Adjuvant trastuzumab therapy for HER2-overexpressing breast cancer: What we know and what we still need to learn

doi:10.1016/j.ejca.2006.04.008

European Journal of Cancer

Volume 42, Issue 12, August 2006, Pages 1715-1719

https://doi.org/10.1016/j.ejca.2006.04.008 Get rights and content

Abstract

With the reporting of five studies with different and complementary designs, but all demonstrating a similar and striking benefit from the targeted drug trastuzumab in HER2-overexpressing breast cancer, the year 2005 has profoundly marked the history of randomised adjuvant breast cancer trials. In view of the halving in recurrence risk, obtained at the real but small risk of cardiotoxicity, these results are generating hope in women affected with this aggressive form of the disease. But at the same time these results pose real challenges to healthcare authorities faced with the high cost of the anti-HER2 monoclonal antibody. These results also leave oncologists and patients to deal with a complex treatment tailoring process that needs to take into account risk of an early relapse as well as the benefit versus risk of trastuzumab according to the different patterns of administration used in the clinical trials.

Introduction

The rational development of trastuzumab, a humanised anti-HER2 monoclonal antibody and the second molecular targeted therapy for breast cancer after tamoxifen, started in 1984 with the identification of the HER2-neu oncogene.¹ This was soon followed by its cloning2, 3 and the demonstration that an anti-HER2 monoclonal antibody is able to inhibit neu transformed cells.⁴ The bench-to-bedside process was initiated in 1987 when the correlation of HER2 amplification with poor prognosis in breast cancer was found;⁵ it received considerable attention in the late 1990s and early 2000 when trastuzumab, given in combination with chemotherapy, was shown to improve survival of metastatic HER2-positive disease,⁶ and it culminated in 2005 by the demonstration that adjuvant trastuzumab – in 5 randomised clinical trials – reduces the risk of recurrence of HER2-positive disease by roughly 50%, a magnitude rarely observed in breast cancer trials.7, 8, 9, 10 These trials are analysed and discussed below.

Section snippets

Published and/or reported adjuvant trastuzumab trials: similarities, differences and design issues

Table 1 summarises the design of the published trials, namely the HERceptin^® Adjuvant (HERA) trial,⁷ the combined North American trials, NSABP-B31 and NCCTG/N9831,⁸ the BCRIG 006 trial⁹ and the Finnish trial.¹⁰

While a total of 13,353 patients were accrued, a substantial number of patients are not included in the current analysis: 1694 patients belonging to the 2-year trastuzumab arm of the HERA trial (the data for which are still accumulating); 842 patients enrolled in the sequential

Patient populations

Table 1 highlights similarities and differences in patient characteristics across the five trials. Similarities include young age (median around 50 years), high proportion of high-grade tumours (60–70%) and planned endocrine therapy in view of positive hormone receptors in roughly 50% of the patients.

Differences relate to the proportion of node-negative disease (very low in the B31/N9831 combined trial and absent in the Finnish trial, while substantial in HERA and BCRIG 006); the use of taxanes

Safety and compliance

With the exception of hypersensitivity, which has been seen mainly and only occasionally with the first infusion, cardiotoxicity (principally congestive heart failure (CHF)) is the most important adverse effect of trastuzumab. Its incidence is around 1.4% in women receiving the drug as single agent.15, 16, 17 Cardiac dysfunction (symptomatic or not) occurs in 13% and 27% percent of patients receiving trastuzumab concomitantly with paclitaxel or anthracyclines, respectively.⁶ For this reason,

Efficacy

The highly reproducible and striking therapeutic benefit of adjuvant trastuzumab is shown in Table 3: 39–52% reductions in the rates of recurrences – all highly statistically significant – are observed in the trials at median follow-up times ranging from 1 year to 36 months. Importantly, these early recurrences are distant in roughly two-thirds of the cases and are essentially incurable. A statistically significant survival benefit is currently seen only in B31/N9831.

Subsets that benefit most from trastuzumab

Trastuzumab does not alter the natural history of all cases of HER2-overexpressing breast cancer: experience with the drug in advanced disease tells us that de novo resistance does exist. Unfortunately, our current knowledge of resistance mechanisms is still limited.¹⁸

Collection of tumour blocks and serum is ongoing in the context of the adjuvant trials. It is hoped that translational research conducted with these samples will help to identify ‘molecular signatures’ of success or failure of

Adjuvant chemotherapy ‘optimisation’ for HER2-positive disease

The magnitude of the trastuzumab’s treatment effect is substantial in all trials and raises the question of whether less aggressive and safer chemotherapy regimens could be developed in the future. A very interesting, although retrospective, analysis carried out by the BCRIG 006 investigators, suggests that co-amplification of the topoisomerase II alpha gene occurs in one-third of HER2-positive patients and may confer a therapeutic advantage to anthracycline-based regimens; HER2-positive

