Neoadjuvant therapy for patients with HER2-positive breast cancer

INTRODUCTION — Amplification of the gene that encodes for human epidermal growth receptor 2 (HER2), a somatic mutation found in the malignant cells of 15 to 20 percent of patients with newly diagnosed breast cancer, leads to constitutive activation of signaling pathways that promote cell proliferation, resistance to apoptotic signals, increased cell motility, and neoangiogenesis. This gives rise to a biologically aggressive malignancy, with heightened sensitivity to cytotoxic chemotherapy; as a result, these patients may achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) [1,2]. However, concurrent administration of agents that block activation of these pathways enhances the cancer's chemosensitivity, significantly increasing the pCR rate. Clinical trial results from the last several years suggest that new approaches, including newer HER2-targeted agents and combinations of HER2-targeted therapies, more effectively block HER2-activated signaling, enhancing the susceptibility of HER2-positive breast cancers and expanding options for neoadjuvant 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, including those who 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 response to treatment may allow both less extensive surgery and improved surgical outcomes. We generally define locally advanced as clinical stage III cancers as well as the subset of clinical IIB cancers with T3 disease. In addition, patients with earlier-stage, HER2-positive cancers (clinical stage I or II) may also be candidates for neoadjuvant therapy. Our approach to HER2 testing and interpretation of the results is summarized 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 may also be 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 the cancer.

●The patient has limited axillary nodal involvement by clinical assessment (cN1), for which axillary lymph node dissection would be standard surgical management, but could be a candidate for sentinel lymph node biopsy alone if converted to clinically node-negative (ycN0) 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].

Adjuvant chemotherapy with HER2-targeted therapy is the standard of care for almost all patients with HER2-posiitve breast cancer who undergo surgery first; treatment recommendations for these patients are discussed elsewhere. (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, disease-free survival, and overall survival (OS), which are used to assess treatment efficacy in the adjuvant setting, pathologic response, especially the pathologic complete response (pCR) rate, is a useful measure of treatment efficacy in comparing regimens among patients receiving neoadjuvant therapy. While some of the clinical trials discussed below used different definitions of pCR, including the absence of residual invasive disease in the breast regardless of the status of the axillary nodes (ypT0/is Nany), the most widely accepted definition of pCR requires the absence of residual invasive disease in the breast and the absence of cancer in any sampled axillary nodes (ypT0/is ypN0). Although a surrogate other outcome measure, achievement of pCR is associated with highly significant improved rates of event-free survival (EFS) and OS in patients with HER2-positive disease [1,6,7].

In a 2016 meta-analysis of 36 trials enrolling nearly 5800 patients with HER2-positive disease who received neoadjuvant therapy, those who achieved a pCR (ypT0/is N0) 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) [8]. The association was even stronger in the hormone receptor-negative (HR-negative) subgroup (HR EFS 0.29, 95% CI 0.24-0.36). A subsequent meta-analysis confirmed improved EFS and OS in all subsets of HER2-positive patients who experienced a pCR, but demonstrated that pretreatment clinical stage remains prognostic even among pCRs, with baseline T3 to 4 and node-positive patients having higher event and mortality rates than baseline T1 to 2 or node-negative patients [9]. Among patients who failed to achieve pCR, pretreatment T stage, nodal status, and hormone receptor (HR) status were all prognostic for EFS and OS, with HR-negative patients having poorer outcomes than HR-positive patients. The same authors assessed the association between trial-level improvements in pCR rates and EFS/OS and found a weak correlation between these outcomes, suggesting that while achievement of pCR (or not) may be a valid prognostic variable for an individual patient, and may be useful in terms of selecting treatment in the adjuvant setting, changes in pCR rates may not be a useful surrogate for longer-term outcomes when comparing neoadjuvant regimens [10]. (See 'Tumor prognostic features' below.)

Among patients with HER2-positive cancers who do not achieve a pCR with neoadjuvant therapy, 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, which stratifies patients by the extent of residual invasive disease in the breast and axillary nodes, 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 [11].

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 role of pertuzumab 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 rationale for administering it in the neoadjuvant setting is to shrink the breast tumor prior to surgery, potentially allowing for less extensive surgery and improved cosmetic outcomes, to downstage a clinically positive axilla and to assess response to treatment, which may influence adjuvant therapy recommendations [12-16]. As noted above, HER2-positive disease (along with triple-negative disease) is associated with a high likelihood of both clinical and pathologic response. (See 'Indications' above.)

