Arch Gynecol Obstet (2013) 288:1203–1212 DOI 10.1007/s00404-013-3069-4
REVIEW
Breakthroughs in research and treatment of early breast cancer: an overview of the last three decades Manfred Kaufmann • Gunter von Minckwitz • Jonas Bergh • Pier-Franco Conte Sarah Darby • Wolfgang Eiermann • Antony Howell • Marion Kiechle • Davide Mauri • Hans-Jo¨rg Senn • Giuseppe Viale • Sibylle Loibl
•
Received: 20 September 2013 / Accepted: 22 October 2013 / Published online: 5 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Breast cancer has become curable for the majority of women in Western Europe and North America. Advances have been made in imaging diagnostics as well as the implementation of nationwide screening programmes. Nowadays, we talk about prevention as well as treatment. Pathology has moved from pure morphology (tumour type, grade and stage) to biological characterisation of the tumour. Treatment has changed considerably through a better understanding of the disease; from a local disease predominated by extensive and mutilating surgical techniques to a point where breast cancer has come into its own as a systemic disease with equal ‘‘rights’’ to local as well as systemic
treatment. This paradigm shift has led to a multidisciplinary approach of the understanding and treatment of breast cancer. Molecular classification has changed the understanding of breast cancer and will be the basis for an even more individualised treatment. New (biological) agents will help to further tailor treatment to response or resistance. While systemic treatment has been increased in number and duration surgical/local strategies have been reduced to minimum. Evidence-based medicine has helped to improve and standardise treatment of breast cancer. This review summarises the 10th Biedenkopf meeting that was held to review the advances in breast cancer understanding and treatment.
M. Kaufmann Department of Obstetrics and Gynaecology, J. W. Goethe University, Frankfurt, Germany
A. Howell The Christie Hospital and University Hospital of South Manchester, Manchester, UK
G. von Minckwitz S. Loibl (&) German Breast Group, Martin-Behaim-Str. 12, 63263 Neu-Isenburg, Germany e-mail: [email protected]
M. Kiechle Department of Obstetrics and Gynecology, Technical University Mu¨nchen, Munich, Germany
J. Bergh Radiumhemmet, Karolinska Oncology, Stockholm, Sweden J. Bergh Manchester University, Manchester, UK P.-F. Conte Divisione di Oncologia Medica 2, Universita´ die Padua Regione del Veneto, Padua, Italy
D. Mauri Department of Medical Oncology, General Hospital of Lamia, Lamia, Greece H.-J. Senn Tumor und Brustzentrum ZeTuP St. Gallen and St. Gallen Oncology Conferences, St. Gallen, Switzerland G. Viale Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
S. Darby Clinical Trial Service Unit, University of Oxford, Oxford, UK W. Eiermann Department of Obstetrics and Gynecology, Rot-Kreuz Krankenhaus, Munich, Germany
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Keywords Breast cancer Prevention Chemotherapy Endocrine therapy Targeted agents Surgery Radiotherapy
Introduction Sincethe early 1990s breast cancer mortality declined in the Western European countries [1, 2]. While the 5 year disease-free survival (DFS) rate in the early 1980s was around 70 % and it has increased to 85 % in 2011 in the ‘‘West’’ (Fig. 1). Advances have been made in every aspect of patient care namely prevention, pathology and systemic as well as local treatment [3] (Fig. 2). Medical evidence based on meta-analyses of data from clinical trials has led to the development of (inter)national guidelines. The first St. Gallen Breast Cancer conference convened in 1982 and the first consensus recommendations were published in 1988 in the Journal of the National Cancer Institute (JNCI). The National Institute of Health (NIH) conference in 1990 drew up guidelines based on simple recommendations by nonbreast cancer experts [4]. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) started in 1985 and since then has convened regularly to share the individual patient data from their trials, enabling the worldwide evidence to be collated and analysed, thus providing reliable estimates of the effects of different treatment strategies for both local and systemic therapy (Table 1). A meeting, the tenth in a row of successful and practicechanging gatherings in Biedenkopf was held to review the treatment advances to identify the most important research fields over the next decade. Based on individual presentations by the members on certain topics, the manuscript was written. No formal review has been undertaken.
Prevention The concept of preventing breast cancer is rather new and was born when the early tamoxifen trials revealed that the incidence of contralateral breast cancer could be reduced by it [5]. The first prevention trials [6–9] resulted in an overall risk reduction of 38 % (HR 0.62) using tamoxifen [10]. In spite of this impressive risk reduction, prevention of breast cancer did not become standard. One reason might have been that tamoxifen was a cancer drug with too many unknowns. None of the trials could demonstrate a reduction in oestrogen receptor (ER) negative breast cancers. Raloxifene showed preventive activity in two trials [11, 12]. The Selective Oestrogen Receptor Modulators (SERMs), tamoxifen and raloxifene, were compared in the STAR (Study of TAmoxifen and Raloxifene) trial that showed tamoxifen to be more effective [13]. Aromatase
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Fig. 1 Breast cancer mortality. a UK and USA, b Germany
inhibitor (AIs) prevention trials then began based on the adjuvant trials such as the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial that demonstrated a reduction of contralateral breast cancer [14]. The first one was recently published demonstrating exemestane to be more effective than placebo in reducing the incidence of breast cancer [15]. The ongoing IBIS II (second International Breast cancer Intervention Study) trial investigates the effectiveness of anastrozole in preventing breast cancer in postmenopausal patients. Preventive methods in premenopausal patients (other than BRCA1/2 mutation carriers) apart from tamoxifen are still in the early stages. Luteinizing-hormone-releasing hormone (LHRH) analogues had been investigated, but acceptance and compliance were too low [16, 17]. In BRCA 1/2 carriers prophylactic bilateral salpingoophorectomy and mastectomy are considered to be effective to improve the survival [18, 19]. Lifestyle
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Fig. 2 History of breast cancer treatment (selected milestones)
measures have recently in focus of research. Fat restriction, weight loss, and physical activity have been investigated, but only the latter two have been proven to reduce breast cancer incidence [20–22]. Nevertheless, the results are conflicting and show only limited association with breast cancer. New approaches are required to prevent ER-negative breast cancers. New strategies such as metformin and bone targeting agents might merit further exploration.
