breast cancers.

Neoadjuvant or presurgical therapy refers to administration of therapy before surgery and has been used for over two decades to downstage locally advanced and unresectable primary breast cancers to make them operable [1,2]. Several studies, including the landmark NSABP 18 trial, have demonstrated that administration of the same chemotherapy in the neoadjuvant versus adjuvant setting is associated with similar outcomes [3-5]. While traditionally neoadjuvant chemotherapy has been used to downstage locally advanced and unresectable primary breast cancers, a number of studies have highlighted the role of neoadjuvant endocrine therapy as an alternative option to chemotherapy in HR-positive tumors, particularly for postmenopausal women.

In this topic, we will focus on the approaches and data specific to HR-positive breast cancers. For the purpose of this discussion, the anatomic staging system set forth in the eighth edition of the American Joint Committee on Cancer Staging Manual is used (table 1); however, it is recognized that the studies cited may have used previous editions of the staging system, which is a limitation of existing data. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

The rationale and general approach to neoadjuvant treatment is discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer".)

GOALS AND INDICATIONS — The goal of neoadjuvant therapy is to improve surgical outcomes by causing tumor shrinkage by providing effective systemic therapy. It is appropriate for many patients with locally advanced breast cancer (regardless of subtype), generally defined as stage III cancers, as well as the subset of IIB cancers with T3 disease. For those with stage II disease, either primary surgery or neoadjuvant therapy may be used, the latter being appropriate, for example, for the patient who desires breast-conserving surgery and is not a candidate due to a high tumor size: breast size ratio. It should be recognized, however, that HR-positive, human epidermal growth factor receptor 2 (HER2)-negative cancers are less likely to respond to neoadjuvant chemotherapy than other biologic subtypes [6-10]. For patients with stage I, estrogen receptor-positive, HER2-negative disease, we generally prefer primary surgery rather than neoadjuvant therapy given that such patients are likely to have good surgical outcomes.

Further discussion of appropriate candidates for neoadjuvant therapy is found elsewhere, including for those with HER2-positive disease. (See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection' and "Neoadjuvant therapy for patients with HER2-positive breast cancer".)

THERAPEUTIC OPTIONS

Selection of treatment — The choice of neoadjuvant treatment is informed by studies in the adjuvant setting that include overall survival outcomes, as well as by studies in the neoadjuvant setting for which response rates and rates of breast-conserving therapy are the outcomes assessed.

Typically the choice of therapy is neoadjuvant chemotherapy followed by surgery, neoadjuvant endocrine therapy (NET) followed by surgery, or upfront surgery with adjuvant chemotherapy, if indicated. All patients with estrogen receptor (ER)-positive cancers should receive endocrine therapy in the adjuvant setting (algorithm 1).

HER2-negative cancers

Premenopausal women — Neoadjuvant therapy is typically indicated in women with larger tumors and/or locally advanced breast cancer. In such situations, most premenopausal women should receive chemotherapy rather than endocrine therapy. If a premenopausal woman refuses (or is not a good candidate for) neoadjuvant chemotherapy, we suggest proceeding to surgical treatment, if possible, rather than attempting NET. For such women who are concerned about the extent of definitive surgical treatment, NET may be offered, but patients should be advised that the data in this setting suggest superior outcomes with chemotherapy over endocrine therapy. (See 'Premenopausal women' below.)

Details regarding chemotherapy regimen selection and duration of treatment are found elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen'.)

Postmenopausal women — Most postmenopausal women for whom neoadjuvant treatment is indicated receive chemotherapy, although endocrine therapy may be offered as an alternative for some women, as outlined below. Details regarding chemotherapy regimen selection are found elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen'.)

While historically NET has been reserved for patients with substantial comorbid health problems who would not tolerate chemotherapy, it is coming to be seen as a viable alternative for other patients, especially those with human epidermal growth factor receptor 2 (HER2)-negative, HR-positive tumors that are strongly ER positive. In such patients, it may allow for improved surgical outcomes and cosmesis.

