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Choice of neoadjuvant chemotherapy for HER2-negative breast cancer

Choice of neoadjuvant chemotherapy for HER2-negative breast cancer
Author:
William M Sikov, MD, FACP, FNCBC
Section Editor:
Harold J Burstein, MD, PhD
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Jun 2022. | This topic last updated: Feb 14, 2022.

INTRODUCTION — Neoadjuvant therapy refers to the systemic treatment of breast cancer prior to definitive surgical therapy (ie, preoperative therapy). While all systemic therapy given for non-metastatic invasive breast cancer is intended to reduce the risk of distant recurrence, the purpose of administering it prior to surgery is to downstage the tumor and provide information regarding treatment response. Typically, neoadjuvant treatment has taken the form of chemotherapy, although there is increasing interest in expanding the role of neoadjuvant endocrine therapy in certain subsets of patients.

This topic will review selection of chemotherapy regimen for patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer for whom the decision has been made to pursue neoadjuvant chemotherapy (NACT). Details on how to select patients for neoadjuvant treatment are found elsewhere.

(See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

Outcomes for NACT among patients with hormone receptor-positive cancers, in particular, are discussed elsewhere.

(See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'HER2-negative cancers'.)

The neoadjuvant approach to patients with HER2-positive breast cancers is also found elsewhere.

(See "Neoadjuvant therapy for patients with HER2-positive breast cancer".)

Finally, management of patients after NACT is discussed in detail elsewhere, including a discussion of adjuvant therapy, for appropriate candidates.

(See "General principles of neoadjuvant management of breast cancer", section on 'Adjuvant treatment'.)

(See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

(See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)

PATIENT SELECTION — Patient selection for neoadjuvant treatment is discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

For those with triple-negative disease receiving neoadjuvant treatment, chemotherapy is standard. Selection of regimen is discussed below. (See 'Choosing a regimen' below.)

Chemotherapy remains the standard neoadjuvant approach in patients with locally advanced, hormone receptor-positive disease, although endocrine therapy may be considered in some of these patients. The choice between chemotherapy and endocrine neoadjuvant therapy is discussed in detail elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Therapeutic options'.)

BENEFITS OF NEOADJUVANT CHEMOTHERAPY — NACT is associated with high rates of clinical response and a greater likelihood of facilitating cosmetically acceptable surgery. For example, patients who were not candidates for breast conservation may become eligible after NACT; those with limited node-positive disease (cN1) may be appropriate for more limited axillary surgery after NACT. However, NACT has not been shown to improve disease-free or overall survival compared with the same treatment administered after surgery [1,2].

Outcomes for patients receiving neoadjuvant versus adjuvant chemotherapy were demonstrated in an individual patient data meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group, which was based on data from 4756 women in 10 trials initiated between 1983 and 2002 [3]. Compared with adjuvant chemotherapy, NACT resulted in:

An increased frequency of breast-conserving surgery (65 versus 49 percent).

Equivalent risks of distant recurrence (38 percent at 15 years in both arms) and breast cancer mortality (34 percent at 15 years in both arms).

An increased risk of local recurrence (21 versus 16 percent at 15 years; hazard ratio 1.37, 95% CI 1.17-1.61), which has been attributed to the increase in breast-conserving surgery, but is of limited concern since it apparently does not increase the risk of distant recurrence or breast cancer mortality.

Among patients treated with NACT, achievement of a pathologic complete response at surgery is prognostically significant, particularly in patients with more aggressive breast cancer subtypes, including triple-negative breast cancer (TNBC). This is discussed in detail elsewhere. (See "General principles of neoadjuvant management of breast cancer" and "General principles of neoadjuvant management of breast cancer", section on 'Pathologic assessment'.)

Finally, emerging studies suggest that NACT may allow for a tailored approach to systemic therapy after breast surgery. In particular, studies have shown that administering capecitabine as adjuvant treatment to women with TNBC and residual cancer after NACT (CREATE-X trial) or administering trastuzumab emtansine as adjuvant treatment to women with HER2-positive breast cancer and residual cancer after NACT and HER2-targeted therapy (KATHERINE study) can improve long-term outcomes. Thus, in some patient populations, administration of NACT plays a role in identifying patients more likely to benefit from subsequent treatment. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Residual disease'.)

CHOOSING A REGIMEN — The sections below describe chemotherapy options for patients with HER2-negative disease. Special considerations for those with triple-negative breast cancer (TNBC) are discussed afterwards. (See 'Special considerations for triple-negative disease' below.)