Hereditary breast cancer (HBC) Twenty percent of breast cancers are associated with a family history [23, 24]. A major breakthrough was the detection of the first breast cancer gene (BRCA) in 1994 [25]. Other genes that have recently been found, RAD51C [26] and RAD51D [27], have lower penetrating abilities. GWAS (Genome-Wide Association Study) data suggest that it is very unlikely that there will be genes beyond BRCA1/2 that will be as strongly associated with breast cancer risk. The life penetration risk for hereditary breast cancer can be up to 80 % varying between BRCA 1 and 2, and can be modified by epigenetic factors. The risk of developing breast cancer increased also in mutation carriers from 25 % for those born in 1940 to 67 % for those women born after 1940 [28]. Structured screening programmes are needed, especially for those who do not want to undergo prophylactic surgery.
Pathology Originally, pathology was basically the morphology determining the tumour type, grade and stage of the
disease. However, with the investigation of the oestrogen receptor in 1968, initially measured by a ligand binding assay depending on fresh frozen tissue, assessment of the biological features of the tumours became an important prognostic and predictive tool [29]. When antibodies suitable for formalin fixed paraffin embedded (FFPE) tissue became available, the estimation of the biological parameters became easier and was included into routine examination. To this, day experts continue to discuss how best to determine the steroid hormone receptor status [30]. In 1985/86, the HER2 gene was detected [31, 32]. The determination of the HER2 status is part of the standard pathological report today. Accuracy and reproducibility in the assessment of these biological parameters are fostered by following the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines [33, 34]. In the beginning, these parameters were considered to be purely prognostic. The identification of targeted therapies such as tamoxifen and the newer endocrine agents, as well as the anti-HER2 agent trastuzumab has led to the consideration of the biological markers as powerful predictive factors. The role of the pathologist has, therefore, changed from the traditional and purely diagnostic one to a novel and more clinical one. The accurate and complete pathological evaluation of breast cancer forms the choice of the systemic treatment for individual patients. Ki-67 detected 30 years ago in Kiel by Harald Stein is a proliferation marker which is widely used (despite not recommended by the ASCO) for assessing the tumour aggressiveness and estimating the need of chemotherapy [35, 36]. At the turn of the century the next leap which once again changed the understanding of breast cancer was molecular characterisation [37]. Immunohistochemical surrogates have been developed to mimic the molecular classification,
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Table 1 Overview on the EBCTCG publications and their scientific impact (according to Liz MacKinnon) Year of EBCTCG main meeting
Main topic of the publication in patients with early breast cancer
Reference and year of main publication
Times citeda
1985
Effects of adjuvant tamoxifen and chemotherapy on mortality demonstrating a reduction of the 5-year mortality
NEJM 319:1681, 1988
754
1990
Efficacy of systemic treatment of by hormonal, cytotoxic, or immune therapy
Lancet 339:1 and 71, 1992
2,090
Radiotherapy and surgery affect the rates of local recurrence but not clearly the overall survival at 10 years
NEJM 333:1444, 1995
678
Ovarian ablation improves recurrence-free and overall survival in patients\50 years
Lancet 348:1189, 1996
342
1995
2000
2005
Adjuvant tamoxifen treatment improves the 10-year survival in ER pos. women
Lancet 351:1451, 1998
2,438
Adjuvant polychemotherapy improves survival in pre- and postmenopausal women with aggressive tumours. Favourable and unfavourable effects on long-term survival of radiotherapy
Lancet 352:930, 1998
1,357
Lancet 355:1757, 2000
654
Adjuvant hormonal therapy and chemotherapy reduce 5-year recurrence rates and 15-year mortality rates
Lancet 365:1687, 2005
2,173
Effects of radiotherapy and of differences in the extent of surgery on local recurrence and 15-year survival
Lancet 366:2087, 2005
1,140
Radiotherapy in DCIS halves the rate of ipsilateral events after BCS
JNCI monograph 41:162-177, 2010
–
5 years of adjuvant tamoxifen reduces 15-year risks of recurrence and death
Lancet 378:771, 2011
–
Radiotherapy halves the recurrence rate and reduces the BC death rate by about a sixth after BCS in a 10- and 15-year analysis.