Other investigational biomarkers are being studied to further define the most appropriate population to receive endocrine neoadjuvant therapy. (See 'Biomarkers' below.)

Medically fit — For most medically fit patients requiring neoadjuvant treatment, we treat with chemotherapy based on a robust literature documenting response rates and survival benefits [11]. However, for those with HER2-negative tumors that are strongly HR positive, NET is an acceptable alternative option. Tumors that are more likely to respond to neoadjuvant endocrine treatment have strong HR expression (eg, ≥50 percent staining for ER or an Allred score of 7 or 8) and a low proliferative index (Ki67 <10 or 15 percent). Further details regarding efficacy, selection of, and duration of endocrine therapy are found below. (See 'Neoadjuvant endocrine therapy' below and 'Choice of endocrine therapy' below and 'Duration of endocrine treatment' below.)

Response to endocrine therapy has been shown to correlate with levels of ER expression, as quantified by the Allred score. In a study of 324 postmenopausal women with HR-positive breast cancer randomly assigned to four months of tamoxifen or letrozole, response rates among those with Allred scores of 7 to 8 were over 60 percent for letrozole and approximately 30 to 45 percent for tamoxifen, while response rates for patients with Allred scores of 0 to 2 were 0 percent [12].

Discussion of appropriate candidates for chemotherapy is found elsewhere. (See "Overview of the approach to early breast cancer in older women", section on 'Chemotherapy'.)

Medically frail — In patients with HR-positive, HER2-negative disease who are unfit for chemotherapy due to significant comorbidities or extent of disease, options include upfront surgery (if feasible) or NET, which can enable tumor volume reduction prior to resection under local anesthesia, possibly facilitating less extensive surgery. Further details regarding efficacy, selection of, and duration of endocrine therapy are found below. (See 'Neoadjuvant endocrine therapy' below and 'Choice of endocrine therapy' below and 'Duration of endocrine treatment' below.)

For those who are unlikely to become surgical candidates regardless of their response to neoadjuvant treatment, primary endocrine therapy may be offered. In frail patients with a poor response to endocrine therapy, primary radiation therapy (RT) may also be an option. Patients can often receive endocrine therapy alone for years. (See "Overview of the approach to early breast cancer in older women", section on 'Hormone receptor-positive breast cancer' and "Overview of the approach to early breast cancer in older women", section on 'Primary RT' and "Overview of the approach to early breast cancer in older women", section on 'Nonsurgical candidates'.)

HER2-positive cancers — Patients receiving neoadjuvant treatment for HR-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancers are usually treated with chemotherapy with HER2-directed therapy. Further details are found elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Components of therapy'.)

Neoadjuvant chemotherapy — This section focuses on results of neoadjuvant chemotherapy among patients with HR-positive disease. A broader discussion of the efficacy of neoadjuvant chemotherapy in breast cancer (irrespective of HR status), and selection of regimen, is found elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer" and "Neoadjuvant therapy for patients with HER2-positive breast cancer".)

Efficacy — Chemotherapy can shrink HR-positive tumors and facilitate better surgical options, but is less likely to achieve a pathologic complete response (pCR) in HR-positive cancers, especially luminal A cancers, than for more proliferative histologies [11,13].

This was demonstrated in a meta-analysis of 12 trials enrolling almost 12,000 patients with early-stage or locally advanced breast cancer, 2616 of whom had HR-positive, HER2-negative disease and 1015 of whom had HR-positive, HER2-positive disease (of whom 701 were also treated with trastuzumab) [11].

●Among patients of all biologic subtypes, the frequency of pCR was 22 percent, with evidence that higher-grade or more aggressive phenotypes such as triple-negative or HER2-positive cancers experience higher rates of pCR (on the order of 30 to 50 percent with chemotherapy and trastuzumab, if indicated, versus less than 20 percent among those with HR-positive disease).