Regimens utilized in the adjuvant setting also demonstrate activity as neoadjuvant treatment. Commonly used regimens for patients with HER2-negative disease include:

Anthracycline-based regimens such as doxorubicin and cyclophosphamide followed or preceded by a taxane (paclitaxel or docetaxel [AC-T]), and

Anthracycline-free regimens such as docetaxel and cyclophosphamide (TC), amongst others.

Results of the Anthracycline in Breast Cancer (ABC) analysis, which evaluated anthracycline-based regimens versus six cycles of TC in the adjuvant setting, inform neoadjuvant choices as well [4,5]. Although, overall, anthracycline-treated patients did slightly better (four-year invasive disease-free survival [IDFS] of 91 percent versus 88 percent for TC), in subset analysis, the benefit of adding the anthracycline was substantial only in node-positive TNBC and hormone receptor-positive patients with four or more involved nodes. Patients with node-negative TNBC or hormone receptor-positive patients with limited (one to three positive nodes) nodal involvement received minimal benefit from the addition of an anthracycline. These data are discussed in more detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)

Many patients warranting neoadjuvant therapy have larger tumors and/or nodal involvement, and thus would qualify as "higher-risk" cases, in whom we favor anthracycline- and taxane-based regimens (eg, AC-T). But for many "intermediate-risk," HER2-negative patients, especially those with hormone receptor-positive cancers, and in patients for whom the potential cardiotoxic effects of anthracyclines are a major concern, an anthracycline-free regimen such as TC is a reasonable alternative. (See 'Anthracycline-free alternatives' below.)

Anthracycline-based regimens — For high-risk patients who are treated with NACT (eg, those with node-positive disease or node-negative TNBC ≥1 cm), we suggest an anthracycline- and taxane-based combination rather than a non-anthracycline-based treatment [6]. Data supporting the addition of carboplatin to weekly paclitaxel and the programmed cell death protein 1-targeted monoclonal antibody pembrolizumab to taxane- and anthracycline-based NACT in stage II and III TNBC are discussed later in this topic. (See 'Special considerations for triple-negative disease' below.)

A major goal of neoadjuvant therapy is to provide effective systemic "adjuvant" therapy. Thus, in HER2-negative patients receiving anthracycline-based regimens, we typically administer four cycles of dose-dense (every two weeks) doxorubicin and cyclophosphamide followed or preceded by paclitaxel given either weekly for 12 weeks (AC-weekly T), or every two weeks for four cycles (AC-T) (table 1). Results from the ECOG 1199 trial demonstrated that, following AC, docetaxel administered every three weeks for four cycles was at least as effective as weekly paclitaxel as adjuvant therapy in patients with hormone receptor-positive cancers, and thus is a reasonable alternative in these patients [7] (see 'Anthracycline-free alternatives' below). In TNBC, we typically administer weekly paclitaxel with either weekly or every-three-week carboplatin followed by four cycles of AC, with concurrent pembrolizumab every three weeks. AC is usually administered every two weeks (referred to as "dose-dense"), though every three weeks is a reasonable alternative, as the superiority of dose-dense AC has not been demonstrated in the neoadjuvant setting.

The Oxford meta-analysis of adjuvant chemotherapy trials demonstrated overall benefit for anthracycline-based regimens over cyclophosphamide, methotrexate, and fluorouracil (CMF), and additional benefit for the sequential administration of a taxane in the adjuvant setting [8]. A subsequent analysis demonstrated a benefit for dose-dense (every two weeks) compared with standard-frequency (every three weeks) adjuvant chemotherapy [9]. Further details are discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Rationale for anthracycline- and taxane-containing regimen'.)

In the neoadjuvant setting, multiple studies have demonstrated that addition of a taxane to an anthracycline-based regimen, either concurrently or sequentially, is associated with increased response rates [10-17]. As an example, in the NSABP B27 trial, 2411 patients received four cycles of neoadjuvant AC, after which they were randomly assigned to receive no further chemotherapy, four cycles of neoadjuvant docetaxel (100 mg/m2) every three weeks, or to undergo surgery followed by four cycles of adjuvant docetaxel [10]. The addition of docetaxel in the neoadjuvant setting increased the pathologic complete response (pCR) rate from 13 to 26 percent, although the addition of this agent, whether given prior to or after surgery, had no demonstrable impact on overall survival (OS; 74 percent with neoadjuvant AC only and 75 percent in the arms containing docetaxel) or disease-free survival (59 and 62 percent).