Chemotherapy — For patients with HER2-positive cancers in whom neoadjuvant chemotherapy (NACT) is indicated, very few large, randomized studies have compared different NACT regimens, particularly in regards their impact on EFS or overall survival (OS). As a result, a number of NACT regimens may be considered appropriate.

Standard regimens — While any of the neoadjuvant regimens described below can be considered as standard options for HER2-positive breast cancer, our preferred regimens are docetaxel and carboplatin every three weeks for six cycles with concurrent trastuzumab and pertuzumab (TCHP) or weekly paclitaxel with carboplatin, administered either every three weeks or weekly, with concurrent trastuzumab and pertuzumab (wPCbHP), given their demonstrated efficacy and avoidance of 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'.)

In addition to NACT and trastuzumab, we typically incorporate pertuzumab into these regimens, particularly for patients with node positive disease or tumors >2 cm (clinical stage II to III), given available evidence that pertuzumab enhances locoregional responses:

●TCH(P) – Docetaxel and carboplatin every three weeks for six cycles with concurrent trastuzumab [17], 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), but reduces the overall duration of treatment by eliminating planned off weeks. (See 'Anthracycline-free 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 [18]. 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 typically 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.

Note that if an interval of more than three weeks is anticipated between completion of NACT and surgery, many oncologists administer an additional one to two doses of every-three-week trastuzumab (with or without pertuzumab) prior to surgery; while there is no evidence that this additional preoperative treatment enhances response to the neoadjuvant regimen, its administration may allow a reduction in the duration of postoperative (adjuvant) HER2-targeted therapy.

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 early studies assessing the benefit of the addition of trastuzumab to NACT in HER2-positive breast cancer employed anthracycline- and taxane-containing regimens, as did the initial randomized trials of the addition of trastuzumab to adjuvant chemotherapy, as this was the standard of care for high-risk breast cancer. In aggregate, these studies suggest a pathologic complete response (pCR) rate approaching 50 percent among operable patients, as detailed below:

●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 trastuzumab [19]. The overall pCR rate, which was similar between the two treatment arms, was 55 percent, including 48 percent of 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 [20].

●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 (ECH-TH), resulting in a pCR rate of 45 percent [21].

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.)

Anthracycline-free treatment — While the antitumor activity of the combination of anthracycline-based NACT regimens and HER2-targeted therapy with trastuzumab was encouraging, the short- and long-term toxicities associated with anthracycline treatment, in addition to the number of patients in whom this treatment was absolutely or relatively contraindicated (eg, due to underlying cardiac disease or a higher risk of cardiac complications, based on age or comorbid conditions such as obesity, diabetes, and hypertension) led investigators to assess anthracycline-free neoadjuvant (and adjuvant) chemotherapy regimens in combination with HER2-targeted therapy in patients with HER2-positive breast cancer.

Based on results from the adjuvant setting [22] and data from the TRAIN-2 study (discussed below), we consider taxane-carboplatin-trastuzumab (with or without pertuzumab) regimens the preferable alternatives to anthracycline-containing regimens as neoadjuvant therapy in patients with stage II to III HER2-positive cancers, given lesser toxicity and equivalent rates of pCR, EFS and OS. Representative data are as follows:

In the phase III TRAIN-2 trial, among 438 patients with stage II to III HER2-positive breast cancer randomly assigned to anthracycline-containing chemotherapy (three cycles of 5-fluoruoracil, epirubicin, and cyclophosphamide followed by six cycles of weekly paclitaxel and carboplatin, administered days 1 and 8 every three weeks) versus an anthracycline-free chemotherapy regimen (nine cycles of weekly paclitaxel and carboplatin, using the same schedule), with trastuzumab and pertuzumab administered every three weeks with all chemotherapy cycles, the pCR rates did not differ between the arms (67 versus 68 percent) [23]. Updated results from this study demonstrate equivalent three-year EFS (94 versus 93 percent) and OS (98 versus 98 percent) for the anthracycline-free versus the anthracycline-containing regimens, respectively [24]. 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 (8 versus 3 percent), as well as two cases of acute leukemia (versus none in the anthracycline-free arm).

Similar results were achieved in previously reported 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 [25].