●Among patients with HR-positive, HER2-negative disease, frequency of pCR was greater for high-grade tumors compared with low- to intermediate-grade tumors (16 versus 8 percent). These rates were lower than for patients with HR-positive, HER2-positive disease (31 percent when trastuzumab was given with chemotherapy). Specific regimens for patients with HR-positive breast cancer are discussed elsewhere, according to whether the cancers are HER2 negative or HER2 positive. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen' and "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Standard regimens'.)

Prognostic features — Multiple meta-analyses have demonstrated that while the prognostic value of a pCR is greatest in patients with aggressive biologic subtypes (triple-negative or HER2-positive disease), patients with HR-positive disease who achieve a pCR also have improved survival outcomes relative to those who do not [11,14]. However, a limitation of using pCR to predict outcomes in patients with ER-positive disease is that only 2 to 10 percent of patients with ER-positive disease achieve a pCR with neoadjuvant chemotherapy, though many more have favorable survival outcomes, possibly because of utilization of endocrine therapy in the adjuvant setting [15,16].

In the meta-analysis discussed above, among patients with HR-positive, HER2-negative disease, the pCR was positively associated with event-free survival (EFS: hazard ratio [HR] 0.49, 95% CI 0.33-0.71) and overall survival (OS: HR 0.43, 95% CI 0.23-0.71) [11]. Presence of pCR was associated with long-term outcome in the HER2-positive subgroup, both among patients with HR-positive and HR-negative disease (EFS: HR 0.39, 95% CI 0.31-0.50; OS: 0.34, 0.24-0.47).

Neoadjuvant endocrine therapy

Efficacy

Premenopausal women — Data regarding NET for premenopausal women are limited to phase II studies [17,18], but suggest worse response rates relative to chemotherapy [18]. For example, subgroup analysis from the Grupo Español de Investigación del Cáncer de Mama (GEICAM) study including 51 premenopausal patients demonstrated response rates of 75 percent among those receiving neoadjuvant chemotherapy versus 44 percent among those receiving NET [18]. The chemotherapy regimen used in this study was four cycles of epirubicin and cyclophosphamide (EC) every three weeks followed by four cycles of docetaxel every three weeks, while endocrine therapy consisted of exemestane plus the luteinizing-hormone-releasing hormone analog goserelin every four weeks for 24 weeks.

Postmenopausal women — Available data suggest that NET is associated with similar response rates and rates of breast-conserving surgery (BCS) as neoadjuvant chemotherapy with lower toxicity, although survival data with NET are not yet available [18-22].

In a meta-analysis of 20 prospective, randomized clinical trials including 3490 patients in which at least one arm incorporated NET, neoadjuvant monotherapy with aromatase inhibitors (AIs) had a similar clinical response rate (odds ratio [OR] 1.08, 95% CI 0.50-2.35), BCS rate (OR 0.65, 95% CI 0.41-1.03), and radiologic response rate (OR 1.38, 95% CI 0.92-2.07) compared with neoadjuvant combination chemotherapy, but with lower toxicity [19]. Most of the studies included in this meta-analysis were not comparing chemotherapy with endocrine therapy, but rather two forms of endocrine therapy or endocrine therapy with or without growth factor pathway inhibitors.

One of the studies included in the meta-analysis that did compare chemotherapy with endocrine therapy was a phase II trial, in which 239 postmenopausal women with HR-positive, stage II to III breast cancer were randomly assigned to neoadjuvant treatment with an AI (either exemestane or anastrozole) for three months versus chemotherapy (four cycles of doxorubicin and paclitaxel every 21 days) [20]. The main results were as follows:

●There were no differences in overall response rates between exemestane, anastrozole, or chemotherapy (67, 62, and 63 percent, respectively). Compared with chemotherapy, neoadjuvant AI treatment resulted in similar median time to clinical response (57 versus 51 days) and a similar rate of pCR (3 versus 6 percent). There was a trend for higher rates of BCS following NET (33 percent) compared with neoadjuvant chemotherapy (24 percent).

