Herceptin and breast cancer: An overview for surgeons

Surgical Oncology (2010) 19, e11ee21

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/suronc

REVIEW

Herceptin and breast cancer: An overview for surgeons N. Patani a, K. Mokbel a,b,* a b

The London Breast Institute, The Princess Grace Hospital, London, England, UK St. George’s University, London, England, UK

Accepted 25 November 2008

KEYWORDS Breast cancer; Herceptin; Trastuzumab; Morbidity; Mortality; Recurrence; Evidence

Abstract Introduction: HER-2 over-expression is implicated in the pathogenesis of breast cancer and represents a key marker and determinant of patient outcome. Trastuzumab/Herceptin (TZ) is a recombinant humanised monoclonal antibody which targets HER-2. Introduction into clinical practice has significantly improved the natural history of HER-2 over-expressing tumors and has altered the standard of care for these women. This article reviews the established and emerging roles of TZ in the management of breast cancer (BC). Methods: Literature review facilitated by Medline and PubMed databases. Findings: The clinical utility of TZ was first established in the management of HER-2 over-expressing metastatic breast cancer (MBC), with improvements recognised in both the quality and quantity of life. Prospective randomized controlled trials have consistently demonstrated the efficacy of TZ for early breast cancer (EBC) in the adjuvant setting with significant improvements in disease free and overall survival. Emerging roles for TZ include neo-adjuvant therapy and the treatment of progressive disease. TZ is well tolerated and safe, however, associated cardiac dysfunction remains a significant clinical concern. Conclusion: HER-2 status is critically important in the management algorithm for BC and should be determined in all cases. Quality assurance of laboratory testing is of paramount importance. TZ has an established role in the management of HER-2 positive MBC and EBC in conjunction with conventional chemotherapy. Appropriate patient selection and monitoring for cardiac dysfunction are required. ª 2008 Published by Elsevier Ltd.

* Corresponding author. London Breast Institute, The Princess Grace Hospital, 45 Nottingham Place, London W1U 5NY, UK. Tel.: þ44 (0)207 908 2040; fax: þ44 (0)207 908 2275. E-mail address: [email protected] (K. Mokbel). 0960-7404/$ - see front matter ª 2008 Published by Elsevier Ltd. doi:10.1016/j.suronc.2008.11.001

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N. Patani, K. Mokbel

Contents Introduction and background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e12 Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e13 Indications for Trastzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e13 Management of advanced breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e13 Management of early breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e13 NSABP B-31 and NCCTG N9831 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e13 HERA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 BCIRG 006 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 FinHer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 Trial meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 Neo-adjuvant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 Management of progressive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e14 Safety considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e15 Testing for HER-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e15 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e16 Conclusions and recommendations for clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e17 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e18

Introduction and background Rational drug design has been associated with several triumphs in the context of breast cancer (BC) management. Advances in molecular biology continue to enable the identification of novel cancer associated structures. In addition to providing valuable mechanistic insights, such features allow biological sub-typing for purposes of prognostication and risk stratification. Furthermore, some offer potential as therapeutic targets and hence can impact upon decisions regarding clinical management. The human epidermal growth factor receptor 2 (HER-2) belongs to a family of receptor tyrosine kinases [1]. Normally, a single copy of the HER-2 gene, also known as HER-2/neu or c-erbB2, is present on the long arm of each chromosome 17. The protein product is a 185-kD trans-membrane receptor for growth factors, important for physiological cellular proliferation and differentiation. Ligand binding results in homoand/or hetero-dimerisation, activation of the intra-cellular kinase domain and subsequent downstream signaling. Amplification of the HER-2 gene and consequent overexpression of the cell-surface receptor have been implicated in the pathogenesis of BC [2,3]. Gene amplification and receptor over-expression occur in approximately onequarter of BCs and represent a key marker and determinant of prognosis [4]. The magnitude of over-expression can be 50e100 that of normal cells and can result in ligand-independent activation of the receptor [2,3]. Several adverse pathological prognostic factors are associated with overexpression including: high proliferative index, poor differentiation, high grade, tumour angiogenesis and micro-vessel density, large size and lymph node involvement [5e8]. Clinically, aberrant HER-2 expression translates into a more aggressive phenotype, increased metastatic potential, relative resistance to conventional therapeutics, poor prognosis, reduced disease free survival (DFS) and overall survival (OS) [4].