Lancet 378:1707, 2011
–
Overview of polychemotherapies used in the last decades
Lancet 379:390, 2012
–
Total citations by 2011 to 1988–2005 reports: 11,626 Proceedings Citation Index-Science 1990–2011 (http://wok.mimas.ac.uk accessed December 2011) a
From cited reference searches of Science Citation Index-Expanded 1945–2011 and Conference
which were originally based on gene expression profiling [38] (Table 2). Meanwhile, multigene assays have been developed to help find the right treatment. Currently, clinical validations of the predictive ability of these multigene tests are ongoing although they are already in use in some areas. In the era of the molecular assays, the clinical responsibilities of the pathologists remain. 1. 2.
3.
To identify special tumour types among luminal and triple negative tumours, To ensure accuracy and reproducibility in the assessment of ER, progesterone receptor (PR), Ki-67 and human epidermal growth factor receptor 2 (HER2), To provide representative tumour samples for molecular assays whenever needed.
Surgical treatment During the last 30 years, surgery for breast cancer has become less radical (Table 3) without increase in mortality. This reflects the fact that many patients can be cured with less aggressive surgery than was usual 30 years ago, especially if it is accompanied by radiotherapy, whilst even
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the most aggressive surgery would not be able to cure a proportion of the patients even when accompanied by radiotherapy. Bernard Fisher and Umberto Veronesi became the pioneers of the new approach [39]. Two independent groups could demonstrate that even after 20 years follow-up there was no significant difference in overall survival in breast conserving surgery vs. mastectomy [40, 41]. Today, the aim of surgery is maximum local control, minimal deformity, exact staging. Breast conservation can be achieved in up to 70 % of the patients. The relationship between tumour size and breast volume determines the possibility of whether breast conserving surgery is possible. In addition, clear margins (invasive and non-invasive tumour) need to be achieved with a satisfying cosmetic result [42]. Neoadjuvant therapy has increased the rate of breast conserving surgery to a maximum of 70 %. One advantage emerged during the last 30 years besides the reduction in surgical radicalness, namely the development and refinement of breast reconstruction techniques with homologous (musculocutaneous flaps) and/or autologous material (inlays and prostheses). Sentinel node biopsy (SNB) has become standard of care in clinically node-negative patients. New data suggest that the omission of axillary node dissection might even be
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Table 2 Overview on subtypes and therapeutic options (adapted to Goldhirsch A et al. Annals Oncol) ‘Subtype’ surrogate IHC markers
Type of systemic therapy (in addition to surgery and, for some patients, radiotherapy)
Notes
‘Luminal A’ ER and/or PgR positive HER2 negative, Ki-67 low (\14 %)
Endocrine therapy alone
Few require cytotoxics (e.g. high nodal status)
‘Luminal B (HER2 neg)’ ER and/or PgR positive HER2 negative, Ki-67 high
Cytotoxics ? endocrine therapy
Inclusion and type of cytotoxics may depend on perceived risk and patient preference
‘Luminal B (HER2 pos)’ ER and/or PgR positive HER2 positive
Cytotoxics ? anti-HER2 ? endocrine therapy
No data are available to support the omission of cytotoxics in this group
‘HER2 positive (non luminal)’
Cytotoxics ? anti-HER2
‘Triple negative (ductal)’
Cytotoxics
Still the standard of care although about 60 % do not benefit
‘Special histological types’ A. Endocrine responsive B. Endocrine non responsive
Endocrine therapy cytotoxics
Medullary and adenoid cystic carcinomas may not require any adjuvant cytotoxics
Breast
Axilla
Rad.mastectomy
Axilla resection [10 lymph nodes (Level I, II ± III)
Mod. rad. mastectomy Skin ± nipple sparing mastectomy Partial/segmental mastectomy Quadrantectomy
Sentinel lymph node biopsy with axillary dissection where a positive node is found. Sentinel lymph node biopsy
Segmental resection, wide excision Lumpectomy, tumorectomy ± in sano No surgery
Reduction of surgical radicality
Table 3 Surgical radicalness in breast surgery
No surgery
Starting with the most radical surgery
possible in patients with a positive SNB, but a clinically free axilla in a subgroup of patients undergoing breast conserving surgery for tumours up to stage T2 [43].