●Phase II studies have suggested high pCR rates with combinations of weekly paclitaxel and carboplatin with trastuzumab in patients with HER2-positive disease [26-28]. 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 (wPCH), 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) [28].

●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 anthracycline- and taxane-containing regimens (FEC-T) with concurrent trastuzumab and pertuzumab, though this difference was not statistically significant [29]. (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 AC-T without trastuzumab. While there were no significant differences between the two trastuzumab-containing arms in regards to disease-free survival or OS, the study was not powered to detect differences between these treatment arms. Patients assigned to TCH experienced less serious cardiac toxicity (clinical congestive heart failure of 0.4 versus 2 percent for AC-TH) [22]. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy'.)

The sum of data suggests that anthracycline-free treatment with a taxane, carboplatin and trastuzumab, with or without pertuzumab, is as effective as anthracycline-based neoadjuvant therapy, with a lower incidence of significant toxicities.

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 to reduce the risk of a hypersensitivity reaction, 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, subsequently reduced to 125 mg/m² due to excessive neurologic toxicity at the original dose) for 12 weeks, followed by four cycles of EC every three weeks, with concurrent trastuzumab and pertuzumab, as neoadjuvant therapy for clinical stage II to III HER2-positive breast cancer [30]. Results in 395 patients were as follows:

●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), which 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 was lower in patients started at 125 mg/m². In addition, fatigue, diarrhea, rash, and myalgias were more common with nabpaclitaxel.

While encouraging in regards the efficacy of nabpaclitaxel in patients with HER2-positive breast cancer, the results of the GeparSepto study are not sufficient to suggest that nabpaclitaxel replace standard paclitaxel or docetaxel in the standard NACT regimens for HER2-positive breast cancer. At present, the role of nabpaclitaxel is limited to patients unable to receive standard paclitaxel or docetaxel.

Alternatives for those with low-risk disease or comorbidities — Several regimens exist that are acceptable for patients with either comorbidities or low-risk disease. (See 'Treatment de-escalation' below.)

●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 (with or without pertuzumab) for 12 weeks may be used, based on its efficacy and tolerability in the adjuvant setting [31].

●Other anthracycline-free chemotherapy options exist. For patients with clinical stage IIA (clinical T2N0) with a tumor size of less than 3.5 cm, in whom reduction in tumor size prior to surgery is desired, a shorter course (12 weeks as opposed to 18 to 20 weeks for TCH[P], wPCbHP, or AC-TH[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 [32].

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 impact of the addition of pertuzumab on the risk of breast cancer recurrence following neoadjuvant therapy with chemotherapy and trastuzumab is unknown, and may be modest, based on results from the adjuvant setting [33]. However, when giving NACT plus trastuzumab in patients with clinical stage II to III disease, we routinely add pertuzumab to the regimen, given evidence that it 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 prior to surgery, the addition of trastuzumab to NACT increased the pCR rate from 23 to 40 percent [1]. Achievement of pCR was associated with superior long-term outcomes, irrespective of hormone receptor status (EFS: hazard ratio [HR] 0.39, 95% CI 0.31-0.50; OS: 0.34, 0.24-0.47), compared with patients who did not achieve pCR.

●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 [34,35]. Long-term (5.4 years) follow-up revealed improved EFS with the addition of trastuzumab (58 versus 43 percent; HR 0.64, 95% CI 0.544-0.930) [35].

●In 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 NACT plus HER2-targeted therapy at eradicating occult metastatic disease even among patients with an excellent locoregional response [35].

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 are believed to be an important mechanism of resistance to trastuzumab. While single-agent pertuzumab has demonstrated modest antitumor activity in patients with HER2-positive metastatic disease who progressed on trastuzumab, it is more effective when given in combination with trastuzumab to optimize blockade of HER2 activation. 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 clinical stage II to III 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 comorbidities or lower risk (clinical stage I to IIA) disease, the potential for added toxicity associated with pertuzumab may outweigh its potential 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'.)

Data supporting the administration of pertuzumab in combination with NACT and trastuzumab derive come from the following studies:

●NeoSphere trial – In the randomized phase II NeoSphere trial, 417 HER2-positive patients receive 12 weeks of neoadjuvant therapy composed of four cycles of single-agent docetaxel with trastuzumab, pertuzumab or both, or the combination of trastuzumab and pertuzumab without concurrent docetaxel [36]. 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:

•Patients 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 significant benefit from the addition of pertuzumab to docetaxel and trastuzumab (HR 0.69, 95% CI 0.34-1.40), the study was not powered for this endpoint [37].

