Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer

comprehensive review Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer Mohammad Jahanzeb Abstract HER2 is overexpressed or gene amplified in 20%-25% of breast cancers. The anti-HER2 monoclonal antibody trastuzumab targets HER2-positive tumors, inhibiting proliferation and inducing cell death via extracellular and intracellular mechanisms. The clinical benefits observed with trastuzumab in the metastatic setting provided the rationale for assessing trastuzumab in the treatment of early breast cancer. Four large phase III adjuvant trials (NSABP B-31, NCCTG N9831, HERA, and BCIRG 006) investigated the efficacy and safety of 1 or 2 years of trastuzumab given in combination with or after standard adjuvant chemotherapy. The addition of 1 year of trastuzumab to adjuvant chemotherapy significantly improved disease-free survival (DFS) by 33%-52% and overall survival by 34%-41% in the 4 trials. The DFS benefits were observed regardless of age, nodal status, hormonal status, or tumor size in all trials. The cumulative incidence of congestive heart failure or cardiac death ranged from 0-0.9% in the control arms and 0-3.8% in the trastuzumab-containing arms. These were below the safety cutoff points set by the individual studies’ independent data monitoring committees, indicating acceptable cardiac safety. Risk factors associated with cardiac dysfunction included baseline left ventricular ejection fraction level, hypertension, and older age. The addition of trastuzumab to adjuvant chemotherapy provides significant survival benefits with a positive benefit/risk ratio. Ongoing and planned trials correlated with basic science will enhance our understanding of HER2-positive disease, leading to treatment optimization and further improvements in patient outcomes. Clinical Breast Cancer, Vol. 8, No. 4, 324-333, 2008; DOI: 10.3816/CBC.2008.n.037 Keywords: Cardiac toxicity, Chromosome 17, c-Myc, Paclitaxel, Topoisomerase IIα

Introduction In the United States, approximately 182,460 women are expected to be diagnosed with breast cancer in 2008,1 and 20%-25% of primary breast cancers will have gene amplification or protein overexpression of HER2.2-4 HER2 gene amplification and protein overexpression are associated with aggressive disease and poor prognosis.3,5 HER2 positivity is also predictive for response to different breast cancer–directed therapies. For example, HER2 gene amplification is correlated with increased benefit from adjuvant anthracycline6-8 and paclitaxel.9 Additionally, HER2 expression or amplification is used to identify patients who might be eligible for treatment with the anti-HER2 antibody trastuzumab.10 Trastuzumab is a monoclonal antibody (MoAb) that specifically targets and binds to the extracellular domain of the HER2 receptor.11 The mechanisms of action of trastuzumab involve both the intracellular and extracellular domains of HER2. When trastuzumab binds Aptium Oncology, Los Angeles, CA Submitted: Dec 27, 2007; Revised: May 16, 2008; Accepted: May 21, 2008 Address for correspondence: Mohammad Jahanzeb, MD, 21020 State Road 7, Boca Raton, FL 33428 Fax: 561-218-6300; e-mail: [email protected]

to the HER2 extracellular domain, this initiates antibody-dependent cell-mediated cytotoxicity coupled with constant HER2 receptor inhibition. Trastuzumab also acts intracellularly to inhibit downstream signal transduction, leading to cell cycle arrest, reduction in angiogenesis, and inhibition of extracellular domain cleavage, resulting in HER2-positive cell stasis and death.11-21 Trastuzumab has been shown to significantly improve clinical benefits for patients with HER2positive breast cancer when used alone or in combination with chemotherapy.22-24 Following assessment in several pivotal trials,10,22-25 trastuzumab was approved by the Food and Drug Administration (FDA) as first-line treatment in combination with paclitaxel and as a single agent for patients who have previously received chemotherapy for metastatic breast cancer (MBC). Since approval, trastuzumab has been used as the foundation of care for > 420,000 patients with HER2-positive breast cancer over the past decade.26 Based on the clinical benefits of trastuzumab observed in HER2positive MBC, several large trials were designed to assess the efficacy and safety of adding trastuzumab to chemotherapy in the adjuvant setting. The results from these trials are available and led to FDA approval of trastuzumab for the adjuvant treatment of HER2positive, node-positive or high-risk node-negative breast cancer. Trastuzumab may be used as part of a treatment regimen with doxorubicin, cyclophosphamide, and paclitaxel or docetaxel, or in com-

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Figure 1 Summary of the Large Adjuvant Trial Designs 1. NSABP B-31 Key Eligibility Criteria: HER2+ (IHC 3+ or FISH+) Node positive Normal LVEF (N = 2130)

2. NCCTG N9831 Key Eligibility Criteria: HER2+ (IHC 3+ or FISH+) Node positive or high-risk node-negative; normal LVEF (N = 3505)

g1

AC (every 3 weeks × 4) P (every 3 weeks × 4 or every week × 12)

g2

AC (every 3 weeks × 4) P (every 3 weeks × 4 or every week × 12) H (every week × 52) h RT

gA

AC (every 3 weeks × 4)

P (every week × 12)

gB

AC (every 3 weeks × 4)

P (every week × 12)

gC

AC (every 3 weeks × 4)

P (every week × 12)

H (every week × 52)

H (every weeks × 52) h RT

3. BCIRG 006 Key Eligibility Criteria: HER2+ (FISH+) Node positive or high-risk node negative; normal LVEF (N = 3222)

gA

AC (every 3 weeks × 4)

gB

AC (every 3 weeks × 4)

D (every week × 4) H (every week × 13)

D (every week × 4) H (every week × 12)

gC Carboplatin + D (every 3 weeks × 6), H (every week × 18)

