INTRODUCTION — Persistent activation of signaling pathways as a result of amplification of the human epidermal growth factor receptor 2 (HER2) in patients with HER2-positive breast cancer leads to a biologically aggressive malignancy with heightened sensitivity to cytotoxic chemotherapy. Compared with most other subtypes of breast cancer, a higher percentage of HER2-positive patients achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT), even in the absence of HER2-targeted therapy [1,2]. Using targeted therapy to block activation of those pathways further enhances the chemosensitivity of HER2-positive breast cancer, increasing the pCR rate. Clinical trial results from the last few years suggest that newer HER2-targeted agents may allow more effective inhibition of HER2 and expand options for the NACT regimen administered with HER2-targeted therapy based on the patient’s risk factors and overall medical condition.
This topic will review issues pertaining specifically to administration of neoadjuvant therapy in patients with HER2-positive breast cancer. Where clinical guidance is provided in this topic, 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".)
General principles of NACT, including patient selection for neoadjuvant therapy, assessment of response to therapy, and surgical management after NACT, are discussed in detail elsewhere. (See "General principles of neoadjuvant management of breast cancer".)
Adjuvant treatment for patients with HER2-positive disease who have received neoadjuvant treatment is also discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)
INDICATIONS — Neoadjuvant chemotherapy (NACT) is appropriate for many patients with locally advanced breast cancer regardless of subtype, because a response may allow both less extensive surgery and improved surgical outcomes. We generally define locally advanced as stage III cancers as well as the subset of IIB cancers with T3 disease. In addition, patients with earlier-stage, HER2-positive disease (stage I or II) may also be candidates for neoadjuvant therapy. Our approach to HER2 testing and interpretation of the results is included in the algorithm (algorithm 1), and is consistent with American Society of Clinical Oncology (ASCO) guidelines [3].
Patients with stage I or II HER2-positive cancers are appropriate candidates for neoadjuvant therapy if one or more of the following criteria apply:
●The patient desires breast-conserving surgery (BCS) but is not a candidate for BCS or is likely to have a suboptimal cosmetic outcome with BCS due to tumor location or size relative to the size of the patient’s breast, and may be a better candidate if neoadjuvant therapy decreases the extent of her tumor.
●The patient has limited axillary nodal involvement (N1), for which axillary lymph node dissection would be standard surgical management, but could be a candidate for sentinel lymph node sampling alone if converted to node-negative disease with neoadjuvant therapy.
●Surgery must be postponed awaiting consultation with plastic surgery regarding breast reconstruction, results of genetic testing or resolution of an intercurrent illness, including pregnancy, and the patient and treating clinicians do not wish to delay initiation of treatment.
●Postoperative treatment with ado-trastuzumab emtansine (T-DM1) would be considered if the patient were found to have residual invasive disease in the breast or axillary nodes following NACT with single or dual HER2-targeted therapy. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'T-DM1'.)
These considerations are particularly suited to patients with HER2-positive breast cancer, given the high rates of both clinical and pathologic response seen with neoadjuvant therapy, particularly if treatment includes a HER2-directed agent [2,4,5]. Our approach to HER2 testing and interpretation of the results is included in the algorithm (algorithm 1), and is consistent with ASCO guidelines [6].
For patients with HER2-positive disease who proceed directly to surgery without receiving neoadjuvant treatment, adjuvant chemotherapy with HER2-directed therapy is appropriate. Adjuvant therapy for such patients is discussed elsewhere [1,2]. (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Treatment overview'.)
OUTCOME MEASURES — In addition to outcome measures such as recurrence rate, event-free survival (EFS), and overall survival (OS), which are frequently used to assess treatment efficacy in the adjuvant setting, pathologic response, including the pathologic complete response (pCR) rate, is a useful measure of treatment efficacy in patients receiving neoadjuvant therapy. While some of the clinical trials discussed below used different definitions of pCR, including absence of residual invasive disease in the breast regardless of the status of the axillary nodes (ypT0/is Nany), the most widely accepted definition requires the absence of residual invasive disease in the breast and the absence of cancer in any sampled axillary nodes (ypT0/is ypN0). Although it is a surrogate outcome measure, achievement of pCR is associated with highly significant improved rates of disease-free and overall survival in patients with HER2-positive disease [1,7,8].
In a 2016 meta-analysis of 36 trials enrolling nearly 5800 patients with HER2-positive disease receiving neoadjuvant therapy, those who achieved a pCR (including breast and axilla) had superior EFS and OS compared with those who did not (hazard ratio [HR] EFS 0.37, 95% CI 0.32-0.43; HR OS 0.34, 95% CI 0.26-0.42) [9]. The association was even stronger in the hormone receptor-negative subgroup (HR EFS 0.29, 95% CI 0.24-0.36). A previous meta-analysis including approximately 2000 patients with HER2-positive disease showed similar results [1]. (See 'Tumor prognostic features' below.)
Among patients with HER2-positive cancers who do not achieve a pCR with neoadjuvant chemotherapy, those with minimal residual invasive disease at surgery have a better prognosis than those with more extensive residual disease. Though not yet validated in prospective clinical trials, retrospective analyses using the Residual Cancer Burden (RCB) scoring system have shown it to be predictive of relapse-free survival at 5 and 10 years in patients with HER2-positive cancers and that patients with minimal residual disease (RCB class I) have improved outcomes compared with the overall group of non-pCRs [10].
COMPONENTS OF THERAPY — Standard neoadjuvant therapy for patients with HER2-positive disease consists of chemotherapy and HER2-directed therapy, specifically trastuzumab, with or without pertuzumab (see 'Chemotherapy' below and 'Biologic therapy' below). The use of pertuzumab is somewhat controversial and is discussed in further detail below. (See 'Addition of pertuzumab' below.)
While all systemic therapy given for non-metastatic invasive breast cancer is intended to reduce the risk of distant recurrence, the additional rationale for administering it in the neoadjuvant setting is to downstage a tumor preoperatively, potentially allowing for less extensive surgery and improved cosmetic outcomes [11-15]. As noted above, HER2-positive disease (along with triple-negative disease) is associated with a high likelihood of response. (See 'Indications' above.)