●TRYPHAENA trial – The phase II TRYPHAENA trial assessed cardiotoxicity related to the timing of administration of trastuzumab and pertuzumab with an anthracycline-based chemotherapy regimen or an anthracycline-free 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) [29]. 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 myeloid colony-stimulating factor, the incidence of febrile neutropenia was 18 percent among patients receiving FECHP-THP, 9 percent with FEC-THP, 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 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 [38]. (See 'Choice of taxane' above.)

Alternative 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 with the intravenous (IV) forms of these agents when administered with NACT [39-43]. 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 while treating patients with concurrent NACT and HER2-targeted therapy, but consider the SC formulations (which can be administered in the patient's home) reasonable alternatives especially after completion of chemotherapy, in patients with limited venous access or who prefer SC administration, or if there are safety concerns, such as potential exposure to the novel coronavirus, or if impaired patient mobility complicates administration of 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 breast cancers were randomly assigned to IV trastuzumab and pertuzumab versus an SC formulation of a combination of these two agents [43]. In both arms, trastuzumab and pertuzumab were started 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.

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 [40]:

•The serum trough concentration (drawn just prior to the last preoperative dose of trastuzumab) for trastuzumab was higher with the SC preparation.

•The pCR rates were similar (39 versus 34 percent for the SC and IV formulations, respectively), as were median time to response and rate of progression on treatment. Updated results from this study presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated equivalent outcomes between the SC and IV arms, with 88 percent of patients who achieved a pCR and 68 percent of those who did not remaining event-free at three years [44].

•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 surgery and neoadjuvant or adjuvant chemotherapy [41]. 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.

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). Greater differences were seen in patients with obesity, with only 20 percent who received the SC formulation exceeding the pharmacokinetic target [45]. The clinical relevance of these findings remains to be determined.

●Subcutaneous formulations – The subcutaneous preparations of trastuzumab and combined trastuzumab-pertuzumab are FDA approved, leaving it to insurers, institutions, clinicians, and their patients to decide whether and when to utilize these treatment options.

●Trastuzumab biosimilars – Pharmaceutical companies have developed trastuzumab biosimilars to compete with the original formulation, a number of which have been approved by the FDA and/or European regulators, based on phase III trials that demonstrated equivalent outcomes, largely in the neoadjuvant setting. Based on these results, we consider these agents interchangeable with the original formulation when give in combination with NACT (with or without concurrent pertuzumab) in the treatment regimens described above.

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.

Treatment de-escalation — Given the antitumor efficacy of NACT with HER2-targeted therapy, a number of phase II studies have been conducted to determine whether the intensity and/or duration of chemotherapy can be reduced. Among these:

●In the DAPHNE trial, 98 patients with clinical stage II (n = 84) or III (n = 14) HER2-positive breast cancer received weekly paclitaxel with every-three-week trastuzumab and pertuzumab (THP) for 12 weeks [46]. The overall pCR rate was 57 percent, including 85 percent among 33 patients with HR-negative and 47 percent among 64 patients with HR-positive cancers. While adjuvant therapy was at the discretion of the treating clinician, almost no patients with pCR or minimal residual disease (RCB class I) received adjuvant chemotherapy, while about half of patients with more extensive residual disease (RCB class II or III) received adjuvant AC; others received adjuvant T-DM1. All patients were to receive adjuvant trastuzumab and pertuzumab to complete a year of HER2-targeted therapy. At a median follow-up of only 19 months there had been no breast cancer recurrences.

●In one arm of the WSG ADAPT trial, 92 patients with HR-negative, HER2-positive breast cancer were assigned to receive 12 weeks of weekly paclitaxel with every-three-week trastuzumab and pertuzumab (THP); 90 percent achieved pCR [47].

While results from these two pilot studies are encouraging, outside of a clinical trial we recommend that patients with clinical stage II to III HER2-positive breast who have no contraindication to standard treatment should receive one of the regimens listed above (TCHP, wPCbHP, or AC/EC-THP). The ongoing CompassHER2-pCR trial is assessing pCR rates with the THP regimen in 1250 patients.

Lapatinib, neratinib and other HER2-targeted tyrosine kinase inhibitors (TKIs) — Other TKIs are investigational in the neoadjuvant setting.