●Longer-term follow-up at 34 months suggests that there was no difference in the rates of local recurrence (3.3 and 3.4 percent among patients who received endocrine therapy and chemotherapy, respectively).

●Commonly reported adverse events were greater among patients receiving chemotherapy, including grade 2 to 4 neutropenia (43 percent), grade 2 neuropathy (30 percent), and alopecia (79 percent). While these adverse effects were not observed among patients receiving endocrine therapy, the rates of hot flashes, fatigue, and vaginal bleeding were higher in this group.

Another trial was performed by GEICAM and enrolled 95 patients with HR-positive, HER2-negative breast cancer, 44 of whom were postmenopausal [18]. Postmenopausal patients were assigned treatment with four cycles of EC every three weeks followed by four cycles of docetaxel every three weeks versus 24 weeks of exemestane. Overall, patients assigned to chemotherapy were more likely to respond compared with those assigned to endocrine therapy; however, the effect appeared to be driven primarily by results in the premenopausal subgroup (see 'Premenopausal women' above). Among postmenopausal patients, the response rate for chemotherapy was 57 percent versus 52 percent among those receiving hormone therapy, a difference that was not statistically significant.

There are few published data on long-term control rates in patients treated with NET followed by surgery. A series of 242 patients (median age, 76 years) had BCS after neoadjuvant letrozole [23]. One hundred eighty two of 242 (78 percent) had postoperative radiotherapy, and in those who did have radiotherapy, the local recurrence rate at five years was less than 2 percent.

Choice of endocrine therapy — For postmenopausal women receiving NET, we suggest the administration of an AI instead of tamoxifen, based on evidence suggesting better outcomes with AIs across clinical trials and meta-analyses [19,24-30]. For example, in the meta-analysis discussed above, neoadjuvant monotherapy with AIs was associated with a higher clinical response rate (OR 1.69, 95% CI 1.36-2.10), radiologic response rate (OR 1.49, 95% CI 1.18-1.89), and BCS rate (OR 1.62, 95% CI 1.24-2.12) compared with tamoxifen [19]. The different AIs are comparably effective in trials and each may be used in the neoadjuvant setting. For women who are not tolerant of AIs (for example, those with an osteoporotic fracture on AIs), or those who prefer to avoid the risk of osteoporosis associated with AIs, tamoxifen is a reasonable alternative.

Evidence suggests similar clinical outcomes among the AIs when used in the neoadjuvant setting. In the ACOSOG Z1031 trial, 377 postmenopausal women with stage II or III strongly ER-positive breast cancer were randomly assigned to treatment with exemestane, letrozole, or anastrozole for 16 to 18 weeks before surgery [29]. Treatment with any of the three agents resulted in similar clinical response rates: 63 percent with exemestane, 75 percent with letrozole, and 69 percent with anastrozole, differences that were not statistically significant. There were no differences in the rate of BCS.

Response rates associated with other regimens were provided in individual studies, with some of the largest studies discussed below:

●Letrozole versus tamoxifen – A multinational, double-blind trial randomly assigned 337 women who were ineligible for BCS to treatment with four months of letrozole (2.5 mg daily) or tamoxifen (20 mg daily), followed by surgery [24,25]. Compared with tamoxifen, letrozole resulted in:

•A higher overall response rate (55 versus 36 percent).

•A higher rate of BCS (45 versus 35 percent).

•A higher response rate among HER2-positive patients (88 versus 21 percent) and a trend towards a higher overall response rate among HER2-negative patients (55 versus 42 percent).

●Anastrozole versus tamoxifen – In the PROACT trial, 451 women with HR-positive breast cancer were randomly assigned to treatment with three months of neoadjuvant anastrozole or tamoxifen [27]. Concomitant chemotherapy was given to 29 and 32 percent of patients, respectively. The main results were [27]:

•There was no significant difference in overall response rate between patients who received anastrozole or tamoxifen (40 versus 35 percent, respectively).