Chemotherapy — For patients with HER2-positive cancers in whom neoadjuvant chemotherapy (NACT) is indicated, there are few data comparing various chemotherapy regimens, particularly in regards to their impact on event-free survival (EFS) or overall survival (OS). In this setting of limited data, a number of neoadjuvant regimens can be considered as standard for HER2-positive breast cancer.
Standard regimens — The neoadjuvant regimens below can be considered as standard for HER2-positive breast cancer. Either TCHP or wPCbHP are our preferred regimens given that they avoid the risks and toxicities associated with anthracyclines. Others, however, may reasonably choose to offer one of the anthracycline-based regimens discussed below to patients who lack cardiac risk factors. Risk factors for cardiotoxicity among patients being treated with an anthracycline-based regimen and trastuzumab are discussed elsewhere. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Risk factors'.)
We typically also incorporate pertuzumab into these regimens, particularly for those with node positive disease or tumors >2 cm, given available evidence that pertuzumab enhances locoregional responses:
●TCH(P) – Docetaxel and carboplatin every three weeks for six cycles with concurrent trastuzumab [16], with or without pertuzumab. (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Non-anthracycline-based therapy'.)
●wPCbH(P) – Weekly paclitaxel with carboplatin, administered either every three weeks or weekly, with concurrent trastuzumab, with or without pertuzumab, for 18 weeks. This is a variation of the regimen used in the TRAIN-2 study (described below), which reduces the overall duration of treatment by eliminating planned off weeks. (See 'Non-anthracycline-based treatment' below.)
●AC-TH(P) – Doxorubicin and cyclophosphamide (AC) every two (our preferred approach) or three weeks for four cycles, followed by paclitaxel, weekly for 12 weeks (wP), or docetaxel every three weeks for four cycles. Trastuzumab, weekly for 12 weeks or every three weeks for four cycles, is started concurrent with initiation of the taxane [17]. If pertuzumab is added, it should also be started with the initiation of the taxane and given every three weeks for four cycles.
●TH(P)-AC – The same treatments discussed above administered in the reverse order, which may cause less cardiotoxicity. Note that trastuzumab (and pertuzumab, if added) is held during the AC portion of this treatment.
●FEC/EC-TH(P) or TH(P)-FEC/EC – Fluorouracil, epirubicin, and cyclophosphamide (FEC) every three weeks for three to four cycles or epirubicin and cyclophosphamide (EC) every three weeks for four cycles is often used in place of AC in the above regimens in Europe and certain other countries. These epirubicin- and docetaxel-based regimens were also listed in the US Food and Drug Administration (FDA)’s accelerated approval for the addition of pertuzumab to neoadjuvant treatment of HER2-positive breast cancer. As with AC-TH(P), trastuzumab with or without pertuzumab is administered concurrent with the taxane only.
Chemotherapy regimens for patients with comorbidities or low-risk disease are discussed elsewhere. (See 'Alternatives for those with low-risk disease or comorbidities' below.)
Anthracycline-based treatment — Most large, randomized studies of neoadjuvant therapy in HER2-positive breast cancer have employed anthracycline and taxane-based NACT regimens, the historic standard for high-risk breast cancer. In the aggregate, these studies suggest a pathologic complete response (pCR) rate approaching 50 percent among patients with operable HER2-positive disease receiving anthracycline-, taxane-, and trastuzumab-based therapy.
●In the American College of Surgeons Oncology Group (ACOSOG) Z1041 study, 282 patients with operable HER2-positive cancers were treated with four cycles of FEC followed by paclitaxel with trastuzumab versus paclitaxel with trastuzumab followed by FEC with concurrent trastuzumab [18]. The overall pCR rate, which was similar between the two treatment arms, was 55 percent, including 48 percent of the 179 patients who were clinically node positive at baseline.
●In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 study, 177 patients with operable HER2-positive cancers were assigned to receive four cycles of doxorubicin and cyclophosphamide (AC) every three weeks followed by weekly paclitaxel-trastuzumab (wPH); the overall pCR rate was 49 percent, including 43 percent of 92 clinically node-positive patients [19].
●In the German Breast Group (GBG) GeparQuinto study, 309 HER2-positive patients, of whom approximately 70 percent had clinically node-positive disease, received four cycles of epirubicin and cyclophosphamide with trastuzumab followed by four cycles of docetaxel with trastuzumab every three weeks (ECH-TH), resulting in a pCR rate of 45 percent [20].
In each of these studies, the pCR rate was higher among patients with hormone receptor (HR)-negative disease versus HR-positive disease. (See 'Tumor prognostic features' below.)
Non-anthracycline-based treatment — Based on results from the adjuvant setting [21] and data from the TRAIN-2 study (discussed below), we consider taxane-carboplatin-trastuzumab (with or without pertuzumab) regimens as preferable alternatives to anthracycline-containing regimens as neoadjuvant therapy in patients with HER2-positive cancers, given lesser toxicity and equivalent rates of pCR. Representative data are as follows:
In the phase III TRAIN-2 trial of 438 patients with stage II to III HER2-positive breast cancer randomly assigned to anthracycline-containing chemotherapy (three cycles 5-fluoruoracil, epirubicin, and cyclophosphamide followed by six cycles paclitaxel and carboplatin) versus non-anthracycline-based chemotherapy (nine cycles paclitaxel and carboplatin), with trastuzumab and pertuzumab administered every three weeks with all chemotherapy cycles, the rates of pCR did not differ between the arms (67 versus 68 percent) [22]. Updated results from this study demonstrate equivalent three-year event-free (94 versus 93 percent) and overall (98 versus 98 percent) survival for the anthracycline-free versus the anthracycline-containing regimens, respectively [23]. No patient subgroup could be identified whose long-term outcomes benefited from inclusion of the anthracycline, and patients who received the anthracycline experienced higher rates of febrile neutropenia (10 versus 1 percent) and significant decline in left ventricular ejection fraction (36 versus 22 percent).
Similar conclusions have been noted in previous phase II studies:
●Among 56 patients with centrally confirmed HER2-positive cancers, the combination of every-three-week docetaxel and carboplatin for six cycles with weekly trastuzumab (TCH) resulted in a pCR rate of 43 percent [24].