Radiotherapy The use of less aggressive surgery in recent years is safe in combination to adjuvant radiotherapy of the breast. A recent meta-analysis including data from 10,000 patient treated in randomised trials comparing adjuvant radiotherapy versus no radiotherapy after breast conserving surgery that started before the year 2000 found that radiotherapy reduced recurrence rates by 50 % and breast cancer death rate by about 15 %. These proportional reductions varied little between different groups of women,
but the absolute benefits from radiotherapy were found to vary substantially according to the characteristics of the patient, with greater absolute benefits in women with nodepositive and high risk node-negative disease and smaller absolute benefits in women with intermediate or lower risk node-negative disease. For all groups of women, about one breast cancer death was avoided for every four recurrences avoided by radiotherapy, after breast conserving surgery [44]. For women with involved lymph nodes, the addition of radiotherapy to mastectomy with axillary dissection reduced recurrence substantially and also reduced breast cancer mortality by around 10 % [45]. In an earlier metaanalysis of trials of radiotherapy after mastectomy there was little evidence to suggest that radiotherapy provided any benefit for women with node-negative disease who have had mastectomy and full axillary dissection [45]. Radiotherapy may, however, provide some benefit in terms of a reduced 10-year recurrence risk for women with an incomplete axillary dissection. Radiotherapy for breast cancer inevitably involves some incidental exposure of normal tissues, including the heart and the lung, which can lead to considerable side effects. In the past, irradiated breast cancer patients have been at increased risk of mortality from both lung cancer and heart disease [46]. In recent years, improved radiotherapy techniques have resulted in lower doses to normal tissues [47]. It seems likely, therefore, that the risk of fatal side effects has also reduced, although some risks may still remain especially for women with additional diagnosis of lung or heart diseases or unfavourable anatomy. To avoid the side effects of radiotherapy, intraoperative radiotherapy (IORT) using different techniques has been developed and shown to be of some benefit for certain subgroups [48]. It is likely that in the next 10 years these new techniques will be further developed. Also increased knowledge on appropriate selection of patients for IORT rather than conventional radiotherapy or even no
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radiotherapy for certain subgroups will improved treatment outcome.
Adjuvant chemotherapy Schabel first investigated adjuvant chemotherapy in the 1970s [49]. The first clinical trials with adjuvant chemotherapy in operable breast cancer were started in the USA by the NSABP (L-phenylalanine mustard; L-PAM) and in Europe in Milano/Italy (cyclophosphamide, methotrexate, and 5-fluorouracil; CMF) and by the OSAKO-Group in St. Gallen/Switzerland. All three demonstrated an improvement in disease-free and/or overall survival. These first results were validated in more than 100 clinical trials by over 40 study groups worldwide, periodically collated and analysed by the EBCTCG in Oxford/UK, supplemented by tri- and then bi-annually published breast cancer treatment consensus recommendations by the St. Gallen international consensus panel since 1988. The inclusion of anthracyclines in the 80s and of taxanes in the 90s improved disease-free and overall survival independent of nodal involvement. Numerous trials investigated chemo-endocrine adjuvant therapy of different designs in postmenopausal patients between 1980 and 90 [50]. The 2011 St. Gallen recommendations suggest tailoring the use of chemotherapy according to subtypes defined by ER/PR, HER2 and Ki67. The recently published EBCTCG overview on polychemotherapy clearly demonstrates that chemotherapy adds value of about a 30 % relative risk reduction independently of ER/PR and HER2 status and endocrine treatment [51]. It also demonstrated clearly that anthracycline-/taxane-based therapies are at present the most effective adjuvant chemotherapies even though some data suggest that anthracycline-free regimen might be of similar effect. High dose chemotherapy with stem cell support as opposed to conventionally dosed chemotherapy has been shown to increase progression free, but not overall survival [52]. However, the idea of giving more chemotherapy in a shorter time was transferred into the dose-dense, doseintensified concept, which proved to increase disease-free and overall survival especially in ER-negative tumours [53–55].
Neoadjuvant therapy Neoadjuvant therapy was first used in inoperable breast cancer patients and then transferred to primary operable breast cancer patients. This was first investigated in the NSABP-B18 study. Those first generation trials had DFS and overall survival (OS) as primary endpoints and
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compared the neoadjuvant with the adjuvant approach, demonstrating no difference in overall survival [56]. The second generation looked primarily at the pathological complete response rate (pCR) [57]. Current third generation trials with pCR as primary endpoint were focusing in addition on predictive biomarkers. Meanwhile, pCR is an acknowledged surrogate endpoint because it correlates with disease-free and overall survival, at least in certain subtypes [58, 59]. The patients who do not achieve a pCR have a worse prognosis especially in the group with TNBC (triple negative breast cancer) or HER2-positive tumours [60–62]. The pCR rate, depending on definition, in an unselected patients’ population with an anthracycline/taxane is below 20 % and can rise to around 30 % by adding trastuzumab in the HER2-positive group, depending on the duration of chemotherapy and trastuzumab. The rate of pCR varies between biological subgroups (Luminal A: 5 %; Luminal B: HER2- 10–20 %; HER2 ? 30 % and TNBC up to 50 %). New agents and treatment strategies, i.e. the double anti-HER2 blockade might further improve the pCR rate and eventually the long-term outcome [63– 66] (Table 4). The future of neoadjuvant therapy lies in selecting the most promising drugs to move forward to early breast cancer.
Endocrine therapy In 1983 survival advantage was shown in early breast cancer using tamoxifen and later confirmed by the Oxford overview data [67]. AIs were introduced about 30 years ago. Aminogluthetimide, was originally used as an antiepileptic drug [68]. In search of better tolerated aromatase inhibitors two classes of AIs could be identified, the steroidal such as formestane and exemestane and the nonsteroidal such as the triazoles (e.g. letrozole and anastrozole). Third generation AIs (exemestane, letrozole, anastrozole) are far better tolerated and highly efficient and have been shown to reduce the risk of recurrence, but not the risk of dying of breast cancer in postmenopausal breast cancer patients. After treating more than 40,000 women in adjuvant aromatase inhibitor studies many questions are still open, e.g. optimal duration, sequence and defining the subgroup of patients who derive the largest benefit [69–72]. Extended endocrine therapy seems to be of some advantage for node-positive breast cancer, but it is not absolutely clear who will need this long-term treatment [73–76]. These open questions emphasise the importance to further define the group of patients who benefits most of endocrine therapy. Therefore, it is of great importance to phrase biomarker questions prior to study start and link them to translational research questions.