•In patients who did not receive chemotherapy and who were not considered candidates for BCS at study entry, treatment with anastrozole improved surgical options in 43 percent compared with 31 percent with tamoxifen.

●Fulvestrant, with or without anastrozole, versus anastrozole – The phase III ALTERNATE trial randomly assigned women with T2 to 4 N0 to 3 M0 ER-positive/HER2-negative invasive breast cancer to either anastrozole, fulvestrant, or a combination of the two as NET with approximately 430 patients in each arm, respectively. Results showed that neither fulvestrant nor fulvestrant plus anastrozole improved the rate of endocrine-sensitive disease compared with anastrozole alone. The rates of endocrine-sensitive disease (defined using pathological response to NET) were 22.7, 20.5, and 18.6 percent, respectively [31].

Duration of endocrine treatment — A response to endocrine therapy may not be evident for three to four months or more, and maximal response may not be achieved until much later. Thus, the duration of endocrine treatment prior to surgery must be individualized based on the patient’s clinical status and the clinical response. In general, our approach is as follows:

●For patients undergoing NET, we initiate treatment with a planned course of four to six months. However, if disease progression occurs at any point, we proceed directly to surgery, if feasible. In the absence of disease progression:

•If the tumor is amenable to BCS after four to six months of endocrine therapy, we proceed with definitive surgical treatment. In a study of 102 women treated with neoadjuvant exemestane for 24 weeks, the response rate was 58 percent, and the rate of BCS was 68 percent among those initially requiring mastectomy [32]. For patients receiving neoadjuvant tamoxifen, the majority of those who experience a response will do so within the first three months of therapy, though a minority experience it between months 3 and 6 [33].

•If the tumor is either stable or responding to endocrine therapy, but not yet amenable to BCS, we discuss the risks and benefits of extending treatment to a total treatment duration of 6 to 12 months versus proceeding with mastectomy, if feasible. Extension of treatment, with clinical monitoring of response, may enable BCS, although there is also a low risk of progression. In a study of 134 patients with ER-positive, locally advanced breast cancer or breast cancer initially requiring mastectomy, extension of the course of letrozole treatment beyond three months increased the percentage of patients who were suitable for BCS from 60 to 72 percent [34]. While 2 percent of patients experienced disease progression, all patients were able to undergo surgical resection. Treatment durations ranged from six months to over two years.

•For some patients, surgery of any type may never become feasible, even with six months or greater of endocrine therapy. For those who are candidates for chemotherapy, we offer treatment, along similar lines as for those who did not receive NET. For patients who are not candidates for chemotherapy or surgery, continuing primary endocrine therapy or primary radiation may be appropriate and are discussed elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen' and "Overview of the approach to early breast cancer in older women", section on 'Nonsurgical candidates'.)

Investigational options

Biomarkers — A number of approaches are being studied to predict which patients are most likely to benefit from NET. Biomarkers of response to endocrine treatment are also under study. At present, however, these biomarkers are investigational and should not be used in routine clinical decision-making.

●Predictive biomarkers – Gene expression has been studied in multiple studies as a predictor of response to endocrine therapy. Examples of available data are as follows:

•The 21-gene Oncotype DX Recurrence Score (RS) has been evaluated in several studies [35-40]. As in the adjuvant setting, a lower RS is associated with less benefit from chemotherapy and more benefit from endocrine therapy, and vice versa for a higher RS.

For example, in a systematic review of seven studies involving 1744 patients who had an RS performed on a core needle biopsy specimen, followed by neoadjuvant chemotherapy, the pCR rate was higher in the group with a high RS than in the group with a low-intermediate score (10.9 versus 1.1 percent) [41]. We note pCR has limited sensitivity in this setting, however. (See 'Prognostic features' above.)