Choice of taxane to pair with an anthracycline — Among patients receiving anthracyclines, we typically use paclitaxel as our taxane of choice, though docetaxel is a reasonable alternative in patients with hormone receptor-positive cancers, as discussed above. For patients who have had a previous hypersensitivity reaction to a taxane not amenable to conservative management, or a contraindication to the steroids administered with it, nanoparticle albumin-bound paclitaxel (nabpaclitaxel) is an acceptable alternative. Further details on the approach to taxane hypersensitivity are found below. (See 'Anthracycline-based regimens' above and 'Management of hypersensitivity reaction to a taxane' below.)

Results from the GeparSepto trial suggest that nabpaclitaxel improves pCR rates and IDFS relative to standard paclitaxel but is associated with greater toxicity. In this trial, over 1200 patients (two-thirds with HER2-negative disease) were randomly assigned to 12 weeks of neoadjuvant weekly paclitaxel (80 mg/m2) versus weekly nabpaclitaxel (150 mg/m2, subsequently reduced to 125 mg/m2 due to excessive hematologic and neurologic toxicity at the higher dose), both followed by epirubicin plus cyclophosphamide (EC), with the addition of trastuzumab and pertuzumab in HER2-positive patients [18,19].

Those receiving nabpaclitaxel experienced a higher pCR rate compared with those receiving standard paclitaxel (38 versus 29 percent, respectively; odds ratio [OR] 1.53, 95% CI 1.20-1.95). On subtype analysis, the improvement in the pCR rate was primarily seen in patients with TNBC (48 percent with nabpaclitaxel versus 26 percent with standard paclitaxel).

In subsequently reported results with a median follow-up of 50 months, patients who received nabpaclitaxel had superior four-year IDFS (84 versus 76 percent; hazard ratio [HR] 0.66, 95% CI 0.51-0.86) [19]. Subset analysis revealed improvements in IDFS in all patient subtypes, but this achieved statistical significance only among those with hormone receptor-positive, HER2-negative cancers.

Overall, the difference in OS between the two treatment arms was not statistically significant (90 with nabpaclitaxel versus 87 percent with standard paclitaxel; HR 0.82, 95% CI 0.59-1.16).

The incidence of serious (grade >3) adverse events was greater among patients receiving nabpaclitaxel (26 versus 21 percent), including higher rates of grade 3 peripheral neuropathy, even after its dose was reduced.

In a smaller phase III trial of 695 patients with HER2-negative breast cancer, improvement in the pCR rate with nabpaclitaxel versus paclitaxel (followed in either case by an anthracycline-based regimen) did not reach statistical significance (22 versus 19 percent; OR 0.77, 95% CI 0.52-1.13), even among those with TNBC (41 versus 37 percent) [20]. This study also reported higher rates of grade >3 adverse events with nabpaclitaxel (22 versus 17 percent), including a slightly higher incidence of grade 3 peripheral neuropathy (4 versus 2 percent).

While the findings from the GeparSepto study are encouraging, we favor continuing to use standard paclitaxel, largely on the bases of toxicity and cost, except in patients with contraindications to this agent.

Anthracycline-free alternatives — As in the adjuvant setting, an anthracycline-free neoadjuvant regimen may be a preferable option for some patients, particularly those with cardiac disease, advanced age, cardiac risk factors such as hypertension and diabetes mellitus, or those unwilling to accept the rare but serious risks of anthracyclines, including congestive heart failure and secondary leukemia. The TC combination is widely used in the adjuvant setting for HER2-negative disease and employing this regimen in the neoadjuvant setting is acceptable, particularly in low- and intermediate-risk patients.

There are relatively few neoadjuvant trials of TC. The available data on its efficacy suggest relatively low pCR rates (7 and 17 percent), but these studies were conducted in cohorts of patients with hormone receptor-positive, HER2-negative cancers, a group known to have a lower likelihood of achieving pCR [21,22]. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)

TC is a reasonable neoadjuvant alternative for patients with TNBC in whom there is a good reason to avoid use of an anthracycline. However, given evidence of the benefit of inclusion of a platinum agent in the neoadjuvant and adjuvant settings in patients with TNBC, regimens such as every-three-week docetaxel and carboplatin, or weekly paclitaxel and carboplatin can also be considered. (See 'Special considerations for triple-negative disease' below.)

Management of hypersensitivity reaction to a taxane — The rate of severe reactions to taxanes with appropriate premedication (eg, glucocorticoids and antihistamines) is less than 5 percent. Further details on the presentation of taxane hypersensitivity are found elsewhere. (See "Infusion reactions to systemic chemotherapy", section on 'Taxanes'.)