●Phase II studies have suggested high pCR rates with combinations of carboplatin and weekly paclitaxel with trastuzumab among patients with HER2-positive disease [25-27]. As an example, in a randomized phase II study of 56 HER2-positive patients that compared weekly versus every-three-week administration of paclitaxel and carboplatin with trastuzumab (TCH), the overall pCR rate was 55 percent, and the weekly schedule was associated with a higher pCR rate (69 versus 41 percent for the every-three-week schedule) [27].
●In the randomized phase II TRYPHAENA study, discussed in further detail below, the pCR rate reported for the docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) regimen was 64 percent compared with 55 percent among those treated with an anthracycline-based regimen (FEC-THP) containing trastuzumab and pertuzumab, a difference that was not statistically significant [28]. (See 'Addition of pertuzumab' below.)
In the adjuvant setting, the Breast Cancer International Research Group (BCIRG) 006 study demonstrated that both AC-TH and TCH (with docetaxel as the taxane) were superior to ACT without trastuzumab. While there were no significant differences between the two trastuzumab-containing arms in regards to overall or progression-free survival, the study was not powered to detect differences between these outcomes. In addition, patients assigned to TCH experienced less cardiac toxicity (clinical congestive heart failure of 0.4 versus 2 percent) [21]. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy'.)
The sum of data suggests that non-anthracycline-based treatment with a taxane, carboplatin and trastuzumab, with or without pertuzumab, is a reasonable alternative to anthracycline-based neoadjuvant therapy.
Choice of taxane — Standard neoadjuvant therapy in patients with HER2-positive breast cancer utilizes either every-three-week docetaxel or weekly paclitaxel. Given the efficacy and tolerability of these agents, they remain our preferred options. However, nanoparticle albumin-bound paclitaxel (nabpaclitaxel) is an option for patients who have had a hypersensitivity reaction to paclitaxel or have a contraindication to the steroids typically administered with either docetaxel or paclitaxel, such as poorly controlled diabetes mellitus or a history of steroid psychosis. (See "Infusion reactions to systemic chemotherapy", section on 'Incidence with paclitaxel' and "Infusion reactions to systemic chemotherapy", section on 'Incidence with docetaxel' and "Infusion reactions to systemic chemotherapy", section on 'Nabpaclitaxel'.)
The GBG GeparSepto study compared weekly paclitaxel with weekly nabpaclitaxel (initially 150 mg/m2, eventually reduced to 125 mg/m2 due to excessive neurologic toxicity) for 12 weeks, followed by four cycles of EC every three weeks, as neoadjuvant therapy for clinical stage II to III breast cancer [29]. Results in 395 patients with HER2-positive cancers, who also received concurrent trastuzumab and pertuzumab, demonstrated a trend toward improved pCR but increased adverse events:
●Patients treated with nabpaclitaxel had a trend towards a higher pCR rate compared with patients treated with standard paclitaxel (62 [55 to 69] versus 54 [47 to 61] percent). This was seen in both the HR-positive and HR-negative cohorts.
●While patients treated with nabpaclitaxel had a higher rate of neutropenia (all grades), rates of grade 3 to 4 neutropenia and febrile neutropenia were similar. Nabpaclitaxel was also associated with a higher rate of grade >3 peripheral sensory neuropathy (10 versus 3 percent), though the frequency of this toxicity decreased with reduction in the starting dose of nabpaclitaxel. In addition, fatigue, diarrhea, rash, and myalgias were more common with nabpaclitaxel.
At present, the role of nabpaclitaxel is limited to patients unable to receive standard paclitaxel.
Alternatives for those with low-risk disease or comorbidities — Several regimens exist that are acceptable for patients with either comorbidities or low-risk disease.
●For patients with low-risk, HER2-positive cancers, such as clinical stage I (T1N0), in whom neoadjuvant therapy is felt to be warranted based on tumor size (relative to the patient’s breast) or location or the need to delay surgery, weekly paclitaxel with trastuzumab for 12 weeks may be used, also based on its efficacy and tolerability in the adjuvant setting [30].
●Other non-anthracycline, less intensive chemotherapy options exist. For patients with low- or intermediate-risk, HER2-positive breast cancers, such as clinical stage IIA with a tumor size of less than 3.5 cm in greatest dimension, in whom reduction in tumor size prior to surgery is desired, a shorter course (12 weeks as opposed to 18 to 20 weeks for AC-TH or TCH[P]) of neoadjuvant treatment consisting of docetaxel and cyclophosphamide every three weeks for four cycles with trastuzumab may be considered, based on its efficacy and tolerability in the adjuvant setting [31].
Biologic therapy — We recommend the addition of trastuzumab to NACT in patients with HER2-positve breast cancer, when employing any of the chemotherapy regimens discussed above. The effect of pertuzumab on the risk of tumor recurrence following neoadjuvant therapy with chemotherapy and trastuzumab remains unknown. However, when giving NACT plus trastuzumab, we routinely also incorporate pertuzumab into the regimen, given evidence that pertuzumab enhances locoregional responses. (See 'Addition of pertuzumab' below and 'Alternatives for those with low-risk disease or comorbidities' above.)
Trastuzumab — Trastuzumab's beneficial role as a component of neoadjuvant therapy for HER2-positive tumors is well substantiated, with randomized studies and meta-analyses demonstrating improvements in pCR rate, EFS, and OS, as detailed below:
●In a 2012 meta-analysis, among almost 2000 patients with HER2-positive disease treated neoadjuvantly, the addition of trastuzumab to NACT increased the pCR rate from 23 to 40 percent [1]. pCR was associated with long-term outcome among patients with HER2-positive disease, irrespective of hormone receptor status (EFS: hazard ratio [HR] 0.39, 95% CI 0.31-0.50; OS: 0.34, 0.24-0.47).
●In the phase II NOAH trial (n = 235), the addition of every-three-week trastuzumab to neoadjuvant anthracycline- and taxane-based chemotherapy was associated with a pCR rate of 38 percent compared with 19 percent with chemotherapy alone; patients assigned to trastuzumab resumed this treatment after surgery to complete a full year of treatment [32,33]. Long-term (5.4 years) follow-up revealed improved EFS with the addition of trastuzumab (43 versus 58 percent; HR 0.64, 95% CI 0.544-0.930) [33].