●Lapatinib – Lapatinib is a small molecule orally administered inhibitor of the tyrosine kinase domains of both HER2 and the epidermal growth factor receptor (EGFR; sometimes also referred to as HER1) and has demonstrated activity in HER2-positive metastatic breast cancer that progressed on a trastuzumab-containing regimen, especially when given in combination with trastuzumab. While the addition of lapatinib to NACT plus trastuzumab has been shown to improve pCR rates in a number of clinical trials, and in one of these studies to significantly improve relapse-free and overall survival at seven years, superior longer-term outcomes have not been consistent across trials; moreover, the addition of lapatinib is associated with increases in grade >3 adverse events including diarrhea, rash, and liver function test abnormalities [48-56]. Its use in the neoadjuvant setting is therefore not recommended.

●Neratinib – Neratinib is an oral agent that binds irreversibly to and inhibits the tyrosine kinase domains of both HER2 and EGFR. In an 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 [57].

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) [58].

●Pyrotinib – Pyrotinib is an irreversible inhibitor of the tyrosine kinase domains of EGFR, HER2, and HER4. In the phase II Panphila study, the combination of daily pyrotinib with six cycles of docetaxel, carboplatin, and trastuzumab resulted in a pCR rate of 55 percent in 69 patients with stage II to III HER2-positive breast cancer, but was associated with high rates of grade >3 diarrhea (43 percent), anemia, vomiting and thrombocytopenia [59].

While HER2-tageted TKIs demonstrate efficacy in combination with NACT and trastuzumab in HER2-positive breast cancer, they are associated with significant toxicities, much of it apparently related to off-target inhibition of EGFR, and none has been compared (for efficacy or toxicity) with the addition of pertuzumab in this setting. A more HER2 selective TKI, tucatinib, has been approved for the treatment of HER2-positive metastatic breast cancer, but there is at yet no data on its activity in the neoadjuvant setting. Thus, the use of any of the agents cannot be recommended outside of a clinical trial. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Tucatinib, capecitabine, and trastuzumab'.)

HER2-targeted therapy without chemotherapy — Administering HER2-targeted therapy in combination with NACT is the only strategy that has been shown to improve survival in HER2-positive breast cancer, and is thus the preferred and standard approach for nearly all such patients.

However, for patients in whom other health conditions preclude the use of chemotherapy, or as part of a clinical trial, there has been interest in assessing the activity of combinations of HER2-targeted therapies without concurrent chemotherapy. While this approach has demonstrated antitumor activity, and even possible achievement of pCR, it remains investigational, given the superior results achieved with concomitant administration of NACT 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. In the neoadjuvant setting, the combination of chemotherapy with trastuzumab and pertuzumab has been shown to have superior pCR rates over nonchemotherapy alternatives [36,60]. For those with HR-positive disease, we add endocrine therapy, based on results from TBCRC006 and TBCRC023, described below [61,62].

●Trastuzumab and pertuzumab – On one arm of the NeoSphere trial, described in more detail above, 107 patients received 12 weeks of trastuzumab and pertuzumab without chemotherapy prior to surgery [36]. (See 'Addition of pertuzumab' above.)

In the WSG-ADAPT trial mentioned above, 42 patients with HR-negative/HER2-positive breast cancer were assigned to receive 12 weeks of every-three-week trastuzumab and pertuzumab without concurrent paclitaxel; in these patients, the pCR rate was 36 percent [47]. While administration of adjuvant chemotherapy was mandated for all non-pCRs on this arm of the study, most of the patients who achieved pCR did not receive post-operative chemotherapy; despite this, patients assigned to dual-HER2-targeted neoadjuvant therapy alone had a five-year relapse-free survival of 89 percent, not substantially lower than for those randomized to paclitaxel with trastuzumab and pertuzumab (98 percent) [47,63]. These results suggest that there is a subset of 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 NACT and 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 trastuzumab and lapatinib, 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; those with HR-positive tumors also received letrozole (and goserelin if premenopausal) [61]. The main results were as follows:

•The overall pCR (breast and axilla) rate was 22 percent (28 and 18 percent in HR-negative and HR-positive patients, respectively).

•The pCR breast (yp T0/is Nany) 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 greatest dimension 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 [62].

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 complex, bound to HER2, is endocytosed and catabolized by 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, wPCbHP, or AC-THP.