Many patients with mild hypersensitivity reactions to taxanes can safely resume treatment with the same agent, often later the same day, after being given time for their symptoms to resolve and receipt of additional intravenous doses of diphenhydramine and dexamethasone. Even patients with a more severe reaction can often be successfully rechallenged a day or more later after premedication with high-dose glucocorticoids plus H1- and H2-receptor antagonists and administration of the agent at a slower infusion rate. Desensitization is seldom necessary. This is discussed in detail elsewhere. (See "Infusion reactions to systemic chemotherapy", section on 'Retreatment after an infusion reaction'.)

For patients who have an initial life-threatening hypersensitivity reaction to a taxane in a neoadjuvant breast cancer regimen, or a second reaction to the same agent despite more intensive premedication, our practice is to switch to an alternative agent rather than attempting to desensitize the patient to the original taxane. Since most hypersensitivity reactions are caused by the detergent used to solubilize the hydrophobic taxane molecule, not the taxane itself, it is often safe switch from paclitaxel to docetaxel (or vice-versa), or to nabpaclitaxel, which, by binding paclitaxel to albumin creates a polar molecule that does not require addition of detergent to make it soluble in saline or water (table 2).

Scheduling considerations — Because the primary goal of neoadjuvant therapy is reduction in disease extent to facilitate more limited surgery, it is standard to administer all planned chemotherapy prior to definitive surgery, provided there is no evidence of disease progression during treatment. NACT is often administered using standard adjuvant chemotherapy agents, doses, and schedules; there are no data to suggest that different regimens should be used in the neoadjuvant setting compared with the adjuvant setting, with the possible exception of the addition of carboplatin and pembrolizumab to the neoadjuvant regimen in patients with TNBC. (See 'Special considerations for triple-negative disease' below.)

Otherwise, in patients without a contraindication to administration of an anthracycline, our approach is to administer dose-dense AC either preceded or followed by paclitaxel weekly (for 12 weeks) or every two weeks (for eight weeks) in most HER2-negative patients, given the benefits of dose-dense sequential anthracycline and paclitaxel chemotherapy in the adjuvant setting [23]. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Importance of chemotherapy schedule'.)

In a randomized trial in 311 patients receiving neoadjuvant therapy for HER2-negative breast cancer, those assigned to conventional versus reverse chemotherapy sequence with epirubicin/cyclophosphamide and docetaxel experienced similar rates of residual cancer burden class 0 or I (40 versus 37 percent) and pCR rates (24 versus 25 percent) [24]. By contrast, in the Neo-tAnGo trial, in which 831 patients were randomly assigned to EC for four cycles followed by paclitaxel (with or without concurrent gemcitabine) for four cycles, versus the opposite sequence, patients who received paclitaxel (with or without gemcitabine) first had a pCR rate of 20 percent, compared with 15 percent for those who received EC first, a difference that was statistically significant [25].

Although one trial suggests a modest benefit in pCR with administering the taxane first, the data are not compelling enough to suggest that this should be considered the preferred approach, and thus either sequence should be considered acceptable.

SPECIAL CONSIDERATIONS FOR TRIPLE-NEGATIVE DISEASE

Incorporation of carboplatin

In an anthracycline-containing regimen — For patients with stage II to III triple-negative breast cancer (TNBC), we suggest a carboplatin-containing neoadjuvant regimen be administered concurrently with pembrolizumab, as was used in KEYNOTE 522. (See 'Incorporation of immunotherapy with NACT in TNBC' below.)

In patients with a contraindication to receipt of an immunostimulatory agent, such as an underlying autoimmune disorder, or if pembrolizumab is not available, we suggest a carboplatin-containing NACT regimen similar to the control regimen of KEYNOTE-522.

Three randomized trials demonstrated improved pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel- and anthracycline-containing NACT regimens (table 3) [26-28]. While none of these studies were designed for definitive determination of the impact of carboplatin on long-term outcomes, two have reported improvements in event-free survival (EFS) or disease-free survival (DFS) with the addition of carboplatin.

In the double-blind phase III BrighTNess trial, 634 patients with stage II to III TNBC received neoadjuvant weekly paclitaxel followed by doxorubicin and cyclophosphamide (AC), and were assigned to: a) the control regimen, b) the addition of every-three-week carboplatin during paclitaxel, or c) the addition of carboplatin and the oral poly(ADP-ribose) inhibitor veliparib during paclitaxel [29]. While adding carboplatin increased the pCR rate (from 31 to 58 percent), the further addition of veliparib did not (53 percent). An update of the study's results demonstrated that the addition of carboplatin improved four-year EFS (from 69 to 79 percent), while the further addition of veliparib did not (78 percent) [30]. Overall survival (OS) results were immature but trended in the same direction.

