Volume 116, Issue 12 p. 2856-2867
Review Article
Free Access

Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer

Helena R. Chang MD, PhD

Corresponding Author

Helena R. Chang MD, PhD

Revlon/University of California at Los Angeles Breast Center, Los Angeles, California

Fax: (310) 206-2982

Revlon/UCLA Breast Center, 200 UCLA Medical Plaza, Suite B265, Los Angeles, CA 90095===Search for more papers by this author
First published: 11 June 2010
Citations: 73


Overexpression, or gene amplification, of the human epidermal growth factor receptor 2 (HER2) is evident in 20% to 25% of breast cancers. The biologic agent trastuzumab is an HER2-targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved for use in the adjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy suggest that patients with HER2-positive breast cancer also may benefit from preoperative trastuzumab. For this article, the author reviewed efficacy and safety data from key studies of patients who received neoadjuvant trastuzumab-based therapy. Studies were identified from literature searches of publication and congress databases. The results of 3 large phase 3 trials (the M. D. Anderson Cancer Center neoadjuvant trastuzumab trial, the Neoadjuvant Herceptin [NOAH] trial, and the German Breast Group/Gynecologic Oncology Study Group “GeparQuattro” trial) demonstrated that, compared with chemotherapy alone, neoadjuvant trastuzumab plus chemotherapy significantly increased pathologic complete response rates to as high as 65%. Improvements in disease-free, overall, and event-free survival also were reported in the NOAH trial. In addition to demonstrated efficacy, a low incidence of cardiac dysfunction suggests that neoadjuvant trastuzumab is both effective and well tolerated. Similar results have been reported in a range of phase 2 studies using different trastuzumab-based regimens. These encouraging data led the National Comprehensive Cancer Network to recommend treating patients who have operable, locally advanced, HER2-positive breast cancer with neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab. Cancer 2010. © 2010 American Cancer Society.

Breast cancer (BC) is the most frequently diagnosed form of cancer among women in the United States.1 Of the various subtypes of BC, tumors that have gene amplification or protein overexpression of human epidermal growth factor receptor 2 (HER2) are among the most aggressive and are associated with poor clinical outcomes compared with tumors that do not have HER2 overexpression.2-4 Of the total number of patients diagnosed with BC in the United States, 20% to 25% will have tumors that exhibit HER2 gene amplification or protein overexpression.2, 5, 6

Trastuzumab (Herceptin), a humanized, monoclonal antibody that blocks the activity of HER2, is the only anti-HER2 agent that is approved for adjuvant therapy in patients who have HER2-positive disease with either positive or negative lymph node status, estrogen receptor (ER)/progesterone receptor (PR)-negative disease, or a high-risk feature, either in combination with chemotherapy or as a single agent after chemotherapy. Adjuvant trastuzumab significantly improves disease-free survival (DFS) and overall survival (OS) compared with chemotherapy or observation alone.7-10 In metastatic BC (MBC), first-line trastuzumab is approved in combination with paclitaxel; this combination significantly improves response rate, time to progression, and OS in patients with HER2-positive MBC.11 Lapatinib (Tykerb) is an HER2-directed tyrosine kinase inhibitor that also is approved for the treatment of HER2-positive MBC. However, lapatinib is approved for use only in this setting after progression on anthracyclines, taxanes, and trastuzumab.

Trastuzumab is not currently approved for use in the neoadjuvant setting; however, its use in this setting is an active area of clinical investigation. Trastuzumab may provide additional clinical benefit by increasing the rate of breast conservation, decreasing the rate of distant metastases, and increasing the likelihood of achieving a pathologic complete response (pCR).12, 13

In this article, we review efficacy and safety data from studies of patients with HER2-positive BC who received neoadjuvant trastuzumab-based therapy. Studies were identified from a literature search using the PubMed database and congress Web sites from 2002 to 2008. The following search terms were used: neoadjuvant or preoperative AND trastuzumab or Herceptin AND breast cancer.

Neoadjuvant Chemotherapy for the Treatment of Breast Cancer

The extent of survival benefit gained with neoadjuvant chemotherapy remains unclear. Studies suggest either equivalence or no clear benefit in survival, regardless of whether therapy was administered in the neoadjuvant or adjuvant settings.14, 15 However, 1 study that compared patients who received neoadjuvant therapy with those who received postoperative therapy suggested a trend toward improved DFS (hazard ratio [HR], 0.85; P = .09) and OS (HR, 0.81; P = .06) in patients with BC aged ≤50 years. At 16 years of follow-up, both OS rates (61% vs 55%) and DFS rates (44% vs 38%) were greater in the preoperative therapy group. In addition, among patients who were event-free for 5 years, regardless of age, DFS was greater in patients who received neoadjuvant therapy compared with the postoperative therapy group (HR, 0.81; P = .053).13