In the early 1990s, several monoclonal antibodies were developed to target the extracellular domain (ECD) of the HER-2 receptor with high specificity and affinity [9]. The success of this approach heralded a paradigm shift in our interpretation of HER-2 positivity, away from prognostic disadvantage towards the potential for targeted therapeutic intervention. Trastuzumab (TZ) (Herceptin, Genentech Inc., San Francisco, California, USA) represents a recombinant humanised version of such a monoclonal antibody, where the antigen binding region has been attached to human IgG1 in order to minimise immunogenicity [10,11]. The mechanism of action is not completely understood, however, multiple biological processes are likely to be involved: TZ binding to the ECD results in HER-2 receptor inhibition, antibody-dependent cellular cytotoxicity (ADCC), impairment of downstream signal transduction, cell cycle arrest, inhibition of metalloproteinase associated ECD cleavage, down regulation of cell surface HER-2 via enhanced endocytosis, sensitization to chemotherapeutics, induction of apoptosis and inhibition of angiogenesis [12e28]. The latter is supported by in-vitro studies of human breast cancer cell lines, demonstrating HER-2 regulation of the endothelial growth factor angiopoietin-2 (Ang-2), which is expressed at sites of vascular remodeling. Furthermore, treatment with TZ has been found to diminish HER-2 associated up-regulation of Ang-2 [29]. HER-2 expression has also been demonstrated to modulate the equilibrium between pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) and anti-angiogenic factors, including thrombospondin-1 (TSP-1), in favour of angiogenesis, whereas HER-2 inhibition with TZ has the reverse effect. The anti-angiogenic effect of TZ has also been confirmed in-vivo by analysis of micro-vessel density and tumour growth in xenograft models. As the molecular mechanisms underlying these distinct pathways are further elucidated there are implications for the potentiation of anti-HER-2

Herceptin and breast cancer therapy and opportunities for novel anti-angiogenic strategies [30]. Although TZ can potentially down-regulate some angiogenic factors, there is no evidence that it increases the incidence of surgical complications related to bleeding or thrombosis. In clinical practice, the anti-angiogenesis effect may selectively target angiogenesis within tumour vasculature. As the mechanism of action is further elucidated, insights into mechanisms of resistance are also being uncovered [25,26,31e33]. The introduction of TZ into clinical practice has significantly improved the natural history of HER-2 overexpressing BC and has altered the standard of care for these women. This article provides an overview of the established and emerging roles of TZ in the management of BC. Efficacy and safety profiles are examined in the context of clinical evidence for metastatic breast cancer (MBC), early breast cancer (EBC), neo-adjuvant therapy and progressive disease (PD). Particular reference is made to the determination of HER-2 status by laboratory testing and current controversies are discussed.

Search strategy and selection criteria Articles were identified by searches of MEDLINE and PubMed up to September 2008 using the terms: ‘‘breast cancer’’ and ‘‘trastuzumab’’ or ‘‘herceptin’’ and ‘‘evidence’’ or ‘‘prognosis’’ or ‘‘morbidity’’ or ‘‘mortality’’ or ‘‘survival’’ or ‘‘recurrence’’. Studies identified were screened for those that focused on the role of TZ in the management of BC. All randomized controlled trials and large retrospective series were included. The reference articles in this review were selected to provide a balanced and representative overview of a complex subject with an extensive base of published work.

Indications for Trastzumab Management of advanced breast cancer Patients with MBC were the first group to benefit from the introduction of TZ into clinical practice. The goals of treatment are primarily those of symptom management and increased survival. TZ was first approved in 1998 by the U.S. Food and Drug Administration (FDA) for the treatment of HER-2-positive MBC, either in the first-line setting in combination with paclitaxel, or as monotherapy for patients who had received at least one prior chemotherapy regimen. TZ is now predominantly used in combination with chemotherapy in the first-line setting due to its clear advantage in improving clinical outcome. Phase III clinical trials have evaluated the addition of TZ to chemotherapy in HER-2 over-expressing MBC (N Z 469). Patients receiving chemotherapy, doxorubicin and cyclophosphamide were compared to those receiving single-agent paclitaxel with or without TZ. The addition of TZ resulted in a significantly higher overall response rates (objective response 50% vs. 32%, P < 0.001), with a longer median time to disease progression and an improvement in median OS from 20.3 to 25.1 months (P Z 0.046). Time to disease progression increased from 4.6 to 7.4 months (P < 0.001) and a longer

e13 duration of response (median, 9.1 vs. 6.1 months, P < 0.001) were demonstrated. TZ treated patients had a lower death rate at 1 year (22% vs. 33%, P Z 0.008) and a 20% reduction in the risk of death [34]. Similarly, trials evaluating single-agent docetaxel, with or without TZ, as first-line therapy for MBC also showed a significant improvement in median OS from 22.7 to 31.2 months. Furthermore, patients who went on to receive TZ at progression had a worse survival, compared with those who received the combination initially [35]. Studies have also supported the use of TZ in combination with carboplatin and taxanes for HER-2 over-expressing MBC [36]. Importantly, the addition of TZ to chemotherapy regimes has been associated with a significant improvement in fatigue and improved global quality of life (QOL) [37].