Of patients who achieved a pCR, those treated with trastuzumab had significantly better EFS than those who did not (HR 0.29, 0.11-0.78), demonstrating the superiority of the NACT plus HER2-targeted therapy combination at eradicating occult metastatic disease even among patients with an excellent locoregional response [33].
Schedule, dosing, and available formulations of trastuzumab are discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Prescribing information and formulations'.)
Addition of pertuzumab — Pertuzumab is a monoclonal antibody that binds to a different epitope on HER2 than trastuzumab, blocking the formation of HER2:HER3 heterodimers, which is believed to be an important mechanism of resistance to trastuzumab. While single-agent pertuzumab has demonstrated antitumor activity in patients with HER2-positive metastatic disease who progressed on trastuzumab, it is typically given in combination with trastuzumab to maintain suppression of signaling initiated by HER2 homodimers. In 2013, the FDA granted accelerated approval for the addition of pertuzumab to NACT and trastuzumab for patients with HER2-positive locally advanced, inflammatory, or early-stage (either greater than 2 cm in diameter or node positive) breast cancer. We routinely add pertuzumab in patients receiving NACT and trastuzumab, given evidence that pertuzumab enhances locoregional responses, even though it increases the incidence and severity of treatment-related diarrhea as well as modestly increasing the frequency of hematologic toxicities. For some patients with significant comorbidity or low-risk (clinical stage I to IIA) disease, the potential for added toxicity associated with pertuzumab may outweigh the benefit. For such patients, we engage in a risk-benefit discussion regarding the use of pertuzumab. (See 'Alternatives for those with low-risk disease or comorbidities' above.)
The use of pertuzumab in the metastatic setting is discussed elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Trastuzumab plus pertuzumab plus a taxane'.)
●NeoSphere trial – In the phase II NeoSphere trial, 417 HER2-positive patients received 12 weeks of neoadjuvant therapy composed of either four cycles of single-agent docetaxel with trastuzumab, pertuzumab, or both, or the combination of trastuzumab and pertuzumab without concurrent docetaxel [34]. After surgery, all patients received anthracycline-based adjuvant chemotherapy (those randomized to trastuzumab and pertuzumab alone also received adjuvant docetaxel) and completed a year of treatment with trastuzumab. Results were as follows:
•Those randomly assigned to docetaxel with pertuzumab and trastuzumab had a higher pCR rate (46 percent) compared with those receiving docetaxel with just trastuzumab (29 percent) or just pertuzumab (24 percent). Patients receiving pertuzumab and trastuzumab without docetaxel had a pCR rate of 17 percent. (See 'HER2-targeted therapy without chemotherapy' below.)
•Aside from diarrhea (mostly grade 1 to 2), the addition of pertuzumab to the docetaxel plus trastuzumab combination did not appear to increase toxicity, including the risk of cardiac adverse events.
•While five-year progression-free survival (PFS) results do not demonstrate a benefit associated with the addition of pertuzumab to docetaxel and trastuzumab (HR 0.69, 95% CI 0.34-1.40), the study was not powered to detect differences in this endpoint [35].
●TRYPHAENA trial – The phase II TRYPHAENA trial assessed cardiotoxicity related to the timing of administration of trastuzumab and pertuzumab relative to an anthracycline-based chemotherapy regimen, as well as pCR rates compared with a non-anthracycline-containing regimen. Over 200 women with HER2-positive breast cancer were randomly assigned to FEC followed by docetaxel, with trastuzumab and pertuzumab starting either concurrently with FEC (FECHP-THP) or upon initiation of docetaxel (FEC-THP); or to docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) [28]. The study was not powered to compare pCR rates between the treatment arms and did not include a non-pertuzumab-containing arm. Results were as follows:
•pCR rates were 56 and 55 percent for FECHP-THP and FEC-THP, respectively (thus failing to demonstrate a pCR benefit for concurrent administration of the HER2-targeted agents with the anthracycline-containing portion of the NACT regimen), and 64 percent for TCHP.
•In the absence of prophylactic colony-stimulating factor, the incidence of febrile neutropenia was 18 percent among patients receiving FECHP-THP, 9 percent with the FEC-THP regimen, and 17 percent with TCHP. Grade >3 diarrhea occurred in 4, 5, and 12 percent in these groups, respectively; grade 3 anemia and thrombocytopenia were rare except in patients assigned to TCHP, in whom they occurred in 17 and 12 percent, respectively.
•Rates of cardiotoxicity were comparable between the two groups receiving anthracycline-based treatment and slightly lower in the TCHP arm. (See 'Timing of HER2-directed agents' below.)
The GBG GeparSepto study (described above) reported a similar pCR rate of 58 percent among almost 400 patients with stage II to III HER2-positive breast cancer treated with neoadjuvant paclitaxel or nabpaclitaxel followed by EC, with concurrent trastuzumab and pertuzumab throughout [36]. (See 'Choice of taxane' above.)
Formulations — Subcutaneous (SC) formulations of trastuzumab as well as combined trastuzumab and pertuzumab have been approved by the FDA based on similar pCR rates as the intravenous (IV) forms of these therapies, when administered with chemotherapy in the neoadjuvant setting [37-41]. However, the IV formulations were used in all the major trials of therapy for both early- and advanced-stage, HER2-positive breast cancer. As a result, we typically use IV formulations, but the SC formulations (which can be administered in the patient's home) are reasonable alternatives. They may be preferable in patients who prefer SC administration, or if there are safety concerns, such as potential exposure to the novel coronavirus, or if impaired patient mobility complicates treatment at an infusion center.
As an example of available data, in the phase III FeDeriCa trial, 500 patients receiving neoadjuvant anthracycline- and taxane-based chemotherapy for operable or locally advanced, HER2-positive cancers were randomly assigned to IV trastuzumab and pertuzumab versus an SC formulation of a combination of these two agents [41]. In both arms, trastuzumab and pertuzumab were administered concurrently with the taxane and continued after surgery to complete 18 cycles. The pCR rates were 60 percent in both arms, and overall toxicity was comparable.