One important caveat with neoadjuvant chemotherapy, however, has been raised by a meta-analysis that compared the outcomes of neoadjuvant versus adjuvant treatment in BC. That analysis demonstrated an increase in locoregional failure for patients who had received neoadjuvant therapy if they subsequently did not undergo surgery and, instead, received radiotherapy. It should be noted, however, that the apparent increase in risk of locoregional recurrence was accounted for by 6 trials, and no association with locoregional recurrence was reported in the other 3 trials in that analysis.16

In addition to potential survival improvements, neoadjuvant chemotherapy can contribute to surgical downstaging and increased rates of breast-conserving surgery.12, 17 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial demonstrated that, in a population with predominantly T2 disease (≤60%), neoadjuvant chemotherapy-associated tumor shrinkage altered the BC surgical intervention from a 60%/40% lumpectomy/mastectomy ratio after adjuvant chemotherapy to a 68%/32% lumpectomy/mastectomy ratio.13 More recently, in a group of patients with mostly T3/T4 disease (80%), those with HER2-positive disease who received a neoadjuvant trastuzumab-based regimen exhibited a mean decrease in tumor size from 7.75 cm at baseline to 2.20 cm after neoadjuvant therapy, resulting in a 43.7% lumpectomy rate (unpublished data). In addition to treating detectable disease before surgery, neoadjuvant chemotherapy provides the earliest chance to treat micrometastatic disease, saving time that potentially could be lost to local treatment.18 Unlike adjuvant therapy in which considerable vascular remodeling can occur at the site of tumor excision, neoadjuvant therapy is able to use the tumor's local vasculature, potentially enhancing the local effect of chemotherapy through an undisturbed blood supply.19, 20

Neoadjuvant therapy already is the standard of care in locally advanced BC (LABC) and inflammatory BC (IBC).12, 21 Because of its potential to improve patient outcomes, neoadjuvant therapy may become the standard approach for many patients with early BC.

Evaluating the Efficacy of Neoadjuvant Therapy

Before neoadjuvant therapy, patients are assessed using a range of techniques, including mammography, ultrasound of the breast or axilla (with or without biopsy), magnetic resonance imaging (MRI), or a metastatic workup if the tumor appears to be LABC. Physical examination of the tumor remains the gold standard for assessing tumor size and the patient's suitability to receive neoadjuvant chemotherapy.22

Survival-based endpoints are the most important endpoints when assessing the benefit of any therapy. However, accurately assessing the tumor response to neoadjuvant therapy also is critical. If a tumor fails to respond (shrink), then the oncologist may consider adjusting the regimen.12 In addition, these evaluations can provide important prognostic information. Response currently is evaluated using 2 endpoints: clinical complete response (cCR) and pCR.

A cCR of in-breast disease usually is defined as no detectable disease on physical examination or on an MRI scan after neoadjuvant therapy. It is noteworthy that the detection of a neoadjuvant response by mammography is a less accurate tool, because it has a considerable rate of false-negative results. Compared with pCR, assessment of cCR by clinical examination or mammography may overestimate the response to neoadjuvant therapy, with cCR rates usually higher than pCR rates (unpublished data).22, 23

Physical examination of the axillary lymph nodes is another useful technique that can be used for disease staging in patients who receive neoadjuvant therapy, although the use of positron-emission tomography (PET) for the assessment of metastases to the lymph nodes is increasing. A prospective clinical study of patients with T3 or T4M0 breast tumors (N = 45) indicated that both physical examination and PET had high specificity but low sensitivity, correctly predicting pathologically positive lymph nodes, but not negative lymph nodes, after neoadjuvant therapy.22 Those results suggest that, although these techniques are useful, they should not replace pathologic staging.

A pCR, which usually is defined as no detectable residual cancer in the breast or lymph nodes by histopathology, provides a strong correlation with long-term outcome. Evidence suggests that a pCR correlates with better survival, and it may serve as a surrogate marker of clinical benefit.24, 25 Factors like hormone receptor status play a part in attaining a pCR with neoadjuvant chemotherapy. Patients with ER-negative tumors are more likely to achieve a pCR after neoadjuvant chemotherapy than those with ER-positive tumors.26 This also was demonstrated in a retrospective review, which indicated that the pCR rate in studies with anthracycline-based chemotherapies ranged from 1.2% to 14.3% in patients with hormone receptor-positive tumors and from 7.1% to 54.5% in patients with hormone receptor-negative tumors. However, in that analysis, the HER2 status of tumors was not known.27

The Role of Trastuzumab in Neoadjuvant Therapy

Several trials have examined the potential benefits of neoadjuvant trastuzumab combined with chemotherapeutic agents in patients with HER2-positive tumors and have reported pCR rates of up to 67%.28-44 The encouraging data published from clinical trials to date resulted in a recommendation by the National Comprehensive Cancer Network for the use of neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) plus trastuzumab45 based on data reported by Buzdar et al.23

Phase 3 Studies

Three phase 3 neoadjuvant studies have investigated the use of trastuzumab with various chemotherapy regimens.