Management of early breast cancer Following on from the efficacy demonstrated in the management of MBC, prospective randomized controlled trials were undertaken to explore the utility of TZ in the adjuvant setting for EBC. EBC can be considered to represent BC which is node-positive or high-risk node-negative, without evidence of locally advanced or distant disease, stages IeIIIA. In the context of the multi-modal treatment of EBC, the goals of adjuvant therapy are curative. The FDA have approved TZ for use in the adjuvant setting as part of a treatment regimen containing doxorubicin, cyclophosphamide and paclitaxel for patients with HER-2-positive, node-positive BC [38] and the National Comprehensive Cancer Network (NCCN) guidelines currently recommend adding 1 year of TZ to standard adjuvant chemotherapy for HER-2-positive BC [39]. Several landmark trials were responsible for establishing the utility of TZ, in conjunction with conventional adjuvant chemotherapy, for HER-2-positive EBC and have changed the standard of care for these women. NSABP B-31 and NCCTG N9831 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 study randomized patients (N Z 2043) into a two groups, a chemotherapy group, receiving cyclophosphamide and doxorubicin followed by paclitaxel, and a TZ group who received additional weekly TZ for 52 weeks [40,41]. The North Central Cancer Treatment Group (NCCTG) N9831 trial randomized patients (N Z 1633) receiving chemotherapy as per the NSABP B-31 study, into three groups: TZ was either not given, given concurrently or given sequentially after the completion of all chemotherapy [40,41]. The joint analysis of these two trials, after a median follow-up of 2.9 years, has demonstrated a significantly improved DFS by 52% in patients receiving TZ compared with chemotherapy alone (hazard ratio (HR) Z 0.48, 95% confidence interval (CI) 0.41e0.57, P < 0.001) [42]. Three-year rate of distant recurrence was 90% vs. 81% (HR Z 0.47), representing a difference in DFS of 11e12%. There was also a significantly longer time to first distant recurrence. Furthermore, preliminary analysis has identified a trend towards improved DFS (36%, P Z 0.0114) for patients receiving concurrent TZ, rather than in a sequential fashion with chemotherapy. In the combined

e14 analysis, OS was significantly increased by 35% at 4 years (P < 0.001, HR Z 0.65, 95% CI 0.51e0.84) [42]. Importantly, improvements were observed in all sub-groups assessed and were not influenced by tumour size, grade, hormone receptor status, tumour histological subtype, or patient age [40,41,43]. HERA In contrast to NSABP B-31 and NCCTG N9831, the Herceptin Adjuvant (HERA) trial, included HER-2-positive patients (N Z 5102) who had already received neo-adjuvant or adjuvant chemotherapy and/or radiotherapy prior to enrolling. The control group consisted of no TZ and was compared to one or two years of adjuvant TZ. At 2 years median follow-up, DFS was significantly improved by 36% (P < 0.001) with TZ [44,45]. Significant improvement in OS (34%, P Z 0.01) was also demonstrated in the TZ-containing arms. Maturation of this study should establish any differences in outcome from an extended (2 years) regimen of TZ. BCIRG 006 TZ has also been evaluated in combination with a nonanthracycline containing chemotherapy regimen. The Breast Cancer International Research Group (BCIRG) 006 trial compared a standard treatment arm of doxorubicin and cyclophosphamide followed by docetaxel, with two TZ-containing regimens. One arm included the above regimen followed by one year of TZ and the other was a non-anthracycline regimen of docetaxel plus carboplatin plus one year of concurrent TZ. This trial randomized 3222 women, of which approximately onethird were node-negative. The addition of TZ reduced the risk of recurrence by 33% (P < 0.001) and 39% (P < 0.001) for non-anthracycline and anthracycline containing adjuvant chemotherapy, respectively [43]. Similarly, improvements in OS were 34% (P Z 0.02) and 41% (P < 0.001). There was no significant difference between the two TZ arms. FinHer The smaller Finland Herceptin (FinHer) trial randomized 232 women with HER-2 positive EBC to receive either docetaxel or vinorelbine with or without a short course (9 weeks) of TZ therapy, followed by combination chemotherapy. After 3 years of follow-up, relapse-free survival was higher (58% improvement) in the TZ arm (89% vs 78%, HR Z 0.42, P Z 0.01) [46]. HER-2-positive patients treated with TZ had a similar DFS at 3 years compared with HER-2negative patients (HR Z 1.09, 95% CI 0.52e2.29, P Z 0.82), whereas untreated HER-2-positive patients faired worse than their HER-2-negative counterparts. The results of this study, in particular the comparable magnitude of benefit achieved, have raised questions regarding the necessity of extended treatment with TZ. Trial meta-analyses Viani et al. [47] have undertaken a meta-analysis of the adjuvant trials and found the overall mortality rate to be decreased for TZ arms (217/4555 Z 6%) compared to the control arms (392/4562 Z 8.5%) (pooled odds ratio (OR) Z 0.52, 95% CI 0.44e0.62, P < 0.00001). The DFS rates were 8.2% (400/4555) and 15.3% (700/4562), respectively