Pending questions related to adjuvant trastuzumab

Numerous questions in connection with adjuvant trastuzumab are pending and point to the tremendous amount of work that still needs to be done in HER2-positive breast cancer. They include: (i) Is there an optimal time to initiate trastuzumab? (ii) Will the strong trastuzumab effect weaken over time? (iii) Can we do as well with less trastuzumab (6 months) or better with more trastuzumab (2 years)? (iv)Who does not benefit from trastuzumab? (v) Is there heterogeneity in the magnitude of

Take-home messages for the clinician

There is level 1 evidence that adjuvant trastuzumab is an effective therapy, the benefit of which exceeds the risks in most patients. Nevertheless, a careful benefit versus risk assessment needs to be done for each individual woman and for each of the strategies studied so far: upfront trastuzumab with carboplatin and docetaxel; 4 cycles of an anthracycline regimen followed by trastuzumab in combination with a taxane; or administration of trastuzumab at completion of chemotherapy.

Finally,

Conflict of interest statement

None declared.

References (20)

F. Cardoso et al.
Resistance to trastuzumab: a necessary evil or a temporary challenge?
Clin Breast Cancer
(2002)
A.L. Schechter et al.
The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen
Nature
(1984)
K. Semba et al.
A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma
Proc Natl Acad Sci USA
(1985)
L. Coussens et al.
Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene
Science
(1985)
J.A. Drebin et al.
Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen
Proc Natl Acad Sci USA
(1986)
D.J. Slamon et al.
Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene
Science
(1987)
D.J. Slamon et al.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
(2001)
M.J. Piccart-Gebhart et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer
N Engl J Med
(2005)
E.H. Romond et al.
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer
N Engl J Med
(2005)
D. Slamon et al.
Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in her2 positive early breast cancer patients: BCIRG 006 study
Breast Cancer Res Treat
(2005)

There are more references available in the full text version of this article.