Phase 3 trials of neoadjuvant trastuzumab/chemotherapy in operable disease

The use of neoadjuvant trastuzumab as part of an anthracycline-based treatment regimen was assessed in a randomized phase 3 study conducted at The University of Texas M. D. Anderson Cancer Center (MDACC) (Fig. 1, Top). The primary objective of that study was to compare the pCR rates for patients with stage II to IIIA disease who received chemotherapy with or without concurrent trastuzumab (n = 23 and n = 19, respectively).23

Details are in the caption following the image

(Top) Phase 3 neoadjuvant trastuzumab study designs are illustrated and include the Neoadjuvant Herceptin (NOAH) trial (trastuzumab [H] = 8 mg/kg loading dose followed by 6 mg/kg; anthracycline plus taxane [AT] = 60 mg/m2 doxorubicin plus 150 mg/m2 paclitaxel; taxane [T] = 175 mg/m2; cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] = 600 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, 600 mg/m2 5-fluorouracil); the M. D. Anderson Cancer Center (MDACC) neoadjuvant trial (H = 4 mg/kg loading dose followed by 2 mg/kg; T = 225 mg/m2; 5-fluorouracil, epirubicin, and cyclophosphamide [FEC] = 500 mg/m2 5-fluorouracil, 75 mg/m2 epirubicin, 500 mg/m2 cyclophosphamide); and the German Breast Group/Gynecologic Oncology Study Group “GeparQuattro” trial (H = 8 mg/kg loading dose followed by 6 mg/kg [an asterisk indicates that patients received trastuzumab only if they had HER2-positive disease; a dagger indicates that an aromatase inhibitor was given only to patients who had endocrine-responsive disease]; epirubicin and cyclophosphamide [AC] = 90 mg/m2 epirubicin plus 600 mg/m2 cyclophosphamide; T = 75 mg/m2 in the capecitabine arms, 100 mg/m2 in the other arm; X = 1800 mg/m2). HER2+ LABC indicates human epidermal growth factor 2-positive locally advanced breast cancer; q3w, every 3 weeks; qw, weekly; RT, radiotherapy; AI, aromatase inhibitor. (Bottom) Ongoing neoadjuvant trastuzumab clinical study designs are illustrated and include the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (Neo-ALTTO) trial (H = 4 mg/kg loading dose followed by 2 mg/kg; lapatinib [L] = 1000 mg daily in the monotherapy arm, 1500 mg daily in the combination arm; T = 80 mg/m2; FEC = 500 mg/m2 5-fluorouracil, 75 mg/m2 epirubicin, 500 mg/m2 cyclophosphamide [after surgery, H was given as an 8-mg/kg loading dose followed by 6 mg/kg every 3 weeks]); National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-41 (doxorubicin and cyclophosphamide [AC] = 60 mg/m2 doxorubicin plus 600 mg/m2 cyclophosphamide; T = 80 mg/m2; H = 4 mg/kg loading dose followed by 2 mg/kg [an asterisk indicates that patients were randomized further to receive L at either 1250 mg daily or 750 mg daily); and the American College of Surgeons Oncology Group (ACOSOG) Z1041 trial (FEC = 500 mg/m2 5-fluorouracil, 75 mg/m2 epirubicin, 500 mg/m2 cyclophosphamide; H = 4 mg/kg loading dose followed by 2 mg/kg; T = 80 mg/m2). BC indicates breast cancer; AC, anthracycline plus cyclophosphamide; BC, breast cancer; qd, daily.

The addition of trastuzumab to neoadjuvant chemotherapy increased the pCR rate significantly compared with chemotherapy-alone arm (65.2% vs 26.3%; P = .016) (Table 1).23 The data monitoring committee for the study recommended halting accrual once the primary endpoint had been met after recruiting only 42 patients (planned accrual was 164 patients). A third, open-label, nonrandomized cohort (n = 22) was added to the study, and all of those patients were assigned to the trastuzumab arm.31 The combined pCR rate for the randomized and open-label trastuzumab arms was 60%, which was considerably greater than the rate in the chemotherapy-alone arm (26.3%). Both the 1-year DFS rate (100% vs 94.7% in the chemotherapy with trastuzumab and chemotherapy-alone arms, respectively) and the 3-year DFS rate (100% vs 85.3%, respectively) improved with the addition of trastuzumab.31 The addition of trastuzumab to neoadjuvant therapy had a minimal effect on the rate of breast-conserving therapy (BCT) performed (52.6% and 56.5% of patients in the chemotherapy alone and chemotherapy with trastuzumab arms, respectively).23