N. Patani, K. Mokbel (OR Z 0.53, 95% CI 0.46e0.60). The metastases rates were different; 6% (276/4555) for TZ patients vs. 10.8% (497/ 4562) for controls (P < 0.00001). Bria et al. [48] have also undertaken a meta-analysis of the same trials and similarly found that when considering patients who had received TZ for 1 year, the DFS was significantly prolonged (Relative Risk (RR) Z 0.63, 95% CI 0.51e0.77, P Z 0.00001), with an absolute difference (AD) of 6%, which translates into a number needed to treat (NNT) of 16. The OS was also significantly prolonged (RR Z 0.66, 95% CI 0.55e0.78, P < 0.00001), with an AD of 1.96%, which translates into a NNT of 51.

Neo-adjuvant therapy Current indications for neo-adjuvant chemotherapy include the management of inflammatory BC, improving the operability of locally advanced BC and down-staging to enable breast conservation or enhance cosmesis. The addition of TZ to neo-adjuvant strategies has been evaluated in a number of phase II trials [49e54]. Buzdar et al. [55] have reported encouraging results from a phase III trial supporting the addition of TZ to neo-adjuvant regimes in patients with HER-2 positive BC. Forty-two patients were randomized to paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without weekly TZ for 24 weeks, prior to surgery. The pathological complete response (PCR) rate for the TZ arm was 65.2% vs. 26.3% for chemotherapy alone. Complete clinical response (by ultrasound and mammography) was 86.9% in the TZ group compared with 47.4% in the chemotherapy-alone group. Gianni et al. [56] have recently reported data from the phase III Neo-Adjuvant Herceptin (NOAH) trial. 228 patients with HER-2-positive locally advanced BC were treated with sequential doxorubicin and paclitaxel followed by paclitaxel, cyclophosphamide, methotrexate, and 5-fluorouracil, with or without concurrent TZ. The PCR rate was significantly better in the TZ arm (43% vs. 23%, P Z 0.002). The benefits were even more apparent in a sub-group with inflammatory BC (55% vs. 19%, P Z 0.004). This subject has recently been reviewed by Lazaridis et al. [57] and further trials are underway to clarify the role of TZ in the neoadjuvant setting.

Management of progressive disease The role of TZ in the management of MBC which continues to progress despite palliative chemotherapy is less well defined. However, data from retrospective and uncontrolled studies on response rate and time to progression (TTP) are available. Patients with MBC enrolled in the H0648g trial, which went on to develop progressive disease despite treatment, were further recruited into the H0659g study and allowed receive TZ. A clinical benefit rate (complete response (CR) þ partial response (PR) þ stable disease) of 32% was seen in patients who had not received prior TZ, compared to 22% in patients who had originally received TZ [10,58]. Von Minckwitz et al. [59] have recently reported outcomes from a phase III trial involving patients with HER-2

Herceptin and breast cancer positive, locally advanced or metastatic disease who progressed during treatment with TZ, with or without adjuvant and/or palliative chemotherapy. Patients (n Z 156) were randomized to capecitabine with or without continuation of TZ. After a median follow-up of 11.8 months, progression free survival was improved in the TZ arm, 8.5 months vs. 5.6 months, however, overall survival remained similar. The authors conclude that beyond progression, the continuation of TZ alongside second line chemotherapy is associated with higher efficacy and similar toxicity [59]. Additional trials are ongoing comparing chemotherapy with or without TZ in patients with progressive disease.