In the GeparSixto trial, 315 patients with TNBC received a control neoadjuvant regimen of weekly paclitaxel and nonpegylated liposomal doxorubicin with every-three-week bevacizumab and were randomized to receive weekly carboplatin or not. The addition of carboplatin increased the pCR rate from 43 to 57 percent. Subsequent data demonstrated that the addition of carboplatin improved three-year DFS from 76 to 86 percent; there was also a nonsignificant improvement in OS.

In the CALGB/Alliance 40603 trial, 443 patients with stage II to III TNBC received weekly paclitaxel followed by every-two-week AC and were separately randomized to every-three-week carboplatin during paclitaxel and bevacizumab throughout their NACT. The addition of carboplatin increased the breast pCR rate from 46 to 60 percent but did not improve five-year EFS or OS [31]. While these results appear to contradict the positive findings from BrighTNess, dosing modification criteria in Alliance may have had a disproportionate impact on treatment delivery in a subset of patients assigned to carboplatin, skewing results for the overall study population. Moreover, the study was not powered to assess survival outcomes.

In all of these studies, patients assigned to carboplatin had higher rates of hematologic toxicities and early treatment discontinuation. Permitting patients to delay treatment for low blood counts, as in BrighTNess, as opposed to omitting it, as in CALGB/Alliance 40603, appeared to allow most patients to receive all treatments as planned and receive the maximal antitumor benefit.

In summary, existing data demonstrate that the addition of carboplatin to standard NACT for TNBC (ie, weekly paclitaxel followed by AC or epirubicin plus cyclophosphamide [EC]) increases absolute pCR rates by at least 13 percent and improves EFS (table 3). When adding carboplatin to standard NACT for TNBC, it is important that the treatment regimen is sufficiently flexible (eg, including permitting treatment delays or dose modifications for hematologic or other toxicities), to avoid omitting multiple doses of weekly paclitaxel; the rationale is to optimize its impact on pCR (and, possibly, long term outcomes), based on results from CALGB 40603, BrighTNess, and two studies presented at the 2019 San Antonio Breast Cancer Symposium, GeparX and KEYNOTE-522 [32].

The addition of other agents to standard AC followed or preceded by taxane (paclitaxel or docetaxel [AC-T]) chemotherapy, including gemcitabine, capecitabine, and bevacizumab, has not been shown to provide clinically meaningful improvements in neoadjuvant treatment outcomes in TNBC [25,26,29,33-40].

Three-week versus weekly carboplatin — No randomized trial has directly compared every-three-week and weekly carboplatin when administered with weekly paclitaxel during NACT for TNBC. However, in the KEYNOTE-522 trial, in which investigators were allowed to select between every-three-week (area under the curve [AUC] 5) and weekly (AUC 1.5) schedules, 58 percent of the 596 patients received the weekly schedule, with superior dose delivery and similar pCR rates compared with patients who received the every-three-week schedule [32].

In BRCA wildtype versus BRCA carriers — Investigators have explored whether platinum-based therapy would be particularly beneficial in women with hereditary breast cancer susceptibility gene 1/2 (BRCA1/2) mutations. In clinical trials, while both germline BRCA-mutation carriers and BRCA-wildtype patients with TNBC were more likely to achieve a pCR with the addition of carboplatin to NACT, patients without a germline BRCA mutation exhibited a much larger increase in pCR rates than BRCA-mutated patients, contrary to expectations [41]. For example, in BrighTNess, the addition of carboplatin increased the pCR rate in BRCA-wildtype patients from 29 to 59 percent, versus a more modest increase (from 41 to 50 percent) in BRCA carriers [29]. The magnitude of improvement in EFS with the addition of carboplatin did not differ between BRCA-mutated and BRCA-wildtype patients, although the relatively small number of BRCA mutation carriers limits confidence in this result. In outcomes analysis from GeparSixto, the absolute improvement in DFS at 35 months with the addition of carboplatin was greater in BRCA-wildtype patients (11 percentage points, 85 versus 74 percent; hazard ratio [HR] 0.53, 95% CI 0.29-0.96), versus in BRCA-mutated patients (4 percentage points, 86 versus 82 percent) [41,42].

Consideration in patients with contraindication to receiving an anthracycline — In patients with a contraindication to receipt of an anthracycline, such as underlying cardiac disease or risk factors associated with an increased risk for cardiac complications, and for patients with clinical stage I TNBC in whom NACT is indicated, treatment options include non-carboplatin-containing regimens such as docetaxel and cyclophosphamide (TC) as well as carboplatin-containing regimens such as docetaxel or paclitaxel with carboplatin. (See 'Pembrolizumab' below.)