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Table 4 Overview of most recent neoadjuvant trials in HER2-positive breast cancer investigating double anti-HER2 treatment Trial
Treatment
pCR ypT0/Tis (breast) %
pCR ypT0/Tis/ypN0 (%)
pCR breast HR? (%)
pCR breast HR- (%)
Neosphere (63), n = 417
TH
29
21.5
20
36.8
THP
45.8
39.3
26
63.2
HP
16.8
11.2
5.9
29.1
TP
24
17.7
17.4
30
PL
24.7
20
16.2
33.8
PH
29.5
27.6
22.7
36.5
PHL
51.3
46.9
41.6
61.3
Neo-ALTTO (64), n = 450
pCR (ypT0, ypN0) Geparquinto (62), n = 620
Trial Cherlob (65), n = 131
Holmes (62), n = 78
Chang (62), n = 61
ECH-TH
50.4
45
31.3
ECL-TL
35.2
29.9
21.7
Treatment
pCR ypT0/Tis (breast) %
ypT0/Tis/ypN0 (%)
pCR HR? (%)
pCR HR- (%)
PwH-FEC-H
26
25
26.6
PwL-FEC-L
28
22.7
35.7
PwHL-FEC-HL
43
35.7
56.2
FEC-H-PwH
54
FEC-L-PwL
45
FEC-HL-PwHL
74
HL(?EH)
30
21
46
T docetaxel, H trastuzumab, P paclitaxel, E eprirubicin, C cyclophosphamide, w weekly, F 5-fluorouracil, L lapatinib
Several trials have shown that LHRH analogues are effective in treating breast cancer in premenopausal patients [77]. Due to the trials limitations, it is still not clear if the addition of an LHRH agonist adds an independent effect to chemotherapy and tamoxifen in young women. The SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) trials will hopefully answer this question [78].
Biological treatment Trastuzumab was the leading breakthrough for the treatment of early breast cancer. Approximately 20 % of breast cancers overexpress HER2, which is a negative prognostic factor in early breast cancer [79]. Slamon et al. demonstrated that the addition of trastuzumab to either paclitaxel or AC improved progression-free survival and overall survival in first-line metastatic HER2-positive breast cancer [80]. The dogma of changing the treatment at the time of progression could be overcome by a trial that demonstrated that the treatment beyond progression is possible with trastuzumab in combination with capecitabine [81]. But also changing the antiHER2 agent as well as the chemotherapy is superior to continuing with chemotherapy alone [82]. In 2005, an interim analysis of the HERA (HERceptin Adjuvant) trial was destined to change clinical practice in
early HER2-positive breast cancer therapy [83]. DFS advantages were evident for all subgroups analysed. Data were validated by the combined analyses of NSABP B-31 and NCCTG trial N9831 as well as the BCIRG 006 trial [84, 85]. There is consistent evidence that early concurrent use of trastuzumab with chemotherapy may result in OS benefits which could not be proven in trials that begin with trastuzumab sequentially after chemotherapy. However, the data should be interpreted carefully as the cross-over effect of the standard arm in HERA might have damned the results. Despite the large amount of randomised evidence for early breast cancer it is still questionable in how far patients with pT1a,b tumours should receive trastuzumab as these patients have not been included in the trials. The potential risk of developing cardiac toxicity may jeopardize the long-term survival especially in these patients. Indeed, the potential risk of surviving from breast cancer, but developing heart failure for women undergoing targeted therapies had been raised [86, 87]. Patients at higher risk for cardiac failure were never included in trastuzumab trials. New anti-HER2 agents (lapatinib, pertuzumab, neratinib) have been introduced and the double/triple blockade with or without chemotherapy will focus on research in the next decade. Due to the high costs of these combined therapies, future clinical studies should include translational research to better select those patients with a clear OS benefit and reduce side effects.
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Bevacizumab, an antibody targeting vascular endothelial growth factor receptor (VEGF) was demonstrated in the neoadjuvant setting to increase the pCR in early breast cancer [88, 89]. The adjuvant trials investigating bevacizumab have completed recruitment and results will be available shortly. The potential of bisphosphonates to improve DFS and OS has been investigated in the adjuvant setting showing a benefit only for clearly postmenopausal women or women with ovarian function suppression [90, 91].
10.
Conclusion
13.
The paradigm shift in understanding breast cancer has been of major importance. Breast cancer is a heterogeneous disease with early haematological micrometastatic spread. The greatly improved outcome is due to a multidisciplinary concept, not least driven by new therapies, drugs and better insight into breast cancer biology and early diagnosis. Acknowledgments We thank the independent, non-profit BANSS Foundation, Biedenkopf/Lahn, Germany, for financial support, and the GBG Forschungs-GmbH, Neu-Isenberg, Germany for logistical support of the meeting. All members of the panel had input in the discussion and formulation of the article. The symposium as well as the manuscript preparation was conducted independent of the pharmaceutical industry. The report was drafted entirely by the meeting participants without any paid assistance. Conflict of interest interest to declare.