Table 1. Results of Completed Phase 3 Trials of Neoadjuvant Trastuzumab
Neoadjuvant Regimen Reference Tumor Classification at Enrollment, % pCR, % [95% CI]
T (±H)→FEC (±H) Buzdar 2005, 200723, 31 T1, 10.9; T2, 65.6; T3, 21.9; T4, 1.6 CT arm, 26.3 [9.1-51.2]; CT+H arm, 60 [44.3-74.3]
AT (±H)→T (±H)→CMF (±H) Gianni 2007, 200836, 47 T4, 42 CT arm, 23; CT+H arm,43a
AC (±H)→T (±H)→X (±H); AC (±H)→TX (±H); AC (±H)→T (±H) Von Minckwitz 200840 T1-T3, 81.6; T4, 18.4 CT arm, 15.7; CT+H arm, 31.7b
  • pCR indicates pathologic complete response; CI, confidence interval; T, taxane; ±, with or without; H, trastuzumab; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; CT, chemotherapy; AT, anthracycline plus taxane; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; AC, anthracycline plus cyclophosphamide; X, capecitabine.
  • a P = .002.
  • b P < .001.

Trastuzumab-based therapies have been associated with an increased incidence of cardiac dysfunction (CD). In the extended study with longer follow-up in the original cohort (36.1 months; range, 12.3-54.8 months), no patients who received trastuzumab plus chemotherapy experienced CD.31 In the initial study, a decrease in left ventricular (LV) ejection fraction (LVEF) ≥10 percentage points was observed in 5 patients (26%) in the chemotherapy-alone arm and in 7 patients (30%) in the chemotherapy plus trastuzumab arm. The LVEF returned to baseline levels for all but 1 of these patients, whose LVEF remained in the low normal range.23 An assessment of noncardiac adverse events (AEs) indicated a significant difference in the incidence of grade 4 neutropenia (91% vs 58%; P = .03), but not febrile neutropenia, between the chemotherapy plus trastuzumab and control arms, respectively.

Neoadjuvant trastuzumab in locally advanced breast cancer

The Neoadjuvant Herceptin (NOAH) trial is a large, international, phase 3 trial assessing the efficacy and safety of sequential doxorubicin and paclitaxel followed by paclitaxel, then cyclophosphamide, methotrexate, and 5-fluorouracil with (n = 115) or without (n = 113) concomitant trastuzumab, in patients with newly diagnosed LABC (Fig. 1, Top).46 The study also includes a third arm of patients (n = 99) with HER2-negative disease who received the same regimen without trastuzumab.

Patients with HER2-positive disease who received neoadjuvant chemotherapy with concurrent trastuzumab had a significantly improved overall response rate (89% vs 77%; P = .02) (Table 1) and pCR rate (43% vs 23%; P = .002) compared with those who received neoadjuvant chemotherapy alone.46 A significant improvement in the pCR rate also was observed in a subgroup analysis of patients with IBC who received trastuzumab compared with those who did not (39% vs 20%; P = .002).46 At a median follow-up of 3 years, event-free survival (EFS) improved significantly in patients with HER2-positive disease who received chemotherapy plus trastuzumab compared with those who received chemotherapy alone (70.1% vs 53.3%; HR, 0.56; P = .007).46

Exploratory biomarker studies from the NOAH trial also have been reported.47 The objective of these studies was to correlate standard clinical variables, including clinical tumor (T) classification, lymph node (N) status, and hormone receptor status, and potential biomarkers with pCR (defined as no residual invasive cancer in breast or lymph nodes regardless of the presence of ductal carcinoma in situ [DCIS]). In total, 247 pretreatment core biopsies (75.5%) were assayed for c-myc (by fluorescent in situ hybridization [FISH]), phosphatase and tensin homolog (by immunohistochemistry [IHC]), and insulin-like growth factor 1 receptor (by IHC), in addition to ER and PR. Of the variables that were tested in the trastuzumab-treated group, negative PR status was associated with a significantly greater pCR benefit than positive PR status in patients who received trastuzumab (51% vs 16%; P ≤ .008). Therefore, it was determined that PR status was predictive of a pCR.47 In a multivariate analysis of patients with HER2-positive disease who received trastuzumab, c-myc amplification and lower HER3 total immunoreactivity were associated significantly with the likelihood of achieving a pCR (P < .05). Further analyses of additional biomarkers, including gene expression and Fc-γ receptor polymorphisms, are planned.47