Previous data also demonstrated comparable pCR rates with neoadjuvant SC versus IV trastuzumab [38]. However, there were more serious adverse events with SC administration (21 versus 12 percent, respectively), largely attributable to infections. A separate pharmacokinetic study suggested that the proportion of patients achieving adequate plasma concentration of trastuzumab was higher with IV versus SC administration (94 versus 68 percent), with even greater differences seen in obese patients, with only 20 percent of these patients exceeding the pharmacokinetic target [42]. The clinical relevance of these findings remains to be determined.
Investigational approaches — While we recommend selecting one of the regimens described above as standard neoadjuvant therapy for HER2-positive breast cancer, a number of novel therapies have demonstrated activity in this setting. They are briefly discussed below.
Lapatinib with chemotherapy — Lapatinib is a small molecule inhibitor of the tyrosine kinase domains of both the epidermal growth factor receptor (EGFR, sometimes also referred to as HER1) and HER2 and has demonstrated activity in HER2-positive metastatic breast cancer that had progressed on a trastuzumab-containing regimen. While the addition of lapatinib to NACT plus trastuzumab has been shown to improve pCR rates, and in one study significantly improved relapse-free and overall survival at seven years, these longer-term outcomes have not been consistent across trials, and the addition of lapatinib is associated with increases in grade >3 adverse events including diarrhea, rash, and liver function test abnormalities and thus is not recommended [43-51].
HER2-targeted therapy without chemotherapy — Administering chemotherapy with anti-HER2 therapy is the standard of care, is the only strategy that has been shown to improve survival in HER2-positive breast cancer, and is the preferred and standard approach for nearly all such patients. In the neoadjuvant setting, chemotherapy plus trastuzumab/pertuzumab has been shown to have superior efficacy to nonchemotherapy alternatives.
For patients in whom other health conditions preclude use of chemotherapy, or as part of clinical trials, there may be interest in considering nonchemotherapy combinations of HER2-targeted therapy. While combinations of HER2-targeted agents have demonstrated antitumor activity, and even achievement of pCR, without chemotherapy, this strategy remains investigational, given the proven superior results with concomitant administration of chemotherapy and trastuzumab (with or without pertuzumab). In exceptional cases, when the patient is not a candidate for or refuses chemotherapy, we have given the combination of trastuzumab and pertuzumab for up to 24 weeks, which we prefer to the combination of trastuzumab and lapatinib, based on toxicity. For those with HR-positive disease, we add endocrine therapy, based on results from TBCRC006 and TBCRC023, described below [52,53]. However, concurrent administration of chemotherapy with HER2-targeted therapy is the standard of care, and the only strategy that had been shown to improve survival in HER2-positive breast cancer, and thus remains the recommended approach for nearly all such patients. In the neoadjuvant setting, the combination of chemotherapy with trastuzumab and pertuzumab has been shown to have superior efficacy, based on pCR rates, over nonchemotherapy alternatives [34,54].
For patients in whom comorbid conditions or other considerations preclude the use of chemotherapy, we favor administration of dual HER2-targeted neoadjuvant therapy based on results from the following phase II trials:
●Trastuzumab and pertuzumab – On one arm of the NeoSphere trial, discussed in more detail above, 107 patients received 12 weeks of trastuzumab and pertuzumab without chemotherapy prior to surgery [34]. In contrast with TBCR006, no neoadjuvant endocrine therapy was administered to patients with HR-positive tumors. The pCR rate was only 6 percent among HR-positive patients but was 27 percent in HR-negative cancers, thus demonstrating some efficacy albeit substantially inferior to that observed with combined chemotherapy and antibody therapy. (See 'Addition of pertuzumab' above.)
In one arm of the WSG-ADAPT trial, 134 patients with hormone receptor-negative/HER2-positive cancers were randomly assigned to neoadjuvant trastuzumab and pertuzumab with or without weekly paclitaxel [55]. Administration of adjuvant chemotherapy was mandated for patients who failed to achieve pCR but left to the discretion of the treating investigator in patients with pCR. Patients assigned to receive neoadjuvant paclitaxel were more likely to achieve pCR (90 percent versus 36 percent). In subsequently reported results at median follow-up of 60 months, patients assigned to paclitaxel had five-year relapse-free survival of 98 percent versus 89 percent in those assigned to dual HER2-targeted antibody therapy alone (although this difference was not statistically significant) [56]. These results suggest that there are patients with hormone receptor-negative/HER2-positive cancers who can achieve pCR and have favorable long-term outcomes while being spared exposure to cytotoxic chemotherapy; however, until these patients can be prospectively identified, the standard of care for neoadjuvant therapy in these patients remains the combination of chemotherapy and dual HER2-targeted therapy.
●Trastuzumab and lapatinib – The largest reported trial of dual HER2-targeted neoadjuvant therapy without concurrent chemotherapy is the PAMELA study, a multicenter phase II trial on which 151 patients received 18 weeks of lapatinib and trastuzumab, with concurrent endocrine therapy in HR-positive patients. The primary endpoint was pCR breast, which was achieved in 30 percent of the patients, including 18 percent of patients with HR-positive cancers and 43 percent of patients with HR-negative cancers. Achievement of pCR was strongly correlated with tumor intrinsic subtype. (See 'Tumor prognostic features' below.)
In the TBCRC006 trial, 64 women, many with large tumors (median size 6 cm), received a combination of weekly trastuzumab and lapatinib 1000 mg daily for 12 weeks; in addition, those with HR-positive tumors also received letrozole (and goserelin if premenopausal) [52]. The main results were as follows:
•The overall pCR rate was 22 percent (28 and 18 percent in HR-negative and HR-positive patients, respectively).
•The pCR (breast only) rate was 27 percent (36 and 21 percent in HR-negative and HR-positive patients, respectively). Residual invasive tumor in breast was less than 1 cm in another 22 percent of patients.
•Treatment was well tolerated. The most common toxicities included grade 1 to 2 diarrhea, rash, and fatigue. Grade 3 to 4 toxicities were limited to a few cases of elevated transaminases.
A subsequent study (TBCRC023) randomized 94 patients to 12 versus 24 weeks of neoadjuvant trastuzumab and lapatinib (with endocrine therapy for those with HR-positive disease). The pCR breast (ypT0/is Nany) rate increased from 12 to 28 percent with the additional 12 weeks of treatment, but this increase was seen only in patients with HR-positive tumors (33 versus 9 percent), while there was no increase in the pCR rate with longer-duration treatment in HR-negative disease [53].