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None of the co-authors has any conflict of 18.
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REVIEW
Breakthroughs in research and treatment of early breast cancer: an overview of the last three decades Manfred Kaufmann • Gunter von Minckwitz • Jonas Bergh • Pier-Franco Conte Sarah Darby • Wolfgang Eiermann • Antony Howell • Marion Kiechle • Davide Mauri • Hans-Jo¨rg Senn • Giuseppe Viale • Sibylle Loibl
•
Received: 20 September 2013 / Accepted: 22 October 2013 / Published online: 5 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Breast cancer has become curable for the majority of women in Western Europe and North America. Advances have been made in imaging diagnostics as well as the implementation of nationwide screening programmes. Nowadays, we talk about prevention as well as treatment. Pathology has moved from pure morphology (tumour type, grade and stage) to biological characterisation of the tumour. Treatment has changed considerably through a better understanding of the disease; from a local disease predominated by extensive and mutilating surgical techniques to a point where breast cancer has come into its own as a systemic disease with equal ‘‘rights’’ to local as well as systemic
treatment. This paradigm shift has led to a multidisciplinary approach of the understanding and treatment of breast cancer. Molecular classification has changed the understanding of breast cancer and will be the basis for an even more individualised treatment. New (biological) agents will help to further tailor treatment to response or resistance. While systemic treatment has been increased in number and duration surgical/local strategies have been reduced to minimum. Evidence-based medicine has helped to improve and standardise treatment of breast cancer. This review summarises the 10th Biedenkopf meeting that was held to review the advances in breast cancer understanding and treatment.
M. Kaufmann Department of Obstetrics and Gynaecology, J. W. Goethe University, Frankfurt, Germany
A. Howell The Christie Hospital and University Hospital of South Manchester, Manchester, UK
G. von Minckwitz S. Loibl (&) German Breast Group, Martin-Behaim-Str. 12, 63263 Neu-Isenburg, Germany e-mail: [email protected]
M. Kiechle Department of Obstetrics and Gynecology, Technical University Mu¨nchen, Munich, Germany
J. Bergh Radiumhemmet, Karolinska Oncology, Stockholm, Sweden J. Bergh Manchester University, Manchester, UK P.-F. Conte Divisione di Oncologia Medica 2, Universita´ die Padua Regione del Veneto, Padua, Italy
D. Mauri Department of Medical Oncology, General Hospital of Lamia, Lamia, Greece H.-J. Senn Tumor und Brustzentrum ZeTuP St. Gallen and St. Gallen Oncology Conferences, St. Gallen, Switzerland G. Viale Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
S. Darby Clinical Trial Service Unit, University of Oxford, Oxford, UK W. Eiermann Department of Obstetrics and Gynecology, Rot-Kreuz Krankenhaus, Munich, Germany
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Keywords Breast cancer Prevention Chemotherapy Endocrine therapy Targeted agents Surgery Radiotherapy
Introduction Sincethe early 1990s breast cancer mortality declined in the Western European countries [1, 2]. While the 5 year disease-free survival (DFS) rate in the early 1980s was around 70 % and it has increased to 85 % in 2011 in the ‘‘West’’ (Fig. 1). Advances have been made in every aspect of patient care namely prevention, pathology and systemic as well as local treatment [3] (Fig. 2). Medical evidence based on meta-analyses of data from clinical trials has led to the development of (inter)national guidelines. The first St. Gallen Breast Cancer conference convened in 1982 and the first consensus recommendations were published in 1988 in the Journal of the National Cancer Institute (JNCI). The National Institute of Health (NIH) conference in 1990 drew up guidelines based on simple recommendations by nonbreast cancer experts [4]. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) started in 1985 and since then has convened regularly to share the individual patient data from their trials, enabling the worldwide evidence to be collated and analysed, thus providing reliable estimates of the effects of different treatment strategies for both local and systemic therapy (Table 1). A meeting, the tenth in a row of successful and practicechanging gatherings in Biedenkopf was held to review the treatment advances to identify the most important research fields over the next decade. Based on individual presentations by the members on certain topics, the manuscript was written. No formal review has been undertaken.
Prevention The concept of preventing breast cancer is rather new and was born when the early tamoxifen trials revealed that the incidence of contralateral breast cancer could be reduced by it [5]. The first prevention trials [6–9] resulted in an overall risk reduction of 38 % (HR 0.62) using tamoxifen [10]. In spite of this impressive risk reduction, prevention of breast cancer did not become standard. One reason might have been that tamoxifen was a cancer drug with too many unknowns. None of the trials could demonstrate a reduction in oestrogen receptor (ER) negative breast cancers. Raloxifene showed preventive activity in two trials [11, 12]. The Selective Oestrogen Receptor Modulators (SERMs), tamoxifen and raloxifene, were compared in the STAR (Study of TAmoxifen and Raloxifene) trial that showed tamoxifen to be more effective [13]. Aromatase
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Fig. 1 Breast cancer mortality. a UK and USA, b Germany
inhibitor (AIs) prevention trials then began based on the adjuvant trials such as the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial that demonstrated a reduction of contralateral breast cancer [14]. The first one was recently published demonstrating exemestane to be more effective than placebo in reducing the incidence of breast cancer [15]. The ongoing IBIS II (second International Breast cancer Intervention Study) trial investigates the effectiveness of anastrozole in preventing breast cancer in postmenopausal patients. Preventive methods in premenopausal patients (other than BRCA1/2 mutation carriers) apart from tamoxifen are still in the early stages. Luteinizing-hormone-releasing hormone (LHRH) analogues had been investigated, but acceptance and compliance were too low [16, 17]. In BRCA 1/2 carriers prophylactic bilateral salpingoophorectomy and mastectomy are considered to be effective to improve the survival [18, 19]. Lifestyle
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Fig. 2 History of breast cancer treatment (selected milestones)
measures have recently in focus of research. Fat restriction, weight loss, and physical activity have been investigated, but only the latter two have been proven to reduce breast cancer incidence [20–22]. Nevertheless, the results are conflicting and show only limited association with breast cancer. New approaches are required to prevent ER-negative breast cancers. New strategies such as metformin and bone targeting agents might merit further exploration.