H (every 3 weeks × 12) h RT

4. HERA Key Eligibility Criteria: HER2+ (IHC 3+ or FISH+) Node positive or high-risk node negative; LVEF q 55% q 4 Cycles per 3 months (Neo)adjuvant CT ± RT (N = 5090)

gA

(Neo)adjuvant CT × 4

gB

(Neo)adjuvant CT × 4

H (every 3 weeks × 52)

gC

(Neo)adjuvant CT × 4

H (every 3 weeks × 104)

Observation only

Treatment plans: AC (60/600 mg/m2); paclitaxel (every week = 80 mg/m2; every 3 weeks = 175 mg/m2); docetaxel (75 mg/m2); carboplatin (area under the curve 6); trastuzumab (every week = 4 mg/kg loading dose, 2 mg/kg thereafter; every 3 weeks = 8 mg/kg loading dose, 6 mg/kg thereafter). Abbreviations: AC = doxorubicin/cyclophosphamide; BCIRG = Breast Cancer International Research Group; CT = chemotherapy; D = docetaxel; FISH = fluorescence in situ hybridization; H = trastuzumab; HERA = Herceptin Adjuvant trial; IHC = immunohistochemistry; LVEF = left ventricular ejection fraction; NCCTG = North Central Cancer Treatment Group; NSABP = National Surgical Adjuvant Breast and Bowel Project; P = paclitaxel; RT = radiation therapy

bination with docetaxel and carboplatin. Alternatively, trastuzumab can be used as a single agent following treatment with multimodality anthracycline-based therapy.10 The aim of this review is to consolidate data from the trastuzumab adjuvant trials and provide insights into current and future treatment and patient management practices.

Overview of the Trastuzumab Adjuvant Trials Four large-scale trials have assessed the efficacy and safety of trastuzumab use in the adjuvant setting: National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial (United States), North Central Cancer Treatment Group (NCCTG) N9831 trial (United States), Herceptin Adjuvant (HERA) trial (ex United States), and Breast Cancer International Research Group (BCIRG) 006 trial (worldwide). In addition, 2 small randomized trials have been conducted, the Finnish Herceptin trial (FinHER) and the PACS-04 trial. To date, findings for all trials have been published with the exception of BCIRG 006 and PACS-04; data for these trials have been reported at recent San Antonio Breast Cancer Symposia.27-29

Patient Eligibility Criteria Eligibility criteria for these trials are summarized in Figure 1. Eligible patients must have had confirmed HER2-positive breast cancer as

assessed by immunohistochemistry (IHC; score IHC 3+) or fluorescence in situ hybridization (FISH). Patients must also have undergone surgical resection for invasive cancer by lumpectomy or mastectomy, and have adequate hematopoietic, hepatic, and renal function, and a cardiac function/left ventricular ejection fraction (LVEF) that met or was above the lower limit of normal (LLN). Each trial had additional specific eligibility criteria. In NSABP B-31, NCCTG N9831, and HERA, patients had to be aged ≥ 18 years with no upper age limit. In BCIRG 006, eligible patients were aged 18 to 70 years. The NSABP B-31 and NCCTG N9831 trials initially recruited patients with only node-positive disease. However, partway through the NCCTG N9831 trial, the study protocol was amended to include patients with high-risk node-negative disease; tumors > 2 cm in diameter and ER/PgR receptor (ER; PgR) positive, or tumors > 1 cm in diameter and ER/PgR negative.30 The HERA and BCIRG 006 trials both included patients with either node-positive or node-negative disease. In the HERA trial, patients with node-negative disease were eligible if tumor size was ≥ 1 cm in diameter. Participants in the HERA trial must also have completed ≥ 4 cycles of predefined adjuvant or neoadjuvant chemotherapy, or both, before randomization.31 The BCIRG 006 trial required that patients with node-negative disease had ≥ 1 of the following: tumor size > 2 cm, ER/PgR–negative histology, histologic and/or nuclear grade 2/3; and/or be aged < 35 years.28

Clinical Breast Cancer August 2008 • 325

Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer Exclusion criteria were similar across the trials. Patients were excluded if they had cardiac dysfunction, classified as having angina pectoris requiring antiangina medication, arrhythmia requiring medication, severe conduction abnormality, clinically significant valve disease, cardiomegaly, left ventricular hypertrophy (NSABP B-31 only),30 poorly controlled hypertension, clinically significant pericardial effusion (NCCTG N9831 only), or a history of myocardial infarction, congestive heart failure (CHF), cardiomyopathy, or coronary artery disease (HERA only).31 The HERA trial also excluded patients with suspicious internal mammary nodes and treatment with cumulative doses of anthracyclines (doxorubicin > 360 mg/m2 or epirubicin > 720 mg/m2). The NSABP B-31, NCCTG N9831, and BCIRG 006 trials all excluded patients who had received previous systemic therapy or radiation therapy for breast cancer.