Safety considerations TZ is generally well tolerated by patients and the conventional toxicities associated with the use of cytotoxic agents appear to be less problematic. However, cardiac dysfunction is a significant and clinically important adverse effect [60]. The spectrum extends from left ventricular systolic dysfunction to congestive heart failure (CHF). The mechanisms for this have been postulated to include: modification of anthracycline induced cardiotoxicity, immune-mediated cardiomyocyte injury, interference with HER-2 signaling necessary for cardiac contractility and dependence on HER2 for myocyte survival [61]. Interestingly, TZ-associated cardiac dysfunction is not dose related and often reversible, unlike that seen with anthracyclines [62,63]. The incidence and severity of TZ-associated cardiac dysfunction have been difficult to establish, particularly because the definitions used and cardiac monitoring employed have not been consistent across the clinical trials. The overall incidence of cardiac dysfunction was found to be 27% when TZ was used in combination with anthracyclines (8% with anthracyclines alone), 13% when combined with paclitaxel (1% with paclitaxel alone) and 3e 7% when used as a single agent [34,60,64]. Approximately three-quarters of TZ related cardiac dysfunction was symptomatic and of these, a similar proportion improved with standard treatment. The NSABP and NCCTG trials reported an incidence of CHF and cardiac death of 4.1% and 2.9% in the TZ containing arms, respectively, as compared to 0.8% and 0% in the control arms [40,41]. Perez et al. [65] reported that adjuvant TZ after anthracycline-based chemotherapy leads to a three-year cumulative incidence rate of 2.5e3.5% significant clinical cardiac events. A higher proportion of patients experienced 15% decrease in the left ventricular ejection fraction (LVEF) at any time point in the TZ containing arms when compared with the non-TZ containing arm. Furthermore, approximately 15% of patients randomized to concurrent TZ and paclitaxel, who had a satisfactory cardiac evaluation after doxorubin and cyclophosphamide, had to discontinue TZ due to cardiac adverse events. There appeared to be no correlation between radiation therapy and the risk of cardiac toxicity [65]. Analysis of the HERA trial identified a 4.3% incidence of TZ discontinuation due to cardiac dysfunction. A higher incidence of cardiac dysfunction was reported including: severe CHF (0.6% vs. 0.0%), symptomatic CHF (2.15% vs. 0.12%), confirmed significant LVEF drop (3.04%

e15 vs. 0.53%) and 1 episode of significant LVEF drop (7.03% vs. 2.05%) [66]. Cardiac dysfunction, defined as a decrease in LVEF of 10% or <50% total, was identified in 7.1% of patients receiving TZ for 1 year vs. 2.2% of controls [44]. In their meta-analysis of the adjuvant trials, Viani et al. [47] have found more New York Heart Association (NYHA) grade III or IV cardiac toxicity after TZ (203/4555 Z 4.5%) vs. (86/4562 Z 1.8%). The likelihood of cardiac toxicity was 2.45-fold higher (95% CI 1.89e3.16). Another meta-analysis of the same trials has also confirmed an excess of cardiovascular events. Administration of TZ for 1 year, significantly increased the risk of grade IIIeIV CHF in the TZ arm (RR Z 7.05, 95% CI 3.88e12.83, P < 0.0001), AD Z 1.61%, equivalent to 62 patients being treated to harm one (NNH). Again the incidence of asymptomatic LVEF reduction was found to be greater (RR Z 2.18, 95% CI 1.45e3.27, P < 0.00015) with an AD of 7.20%, which translates into a NNH of 14 [48,67]. The results from all of the trials incorporating one year of TZ into the adjuvant regimen demonstrate a significant increase in the incidence of symptomatic cardiac dysfunction and asymptomatic decreases in LVEF. The difference in cumulative incidence of congestive heart failure is typically 1.5e2.7% (TZ vs. non-TZ arms) [42,43,45,68]. In contrast, results from the FinHer trial which employed only short course TZ (9 weeks) have demonstrated that LVEFs were maintained during the three-year follow-up, again raising questions about the risk-benefit of extended treatment with TZ [46]. For these reasons, baseline LEVF should be established and monitored in all patients. Established risk factors for cardiac dysfunction include age (>50 years), anti-hypertensive medication, LEVF <55% and pre-existing cardiac dysfunction [65,69,70]. The extent of prior therapy with anthracyclines is also likely to be important. Interestingly, amongst patients who have continued to receive TZ, despite the development of CHF, 75% have improved with treatment and 64% had no further decrease in cardiac function [71]. Despite the fact that TZ-associated cardiac dysfunction is usually responsive to medical intervention [62,63], treatment is often discontinued in the adjuvant setting [47]. In contrast, patients with MBC who develop significant LVEF impairment can be adequately managed with beta-blockade and angiotensin-converting enzyme inhibition and continuation of therapy may be appropriate, although decisions should be made on an individual basis after cardiology review [61e63,72].