The German Women's Healthcare Study Group conducted a randomized phase II study in stage I to III HR-positive/HER2-positive breast cancer on which 375 women were assigned to single-agent T-DM1, T-DM1 with concurrent endocrine therapy, or trastuzumab with concurrent endocrine therapy [64]. Treatment with T-DM1, with or without concurrent endocrine therapy, was associated with higher pCR rates (42 and 41 percent, respectively), compared with trastuzumab with endocrine therapy (15 percent). Treatment with T-DM1 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) [65]. 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) [66].

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/P [60]. Risk of an EFS event, at three years of follow-up, was significantly higher with T-DM1/P (HR 2.6, 95% CI 1.5-5.0) [67]. 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 regimen that combines NACT with trastuzumab and pertuzumab, such as TCHP or wPCbHP. Until we can prospectively identify the subgroup of patients who may be at greater risk for these events, T-DM1cannot be considered standard neoadjuvant therapy, except perhaps in patients who are not candidates for a more intensive regimen.

TIMING OF HER2-DIRECTED AGENTS — The timing of administration of HER2-targeted agents may be important to decrease the risk of toxicities, particularly cardiotoxicity for those who are also being treated with an anthracycline [68]. In patients receiving an anthracycline-based NACT regimen, we typically administer HER2-targeted therapy concurrently with the taxane, either following completion of or prior to administration of the anthracycline. Patients receiving sequential anthracycline-based chemotherapy and HER2-targeted 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, more recent 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) [19]. At the completion of NACT, the incidence of cardiac events was 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 [29].

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 HER2-targeted 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 achieved among HER2-positive patients. They may also have long-term prognostic significance, and may someday help to direct therapy. 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, patients with HR-positive/HER2-positive cancers 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-positive/HER2-positive cancers is that binding of estrogen to cytoplasmic estrogen receptors activates signaling pathways that bypass HER2 blockade, which has been referred to as "cross-talk." To test this hypothesis, the NSABP B-52 trial assessed 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 HR-positive/HER2-positive cancers. Among 311 patients, pCR rates were similar with (46 percent) or without (41 percent) estrogen deprivation, and did not differ between pre- and postmenopausal women [69]. The addition of estrogen deprivation also did not affect the toxicity of the neoadjuvant regimen.

Thus, while the results of this study do not support the routine administration of antiestrogen therapy during neoadjuvant therapy for HR-positive/HER2-positive breast cancer, it also showed no contraindication to its use. Administration of luteinizing hormone-releasing hormone (LHRH) analogs to suppress ovarian function during chemotherapy to preserve ovarian function and fertility is discussed 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 [70]. 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 all 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 [71]. Among HR-positive cancers, the percentage of HER2-enriched tumors was only 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 [72]. 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 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) receive the same benefit in terms of improvement in disease-free survival 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 (7 percent) of patients with basal-like cancers did not appear to benefit from the addition of trastuzumab [73]. 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 cancer that is HER2-positive by standard pathologic analysis 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 [74-77].

●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) [78]. 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, trastuzumab and lapatinib were higher compared with patients whose tumors had lower levels of lymphocytic infiltration (64 versus 27 percent) [79]. 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 [80]. 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'.)

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 – 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. Treatment in the neoadjuvant setting can also identify patients who may benefit from administration of ado-trastuzumab emtansine (T-DM1), in place of trastuzumab, after surgery (ie, those who fail to achieve a pathologic complete response [pCR]). Our approach to HER2 testing is included in the algorithm (algorithm 1). (See 'Indications' above.)

●Outcome measures – In addition to outcome measures such as recurrence rate, disease-free survival, and overall survival, which are frequently used to assess treatment efficacy in the adjuvant setting, pathologic response, including the pCR rate, is a useful measure of treatment efficacy in patients receiving neoadjuvant therapy. (See 'Outcome measures' above.)

●Standard regimens – For patients with HER2-positive cancers in whom neoadjuvant chemotherapy (NACT) is indicated, we suggest docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) (Grade 2C), 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, such as AC-THP, to patients who lack cardiac risk factors, given the body of data regarding these regimens. (See 'Standard regimens' above.)

●Addition of pertuzumab – In most patients receiving neoadjuvant trastuzumab and chemotherapy, we suggest incorporation of pertuzumab (Grade 2C), 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 and 'Treatment de-escalation' above.)

•In patients who are not candidates for, or refuse, 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'.)