Trial Endpoints The primary endpoint for all the trials was disease-free survival (DFS). Common secondary endpoints were overall survival (OS) and time to distant recurrence (NSABP B-31, NCCTG N9831, and HERA only).28,30,31 The primary safety objective of NSABP B-31, NCCTG N9831, and HERA was cardiac safety. Additional secondary endpoints for the NSABP B-31 and NCCTG N9831 trials were death from breast cancer, contralateral breast cancer, and other second primary cancers.30 Other BCIRG 006 secondary endpoints were toxicity and pathologic and molecular markers.28

Adjuvant Trial Design Figure 1 shows the trial schemas. The NSABP B-31 trial compared standard doxorubicin and cyclophosphamide (AC) followed by paclitaxel with or without trastuzumab.30 Patients were randomized to 1 of 2 arms. Arm 1 received 60 mg/m2 of doxorubicin and 600 mg/m2 of cyclophosphamide for four 3-week cycles, followed by 175 mg/m2 of paclitaxel for four 3-week cycles. After study commencement, the protocol was amended to allow weekly paclitaxel (80 mg/m2) for 12 weeks. Arm 2 received the same chemotherapy regimen plus trastuzumab starting concomitantly with paclitaxel and administered at a loading dose of 4 mg/kg followed by weekly doses of 2 mg/kg for 51 weeks (total, 52 weeks). In the NCCTG N9831 trial, patients were randomized to 3 arms.30 Arm A received AC (same dosing as previously described) followed by 12 weekly doses of paclitaxel at a dose of 80 mg/m2. Arm B received AC followed by paclitaxel and sequential trastuzumab therapy for 52 weeks. Standard trastuzumab dosing was given, as previous described. Arm C received AC followed by paclitaxel and concomitant trastuzumab. Both the NSABP B-31 and NCCTG N9831 trials contain arms that received identical AC followed by paclitaxel regimens (arms 1 and A) and AC followed by paclitaxel with concomitant trastuzumab regimens (arms 2 and C). Therefore, an amendment to the NSABP B-31 and NCCTG N9831 protocols approved by the National Cancer Institute and the FDA allowed efficacy data from these trials to be combined in a joint analysis. In both the NCCTG N9831 and NSABP B-31 trials, patients treated by lumpectomy received radiation therapy, as appropriate. Radiation therapy was initiated after the completion of chemotherapy and was concomitant with trastuzumab treatment in the

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relevant arms of the study. Women with ER/PgR–positive tumors received tamoxifen (20 mg per day for 5 years) after chemotherapy or an aromatase inhibitor, as appropriate.30 In the HERA study, patients who had previously received predefined neoadjuvant or adjuvant chemotherapy (for a minimum of 4 cycles or 4 months) with or without radiation therapy were randomized to 1 of 3 arms.31 Patients in arm 1 were under observation only. Treatment arms received an 8 mg/kg loading dose of trastuzumab, followed by 6 mg/kg trastuzumab in 3-week cycles for 1 year (arm 2) or 2 years (arm 3).31,32 In the BCIRG 006 study, patients were randomized to 3 treatment arms.28 Arm A received AC followed by docetaxel (100 mg/m2) for four 3-week cycles. Arm B received the same chemotherapy, and trastuzumab was administered for 1 year, given weekly for 12 weeks in combination with docetaxel, and then every 3 weeks alone after completion of chemotherapy. Arm C was included to assess a nonanthracycline chemotherapy combination because anthracyclines have been associated with an increased risk of cardiac dysfunction in patients receiving trastuzumab and anthracyclines.23,33,34 Arm C was based on the synergy between trastuzumab, carboplatin, and docetaxel observed in a preclinical study.35 This combination has also been shown to be effective in the metastatic setting.36-38 The treatment schedule comprised six 3-week cycles of docetaxel (75 mg/m2) and carboplatin (area under the curve [AUC] 6) with weekly trastuzumab during chemotherapy followed by every-3week dosing for ≤ 1 year. The FinHER trial was a randomized trial designed to compare adjuvant treatment using docetaxel or vinorelbine in patients with early breast cancer with axillary node–positive or high-risk nodenegative early breast cancer.39 Patients were randomized to receive 9 weeks of docetaxel (100 mg/m2 every 3 weeks) or vinorelbine (25 mg/m2 every week). Both groups were then treated with 3 cycles of 5-fluorouracil (5-FU; 600 mg/m2 every 3 weeks), epirubicin (60 mg/m2 every 3 weeks), and cyclophosphamide (600 mg/m2 every 3 weeks; FEC). Patients with HER2-overexpressing tumors (n = 232) were randomized to receive weekly adjuvant trastuzumab treatment for 9 weeks with docetaxel or vinorelbine. The primary endpoint of the study was recurrence-free survival (RFS). The PACS-04 trial compared adjuvant trastuzumab with observation following chemotherapy in patients with axillary node-positive, resected breast cancer.29 Patients were initially randomized to receive 6 cycles of 5-FU (500 mg/m2), epirubicin (500 mg/m2), and cyclophosphamide (100 mg/m2), or epirubicin (75 mg/m2) and docetaxel (75 mg/m2). Patients with HER2-positive disease were then further randomized to receive trastuzumab 6 mg/kg every 3 weeks for 1 year or observation. The primary endpoint of the second randomization was 3-year DFS.

Cardiac Monitoring Previous studies in the metastatic setting indicated that the development of symptomatic cardiac dysfunction (CHF, cardiomyopathy, and decreased LVEF) is associated with trastuzumab in a small proportion of patients. Two key trials investigated trastuzumab alone in the metastatic setting. One of these studies was a preliminary trial of high-dose first-line trastuzumab (N = 114).24 This study found that 2 patients (2%) who received single-agent

Mohammad Jahanzeb Table 1 Summary of Adjuvant Trial Efficacy Data Median Follow-up