Testing for HER-2 In view of the potential for targeted therapeutic intervention, both the American Society of Clinical Oncology (ASCO) [73] and the National Comprehensive Cancer Network [39] recommend establishing the HER-2 status in all newly diagnosed women with invasive BC. The methodology employed to determine the HER-2 profile is crucial and has been the subject of much debate. Immunohistochemical (IHC) analysis and fluorescence in-situ hybridization (FISH) are most commonly used to determine HER-2 receptor overexpression and gene amplification, respectively. Both techniques are usually performed on formalin-fixed,

e16 Table 1

N. Patani, K. Mokbel IHC scoring guidelines and interpretation [81,82].

IHC score

Definition

Interpretation

0 1þ

No immunostaining Weak immunostaining, less than 30% of tumour cells Complete membranous staining, either uniform or weak in at least 10% of cells Uniform intense membranous staining in at least 30% of cells

Negative Negative

2þ

3þ

Equivocal

Positive

paraffin wax embedded tissue. HER-2 amplification at the DNA level and over-expression at the protein level usually occur in conjunction with one another. IHC provides an indication of cell-surface receptor expression, subjectively scored in a semi-quantitative manner as 0, 1þ, 2þ, or 3þ on the basis of the extent and location of staining, Table 1. As with other IHC based approaches, factors such as tissue fixation (both type and duration), the choice of antibody, and the threshold for interpretation of positive staining can directly affect the accuracy and reproducibility of the test [74]. Commercial test kits have been developed, for example, HercepTest (DAKO, Carpinteria, California, USA) or Pathway (Ventana, Tucson, Arizona, USA) in order to minimise inter-laboratory variation. FISH involves the use of fluorescent DNA probes to evaluate the copy number of the HER-2 gene within individual cells. It is considered to be the ‘gold-standard’ for predicting responsiveness to TZ [75,76]. Commercially available FISH kits include, PathVysion (Vysis, Downers Grove, Illinois, USA) and INFORM (Ventana, Tucson, Arizona, USA) which express HER-2 gene copy number, either as a ratio to the centromere of chromosome 17 (CEP17) or in terms of gene copies per nucleus, respectively, Table 2. Recently, contemporary techniques including chromogenic in-situ hybridization (CISH), which potentially combine desirable attributes of the existing methods, have been evaluated. False-negative and false-positive results can dramatically influence clinical decision making and have significant implications for patient outcome. False-negative results may lead to patients being denied treatment, whereas false-positives may be exposed to potential side effects and treatment related costs. HER-2 receptor over-expression has been found to be closely correlated with gene amplification in tumors scored as 3þ by IHC, but less well correlated in tumors scored as 2þ. Gene amplification determined by FISH seems to be a better predictor of response than receptor over-expression determined by IHC, Table 2 [81,82].

FISH scoring guidelines and interpretation

FISH ratio Gene copy Interpretation number (per nucleus) <1.8 1.8e2.2 >2.2

<4 4e6 >6

Negative (non-amplified) Equivocal Positive (amplified)

particularly for scores of 2þ to 3þ. Hence, determination of gene amplification has become critical in the management of these tumors [77]. Evidence from trials demonstrates that IHC 3þ or positive FISH results are equally predictive of therapeutic benefit. In contrast, FISH analysis has been found to be more sensitive, specific, reproducible and predictive of therapeutic benefit than IHC in a combined group of IHC 2þ and 3þ [78]. The consensus of opinion is that IHC 2þ should be confirmed by FISH. Trial data also support the benefits of high volume, experienced laboratories with standardization of methodology to improve concordance of results [79]. Two key areas have been identified, the standardization of testing protocols and differences in test interpretation [80]. The American Society for Clinical Oncologists and the College of American Pathologists have produced new guidelines for HER-2 testing [81,82]. These include tissue fixation for between 6 and 48 h, new scoring threshold of 30% strong immunostaining for classification of 3þ, introduction of the term ‘equivocal’ to characterize HER-2 studies that are 2þ by IHC and/or show HER-2/chromosome 17 ratios of between 1.8 and 2.2 by FISH, requirements for laboratories to validate HER-2 assays through cross-testing with another method and participation in HER-2 proficiency testing [74]. Quality assurance and standardization of testing methodology are essential to achieve accurate and reproducible results.