Other agents
●T-DM1 – Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab linked to a potent antimicrotubule agent (emtansine) that is released only after the drug is internalized into the HER2-positive cell. This agent has demonstrated impressive single-agent activity in patients with HER2-positive metastatic breast cancer who had progressed on a trastuzumab-containing regimen. T-DM1 has also been studied in the neoadjuvant setting in patients with early-stage HER2-positive breast cancer, both as a single agent and in combination. Reported results from randomized studies are discussed below. Based on these results, and the absence of long-term survival data for patients who received T-DM1 in the neoadjuvant setting, we do not administer T-DM1, alone or in combination with pertuzumab, as neoadjuvant therapy in patients with early-stage HER2-positive breast cancer who are candidates for standard therapy such as TCHP.
The German Women’s Healthcare Study Group conducted a phase II study in stage I to III HR-positive/HER2-positive breast cancer on which 375 women were randomized to single-agent T-DM1, T-DM1 with concurrent endocrine therapy, or trastuzumab with concurrent endocrine therapy [57]. Treatment with T-DM1 was associated with higher pCR rates, with or without concurrent endocrine therapy (42 and 41 percent, respectively), compared with trastuzumab with endocrine therapy (15 percent). Treatment with T-DM1, with or without concurrent endocrine therapy, was very well tolerated, with elevated transaminases being the only grade >3 toxicity reported more frequently than in the trastuzumab plus endocrine therapy arm (4.1 versus 0 percent).
The I-SPY2 trial randomized HER2-positive patients to neoadjuvant therapy with either T-DM1 and pertuzumab or paclitaxel and trastuzumab, followed by doxorubicin and cyclophosphamide (AC). Patients receiving T-DM1 and pertuzumab had a higher pCR rate (52 versus 22 percent) [58]. In the Swedish PREDIX HER2 trial, which included women with HER2-positive breast cancers >2 cm, pCR rates with six cycles of neoadjuvant single-agent T-DM1 were similar to those with six cycles of docetaxel, trastuzumab, and pertuzumab (44 versus 46 percent) [59].
However, in the KRISTINE/TRIO-021 study, which compared TCHP to T-DM1 plus pertuzumab (T-DM1/P), patients who received TCHP had a higher pCR rate (56 versus 44 percent) and a higher rate of breast-conserving surgery (53 versus 42 percent) than those assigned to the T-DM1-based regimen [54]. Risk of an EFS event, at three years of follow-up, was higher with T-DM1/P (HR 2.6, 95% CI 1.5-5.0) [60]. However, excluding 15 patients on the T-DM1/P arm who had locoregional progression before surgery (6.7 percent), the frequency of invasive disease recurrence after surgery was identical (11 patients, 4.9 percent on the T-DM1/P arm; and 11 patients, 5.0 percent, on the TCHP arm), as was invasive disease-free survival among patients who achieved pCR (97 percent on both arms).
Thus, while neoadjuvant T-DM1, administered as a single agent or in combination with pertuzumab, is capable of inducing pCRs in patients with early-stage, HER2-positive breast cancer, there may be a higher rate of locoregional disease progression during this treatment than during treatment with a standard regimen that combines chemotherapy with trastuzumab and pertuzumab, such as TCHP. Until we can identify the subgroup of patients who may be at greater risk for these events, T-DM1, as a single agent or in combination with pertuzumab, cannot be considered standard neoadjuvant therapy, except perhaps in patients who are not candidates for a more standard regimen.
●Neratinib – Neratinib is an oral agent that binds irreversibly to and inhibits the tyrosine kinase domains of both EGFR and HER2. In another arm of the I-SPY2 trial, 127 patients with HER2-positive breast cancer were randomized to receive neoadjuvant weekly paclitaxel with either neratinib or trastuzumab for 12 weeks, followed by four cycles of AC. Neratinib was associated with a pCR rate of 56 percent versus 33 percent in patients who received trastuzumab [61].
However, in the NSABP FB-7 randomized trial comparing paclitaxel-neratinib versus paclitaxel-trastuzumab as neoadjuvant treatment for HER2-positive breast cancer, the trastuzumab-based arm was associated with a higher pCR rate (38 versus 33 percent) [62].
●SC trastuzumab – In all of the trials described above, trastuzumab was administered as an IV infusion. To reduce the inconvenience and expense associated with IV administration, an SC preparation of trastuzumab has been developed. As discussed below, SC trastuzumab has been associated with similar disease outcomes as IV trastuzumab, though with potentially higher rates of adverse events.
In the HannaH trial, approximately 600 women with operable, locally advanced, or inflammatory HER2-positive breast cancer receiving docetaxel followed by FEC were randomly assigned to IV or SC trastuzumab concurrent with their NACT. After surgery, patients resumed their assigned trastuzumab preparation to complete a year of treatment. Major findings were as follows [38]:
•The serum trough concentration (drawn just prior to the last preoperative dose of trastuzumab) for trastuzumab was higher with the SC preparation.
•The pCR rate was similar (39 versus 34 percent for the SC and IV formulations, respectively), as was median time to response and rate of progression on treatment (six weeks and 2 percent, respectively, on both arms). Updated results from this study presented at the 2015 American Society of Clinical Oncology annual meeting also demonstrated equivalent outcomes between the SC and IV arms, overall with 88 percent of patients who achieved a pCR and 68 percent of those who did not remaining event free at three years [63].
•Patients assigned to SC trastuzumab had a higher rate of grade 3 to 4 adverse events (21 versus 12 percent), including febrile neutropenia (6 versus 3 percent), and three fatalities during neoadjuvant therapy (versus one on the IV arm).
In a subsequent study, patients were randomized to receive four cycles of SC trastuzumab followed by four cycles of IV trastuzumab or the reverse sequence following completion of surgery and (neoadjuvant or adjuvant) chemotherapy [39]. Ninety-two percent of patients expressed a preference for SC administration, and health economists predicted significant cost savings with the use of this preparation due to reductions in preparation and administration time.