Disease-Free Survival, Percent Event Free

Overall Survival

3351

Arm 1/A: AC followed by T (control) Arm 2/C: AC followed by T + H × 52 weeks

2.9 Years

Control arm: 73.1% H arm: 85.9% HR, 0.48 P = 3 × 10–12

Control arm: 89.4% H arm: 92.6% HR, 0.65 P = .0007

3401*

Arm 1: 4 cycles of CT (control); Arm 2: CT followed by H × 52 weeks

23.5 Months

Control arm: 74.3% H arm: 80.6% HR, 0.64 P < .0001

Control arm: 89.7% H arm: 92.4% HR, 0.66 P = .0115

3222

Arm 1: AC followed by Docetaxel (control); Arm 2: AC followed by Docetaxel + H × 52 weeks (AC l Docetaxel/H); Arm 3: Docetaxel + Carboplatin + H (Docetaxel CH)

Number of Patients

Study Design

NSABP B-31 and NCCTG N9831 (Perez et al, 2007; Rastogi et al, 2007) HERA (Smith et al, 2007; Suter et al, 2007)

Trial

BCIRG 006 (Slamon et al, 2006)

36 Months

Control arm: 77% Control arm: 86% AC l Docetaxel/H arm: 83% AC l Docetaxel/H arm: 92% HR, 0.61 HR, 0.59 P < .0001 P = .004 Docetaxel CH arm: 82% Docetaxel CT arm: 91% HR, 0.67 HR, 0.66 P = .0003 P = .017

*Does

not include the 1694 patients enrolled in the 2-year trastuzumab arm. Abbreviations: AC = doxorubicin/cyclophosphamide; BCIRG = Breast Cancer International Research Group; CT = chemotherapy; H = trastuzumab; HERA = Herceptin Adjuvant trial; HR = hazard ratio; NSABP = National Surgical Adjuvant Breast and Bowel Project; NCCTG = North Central Cancer Treatment Group; T = paclitaxel

trastuzumab experienced cardiac dysfunction; both patients had a history of cardiac disease. Another study assessed the efficacy and safety of trastuzumab alone in patients whose disease had progressed after chemotherapy for metastatic disease.22 The incidence of cardiac dysfunction in patients receiving single-agent trastuzumab for MBC was 4.7%; 90% of these patients had received previous anthracyclines, and all patients had ≥ 1 cardiac risk factor. The incidence of cardiac dysfunction appears to be dependent on history of anthracyclines use as shown by an analysis of data from trastuzumab metastatic trials.33 In the large, phase III, MBC disease trial reported by Slamon et al, severe cardiac dysfunction (New York Heart Association criteria) occurred in 16% of patients receiving trastuzumab with AC compared with 2% of patients receiving trastuzumab with paclitaxel.23 Because of the risk of cardiac dysfunction associated with trastuzumab alone and in patients with a history of anthracycline use,33 trastuzumab was not given concomitantly with anthracyclines in the 4 major adjuvant trials. In addition, cardiac function was monitored before, during, and after therapy in all 4 major adjuvant trials. Patients had not been excluded from the MBC trials based on their cardiac history or baseline LVEF because preclinical and early clinical trial data did not indicate that cardiac dysfunction was a potential side effect of trastuzumab. In the NSABP B-31 and NCCTG N9831 trials, LVEF was assessed before entry, after completion of AC chemotherapy, and at 6, 9, and 18 months after randomization by multiple gated acquisition scan (MUGA) or echocardiogram. Trastuzumab would only be initiated if LVEF after AC therapy met or exceeded the LLN and a decrease of < 16 percentage points from baseline. In the HERA trial, cardiac monitoring included assessment of LVEF by MUGA or echocardiogram at baseline and 3, 6, 12, 18, 24, 30, 36, and 60 months after randomization.31 In NSABP B-31, NCCTG N9831, and HERA, a difference of > 4% in the incidence of severe CHF or cardiac death between the trastuzumab-containing arms and the control arms would have led to

a recommendation for termination or modification of the trial by the independent data-monitoring committee (IDMC).

Efficacy of Adjuvant Trastuzumab In all 4 major trials, the addition of trastuzumab to adjuvant chemotherapy for HER2-positive breast cancer significantly improved DFS and OS (Table 1).28,30,31,32,40 In the joint analysis of NSABP B-31 and NCCTG N9831, DFS improved by 52% (hazard ratio [HR], 0.48; P < .0001) at both the interim analysis and at the 4-year followup (HR, 0.48; P = 3 × 10–12), demonstrating a consistent benefit.30,40 The study also revealed that hazard of recurrence peaks at 2 years and is increased in patients whose tumors show a greater nodal involvement, are ER negative, or are large in size.40 In the HERA trial, the addition of trastuzumab improved DFS by 36% (HR, 0.64; P < .0001) compared with chemotherapy alone.32 In BCIRG 006, the addition of trastuzumab to anthracycline-based or nonanthracycline-based chemotherapy improved DFS by 39% (P < .0001) and 33% (P = .0003), respectively. The trial was not statistically designed to compare the trastuzumab-containing treatment arms with each other.28 In the interim joint analysis of NSABP B-31 and NCCTG N9831, there was a trend toward improved OS,30 which became statistically significant at the 4-year follow-up; the addition of trastuzumab to adjuvant chemotherapy improved OS by 35% (HR, 0.65; P = .0007) compared with chemotherapy alone.40 In the HERA trial, an improvement of 34% in OS was observed for the 1-year trastuzumab-containing arm compared with observation only (HR, 66; P = .0115).32 Significant improvements in OS were also observed in the BCIRG 006 trial. The addition of trastuzumab to anthracycline-based or nonanthracycline-based chemotherapy improved OS by 41% (P = .004) and 34% (P = .017), respectively. The DFS benefits of adjuvant trastuzumab were observed regardless of age, nodal status, hormonal status, or tumor size in all trials.28,30,32 In particular, the addition of trastuzumab to