Grade 3 or 4 AEs reported by more than 1 patient in the trastuzumab arm were febrile neutropenia (1.7%; n = 2) and neutropenia (2.6%; n = 3).46 Incidence rates for these AEs were similar in patients with HER2-positive disease who did not receive trastuzumab (1.8% and 4.4%, respectively). During treatment and follow-up, the majority of patients with HER2-positive disease in both the trastuzumab plus chemotherapy group (73.0%) and the chemotherapy-alone group (83.2%) experienced no change in LVEF. National Cancer Institute Common Toxicity Criteria (CTC) grade 1 LVEF changes during therapy were experienced by 22.6% of patients in the trastuzumab plus chemotherapy arm versus 15.9% of patients in the chemotherapy-alone arm. CTC grade 2 and 3 LVEF changes were infrequent in both study arms (CTC grade 2, 2 patients [1.7%] in the trastuzumab plus chemotherapy arm vs 1 patient [0.9%] in the chemotherapy-alone arm; CTC grade 3, 2 patients [1.7%] in the trastuzumab plus chemotherapy arm vs 0 patients in the chemotherapy-alone arm). The safety data reported to date suggest that the neoadjuvant regimen used in the NOAH trial is tolerated well and has an acceptable cardiac safety profile.

The German Breast Group/Gynecologic Oncology Study Group trial

The 3-arm, phase 3 German Breast Group/Gynecologic Oncology Study Group trial (the GeparQuattro trial) (Fig. 1, Top) was designed to evaluate the effect on pCR rates of epirubicin plus cyclophosphamide followed by 1 of 3 different docetaxel-based regimens. In each arm, patients with HER2-positive disease received trastuzumab starting from the initiation of epirubicin plus cyclophosphamide for 52 weeks. In total, 445 patients with HER2-positive tumors were included; 81.6% of patients with HER2-positive disease had previously untreated stage I to III BC.40 The noninvasive residual pCR rate was 31.7% for patients who had received neoadjuvant trastuzumab plus chemotherapy and 15.7% for patients who received chemotherapy alone; this was a significant improvement in the pCR rate for the patients with HER2-positive disease (P < .001) (Table 1). The addition of trastuzumab to neoadjuvant chemotherapy did not increase hematologic or nonhematologic toxicities.40 Three patients experienced congestive heart failure (CHF) or a decrease in LVEF to <45%.40

Neoadjuvant trastuzumab plus chemotherapy algorithm for operable breast cancer

The importance of HER2 testing both before and after neoadjuvant therapy was highlighted in a study by Mittendorf et al39 In that study, clinicopathologic data were examined for 143 patients with HER2-positive BC who received neoadjuvant therapy with 4 cycles of paclitaxel every 3 weeks followed by 4 cycles of FEC with or without concurrent, weekly trastuzumab for 6 months. Charts were reviewed to determine the pCR rate and the HER2 status of residual tumors in patients who did not achieve a pCR. The results indicated that 72 patients (50.3%) achieved a pCR, a pathologic partial response was achieved by 61 patients (42.7%), 7 patients (4.9%) had stable disease, and 3 patients (2.1%) had progressive disease. Approximately 33% of the patients who did not achieve a pCR had disease that changed phenotype from HER2-positive disease to HER2-negative disease. Because of this, the authors suggested that, in patients who received neoadjuvant trastuzumab and did not achieve a pCR, the HER2 status of residual tumors should be retested.

Phase 2 Trials

H2269s, an anthracycline-free, randomized, phase 2 study, was initiated to compare the efficacy of 4 cycles of neoadjuvant docetaxel (75 mg/m2) and carboplatin (area under the curve = 6) every 3 weeks plus trastuzumab with neoadjuvant docetaxel and carboplatin alone in women with HER2-positive (FISH-positive) LABC. Preliminary results43 and updated data44 were presented at the American Society of Clinical Oncology annual meetings in 2006 and 2008, respectively. Patients were randomized to receive a total 52 weeks of either postoperative trastuzumab only or both preoperative (concurrent with docetaxel and carboplatin) and postoperative trastuzumab. Trastuzumab was administered as a 4 mg/kg loading dose, followed by 2 mg/kg weekly in combination with chemotherapy, and then 6 mg/kg every 3 weeks as monotherapy. Of the 30 patients with HER2-positive BC who completed preoperative therapy, the pCR rate was 40% for those who received preoperative trastuzumab compared with 7.1% for those who did not. In total, 74 patients with biopsy-proven stage II and III BC completed 4 cycles of neoadjuvant docetaxel and carboplatin, including 14 patients (19.2%) who had T2 tumors, 42 patients (57.5%) who had T3 tumors, 17 patients (23.3%) who had T4 tumors, and 11 patients who had IBC. Of all patients who were analyzed, 45.2% had a cCR, and 46.6% had a pCR; an analysis of pCRs in the same group of patients demonstrated an overall pCR rate of 26.8%. Of the 15 patients (53.3%) who were randomized to receive preoperative trastuzumab, 53.3% (n = 8) underwent lumpectomy compared with 42.9% of those who did not receive preoperative trastuzumab. Safety data from the H2269s trial demonstrated that 6.8% of patients in the chemotherapy arm had decreases in LVEF of 10% to 15% from baseline. This increased to 13.3% of patients in the trastuzumab arm; however, this was accounted for by 2 patients (unpublished data).