Data from the neoadjuvant and adjuvant settings support consideration of carboplatin-containing regimens in patients with contraindication to treatment with an anthracycline. Results from studies supporting this approach include:

NeoSTOP was a randomized phase II study that compared a control regimen of weekly paclitaxel with every-three-week carboplatin followed by AC with six cycles of every-three-week docetaxel and carboplatin in 100 patients with TNBC. The pCR rate was 54 percent for both arms of the study and, at a median follow-up of 38 months, EFS and OS were also similar, but the anthracycline-free arm was associated with much lower rates of adverse events, including febrile neutropenia (0 versus 19 percent) [43].

The PATTERN trial was a randomized phase III study that compared adjuvant weekly paclitaxel and carboplatin with a control regimen of three cycles of cyclophosphamide, epirubicin, and fluorouracil followed by three cycles of docetaxel (CEF-T). Five-year DFS was superior with the weekly paclitaxel and carboplatin regimen (86.5 versus 80.3 percent; HR 0.65, 95% CI 0.44-0.96, p = 0.03) [44].

Incorporation of immunotherapy with NACT in TNBC — For patients with stage II or III triple-negative breast cancer (TNBC) receiving NACT who do not have a contraindication to the administration of immunotherapy (eg, a pre-existing autoimmune disorder), we suggest the addition of pembrolizumab to NACT and continuation of this agent after surgery.

This recommendation is based on the results of the KEYNOTE-522 trial and the subsequent US Food and Drug Administration approval of this agent in this setting in late July 2021 [45,46]. KEYNOTE-522, which is discussed in greater detail below, used a regimen of paclitaxel and carboplatin plus pembrolizumab, followed by AC plus pembrolizumab as preoperative treatment, followed by surgery, and then adjuvant pembrolizumab for another nine cycles (27 weeks) after surgery. When incorporating pembrolizumab with NACT, we suggest a carboplatin-containing NACT regimen similar to that administered in the KEYNOTE-522 study. (See 'Incorporation of carboplatin' above and 'Pembrolizumab' below.)

A number of studies have investigated the impact of the addition of immunotherapy agents to NACT on pCR rates in HER2-negative breast cancer, especially TNBC (table 3). However, only pembrolizumab has concluded a phase III study showing longer-term benefit and has received regulatory approval in this setting; the use of other agents remains investigational. Results according to agent are as follows.

Pembrolizumab — In the phase III KEYNOTE-522 trial, 1174 patients with previously untreated stage II or stage III TNBC receiving NACT were randomly assigned to the addition of pembrolizumab versus placebo every three weeks during NACT and continuing for another nine cycles (27 weeks) after surgery, independent of pathologic response to neoadjuvant therapy. NACT consisted of weekly paclitaxel and carboplatin (administered either weekly or every three weeks, by clinician choice) followed by doxorubicin or EC.

The trial demonstrated that the addition of pembrolizumab to NACT raised the overall pCR rate from 51 to 65 percent, and improvements in pCR rates were seen in both programmed cell death ligand 1 (PD-L1)-positive and PD-L1-negative cancers [47].

At longer follow-up, in data presented at a European Society for Medical Oncology virtual plenary, the addition of pembrolizumab also improved 36-month EFS (85 percent with pembrolizumab versus 77 percent with placebo), with a 37 percent reduction in events (HR 0.63, 95% CI 0.48-0.82) [48].

The absolute EFS benefit from the addition of pembrolizumab was larger in patients who failed to achieve pCR with NACT (67 versus 57 percent) than in those who achieved pCR (94 versus 92 percent).

EFS improvement was seen in both PD-L1-positive and PD-L1-negative subsets and did not differ by the chosen schedule of carboplatin administration.

While node-negative patients had superior outcomes compared with node-positive patients irrespective of whether they received pembrolizumab, the addition of pembrolizumab reduced the incidence of EFS events in this group as well.

The magnitude of the benefit from adding pembrolizumab was similar for distant recurrence-free survival. While there was also a numerical, but not statistically significant, improvement in OS (three-year OS of 90 versus 87 percent; HR 0.72, 95% CI 0.51-1.02), the data were immature for this endpoint.

For the combined neoadjuvant and adjuvant phases, grade 3 or 4 treatment-related adverse events were observed in 77 percent of the pembrolizumab-plus-chemotherapy arm and 73 percent of the chemotherapy-alone arm.

While the results of the KEYNOTE-522 study are very encouraging, they raise a number of questions. As examples:

Should pembrolizumab be continued in the adjuvant setting for patients who achieved a pCR after neoadjuvant pembrolizumab and chemotherapy? – Although we do not know the relative contributions of neoadjuvant versus adjuvant administration, we suggest continuation of pembrolizumab in the adjuvant setting, as was done in the trial, irrespective of whether a pCR was achieved. We await publication of the trial for more details of the subgroup analyses to further inform our approach.