Clinical Breast Cancer August 2008 • 327

Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer adjuvant chemotherapy significantly improved DFS in patients with node-negative HER2-positive breast cancer compared with chemotherapy alone, a 68% improvement for patients receiving AC and trastuzumab (P = .0007) and a 53% improvement for patients receiving docetaxel/carboplatin/trastuzumab (P = .0096) compared with chemotherapy alone.28 In the HERA trial, there was no significant difference in magnitude of DFS improvement between women with node-positive and node-negative disease.32 In the joint analysis of NSABP B-31 and NCCTG N9831, the absolute improvements in DFS were similar for patients with hormone receptor–positive or –negative tumors.40 As a result of findings from the trastuzumab adjuvant trials, the National Comprehensive Cancer Network Guidelines recommend that adjuvant trastuzumab be given to patients with HER2-positive breast cancer, regardless of hormone receptor status or nodal status.41 The results of the joint analysis of NSABP B-31 and NCCTG N9831 are in contrast with the difference in benefit from chemotherapy shown in an analysis of Cancer and Leukemia Group B (CALGB) trials.42 In this analysis, patients with ER-negative tumors were shown to have experienced a greater absolute benefit from chemotherapy than patients with ERpositive tumors. Some effect of ER status on outcomes with trastuzumab might also have been expected based on evidence obtained from preclinical work; studies using human breast cancer cell lines have found the existence of bi-directional cross-talk between the ER and HER2 signaling pathways.43-45 In the NSABP B-31 and NCCTG N9831 adjuvant trials, however, the improvement in DFS was observed regardless of ER status. Correlation of HER2 co-amplified genes with response to trastuzumab has also been investigated. Subgroup analysis of the NSABP B-31 trial revealed that patients with c-Myc proto-oncogene amplification who received trastuzumab experienced improved OS and time to first recurrence compared with those who lacked c-Myc amplification.46 Topoisomerase IIα (Topo2α) is a target for anthracyclines; therefore, the BCIRG 006 trial examined whether co-amplification of the Topo2α gene, which is on chromosome 17, adjacent to HER2, was associated with greater benefit from doxorubicin. Preliminary data (n = 2120) indicated a potential correlation, but subsequent analysis with additional samples (n = 2990) showed no relationship between Topo2α amplification and DFS response for each of the treatment arms.27,28 In the FinHER trial, patients who received docetaxel had a better RFS after 3 years than with vinorelbine (91% vs. 86%; HR for recurrence or death, 0.58; 95% CI, 0.40-0.85; P = .005). There was no difference in OS between the 2 chemotherapy regimens (P = .15); however, docetaxel-based therapy was associated with more adverse events than vinorelbine regimens. In the subgroup of patients with HER2-positive disease, those who received trastuzumab had better 3-year RFS than the control group (89% vs. 78%; HR for recurrence or death, 0.42; 95% CI, 0.21-0.83; P = .01). Trastuzumab was not associated with cardiac failure or decreased LVEF. However, because of the small patient population and the short follow-up, it is difficult to draw conclusions without further data.39 In the PACS-04 trial, patients who received trastuzumab did not have a superior DFS compared with observation alone (80.9% vs. 72.7%; HR, 0.86; 95% CI, 0.61-1.22; P = .41).29 It is important to note, however, that this trial was not sufficiently powered to detect

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this difference. Furthermore, a significant proportion of patients in the intent-to-treat analysis did not receive adequate trastuzumab treatment; 18% of patients received trastuzumab treatment for < 30 weeks. Therefore, treatment decisions regarding trastuzumab should not be made based on the results of this trial.

General Safety of Adjuvant Trastuzumab Trastuzumab was generally well tolerated, and no unexpected adverse events were reported.28,30,32 In the joint analysis of NSABP B-31 and NCCTG N9831, there was little difference between the treatment groups in the incidence of adverse events except for a higher incidence in left ventricular dysfunction in the trastuzumab-containing arms. In the HERA trial, the incidence of grade 3/4 events was higher in patients receiving trastuzumab compared with those under observation alone. In the BCIRG 006 trial, patients on the docetaxel/carboplatin/trastuzumab arm experienced significantly lower incidences of grade 3/4 arthralgia, myalgia, palmar-plantar erythrodysesthesia, stomatitis, vomiting, neutropenia, and leukopenia compared with the anthracycline-containing arms.28

Cardiac Safety In the 4 large trastuzumab adjuvant trials, the difference in cumulative incidence of CHF or death because of cardiac causes was less than the IDMC safety cutoff of 4% in patients receiving trastuzumab-containing treatment compared with non-trastuzumab–containing treatment, indicating acceptable cardiac safety.32,40,47,48 Different CHF criteria were used across the trials, so direct comparisons are difficult to make. In the cardiac safety analysis of the NSABP B-31 trial, the cumulative incidence of CHF or cardiac death at 5 years was 3.8% in patients receiving trastuzumab compared with 0.9% for patients receiving chemotherapy alone.48 This includes patients who remained on medication and were symptomatic > 6 months later.48-50 In the NCCTG N9831 trial, the 3-year cumulative incidence of CHF or cardiac death was 0.3%, 2.8%, and 3.3% in arms A (AC followed by paclitaxel), B (AC followed by sequential paclitaxel and trastuzumab), and C (AC followed by concomitant paclitaxel and trastuzumab), respectively.51 It should be noted that recruitment of patients to arm C of NCCTG N9831 was subject to a temporary suspension because of cardiac toxicity issues. A review by the independent cardiac safety monitoring committee found the incidence of cardiac events in arm C was < 4% higher than in arm A, and accrual to arm C resumed.40 In the HERA trial, CHF (defined as New York Heart Association class III or IV) or death from cardiac causes occurred in 0.6% of patients receiving 1 year of trastuzumab and in none of the patients in the observation group.52 In the BCIRG 006 trial, the incidence of CHF (defined as grade 3 or 4 by the National Cancer Institute Common Toxicity Criteria version 2) was 1.9% for patients receiving AC followed by docetaxel plus trastuzumab; 0.4% for patients receiving trastuzumab, carboplatin, and docetaxel; and 0.4% for patients receiving chemotherapy alone. No cases of cardiac death have been reported.28 The incidence of CHF or cardiac death compared with absolute improvements in DFS or deaths from breast cancer are shown in Figure 2,28,30,32 indicating that the benefit gained from adjuvant trastuzumab outweighs the risk of cardiac toxicity. Potential risk factors for cardiac events included baseline LVEF level, hypertension, and older age, either ≥ 50 years49,50 or ≥ 60 years.40,53