On the other hand, in a separate study, among 87 postmenopausal women with HR-positive tumors >3 cm treated with NET (tamoxifen or anastrozole), patients with a low RS had a higher response rate (64 percent) compared with those who had an intermediate or high RS (31 percent for both groups) [37]. Furthermore, there was a trend toward better relapse-free survival (RFS) among those with a low RS compared with those who had an intermediate or high RS (five-year RFS of 100 versus 84 and 73 percent, respectively), though the study had low statistical power due to small number of patients [38,39]. These data fit with the overall understanding that low-RS tumors are more sensitive to endocrine treatment.

•Similarly, in a retrospective study of 217 women with HR-positive, HER2-negative breast cancer, the 12-gene EndoPredict Molecular Score (MS) was associated with pCR to neoadjuvant endocrine and chemotherapy; tumors with low MS were unlikely to benefit from neoadjuvant chemotherapy, whereas a high MS predicted resistance to NET [42].

•A four-gene predictor has been developed that classifies patients into likely responders or nonresponders based on measurement of baseline gene expression of two genes as well as gene expression of two proliferation genes at 14 days of treatment. In an initial test set of 73 patients the model was 96 percent accurate, and in a validation series of 44 patients a 93 percent accuracy rate was reported [43]. Other gene expression analyses have also suggested that responders and nonresponders to NET have distinct genetic profiles and changes to gene expression with therapy [44].

While it was initially thought that tumors with lobular histology would not be suitable for neoadjuvant endocrine treatment given difficulty in assessing response, this has not proved to be the case. One study of 61 patients with invasive lobular carcinomas showed excellent results with three months of neoadjuvant letrozole treatment. The mean reduction in tumor volume measured clinically at three months was 66 percent [45]. However, pCR is variable within lobular cancers treated with either chemotherapy or endocrine therapy.

●Markers of response – While pCR rates are a standard outcome measure of the efficacy of neoadjuvant therapy, they may not fully reflect the response to NET. The histology pattern of response differs between chemotherapy and hormone therapy, with chemotherapy producing significantly more complete pathologic responses and more responses that leave scattered foci of disease than hormone therapy [46]. However, higher rates of central scarring are observed with endocrine therapy (58.5 percent) than for chemotherapy (2 percent), which may affect the natural history of the disease without resulting in pCR.

While contemporary attempts have been made to better evaluate the response to NET, all of these require further prospective validation and correlation with clinical outcome before incorporation into routine clinical practice [47]. Tools that have been studied include gene expression analyses [44]; the preoperative endocrine prognostic index (PEPI) score [48,49], which takes into account tumor and nodal stage, level of ER expression, and Ki67 following NET; and measurement of Ki67 before and during treatment [50,51].

For example, data from the IMPACT trial suggest that measurement of residual proliferation after two weeks of neoadjuvant endocrine treatment, as assessed by Ki67, may predict relapse-free survival (HR 2.01, 95% CI 1.4-3.1) [51]. While changes in Ki67 have been observed with neoadjuvant therapy in a number of studies [29,50,51], there was no relationship between response and change in Ki67 in the IMPACT study [51]. Although patients with elevated Ki67 after an initial period of NET may have a worse prognosis, limited evidence suggests that switching such patients to chemotherapy is not beneficial. In a subset of the ACOSOG Z1031B trial, in which 35 women with Ki67 >10 percent after two to four weeks of neoadjuvant AI therapy were switched to neoadjuvant chemotherapy, only two women (5.7 percent) experienced a pCR [49]. However, the low chemotherapy responsiveness could reflect a selection bias in the study population given the inclusion of postmenopausal women with strong hormone receptor-positive tumors deemed eligible for NET. The relationship between Ki67 and clinical outcomes is being further assessed in the POETIC and ALTERNATE trials. Early data from POETIC confirmed that a low proliferation rate on treatment (low Ki67) was a predictor of outcome with a much higher rate of events in the population with a high Ki67 [52].