The trial of preoperative chemotherapy plus trastuzumab, lapatinib, or both in HER2-positive, operable BC (or CHER LOB trial) is a randomized, 3-arm, phase 2 trial examining the effects of 26 weeks of neoadjuvant biologic therapy combined with chemotherapy.48 Patients received 12 weeks of weekly paclitaxel followed by 4 cycles of FEC every 3 weeks. The 3 arms of the study combined this chemotherapy regimen with 26 weeks of simultaneous weekly trastuzumab, daily lapatinib, or both biologic agents concurrently. Preliminary data for the 18 evaluable patients indicated a 44% pCR rate across the whole study, a decrease in the percentage of patients requiring mastectomies, and a corresponding increase in the percentage of patients receiving BCT. At enrollment, 64% of patients were recommended for mastectomy, and 36% were recommended for BCT; after neoadjuvant therapy, the recommended surgery for patients was 47% mastectomies and 53% for BCT. Current results indicate that this regimen has an acceptable cardiac safety profile with no incidence of clinically meaningful CD. AEs reported include grade 1 and 2 nausea (45.2%), grade 1 through 3 vomiting (38.7%), grade 1 and 2 asthenia (19.3%), grade 1 and 2 rash (77.3%), and grade 1 through 3 diarrhea (74.2%). The reported AEs were not broken down by study arm, making it difficult to draw any comparisons among the regimens tested.

Efficacy in terms of pCR rates and the safety profile of sequential doublets plus trastuzumab were studied in the neoadjuvant setting of patients with LABC.49 In that small study (N = 20 patients), treatment consisted of 2 sequential regimens. The first sequence was 3 cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by a second sequence of 6 cycles of paclitaxel and gemcitabine; trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) was administered concomitantly with paclitaxel and gemcitabine. Objective complete responses were achieved in all 20 patients, and pCRs were obtained in 10 patients (50%). The investigators demonstrated a high pCR rate but suggested that further studies are warranted. The only AEs reported were grade 3 and 4 neutropenia (n = 2 and n = 1, respectively).

The efficacy of a combination of a vascular endothelial growth factor (VEGF) inhibitor with trastuzumab in the neoadjuvant setting has also been investigated.41 Clinical and preclinical studies provide a good rationale for this combination, because data have indicated that elevated serum VEGF levels may have a role in invasive BC. Serum VEGF levels are correlated with microvessel density50 and poor survival in primary BC,51 and preclinical data indicate a transcriptional up-regulation of VEGF in HER2-overexpressing BC cells.52.53 It has been hypothesized that, in HER2-positive BC, up-regulated VEGF may contribute to the aggressive phenotype.54 A preclinical study combining HER2-targeted and VEGF-targeted therapy demonstrated that dual blockade of the VEGF and HER2 pathways resulted in greater growth inhibition of HER2-positive BC xenografts than either of the agents alone.55

A preliminary phase 2 study has assessed the pCR rate of the VEGF inhibitor bevacizumab (5 mg/kg weekly for 23 weeks) administered with trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) and nanoparticle albumin-bound (NAB)-paclitaxel (6 cycles of 100 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) plus carboplatin in patients with HER2-positive BC before surgery.41 After surgery, patients received 1 year of maintenance therapy with bevacizumab (15 mg/kg every 3 weeks) and trastuzumab (6 mg/kg every 3 weeks). Patients underwent surgery no sooner than 4 weeks after the last dose of bevacizumab, and bevacizumab maintenance therapy was resumed no sooner than 4 weeks postsurgery, provided that postsurgical healing was adequate. A pCR was observed in 10 of 15 patients (67%) who received bevacizumab in combination with trastuzumab plus NAB-paclitaxel and carboplatin. LVEF reductions were reported in 2 patients, 1 of whom had an abnormal LVEF at baseline. Grade 3 or 4 neutropenia was reported in 39% of patients. Neutropenia was treated with either erythropoietic stimulation therapy or myeloid growth factors.

Results from 5 additional phase 2 trials of trastuzumab-containing therapy in the neoadjuvant setting were reported at the 2008 San Antonio Breast Cancer Symposium meeting, each using a different regimen. Masuda et al reported a pCR rate of 55.8% in patients who had received 4 cycles of FEC followed by 12 cycles of weekly paclitaxel plus trastuzumab. Grade 3 and 4 neutropenia was observed in 35% of patients, and the incidence of febrile neutropenia was 12%.