SC trastuzumab was approved by the European Commission in 2013. As SC trastuzumab is now commercially available in the United States, clinicians, patients, and insurers are in the process of assessing its convenience and cost-efficacy compared with IV trastuzumab and trastuzumab biosimilars.
●Trastuzumab biosimilars – A number of pharmaceutical companies are working on trastuzumab biosimilars to compete with the original formulation. Results of a large, phase III equivalence trial that compared one of these agents, designated CT-P6, with trastuzumab among patients receiving NACT showed equivalent outcomes between the two arms [64]. Similar results have been reported from phase III neoadjuvant trials conducted with two other proposed trastuzumab biosimilars, designated SB3 and ABP 980 [65,66].
It is not clear whether equivalent pCR results and toxicity, in the absence of long-term endpoints such as disease-free or overall survival, will be sufficient to lead to FDA approval for one or more of these trastuzumab biosimilars. There are not yet data on the combination of any of these agents with pertuzumab, which has become part of the standard of care for neoadjuvant therapy in higher-risk HER2-positive cancers.
TIMING OF HER2-DIRECTED AGENTS — The timing of administration of HER2-directed agents may be important to decrease the risk of toxicities, particularly cardiotoxicity for those who are also being treated with an anthracycline [67]. For patients receiving an anthracycline-based regimen as part of their neoadjuvant chemotherapy (NACT), we typically administer the HER2-targeted therapy concurrently with a taxane, either following completion of or prior to administration of the anthracycline. Patients receiving sequential anthracycline-based chemotherapy and HER2-directed therapy should be monitored closely for cardiotoxicity. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
Although older data suggested high rates of cardiotoxicity when trastuzumab was administered concurrently with anthracyclines in the adjuvant setting, subsequent studies have not confirmed this:
●In the American College of Surgeons Oncology Group (ACOSOG) Z1041 study, 282 patients with operable HER2-positive cancers were treated with four cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by paclitaxel with trastuzumab (sequential); or paclitaxel with trastuzumab followed by FEC with trastuzumab (concurrent) [18]. At the completion of NACT, the incidence of cardiac events was low, and actually higher (7 percent) in the sequential arm than in the concurrent arm (5 percent).
●Similarly, in the TRYPHAENA study discussed above, the incidence of cardiac toxicity during neoadjuvant therapy, defined as a decline in the left ventricular ejection fraction (LVEF) of at least 10 percent to below 50 percent, was 5.6 percent among patients receiving HER2-directed therapy concurrent with the anthracycline, versus 5.3 among those who did not start it until after completion of the anthracycline [28].
While these studies did not demonstrate an increase in cardiac events with concurrent administration of an anthracycline with HER2-targeted therapy, they also did not demonstrate a benefit in terms of the pathologic complete response rate. Thus, we continue to recommend sequential administration of anthracyclines and HER-directed therapies.
TUMOR PROGNOSTIC FEATURES — Intrinsic features of the tumor, such as hormone receptor (HR) status, intrinsic subtype, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation status, or the presence or absence of tumor-infiltrating lymphocytes (TILs), may explain differences in pathologic complete response (pCR) rates between HER2-positive patient groups. They may also have long-term prognostic significance, and may someday help to direct therapy in HER2-positive patients. At the present time, however, outside of a clinical trial, we do not recommend altering a HER2-positive patient's planned neoadjuvant regimen based on these features.
●Hormone receptor status – In essentially all studies to date of neoadjuvant treatment for HER2-positive breast cancer, pCR rates are higher in HR-negative than in HR-positive cancers. Despite the lower pCR rates associated with HR-positive tumors, those who achieve a pCR still experience improved event-free survival (EFS) relative to those who do not [1]. Moreover, data from adjuvant trials in HER2-positive disease demonstrate that HR-positive patients receive the same improvement in disease-free survival with the addition of trastuzumab as those with HR-negative cancers.
One hypothesis regarding the lower pCR rates seen in patients with HR- and HER2-posiitve cancers is that binding of estrogen to cytoplasmic estrogen and other receptors activates signaling survival pathways that bypass HER2 blockade by trastuzumab and other HER2-targeted agents, which has been referred to as "cross-talk." To test this hypothesis, NRG Oncology conducted the NSABP B-52 trial, which tested the impact of the addition of estrogen deprivation with an aromatase inhibitor (plus ovarian suppression in premenopausal women) on pCR rates achieved with six cycles of TCHP in patients with HR-positive, HER2-positive cancers. Among 311 patients, pCR rates were similar with (46 percent) or without (41 percent) estrogen deprivation; this finding did not differ between pre- and postmenopausal women. [68]. The addition of estrogen deprivation did not affect the toxicity of the neoadjuvant regimen.
Thus, while the results of this study do not support the routine administration of estrogen deprivation therapy during neoadjuvant therapy for HR-positive, HER2-positive breast cancer, it also shows no contraindication to its use. Discussion of luteinizing hormone-releasing hormone (LHRH) analogs to suppress ovarian function during chemotherapy to preserve ovarian function and fertility is found elsewhere. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Breast cancer'.)
●Intrinsic subtype – When tumors that are clinically classified as HER2-positive have an intrinsic subtype assigned by gene expression array, a significant degree of heterogeneity is detected [69]. Data suggest that this may explain the lower pCR rates seen in HR-positive, HER2-positive cancers better than the "cross-talk" hypothesis mentioned above. For example, among HER2-positive patients treated on CALGB 40601, only 31 percent displayed a HER2-enriched gene expression pattern, while 60 percent typed as luminal A or luminal B, 5 percent as basal-like, and 3 percent as normal-like or claudin-low [70]. Among HR-positive cancers, the percentage of HER2-enriched tumors was even lower: 17 percent, with the remaining 83 percent being luminal subtypes. Overall, the pCR rate in HER2-enriched tumors was higher than in luminal tumors (70 versus 35 percent, respectively).
The impact of intrinsic subtype on pCR rates was also seen in patients receiving dual HER2-targeted neoadjuvant therapy (trastuzumab and lapatinib) without chemotherapy on the PAMELA trial [71]. Sixty-seven percent of their patients were classified as HER2-enriched (85 percent of their HR-negative patients and 49 percent of their HR-positive patients); among these, the pCR rate was 41 percent. By contrast, the pCR rate in their non-HER2-enriched patients, most of whom were classified as luminal A or B, was only 10 percent.