Mohammad Jahanzeb

HER2 Testing Trastuzumab provides significant clinical benefit for patients with HER2-positive breast cancer; therefore, accurate identification of all eligible patients is paramount. HER2 testing should be considered routine practice, and current guidelines recommend that HER2 status is evaluated in all cases of invasive breast cancer.41,57 There are several methodologies used to assess HER2 positivity; the 2 most common are IHC and FISH. Immunohistochemistry is a semiquantitative methodology that evaluates the amount of HER2 protein overexpression and is scored on a scale of IHC 0 (negative) to IHC 3+ (strongly positive). Fluorescence in situ hybridization is a quantitative methodology that determines the ratio of HER2 gene copies and copies of chromosome 17 (CEP17) within a tumor cell nuclei; a ratio > 2 is considered positive. Federal Drug Administration–approved methodologies for HER2 testing in breast cancer by IHC use the HercepTest (Dako; Carpinteria, CA) or Pathway (Ventana Medical Systems; Tucson, AZ) assays. Federal Drug Administration–approved FISH testing using the PathVysion (Abbott Laboratories; Abbott Park, IL) and INFORM (Ventana Medical Systems; Tucson, AZ) assays. To optimize HER2

Figure 2 Disease-Free Survival Absolute Benefit and Incidence of Severe Congestive Heart Failure, Cardiac Death, and Breast Cancer Death in the Four Major Adjuvant Trials A

14 CHF, Control CHF, Trastuzumab DFS, Absolute Benefit

12

Percent

10 8 6 4 2 0

B

NSABP B-31

NCCTG N9831

HERA

BCIRG 006, AC l T

BCIRG 006, TCH

100 Cardiac Deaths Breast Cancer Deaths (Control Arm) Breast Cancer Deaths (Trastuzumab Arm)

80 Number of Deaths

In the HERA trial, patients who experienced trastuzumab-associated cardiac dysfunction had received a higher cumulative dose of doxorubicin or epirubicin, had a lower LVEF at screening, and had a higher body mass index.52 Preliminary biomarker analyses indicate that baseline brain natriuretic peptide (BNP) and troponin and abnormal serial measurements of BNP warrant further investigation as predictors of trastuzumab-related cardiac toxicity.54 In a further trial by Dang and colleagues, the safety of trastuzumab with dose-dense AC followed by docetaxel was investigated in 70 patients with HER2-positive breast cancer.55 In this singlearm feasibility study, 4 cycles of AC 60/600 mg/m2 was given, followed by 4 cycles of paclitaxel 175 mg/m2 with trastuzumab 2 mg/kg weekly for 1 year. After a median follow-up of 28 months, there were no cardiac deaths, and only 1 patient experienced CHF. Although these results are encouraging, caution should be exercised when interpreting the data because of the small sample size. Careful cardiac monitoring and application of stopping rules for trastuzumab are critical to providing maximal benefit with minimal risk for the greatest number of patients. Cardiac monitoring is recommended at regular intervals for all patients while they receive adjuvant trastuzumab, with more stringent monitoring required for patients with symptomatic declines in LVEF. In the future, cardiac monitoring requirements might be modified based on cardiac risk factor assessments. In most cases, cardiac dysfunction that might be attributed to trastuzumab has been medically managed with CHF medication and reversible in some cases, with or without continued CHF therapy, and LVEF levels return to baseline or close to baseline.48,56 In addition, anthracycline-associated cardiac dysfunction is dose related and appears to cause permanent myocardial damage, whereas trastuzumab-associated cardiac dysfunction is not dose related, is reversible in some cases, and does not appear to cause morphologic changes in cardiomyocytes.56 After carefully considering the benefit/risk balance of trastuzumab treatment, the risk of dying from breast cancer far outweighs the risk of dying from a trastuzumab-associated cardiac adverse event in the vast majority of patients (Figure 2).28,30,32

60

40

20 * 0

NSABP B-31/ NCCTG N9831†

* HERA‡

BCIRG 006§

*All cardiac deaths occurred in observational arms. †From Romond et al, 2005. ‡From Smith et al, 2007. §From Slamon et al, 2006. Abbreviations: BCIRG = Breast Cancer International Research Group; CHF = congestive heart failure; DFS = disease-free survival; HERA = Herceptin Adjuvant trial; NCCTG = North Central Cancer Treatment Group; NSABP = National Surgical Adjuvant Breast and Bowel Project; PFS = progression-free survival; TCH = docetaxel/carboplatin/trastuzumab

testing, it is recommended that accredited/high-volume laboratories are used to alleviate problems with accuracy, reproducibility, and concordance because of interassay variation, reported in low-volume laboratories.41,57,58 The importance of accurate HER2 testing, and the optimal procedures and processes for achieving this, were recently reviewed by Hicks and Kulkarni.59 New guidelines recently published by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) Joint Task Force recognize a ‘grey zone’ of borderline or equivocal results with both methodologies and has recommended that all IHC 2+ tumors be reflex tested by FISH.57 In addition, IHC 3+ is now defined as staining of > 30% of cells; this was originally > 10%.60 Tumors with a FISH HER2/CEP17 ratio of 1.8:2.2

Clinical Breast Cancer August 2008 • 329

Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer Figure 3 HER2 Testing Algorithm Breast Cancer Sample

Does the Laboratory Meet HER2 Testing Quality Assurance Standards?