Hereditary breast cancer (HBC) Twenty percent of breast cancers are associated with a family history [23, 24]. A major breakthrough was the detection of the first breast cancer gene (BRCA) in 1994 [25]. Other genes that have recently been found, RAD51C [26] and RAD51D [27], have lower penetrating abilities. GWAS (Genome-Wide Association Study) data suggest that it is very unlikely that there will be genes beyond BRCA1/2 that will be as strongly associated with breast cancer risk. The life penetration risk for hereditary breast cancer can be up to 80 % varying between BRCA 1 and 2, and can be modified by epigenetic factors. The risk of developing breast cancer increased also in mutation carriers from 25 % for those born in 1940 to 67 % for those women born after 1940 [28]. Structured screening programmes are needed, especially for those who do not want to undergo prophylactic surgery.
Pathology Originally, pathology was basically the morphology determining the tumour type, grade and stage of the
disease. However, with the investigation of the oestrogen receptor in 1968, initially measured by a ligand binding assay depending on fresh frozen tissue, assessment of the biological features of the tumours became an important prognostic and predictive tool [29]. When antibodies suitable for formalin fixed paraffin embedded (FFPE) tissue became available, the estimation of the biological parameters became easier and was included into routine examination. To this, day experts continue to discuss how best to determine the steroid hormone receptor status [30]. In 1985/86, the HER2 gene was detected [31, 32]. The determination of the HER2 status is part of the standard pathological report today. Accuracy and reproducibility in the assessment of these biological parameters are fostered by following the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines [33, 34]. In the beginning, these parameters were considered to be purely prognostic. The identification of targeted therapies such as tamoxifen and the newer endocrine agents, as well as the anti-HER2 agent trastuzumab has led to the consideration of the biological markers as powerful predictive factors. The role of the pathologist has, therefore, changed from the traditional and purely diagnostic one to a novel and more clinical one. The accurate and complete pathological evaluation of breast cancer forms the choice of the systemic treatment for individual patients. Ki-67 detected 30 years ago in Kiel by Harald Stein is a proliferation marker which is widely used (despite not recommended by the ASCO) for assessing the tumour aggressiveness and estimating the need of chemotherapy [35, 36]. At the turn of the century the next leap which once again changed the understanding of breast cancer was molecular characterisation [37]. Immunohistochemical surrogates have been developed to mimic the molecular classification,
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Table 1 Overview on the EBCTCG publications and their scientific impact (according to Liz MacKinnon) Year of EBCTCG main meeting
Main topic of the publication in patients with early breast cancer
Reference and year of main publication
Times citeda
1985
Effects of adjuvant tamoxifen and chemotherapy on mortality demonstrating a reduction of the 5-year mortality
NEJM 319:1681, 1988
754
1990
Efficacy of systemic treatment of by hormonal, cytotoxic, or immune therapy
Lancet 339:1 and 71, 1992
2,090
Radiotherapy and surgery affect the rates of local recurrence but not clearly the overall survival at 10 years
NEJM 333:1444, 1995
678
Ovarian ablation improves recurrence-free and overall survival in patients\50 years
Lancet 348:1189, 1996
342
1995
2000
2005
Adjuvant tamoxifen treatment improves the 10-year survival in ER pos. women
Lancet 351:1451, 1998
2,438
Adjuvant polychemotherapy improves survival in pre- and postmenopausal women with aggressive tumours. Favourable and unfavourable effects on long-term survival of radiotherapy
Lancet 352:930, 1998
1,357
Lancet 355:1757, 2000
654
Adjuvant hormonal therapy and chemotherapy reduce 5-year recurrence rates and 15-year mortality rates
Lancet 365:1687, 2005
2,173
Effects of radiotherapy and of differences in the extent of surgery on local recurrence and 15-year survival
Lancet 366:2087, 2005
1,140
Radiotherapy in DCIS halves the rate of ipsilateral events after BCS
JNCI monograph 41:162-177, 2010
–
5 years of adjuvant tamoxifen reduces 15-year risks of recurrence and death
Lancet 378:771, 2011
–
Radiotherapy halves the recurrence rate and reduces the BC death rate by about a sixth after BCS in a 10- and 15-year analysis.