Treatments — Investigational treatment strategies for patients with HR-positive disease include combinations of endocrine therapy with chemotherapy as well as targeted agents. While in general, combination therapy is associated with a higher response rate relative to single agent endocrine therapy, combination therapy cannot be recommended for routine clinical practice at this time given lack of survival data and concern about added toxicity. Several ongoing trials are investigating the role of combination therapy, including the combination of AIs with cyclin-dependent kinase (CDK) 4/6 inhibitors (neoMONARCH), phosphoinositide-3 kinase (PI3K) inhibitors (LORELEI), and dual endocrine therapy (ALTERNATE).

The strategy of combined chemotherapy and endocrine therapy in the neoadjuvant setting is feasible, but should not be used outside of a clinical trial given lack of known survival benefits. One study randomly assigned 101 postmenopausal women to NET (letrozole) plus chemotherapy versus neoadjuvant chemotherapy alone [53]. The study observed that the combination therapy had a higher clinical response rate (28 versus 10 percent) and pCR rate (26 versus 10 percent) compared with neoadjuvant chemotherapy alone.

Several trials have also investigated the role of endocrine therapy in combination with other targeted therapies. These combinations are investigational, and none have shown superiority over chemotherapy. Tested combinations include endocrine therapy with everolimus [54], celecoxib [55], zoledronic acid [56], gefitinib [51,57], lapatinib [58], taselisib [59], abemaciclib [60], and palbociclib [61-63].

●For example, in one randomized trial of 106 patients with high-risk luminal breast cancer, neoadjuvant palbociclib plus letrozole was associated with a residual cancer burden 0-1 response in 8 percent, versus in 16 percent of those receiving neoadjuvant chemotherapy [64]. Clinical response and BCS rates were comparable, however, and the safety profile with palbociclib/letrozole was better compared with chemotherapy.

●It remains unclear whether the addition of a CDK 4/6 inhibitor to NET improves outcomes relative to an AI alone.

In preliminary results of neoMONARCH, neoadjuvant treatment with the CDK 4/6 inhibitor abemaciclib, either alone or in combination with anastrozole, reduced levels of Ki67 relative to single-agent anastrozole [60]. However, in preliminary results of a separate study, the addition of ribociclib to letrozole did not result in more women with PEPI score of 0 [65]. Further data, including survival outcomes, are needed prior to routine incorporation of CDK 4/6 inhibitors in the neoadjuvant setting. Further discussion of the PEPI score is found above. (See 'Biomarkers' above.)

●As another example of targeted and endocrine therapy combinations, the addition of the alpha-isoform-specific PI3K inhibitor taselisib to neoadjuvant letrozole improved objective response rates (50 versus 39 percent, with and without taselisib, respectively), with greater benefits observed among those with mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene (56 versus 38 percent, respectively) [59]. Further outcome data are required prior to routine neoadjuvant use of CDK 4/6 or PI3K inhibitors.

Other investigational approaches have included alternatives to aromatase inhibition for NET. One study compared different doses of neoadjuvant fulvestrant (500 mg/month versus 250 mg/month) given for 16 weeks prior to surgery [66]. Similar to what has been observed in the metastatic setting, the study demonstrated that the higher dose of fulvestrant was superior and had a greater antiproliferative effect. Fulvestrant has also been compared with aromatase inhibition in the neoadjuvant setting. In the ALTERNATE trial, clinical efficacy, as measured by the proportion of patients achieving a modified PEPI score of 0, was similar between neoadjuvant fulvestrant, anastrozole, and the combination of fulvestrant and anastrozole [67]. Recurrence-free survival data are pending.

The investigational combination of endocrine therapy and HER2-directed therapy for those with HR-positive, HER2-positive cancers is discussed elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'HER2-targeted therapy without chemotherapy'.)