No

Send to Validated Laboratory

Yes

Test HER2 Status by IHC or FISH

IHC Testing

IHC 3+ Uniform, intense staining in > 30% of cells

IHC 2+ Nonuniform, or weak staining in > 10% of cells

FISH Testing

IHC 0/1+ Weak and incomplete or no staining

Borderline/ Equivocal Result

HER2 Positive

Test by Fish

HER2 Negative

FISH Positive HER2: ch17 ratio > 2.2 HER2 Gene copy number

Borderline/ Equivocal Result HER2: ch17 ratio 1.8:2.2 HER2 gene copy number 4-6 per cell

FISH Negative HER2: ch17 ratio < 1.8 HER2 gene copy number < 4 per cell

Count Extra Cells

Restart by FISH

Test by IHC

HER2 Positive

HER2 Negative

Abbreviations: ch17 = chromosome 17; FISH = fluorescence in situ hybridization; IHC = immunohistochemistry

should be reflex tested by IHC or the FISH assay repeated. The algorithms for HER2 testing by IHC and FISH are summarized in Figure 3. Other methods for HER2 testing include chromogenic in situ hybridization and measurement of levels of cleaved HER2 extracellular domain in the circulation. In the trastuzumab prescribing information, however, only IHC and FISH are currently recommended by ASCO/CAP.57 A retrospective analysis of HER2 expression levels and amplification in tumors of patients participating in the NSABP B-31 trial suggested that the definition of HER2 positivity in the adjuvant setting might need to be modified.61 A consistent benefit from trastuzumab was observed in all subsets of patients defined by IHC (IHC 0 to 3+) or FISH (positive or negative). No statistical interaction was found between DFS benefit from trastuzumab and the levels of HER2 protein expression (P = .26) or HER2 gene copy number (P = .60). Similar findings were reported in the NCCTG N9831 trial; both groups reported a HR of 0.5 for the addition of trastuzumab to adjuvant chemotherapy for patients with HER2-negative tumors testing centrally by both IHC and FISH,40,61 although it should be pointed out that all of these patients had tumors deemed HER2 positive by a laboratory before entering the trial. At the present time, the use of trastuzumab for patients with tumors that do not meet current criteria for HER2 positivity is not recommended, pending the availability

330 • Clinical Breast Cancer

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of clinical trial data that assess the benefits and risks of trastuzumab therapy in this population. Positive results could increase the range of patients for whom trastuzumab is an appropriate therapy.

Remaining Questions and Future Directions The addition of trastuzumab to adjuvant therapy is perhaps the greatest therapeutic advance in several decades for patients with HER2-positive breast cancer. The pivotal adjuvant trials have shown that the addition of trastuzumab to adjuvant chemotherapy significantly improves DFS and OS for patients with HER2-positive breast cancer. A number of questions surrounding optimization of trastuzumab-based adjuvant chemotherapy remain. What is the optimal duration of trastuzumab treatment? Current data support the use of adjuvant trastuzumab for 1 year, and this is supported by current treatment guidelines.41,62 The efficacy of a longer duration of trastuzumab therapy will be revealed with the much-awaited data from the 2-year arm of the HERA trial. The FinHER data are interesting and add to the debate, but additional trials of shorterduration trastuzumab are needed before regimens of < 52 weeks can be recommended. A French phase III trial will examine the efficacy of adjuvant trastuzumab administered for 6 months or 1 year and is currently enrolling patients. The 1-year treatment duration has been

Mohammad Jahanzeb Figure 4 Study Schema for the ALTTO Trial Trastuzumab for 52 weeks (every 3 weeks without Paclitaxel, every week with concurrent weekly Paclitaxel)* Key Eligibility Criteria: • HER2+ (IHC 3+ or FISH+) • Node positive or node negative (tumor q 1 cm) • No previous anti-HER2 therapy

Surgery and completion of q 4 cycles of (neo)adjuvant anthracycline-based chemotherapy

Lapatinib orally daily for 52 weeks* Trastuzumab for 12 weeks

Wash out for 6 weeks

Lapatinib orally daily for 34 weeks

Trastuzumab + Lapatinib for 52 weeks*

*ALTTO

has 2 designs: design 1, no concurrent paclitaxel; design 2, concurrent paclitaxel for 12 weeks. Abbreviations: ALTTO = Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Study; FISH = fluorescence in situ hybridization; IHC = immunohistochemistry