Should adjuvant pembrolizumab be administered concurrently with other adjuvant therapy in patients who failed to achieve pCR, eg, with either capecitabine or olaparib (in patients with a germline BRCA mutation [49])? – We suggest concurrent therapy, though there are no available data addressing this question. There are smaller studies suggesting that combinations of capecitabine and pembrolizumab [50], and olaparib and pembrolizumab (in other tumor types) [51], have acceptable safety profiles.

Will the addition of pembrolizumab also improve outcomes in patients treated with a different NACT regimen? – When incorporating pembrolizumab into NACT, we use the same regimen as was used in KEYNOTE-522. It is not known if the particular NACT regimen is critical to obtain the potential benefit from the addition of pembrolizumab nor if carboplatin could be omitted without compromising long-term outcomes. However, in patients with stage II to III TNBC receiving an anthracycline-free regimen due to contraindications to this class of agents, we suggest adding pembrolizumab to their neoadjuvant regimen if the patient has no contraindication to immunotherapy, such as an underlying autoimmune disorder.

How should TNBC patients who have already started NACT without pembrolizumab be managed? – In regard to this question, we favor the addition of pembrolizumab to the patient's NACT regimen as soon as possible, while acknowledging that the KEYNOTE-522 data do not address this situation.

Should adjuvant pembrolizumab be used in patients who did not receive it concurrently with NACT, or in patients who underwent primary surgery? – We believe that it is reasonable to extrapolate the potential benefit of the addition of pembrolizumab to patients with stage II and III TNBC who underwent primary surgery and are receiving adjuvant chemotherapy with a regimen similar to that administered on KEYNOTE-522. On the other hand, given the uncertain benefit of adjuvant single-agent pembrolizumab (ie, not initiated concurrent with chemotherapy), we do not favor its administration to patients who have completed either neoadjuvant or adjuvant chemotherapy without pembrolizumab.

Other checkpoint inhibitors — Other checkpoint inhibitors have also been evaluated with NACT in TNBC, although none has regulatory approval, and we do not incorporate them into NACT regimens, pending further data.

Atezolizumab – The phase III IMpassion031 trial demonstrated that the addition of the PD-L1-targeted monoclonal antibody (mAb) atezolizumab to NACT (weekly nabpaclitaxel followed by AC) increased the overall pCR rate from 41 to 58 percent [52]. Again, increased pCR was seen in both PD-L1-positive and PD-L1-negative patients. While early EFS results are promising, this study was not powered to definitively address this endpoint.

By contrast, the NeoTRIPaPDL1 study did not demonstrate a statistically significant increase in pCR rates with the addition of atezolizumab to NACT consisting of nabpaclitaxel and carboplatin administered on days 1 and 8 every 21 days for eight cycles, overall or in either the PD-L1-positive or PD-L1-negative subsets [53].

Durvalumab – In the German Breast Group's phase II GeparNuevo study, 174 patients received NACT consisting of weekly nabpaclitaxel followed by EC and were randomly assigned to the addition of the PD-L1-targeted mAb durvalumab versus placebo; patients did not resume their assigned study drug after surgery.

While the addition of durvalumab numerically increased pCR rates in all patients, as well as in patients with both PD-L1-positive and PD-L1-negative cancers, these increases did not reach statistical significance [54]. However, among 117 patients who participated in a "window phase" of treatment, receiving a single dose of their assigned study drug two weeks before starting NACT, those who received durvalumab had a significantly higher pCR rate, suggesting a potential benefit for this type of "immune priming."

In subsequent reporting at a median follow-up of 42 months, the addition of durvalumab improved three-year invasive DFS (86 versus 77 percent), and also improved distant DFS and OS, irrespective of whether patients received the "window" treatment with durvalumab or not [55]. While encouraging in regard to the overall benefit of the addition of immunotherapy to NACT in TNBC, given the small size of this study we hesitate to draw conclusions as to the efficacy of this specific agent (durvalumab) when compared with the much larger KEYNOTE-522 trial. (See 'Pembrolizumab' above.)

ON-TREATMENT EVALUATION — Patients undergoing neoadjuvant treatment for breast cancer should undergo periodic clinical evaluations during treatment to assess response and ensure that their tumor is not progressing.

There are no formal guidelines regarding the ideal assessment strategy during neoadjuvant treatment. Our approach is as follows:

We perform a clinical examination every two to four weeks (ie, prior to each cycle of treatment). This should include physical examination of the affected breast and ipsilateral axilla. Clinical evaluation is usually adequate for confirming response or stable disease, or raising concerns about progression, during neoadjuvant treatment.