TREATMENT AFTER NEOADJUVANT THERAPY

Assessment of response — The general approach to evaluation of response to neoadjuvant therapy while on treatment and afterwards is the same regardless of biologic subtype and type of neoadjuvant therapy, and is discussed in further detail elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Post-treatment evaluation and management' and "General principles of neoadjuvant management of breast cancer", section on 'Poor response to or progression on neoadjuvant therapy' and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'On-treatment evaluation'.)

Adjuvant treatment — For patients who did not complete the full course of neoadjuvant treatment, we continue the planned course of treatment in the adjuvant setting, making dose adjustments as necessary for observed toxicities. The use of adjuvant capecitabine for those with residual disease after neoadjuvant therapy is discussed in detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

For patients who received neoadjuvant endocrine therapy (NET) because, for medical or personal reasons, they were not candidates for chemotherapy, we do not utilize chemotherapy in the adjuvant setting, particularly if they have had a partial or complete response to NET. For those with stable disease on NET, who were able to proceed with surgery and have no contraindications to chemotherapy, we utilize the same decision-making regarding adjuvant chemotherapy as for patients who did not receive neoadjuvant treatment. Some patients are found at the time of surgery to have more extensive disease than had been anticipated after NET. At that point, the clinical team must reassess the potential role for adjuvant chemotherapy. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Special populations'.)

All patients with HR-positive breast cancer should continue with adjuvant endocrine therapy, regardless of whether it was administered in the neoadjuvant setting. The choice of agent and duration of treatment is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications' and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)

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: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Neoadjuvant therapy refers to administration of therapy before surgery and is used to downstage locally advanced and unresectable primary breast cancers to make them operable. (See 'Introduction' above and 'Goals and indications' above.)

●For premenopausal women with hormone receptor (HR)-positive disease who warrant neoadjuvant therapy, we recommend chemotherapy over endocrine therapy (Grade 1B). (See 'Premenopausal women' above.)

●For the majority of postmenopausal women with HR-positive disease who warrant neoadjuvant therapy, we suggest chemotherapy (Grade 2B). For those with significant comorbidities, we use neoadjuvant endocrine therapy (NET). For those with tumors that are human epidermal growth factor receptor 2 (HER2) negative and strongly HR positive, NET is another option (algorithm 1). (See 'Medically fit' above and 'Medically frail' above and 'Neoadjuvant endocrine therapy' above.)

●Chemotherapy can shrink HR-positive tumors and facilitate lesser surgery, but is less likely to achieve a pathologic complete response in HR-positive cancers, especially luminal A cancers, compared with more aggressive histologies.

●In postmenopausal women, NET is associated with similar response rates to neoadjuvant chemotherapy, although it may take longer to achieve a response. Survival data with NET versus neoadjuvant chemotherapy are not yet available. (See 'Neoadjuvant endocrine therapy' above.)

●For patients with HR-positive disease receiving neoadjuvant chemotherapy, the approach to chemotherapy regimen selection is similar to that of other biologic subtypes and is discussed in detail elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Neoadjuvant treatment options'.)

●Patients with HR-positive, HER2-positive disease receiving neoadjuvant therapy should usually be treated with a regimen that combines chemotherapy with HER2-directed agents. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Components of therapy'.)

●For postmenopausal women receiving NET, we suggest aromatase inhibitors (AIs) rather than tamoxifen because of higher efficacy (Grade 2A). Some women may, however, prefer the side effect profile of tamoxifen to that of AIs. For such women, tamoxifen is appropriate. (See 'Choice of endocrine therapy' above.)

●Our general approach is to administer NET for four to six months, though a longer duration of treatment may be utilized, if needed, to allow for breast-conserving surgery in patients who have stable disease or partial response to endocrine therapy. If progression of disease occurs at any point, we proceed directly to definitive surgical management. (See 'Duration of endocrine treatment' above.)

●All patients with HR-positive breast cancer should continue with adjuvant endocrine therapy, regardless of whether it was administered in the neoadjuvant setting. The choice of agent and duration of treatment is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications' and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)