shown to be cost-effective in several studies when compared with the cost of other widely accepted oncology products.63-65 A longer duration of trastuzumab will increase treatment costs, and further cost-effectiveness analyses will be required. While trastuzumab remains an extremely effective therapy for treating patients with HER2-positive breast cancer, a subpopulation of patients do experience disease progression.66,67 Disease progression while receiving trastuzumab is thought to occur via many mechanisms, including increased signaling from other receptor tyrosine kinase (TK) cascades.68 However, trastuzumab has been shown to be effective in multiple lines of therapy, demonstrating that “escape” or resistance is not absolute. Objective responses of ≤ 50% have been reported in second-line therapy, and responses have been observed in ≤ 4 lines of consecutive trastuzumab-based therapy.69-73 Several prospective trials have been initiated to examine treatment with multiple lines of trastuzumab and include THOR (Trastuzumab Halted or Retained), PANDORA, GBG (German Breast Group)–26, and GEICAM (Spanish Breast Cancer Research). These will investigate the efficacy and safety of chemotherapy plus trastuzumab in patients with HER2-positive MBC that has progressed on first-line trastuzumab plus chemotherapy. Preliminary results for 112 evaluable patients in the GBG-26 trial have been presented.74 The addition of trastuzumab to capecitabine resulted in a longer progression-free survival compared with capecitabine alone (8.5 months vs. 5.6 months) and OS (20.3 months vs. 19.9 months). Furthermore, the clinical benefit rate was also greater in the combination arm compared with the capecitabine-only arm (84% vs. 73.7%). HER2 overexpression has also been linked with resistance to certain chemotherapy regimens5,75 or endocrine therapies.76,77 Patients with HER2-positive breast cancer treated with trastuzumab have been shown to have increased incidence of brain metastases.78 However, this is not considered a direct effect of trastuzumab therapy and is more likely associated with longer survival times based on systemic disease control.79-81 Indeed, patients with HER2-overexpressing tumors and brain metastases who received trastuzumab had a significantly longer OS (approximately 2-fold; P = .0002) compared with patients who did not receive trastuzumab.82 Optimizing treatment regimens and providing additional options for patients are under investigation. Because trastuzumab given

concurrently or after chemotherapy in adjuvant settings has a similar effect on efficacy and safety (Table 1),28,32,40,48,52 are there any other benefits from differing regimens? Will nonanthracycline-containing regimens provide an option for patients with cardiac risk factors? Additional therapies are being added to and compared with the current trastuzumab-containing adjuvant regimens to investigate the potential clinical benefit of using multiple therapeutic agents that target common signaling cascades. Lapatinib is a small-molecule TK inhibitor (TKI) that targets both HER1 and HER2. It is indicated, in combination with capecitabine, for the treatment of patients with advanced or MBC whose tumors overexpress HER2 and who have received previous therapy including an anthracycline, a taxane, and trastuzumab.83 In the pivotal lapatinib trial, the addition of lapatinib to capecitabine was compared with capecitabine alone in patients with HER2-positive MBC who had progressed after trastuzumab-based treatment.84 The combination regimen significantly improved time to progression compared with capecitabine therapy alone (HR, 0.49; 95% CI, 0.34-0.71; P < .001). Trials that will study the use of lapatinib with trastuzumab include the BETH (Bevacizumab and Trastuzumab Adjuvant Therapy) and ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Study) trials. The large, multicenter, phase III ALTTO trial compares the efficacy and safety of trastuzumab alone, lapatinib alone, trastuzumab followed by lapatinib, or trastuzumab plus lapatinib, all given after anthracycline-based chemotherapy (Figure 4). The BETH trial will compare chemotherapy (docetaxel/carboplatin) combined with trastuzumab, with or without the vascular endothelial growth factor inhibitor bevacizumab, in patients with node-positive or high-risk node-negative HER2-positive breast cancer. Other novel MoAb therapies that target common signaling cascades include the HER2 dimerization inhibitor pertuzumab, and T-DM1 (Genentech, Inc.), a trastuzumab antibody conjugated to a potent antimicrotubule agent, DM1. The addition of pertuzumab to trastuzumab and docetaxel combination therapy for the treatment of patients with MBC is currently being studied in a phase III trial CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), and a neoadjuvant trial of pertuzumab and trastuzumab combination therapy is also planned. A number of other TKIs that reversibly or irreversibly inhibit HER1 and/or HER2 are in the early stages

Clinical Breast Cancer August 2008 • 331

Adjuvant Trastuzumab Therapy for HER2-Positive Breast Cancer of clinical development, such as neratinib (Wyeth), BIBW 2992 (Boehringer Ingelheim), and ARRY-534 (Array BioPharma, Inc). In addition to the data published by Paik and colleagues in 2008,61 further provocative data presented at a recent ASCO annual meeting have fuelled the debate regarding the selection of patients most likely to respond to trastuzumab. The CALGB 150002 companion study to CALGB 9840 examined the relationship of polysomy chromosome 17 with response to paclitaxel with or without trastuzumab in patients with HER2-negative or HER2positive breast cancer.85 An improvement in tumor response was observed in patients with HER2-negative tumors with chromosome 17 polysomy receiving paclitaxel plus trastuzumab compared with paclitaxel alone. This study suggests that there might be a subpopulation of patients with traditionally HER2-negative breast cancer who in fact display low-level HER2 amplification and benefit from trastuzumab-based therapies. This possibility was also raised in a retrospective analysis of NCCTG N9831 data; however, a relationship between polysomy 17 and trastuzumab benefit in patients with HER2-negative tumors was not supported.86 Over the past 2 decades, trastuzumab has transformed the treatment of both early and advanced HER2-positive breast cancer. As we individualize therapies using more sophisticated techniques for patient selection and enhance the efficacy of therapies by combining novel approaches, we will make bigger strides toward improving the therapeutic index of treatments, thereby curing more patients and minimizing toxicity. Ongoing and planned trials correlated with basic science will enhance our understanding of HER2-positive disease, leading to treatment optimization and further improvements in patient outcomes.

Acknowledgement Support for third-party writing assistance for this manuscript was provided by Genentech, Inc.

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