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We chose the year 2000 as intersection point, as the first targeted therapy against HER2 was available in Europe at this time point [35,36]. Patients have received trastuzumab in the adjuvant setting since 2006 [36–39]. Furthermore, new therapies with pertuzumab and T-DM1 are available [40,41].
Visceral metastasis of breast cancer (BC) is an alarming development and correlates with poor median overall survival. The purpose of this retrospective study is to examine the risk factors for developing visceral metastasis by considering tumor biology and patient characteristics.
Using the BRENDA database, the risk factors such as histological and intrinsic subtypes of BC, age at primary diagnosis, grading, nodal status, tumor size and year of primary diagnosis were examined in univariate and multivariate analysis. Categorical variables were compared by using χ2 tests. Furthermore, multivariate Cox proportional hazards regression models, Kaplan–Meier product-limit method and log-rank test were applied. The results of two tree-building algorithms, “exhausted CHAID” (Chi-squared Automatic Interaction Detector) and CART (Classification and Regression Trees) were verified with further multivariate analysis, radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression.
In a patient collective of 886 metastasized patients, 56.9% had developed visceral metastases and 27.1% visceral-only metastases. The different histological and intrinsic subtypes of BC and the grading correlate significantly with the visceral-only metastasis behavior, whereas the age at primary diagnosis, the nodal status, the tumor size and the year of the primary diagnosis had no influence. Patients with ductal/other BC, LuminalB/HER2, TNBC, HER2 overexpressing subtype and grade 3 had an increased risk for the development of visceral-only metastasis.
Intrinsic and histological subtypes as well as the grading of BC affected significantly the visceral metastasis behavior.
Evaluation of a quantitative RT-PCR assay to detect HER2 mRNA overexpression for diagnosis and selection of trastuzumab therapy in breast cancer tissue samples
2014, Experimental and Molecular Pathology
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Therefore, HER2 positive status is regarded as a prognostic factor indicating worse overall survival of patients (Hurvitz et al., 2013). Patients with HER2 amplification or over-expression are eligible for treatment with Trastuzumab (Herceptin, Roche, Penzberg, Upper Bavaria, Germany), which is a humanized monoclonal antibody directed against the extracellular domain of the HER2 (Piccart-Gebhart, 2006). Herceptin is currently the most widely used therapeutic reagent for treatment of metastatic breast cancer, and when it combined with chemical drugs in adjuvant settings, Herceptin has exhibited an enhanced therapeutic activity (Janssen et al., 2006; Levy et al., 2014).
Breast cancer patients who have a positive result for HER2 overexpression are commonly treated with Herceptin, a HER2-targeted therapy. In the present study, the BrightGen HER2 RT-qDx (Syantra, Calgary, Canada), which is based on a one-tube nested RT-qPCR method that detects HER2 mRNA overexpression, was clinically evaluated in a total of 237 formalin-fixed paraffin-embedded (FFPE) tissue samples from breast cancer patients. Among the 38 HER2 positive samples, which were determined via IHC/FISH methods, 13 samples out of 16 (81.3%) that were IHC2 +/FISH + and 22 samples out of 22 (100%) that were IHC3 + have been decided positive for HER2 expression via the RT-qPCR method. The true positivity and false positivity results for the RT-qPCR were 92% (35/38) and 2% (1/65), respectively. The concordance between RT-qPCR and IHC results and RT-qPCR and IHC/FISH was 87.2% and 92.1%, respectively. Conclusively, the BrightGen HER2 RT-qDx may be a reliable and convenient method that can supplement traditional IHC and FISH methods for efficient use of trastuzumab.
How Advances in Genomics are Changing Patient Care
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Breast tumors are tested for their HER2 status at diagnosis and, before the development of drugs such as trastuzumab, the prognosis for women with HER2-positive tumors was poor. Herceptin is a monoclonal antibody that binds to the HER2 receptor, blocking the receptor to reduce its ability to accelerate division and development of cancer cells.43–45 Therefore, it is prescribed only for the subset of women whose tumors express the HER2 receptor, and is an example of how understanding personalized genetic information about a tumor is already used to inform cancer treatment.
HER2-positive breast cancer: From trastuzumab to innovatory anti-HER2 strategies
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Overexpression of HER2 is encountered in approximately 20% of invasive breast cancers. It is an independent adverse prognostic factor and, more importantly, it is currently the best predictive factor for the activity of trastuzumab, an anti-HER2 monoclonal antibody (MoAb), which has revolutionized the treatment of this breast cancer subgroup. Increasing knowledge of molecular pathways involving the HER faily of growth factor receptors has paved the way toward new efficient targeted therapies. Herein, we will review the targeted therapies of clinical importance for HER2-positive breast cancer, which include anti-HER2 MoAbs and tyrosine kinase inhibitors that directly interfere at the receptor level. Clinicians are still facing many uncertainties concerning the optimal use of these new agents, and scientists are working on dissecting the mechanisms of resistance developed by HER2-positive cancer cells. Interesting perspectives in the treatment of HER2-positive breast cancer will be discussed. They consist of designing HER2 peptide-based vaccines, targeting downstream pathway molecules beyond the membrane receptor, and exploring synergistic antineoplasic strategies.
Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes
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Paclitaxel (Taxol^®) has been successfully combined with the monoclonal antibody trastuzumab (Herceptin^®) in the treatment of ErbB2 overexpressing cancers. However, this combination therapy showed an unexpected synergistic increase in cardiac dysfunction. We have studied the mechanisms of paclitaxel/anti-ErbB2 cardiotoxicity in adult rat ventricular myocytes (ARVM). Myofibrillar organization was assessed by immunofluorescence microscopy and cell viability was tested by the TUNEL-, LDH- and MTT-assay. Oxidative stress was measured by DCF-fluorescence and myocyte contractile function by video edge-detection and fura-2 fluorescence. Treatment of ARVM with paclitaxel or antibodies to ErbB2 caused a significant increase in myofilament degradation, similarly as observed with an inhibitor of MAPK-signaling, but not apoptosis, necrosis or changes in mitochondrial activity. Paclitaxel-treatment and anti-ErbB2 reduced Erk1/2 phosphorylation. Paclitaxel increased diastolic calcium, shortened relaxation time and reduced fractional shortening in combination with anti-ErbB2. A minor increase in oxidative stress by paclitaxel or anti-ErbB2 was found. We conclude, that concomitant inhibition of ErbB2 receptors and paclitaxel treatment has an additive worsening effect on adult cardiomyocytes, mainly discernible in changes of myofibrillar structure and function, but in the absence of cell death. A potential mechanism is the modulation of the MAPK/Erk1/2 signaling by both drugs.
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Current PerspectiveAdjuvant trastuzumab therapy for HER2-overexpressing breast cancer: What we know and what we still need to learn

Abstract

Introduction

Section snippets

Published and/or reported adjuvant trastuzumab trials: similarities, differences and design issues

Patient populations

Safety and compliance

Efficacy

Subsets that benefit most from trastuzumab

Adjuvant chemotherapy ‘optimisation’ for HER2-positive disease

Pending questions related to adjuvant trastuzumab

Take-home messages for the clinician

Conflict of interest statement

Clin Breast Cancer

The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen

Nature

A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma

Proc Natl Acad Sci USA

Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene

Science

Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen

Proc Natl Acad Sci USA

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N Engl J Med

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

N Engl J Med

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

N Engl J Med

Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in her2 positive early breast cancer patients: BCIRG 006 study

Breast Cancer Res Treat

Current Perspective
Adjuvant trastuzumab therapy for HER2-overexpressing breast cancer: What we know and what we still need to learn