Discussion HER-2 over-expression in BC remains a significant adverse prognostic factor, reflected both in terms of pathological parameters and clinical course. However, with the advent of targeted therapy, such aberrant expression also provides a unique opportunity for therapeutic intervention. The efficacy and safety of TZ, which were largely established in the context of MBC treatment, have been mirrored by equally impressive results in the adjuvant setting. The five principal randomized controlled prospective trials of adjuvant therapy have clearly demonstrated that TZ represents a cornerstone in the management of EBC. In conjunction with conventional adjuvant regimes, the addition of TZ is associated with a statistically significant and clinically relevant impact on both DFS and OS (36e52% and 33e41%, respectively) [6,7]. The absolute improvements in OS associated with adjuvant TZ (w2%) at 2 year of follow-up are already comparable to the 5-year absolute benefit provided by anthracyclines (w3%) and by taxanes (w2%) in the adjuvant setting [48,83]. It is noteworthy that the absolute benefits continue to increase when examining 10and 15-year follow-up data for anthracyclines and taxanes and hence the results for patients receiving adjuvant TZ could similarly improve further with time [67]. The benefit of adjuvant TZ seems to be enjoyed by all patient subgroups assessed and not influenced by conventional prognostic parameters including tumour size, grade, histological subtype, hormone receptor status or patient age [40,41,43]. These observations are likely to reflect the novel and targeted mechanism of action, accompanied by the potential for synergistic and additive effects when combined with other chemotherapeutics.

Herceptin and breast cancer Given this, it is of paramount importance to accurately identify all patients who are eligible for therapy. The targeted nature of TZ carries with it special implications for the selection of patients to be treated. At present, the determination of HER-2 status by IHC is largely subjective and essentially only semi-quantitative. Whilst FISH analysis appears to be more robust, it is likely that formal and objective quantification of HER-2 amplification and/or overexpression in future may enable improved patient selection and further refinement of therapy. For example, it has been recently demonstrated that tumors with chromosome 17 polysomy, which are conventionally defined as HER-2 negative for amplification by the HER-2/CEP17 ratio, may respond to TZ based therapy [84]. Caution is necessary in the interpretation of this data, which is derived from a retrospective study where the total number of patients with polysomy 17, who were also FISH negative, included in the TZ arm was rather small (n Z 19). Additional studies are therefore needed before any change in clinical practice is warranted. However, such factors may have particular relevance in clinical decision making for the management of patients who are approaching HER-2 positivity by the new criteria. Furthermore, although it may seem counter-intuitive, no significant association has been found between HER-2 gene copy number and benefit from adjuvant TZ. In fact, patients with normal gene copy numbers still appear to benefit (RR for DFS Z 0.40, 95% CI 0.18e0.89, P Z 0.026). In keeping with this, patients from the NSABP B-31 trial with BCs defined as HER-2-negative, according to central criteria and subsequently confirmed by mRNA studies, also appear to benefit (RR for DFS Z 0.34, 95% CI 0.14e0.80, P Z 0.014) [85]. Paik et al. [86] in their review of available tumour blocks from the NSABP B-31 trial, performed both the HercepTest (IHC) and PathyVysion (FISH) assays. Approximately 11.5% of cases were noted to be positive by FISH but negative by IHC, and 15.3% of cases were positive by IHC but negative by FISH. Benefit from TZ therapy was observed in patients that were FISH negative and IHC positive (RR Z 0.28, P Z 0.033). These results imply that TZ activity may not be limited to HER-2 amplified disease [85]. The complexity of HER-2 amplification/over-expression has been reviewed by Vanden Bempt et al. [87] who suggest that co-amplification of adjacent genetic material, for example topoisomerase II (which is the principal target for anthracyclines) or c-MYC, may contribute to tumourigenesis and potentially predict response to TZ [88,89]. In keeping with this, HER-2 expression has also been associated with resistance to alkylating agents and hence anthracyclinebased adjuvant therapies could be preferred for these patients [90]. HER-2 could therefore be interpreted as a surrogate marker for topoisomerase IIa (TOP2A), the anthracycline target, which is located adjacent to the HER2 gene on chromosome 17q [91]. Whilst the efficacy of TZ in the management of BC is readily apparent, the decision to treat patients with TZ cannot be made solely on the basis of HER-2 status. Clinical decision making must involve an analysis of all potential risks and benefits. Thus, for example, whilst the potential risk of cardiac dysfunction may be justified in some patients, careful assessment of cardiac reserve and other co-morbidities may demonstrate an unacceptable risk in others. Munshi et al. [92] point out the limitations of the