Imaging studies (ultrasound or magnetic resonance imaging) should only be performed if disease progression is suspected based on clinical exam or symptoms (or in the setting of a clinical trial, where response to a segment of treatment is being assessed and/or a change in treatment is required in nonresponding patients). Discussion of the management of patients who experience progression during neoadjuvant treatment is found elsewhere. However, clinicians should be aware that interval imaging can be misleading, as radiologic response may lag clinical response. (See "General principles of neoadjuvant management of breast cancer", section on 'Poor response to or progression on neoadjuvant therapy'.)

There is no role for routine repeat biopsy of the index tumor during NACT treatment. Although repeat measurement of biologic factors, such as Ki-67, may identify patients who are unlikely to respond to neoadjuvant endocrine therapy, this finding has not been widely validated, and this should not be used in routine clinical practice [56]. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Selection of treatment'.)

Details regarding post-treatment evaluation are found elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Post-treatment evaluation and management'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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 the systemic treatment of breast cancer prior to definitive surgical therapy (ie, preoperative therapy). Typically, neoadjuvant treatment has taken the form of chemotherapy, although there is increasing interest in expanding the role of neoadjuvant endocrine therapy in certain subsets of patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancers. (See 'Introduction' above.)

Patient selection for neoadjuvant (versus adjuvant) treatment is discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

For most HER2-negative patients receiving neoadjuvant treatment, chemotherapy is standard, including those with locally advanced, hormone receptor-positive disease. However, endocrine therapy may be used in certain hormone receptor-positive patients. The choice between chemotherapy and endocrine neoadjuvant therapy is discussed in detail elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Therapeutic options'.)

For high-risk patients with hormone receptor-positive/HER2-negative cancers who are treated with neoadjuvant chemotherapy (NACT; eg, those with node-positive disease), we suggest an anthracycline- and taxane-based combination rather than a non-anthracycline-based treatment (Grade 2B), such as doxorubicin and cyclophosphamide every two to three weeks for four cycles, followed or preceded by paclitaxel either weekly for 12 weeks or every two weeks for four cycles (AC-T), though substituting docetaxel every three weeks for four cycles for paclitaxel is a reasonable alternative. (See 'Anthracycline-based regimens' above.)

For others with hormone receptor-positive cancer, either AC-T or docetaxel and cyclophosphamide (TC) are options. TC may also be appropriate for those with a history of cardiac disease and those unwilling to accept the risks of anthracycline-based therapy. A decision on the treatment administered should take into account patient convenience and the side effects of each combination. (See 'Choosing a regimen' above and 'Anthracycline-free alternatives' above.)

Many patients with mild hypersensitivity reactions to a taxane can safely resume treatment with the same agent after being given time for their symptoms to resolve and receipt of additional intravenous doses of diphenhydramine and dexamethasone. For patients who have an initial life-threatening hypersensitivity reaction, or a second reaction to the same agent despite more intensive premedication, we suggest switching to an alternative agent rather than attempting to desensitize the patient to the original taxane (table 2) (Grade 2C). The rationale for this recommendation is that alternative regimens with comparable efficacy are typically available and avoid risk of hypersensitivity reactions. (See 'Management of hypersensitivity reaction to a taxane' above.)

For patients with stage II or III triple-negative breast cancer (TNBC) receiving NACT, we suggest the addition of pembrolizumab (Grade 2B), to be initiated concurrently with NACT and continued as a single agent in the adjuvant setting, provided that the patient does not have a contraindication to immunotherapy, such as an underlying autoimmune disorder.

When adding pembrolizumab to NACT for TNBC, we use a NACT regimen similar to that employed in the KEYNOTE-522 study (weekly paclitaxel and carboplatin followed by AC or epirubicin plus cyclophosphamide) unless that patient has a contraindication to one or more of those agents. (See 'Incorporation of carboplatin' above and 'Incorporation of immunotherapy with NACT in TNBC' above.)

For patients receiving NACT, we perform a physical examination (including the breast and ipsilateral axilla) every two to four weeks (ie, prior to each cycle of treatment). Imaging studies (ultrasound or magnetic resonance imaging) should only be performed on treatment if disease progression is suspected based on clinical exam or symptoms (or in the setting of a clinical trial). However, clinicians should be aware that interval imaging can be misleading, as radiologic response may lag clinical response. Discussion of the management of patients who experience progression during neoadjuvant treatment is found elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Poor response to or progression on neoadjuvant therapy'.)

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Topic 122902 Version 19.0

References