These results suggest that patients with HER2-posiitve cancers that do not display a HER2-enriched gene expression pattern are less likely to achieve pCR with neoadjuvant therapy with HER2-targeted therapy. Despite this, data from the N9831 adjuvant trial suggest that patients with luminal subtype HER2-positive cancers (21 percent of the study population) got the same benefit from the addition of trastuzumab to adjuvant chemotherapy (hazard ratio [HR] 0.52) as did patients with HER2-enriched tumors (HR 0.68); only the small subset of patients with basal-like cancers (7 percent) did not benefit from the addition of trastuzumab [72]. Thus, based on available data, there does not appear to be a benefit from routine analysis of tumor intrinsic subtype to assist in deciding what neoadjuvant therapy a patient with a HER2-positive cancer should receive.
●PIK3CA – The phosphatidylinositol 3-kinase (PI3K) pathway is an important intracellular signaling pathway triggered by HER2. Activating mutations of the gene that encodes for its catalytic subunit, p110α, PIK3CA, have been identified in 20 to 25 percent of HER2-positive cancers. The presence of these mutations is associated with an approximately 50 percent reduction in the pCR rate, though no clear effect on cancer recurrence or survival has been demonstrated [73-76].
●Tumor-infiltrating lymphocytes – Retrospective analysis of pretreatment core biopsies have demonstrated a correlation between the extent of lymphocytic infiltration in the tumor or surrounding stroma, referred to as tumor-infiltrating lymphocytes (TILs), and the likelihood of achieving a pCR with neoadjuvant chemotherapy (NACT) [77]. Subsequent reports have evaluated this association in the HER2-positive population.
•In the GeparSixto trial, among the 20 percent of HER2-positive patients classified as having lymphocyte-predominant breast cancer (LPBC, based on pretreatment tumor biopsies in which at least 60 percent of the cells were lymphocytes), pCR rates with NACT with trastuzumab and lapatinib were higher compared with patients whose tumors had lower levels of lymphocytic infiltration (64 versus 27 percent) [78]. The addition of carboplatin increased the pCR rate in LPBC patients (78 versus 50 percent) while reducing the pCR rate in non-LPBC patients (21 versus 33 percent).
•In the NeoALTTO study, patients with greater than 5 percent TILs were more likely to achieve a pCR than those with lower levels of TILs [79]. Moreover, there was a linear association between higher TIL levels and improved EFS.
EVALUATION OF RESPONSE AND SURGICAL MANAGEMENT — The evaluation and management of women with breast cancer after neoadjuvant therapy are discussed separately. (See "General principles of neoadjuvant management of breast cancer", section on 'Post-treatment evaluation and management' and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'On-treatment evaluation'.)
ADJUVANT THERAPY AFTER NEOADJUVANT THERAPY — This issue is discussed in detail elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)
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
●Indications – As with all subsets of breast cancer, patients with locally advanced (clinical stage IIB [T3N0] or stage III), human epidermal growth factor receptor 2 (HER2)-positive breast cancer should receive neoadjuvant rather than adjuvant therapy to improve surgical options. This treatment may also be offered to patients with earlier-stage, HER2-positive breast cancer, especially if the goal of treatment is to facilitate breast-conserving surgery or more limited axillary sampling. Our approach to HER2 testing is included in the algorithm (algorithm 1). (See 'Indications' above.)
Treatment in the neoadjuvant setting can also help to identify patients (ie, those who fail to achieve a pathologic complete response) who may benefit from administration of ado-trastuzumab emtansine (T-DM1), instead of trastuzumab, after surgery. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)
●Outcome measures – In addition to outcome measures such as recurrence rate, event-free survival, and overall survival, which are frequently used to assess treatment efficacy in the adjuvant setting, pathologic response, including the pathologic complete response (pCR) rate, is a useful measure of treatment efficacy in patients receiving neoadjuvant therapy. (See 'Outcome measures' above.)
●Standard regimens – Docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) is our preferred regimen given that it avoids the risks and toxicities associated with anthracyclines. A variation of this regimen utilizing weekly paclitaxel with carboplatin, trastuzumab, and pertuzumab (wPCbHP) appears to be just as effective in terms of pCR rate, with a somewhat different toxicity profile. Others, however, may reasonably choose to offer an anthracycline-based regimen to patients who lack cardiac risk factors, given the greater body of data regarding these regimens. (See 'Standard regimens' above.)
●Addition of pertuzumab – In most patients receiving neoadjuvant trastuzumab and chemotherapy, we incorporate pertuzumab, which improves rates of pCR, although a benefit in survival outcomes has not yet been demonstrated. However, for some patients with significant comorbidity or low-risk (clinical stage I to IIA) disease, the potential for added toxicity associated with pertuzumab may outweigh the benefit. For such patients, we engage in a risk-benefit discussion regarding the use of pertuzumab. (See 'Addition of pertuzumab' above.)
●Alternative chemotherapy regimens
•Less intensive and toxic chemotherapy regimens with trastuzumab may be substituted in patients with less extensive (clinical stage I to IIA) disease and in older patients and those with significant comorbidities. (See 'Standard regimens' above and 'Alternatives for those with low-risk disease or comorbidities' above.)
•In patients who are not candidates for, or refuse, neoadjuvant chemotherapy (NACT), the combination of trastuzumab and pertuzumab for up to 24 weeks (with endocrine therapy for hormone receptor-positive disease) may be utilized. Although possibly associated with a greater risk of locoregional progression during treatment than a standard regimen such as TCHP, another option for these patients could be neoadjuvant therapy with T-DM1, as a single agent or in combination with pertuzumab.
●Timing of HER2-directed agents – For patients receiving an anthracycline-based regimen as part of their NACT, we administer the HER2-targeted therapy concurrently with a taxane, either following or preceding anthracycline treatment. (See 'Timing of HER2-directed agents' above.)
●Adjuvant treatment – All patients treated with preoperative chemotherapy and HER2-targeted therapy should continue anti-HER2 treatment after surgery with choice of therapy directed according to their response to neoadjuvant treatment, as discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)