Chia et al29 reported a 60% pCR rate with a low incidence of CD (n = 3) in patients who received 4 cycles of FEC followed by 4 cycles of docetaxel, carboplatin, and trastuzumab (TCH). Similar results were reported with a TCH-based regimen after doxorubicin plus cyclophosphamide.56, 57

In a single-arm study (N = 53), Ro et al58 used a 6-cycle regimen of paclitaxel, gemcitabine, and trastuzumab and reported a 58.5% pCR rate in both tumors and lymph nodes, a 69.8% pCR rate in primary tumors, and a 73.6% pCR rate in axillary lymph nodes. The only grade 3 or 4 AEs that occurred in more than 1 patient were grade 3 leukopenia (22.7%), grade 3 and 4 neutropenia (43.4% and 9.4%, respectively), and grade 3 alanine aminotransferase elevation (7.5%). No patients developed CHF, and 5 patients had a decrease >10% in LVEF after neoadjuvant therapy; 4 of those patients had improved LV function on follow-up.58

In a prospective, open-label, multicenter, nonrandomized study (N = 103 patients), Wildiers et al30 demonstrated an increased pCR rate for patients who received 6 cycles of capecitabine, docetaxel, and trastuzumab every 3 weeks (48%) compared with patients who received capecitabine and docetaxel alone (19%). The most commonly occurring grade 3 or 4 AEs across the whole study population were diarrhea (22%), hand-foot syndrome (16%), anorexia (14%), vomiting (10%), stomatitis (7.5%), febrile neutropenia (7.5%), and nausea (6%). The authors concluded that the regimens were active and that most AEs were mild or moderate and manageable with dose modification.30

Paz et al42 assessed the efficacy and safety of doxorubicin, cyclophosphamide, and trastuzumab followed by carboplatin and NAB-paclitaxel using 3 different regimens. Patients in Arm A received 6 cycles of docetaxel, doxorubicin, and cyclophosphamide every 3 weeks; patients in Arm B received 4 cycles of doxorubicin and cyclophosphamide every 2 weeks followed by carboplatin plus NAB-paclitaxel; and patients in Arm C received the same regimen as Arm B with the addition of trastuzumab initiated with carboplatin and NAB-paclitaxel. A pCR was achieved in 6 of 15 patients (40%). The addition of trastuzumab to chemotherapy had no major effect on the incidence of neutropenia. Grade 2 through 4 neutropenia was reported in 77.8% of patients in Arm A, 61.1% of patients in Arm B, and 53.3% of patients in Arm C.

Neoadjuvant Trastuzumab in Clinical Trials: Efficacy Summary

All 3 phase 3 trials demonstrated a significant improvement in pCR with the addition of trastuzumab to neoadjuvant chemotherapy. Reported pCR rates with trastuzumab plus chemotherapy ranged from 31.7%40 to 65.2%.31 These differences were expected, because the tumor staging and regimens used, as well as the durations of the neoadjuvant regimens, varied among all reported studies. Nonetheless, the addition of trastuzumab to chemotherapy in patients with HER2-positive disease nearly doubled46 or more than doubled the pCR31, 40 rate compared with the rate achieved in patients who did not receive neoadjuvant trastuzumab. Improvements in DFS,31 OS, and EFS46 also have been reported. The only phase 3 trial that reported the effect of neoadjuvant trastuzumab on the type of surgical intervention indicated similar BCT rates (52.6% vs 56.5%) for patients who received neoadjuvant trastuzumab compared with neoadjuvant chemotherapy, respectively.23

The phase 2 trials demonstrated the efficacy of a wide variety of trastuzumab-containing regimens in the neoadjuvant setting, with pCR rates ranging from 40% to 69.8% (unpublished data).58 In 1 trial, a switch was observed in surgical treatment from mastectomy to BCT48; however, that switch was based on preliminary data for 18 patients and has not been subjected to statistical analysis. The phase 2 data available look promising; however, because of the low numbers of patients enrolled, larger studies are warranted to fully assess the efficacy of neoadjuvant trastuzumab.

Neoadjuvant Trastuzumab in Clinical Trials: Safety Summary

The addition of trastuzumab to neoadjuvant chemotherapy does not appear to compromise the safety profile of primary systemic therapy. Adjuvant trastuzumab may result in the development of clinically manageable LV dysfunction in some patients.59 This has led to the introduction of rules for cardiac monitoring and cessation of therapy.60 CD incidence in patients receiving neoadjuvant trastuzumab ranged from none observed31 to 9.4% experiencing a decrease >10 percentage points in LVEF.58 The H2269s trial reported a low incidence of low-grade CD;—none of the patients who reported a decreased LVEF had a decrease below the normal limit of 55% to 60% (unpublished data). In general, the use of neoadjuvant trastuzumab is tolerated well and is not associated with the mild CD that sometimes is reported with trastuzumab.