e17 trial data, in particular the fact that the length of current follow-up may be inadequate for us to fully appreciate the nature of cardiac dysfunction, its potential reversibility and the long-term effects of even treatable congestive heart failure. This has particular relevance as TZ is often combined with other cardiotoxic chemotherapeutics. Furthermore, radiation therapy can perpetuate cardiac injury. The Early Breast Cancer Trialists’ Collaborative Group demonstrated that patients treated by radiotherapy suffered an increased mortality from cardiovascular events. In a meta-analysis involving 19,582 patients, RT reduced the mortality from BC by 13% but increased the annual mortality rate from other causes by 21%, primarily due to an excess number of deaths from cardiovascular causes. Such effects may take 15 years to manifest completely [93e 95]. Hence, we cannot be completely reassured by studies that have not found any increase in cardiac dysfunction in patients receiving concomitant radiotherapy and TZ [96]. In addition to the long-term cardiovascular implications, another issue regarding the safety profile of TZ has become apparent with regard to particular patterns of relapse such as brain metastases (BMs). The disproportionate number of central nervous system (CNS) metastasis identified in the randomized controlled trials has been supported by two meta-analyses of these trials. Bria et al. [48] reported a higher incidence in the TZ arm (RR Z 1.57, 95% CI 1.03e 2.37, P Z 0.033) with an AD of 0.62, which translates into a NNH of 161. Viani et al. [47] also found the likelihood of BM to be 1.82-fold higher (95% CI 1.16e2.85) in patients who received TZ. These findings are supported by those of other authors [97,98]. The reasons for this association remain unclear, however, explanations have included the fact that patients in control arms may succumb to other systemic metastases sooner and more frequently, whereas TZ treated patients tend to live longer which may allow CNS micrometatasis to become apparent. Furthermore, the bloode brain barrier significantly impedes the passage of TZ and hence the CNS may provide a more hospitable milieu [99,100]. TZ represents the first anti-HER-2 strategy to reach the clinic and has certainly provided ‘proof of principle’. HER-2 directed therapy is now evolving into a diverse collection of molecular interventions and other agents have been developed to target the HER-2 receptor, for example, Pertuzumab (Omnitarg, Genentech) which is thought to inhibit HER-2 receptor dimerisation. Recent efforts have employed small molecule tyrosine kinase inhibitors such as Lapatinib (Tykerb, GlaxoSmithKline), Gefitinib (Iressa, AstraZeneca) and Erlotinib (Tarceva, OSI/Genentech) [101]. These are currently the subject of several pre-clinical and clinical studies. Studies evaluating TZ in combination with endocrine therapies and other biological agents are ongoing. Despite, pre-clinical studies suggesting physiologic ‘‘cross-talk’’ between the HER-2 and the ER signal transduction pathways and conflicting clinical trial data suggesting relative resistance to adjuvant endocrine therapy, HER-2 positivity does not appear to result in a hormone-independent phenotype in ER-positive BC [10]. Therefore, at present HER-2 profiles should not be used to make decisions regarding endocrine therapy and selection should remain based on markers such as ER and PR for which there exists an established evidence base [73]. Further trials will be required to establish the optimal timing of TZ initiation, duration of treatment

e18 (although the present recommendation is one year) and the relative value of concurrent/sequential regimes. Furthermore, questions have been raised as to whether there are women in whom chemotherapy can be safely omitted, such as patients with oestrogen receptor (ER) positive and HER-2 positive disease, patients with negative lymph nodes and tumors <1 cm, where adjuvant TZ alone might represent adequate therapy [47].

Conclusions and recommendations for clinical practice With the advent of novel targeted therapeutics, such as TZ, HER-2 status has become critically important in the management algorithm for BC. It is recommended that HER2 status should be determined in all cases of BC. Careful attention should be paid to the quality of testing and results should be confirmed by multiple methods when there is discordance. TZ improves the quality and quantity of life for patients with MBC and should be considered for all HER-2 positive cases. In conjunction with conventional chemotherapy, TZ is now the standard of care for HER-2 positive EBC and leads to clinically significant improvements in DFS and OS in the adjuvant setting. Toxicity includes a relatively small but significant risk of cardiac dysfunction and patient selection and monitoring is required.

Conflict of interest statement

N. Patani, K. Mokbel

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[12] [13]

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None declared. Authors do not disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.

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