Ongoing Neoadjuvant Trastuzumab Clinical Trials in HER2-Positive Breast Cancer

The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization Study (or NEO-ALLTO Study) is a global, randomized, open-label, phase 3 study comparing treatment with lapatinib, or trastuzumab, or a combination of both biologic agents in reducing the size of breast tumors before surgery.61 Patients receive biologic therapy for 6 weeks followed by biologics plus paclitaxel for 12 weeks before surgery (Fig. 1, Bottom). The pCR rate is assessed at surgery, and then patients receive 3 cycles of FEC followed by maintenance therapy with biologics for an additional 34 weeks. The primary objective of this study is to evaluate and compare the rate of pCR at the time of surgery among the 3 treatment arms. Secondary objectives include comparisons of safety and tolerability, objective tumor response rates, DFS, OS, conversion to BCT, level of lymph node-negative disease at surgery among the 3 neoadjuvant treatment arms, and the identification of molecular features of responding tumors.

The primary objective of the randomized phase 3 NSABP B-41 trial is the pCR rate in patients with palpable, operable, HER2-positive BC.62 Patients are randomized to 3 arms and receive doxorubicin/cyclophosphamide followed by paclitaxel; and followed by paclitaxel with trastuzumab, lapatinib, or a combination of both biologic agents, as summarized in Figure 1 (Bottom).

The phase 3 American College of Surgeons Oncology Group Z1041 study is assessing the combination of paclitaxel and trastuzumab for treating women with palpable, operable BC.63 It will compare the pCR rate in patients who receive neoadjuvant FEC followed by paclitaxel and trastuzumab or paclitaxel with trastuzumab followed by FEC plus trastuzumab (Fig. 1, Bottom).

Neoadjuvant Trastuzumab: Implications for Surgeons

A good grounding in the biology and clinical implications of HER2-positive BC and how best to treat this disease with HER2-directed agents is essential for surgeons. Attaining an optimal outcome with neoadjuvant therapy requires a well coordinated multidisciplinary treatment team. Surgeons play an important role in ensuring that patients with HER2-positive BC are identified correctly and treated appropriately so they can obtain maximal benefit from trastuzumab therapy in the neoadjuvant setting. It is essential to assess tumors pathologically both before the initiation of neoadjuvant therapy and at the time of surgery.21

Surgical decision making may be affected by an increase in the use of neoadjuvant trastuzumab. The number of women who are converted from mastectomy to BCT potentially could increase as a result of the improved pCR rate associated with neoadjuvant trastuzumab, and margins could be secured better during the initial lumpectomy procedure, producing a better cosmetic outcome. If the patient is not a candidate for postoperative chemotherapy, then neoadjuvant treatment also would be contraindicated. If no clinical evidence of disease is detectable before surgery, then it is particularly important to properly mark the tumor bed using image-guided clip placement to ensure that the appropriate area is resected.

Accurate axillary staging information is required to determine whether irradiation of the axilla and supraclavicular lymph nodes is appropriate. The use of neoadjuvant therapy can downstage lymph nodes,64 leading to the retrieval of fewer lymph nodes from postneoadjuvant axillary lymph node dissection procedures.65 This means that it is necessary to consider the timing of sentinel lymph node biopsy for axillary staging, because the use of neoadjuvant trastuzumab potentially may cause a loss of important staging information.66

Although the current review has concentrated on the use of neoadjuvant trastuzumab in treating LABC, trastuzumab also has the potential to be used in other BC subtypes, including IBC67 and early stage disease, including DCIS. Approximately 60% of patients with DCIS are HER2 positive, and HER2 overexpression is more common in high-grade and comedo-type DCIS, both of which have higher local recurrence rates than low-grade or noncomedo-type DCIS.68 The potential use of neoadjuvant trastuzumab for the treatment of HER2-positive DCIS currently is being investigated in an MDACC-run trial.

In conclusion, it is essential for surgeons who are involved in treating BC to keep updated about the biology and clinical implications of HER2-positive BC and the evolving nature of the clinical benefits of HER2-directed agents. In the patient population with HER2-positive disease, taxane-based and anthracycline-based chemotherapy with concurrent trastuzumab has demonstrated the highest pCR rates when used in the neoadjuvant setting and the best survival benefit when given as adjuvant treatment. The efficacy and safety profiles of neoadjuvant trastuzumab currently are being explored in clinical trials, and further studies will contribute to determining the full clinical benefits of neoadjuvant therapy with trastuzumab.


Financial support was received from Genentech, Inc. and Sanofi-Aventis. Support for third-party writing assistance for this article was provided by Genentech, Inc.