Lancet 378:1707, 2011
–
Overview of polychemotherapies used in the last decades
Lancet 379:390, 2012
–
Total citations by 2011 to 1988–2005 reports: 11,626 Proceedings Citation Index-Science 1990–2011 (http://wok.mimas.ac.uk accessed December 2011) a
From cited reference searches of Science Citation Index-Expanded 1945–2011 and Conference
which were originally based on gene expression profiling [38] (Table 2). Meanwhile, multigene assays have been developed to help find the right treatment. Currently, clinical validations of the predictive ability of these multigene tests are ongoing although they are already in use in some areas. In the era of the molecular assays, the clinical responsibilities of the pathologists remain. 1. 2.
3.
To identify special tumour types among luminal and triple negative tumours, To ensure accuracy and reproducibility in the assessment of ER, progesterone receptor (PR), Ki-67 and human epidermal growth factor receptor 2 (HER2), To provide representative tumour samples for molecular assays whenever needed.
Surgical treatment During the last 30 years, surgery for breast cancer has become less radical (Table 3) without increase in mortality. This reflects the fact that many patients can be cured with less aggressive surgery than was usual 30 years ago, especially if it is accompanied by radiotherapy, whilst even
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the most aggressive surgery would not be able to cure a proportion of the patients even when accompanied by radiotherapy. Bernard Fisher and Umberto Veronesi became the pioneers of the new approach [39]. Two independent groups could demonstrate that even after 20 years follow-up there was no significant difference in overall survival in breast conserving surgery vs. mastectomy [40, 41]. Today, the aim of surgery is maximum local control, minimal deformity, exact staging. Breast conservation can be achieved in up to 70 % of the patients. The relationship between tumour size and breast volume determines the possibility of whether breast conserving surgery is possible. In addition, clear margins (invasive and non-invasive tumour) need to be achieved with a satisfying cosmetic result [42]. Neoadjuvant therapy has increased the rate of breast conserving surgery to a maximum of 70 %. One advantage emerged during the last 30 years besides the reduction in surgical radicalness, namely the development and refinement of breast reconstruction techniques with homologous (musculocutaneous flaps) and/or autologous material (inlays and prostheses). Sentinel node biopsy (SNB) has become standard of care in clinically node-negative patients. New data suggest that the omission of axillary node dissection might even be
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Table 2 Overview on subtypes and therapeutic options (adapted to Goldhirsch A et al. Annals Oncol) ‘Subtype’ surrogate IHC markers
Type of systemic therapy (in addition to surgery and, for some patients, radiotherapy)
Notes
‘Luminal A’ ER and/or PgR positive HER2 negative, Ki-67 low (\14 %)
Endocrine therapy alone
Few require cytotoxics (e.g. high nodal status)
‘Luminal B (HER2 neg)’ ER and/or PgR positive HER2 negative, Ki-67 high
Cytotoxics ? endocrine therapy
Inclusion and type of cytotoxics may depend on perceived risk and patient preference
‘Luminal B (HER2 pos)’ ER and/or PgR positive HER2 positive
Cytotoxics ? anti-HER2 ? endocrine therapy
No data are available to support the omission of cytotoxics in this group
‘HER2 positive (non luminal)’
Cytotoxics ? anti-HER2
‘Triple negative (ductal)’
Cytotoxics
Still the standard of care although about 60 % do not benefit
‘Special histological types’ A. Endocrine responsive B. Endocrine non responsive
Endocrine therapy cytotoxics
Medullary and adenoid cystic carcinomas may not require any adjuvant cytotoxics
Breast
Axilla
Rad.mastectomy
Axilla resection [10 lymph nodes (Level I, II ± III)
Mod. rad. mastectomy Skin ± nipple sparing mastectomy Partial/segmental mastectomy Quadrantectomy
Sentinel lymph node biopsy with axillary dissection where a positive node is found. Sentinel lymph node biopsy
Segmental resection, wide excision Lumpectomy, tumorectomy ± in sano No surgery
Reduction of surgical radicality
Table 3 Surgical radicalness in breast surgery
No surgery
Starting with the most radical surgery
possible in patients with a positive SNB, but a clinically free axilla in a subgroup of patients undergoing breast conserving surgery for tumours up to stage T2 [43].
Radiotherapy The use of less aggressive surgery in recent years is safe in combination to adjuvant radiotherapy of the breast. A recent meta-analysis including data from 10,000 patient treated in randomised trials comparing adjuvant radiotherapy versus no radiotherapy after breast conserving surgery that started before the year 2000 found that radiotherapy reduced recurrence rates by 50 % and breast cancer death rate by about 15 %. These proportional reductions varied little between different groups of women,
but the absolute benefits from radiotherapy were found to vary substantially according to the characteristics of the patient, with greater absolute benefits in women with nodepositive and high risk node-negative disease and smaller absolute benefits in women with intermediate or lower risk node-negative disease. For all groups of women, about one breast cancer death was avoided for every four recurrences avoided by radiotherapy, after breast conserving surgery [44]. For women with involved lymph nodes, the addition of radiotherapy to mastectomy with axillary dissection reduced recurrence substantially and also reduced breast cancer mortality by around 10 % [45]. In an earlier metaanalysis of trials of radiotherapy after mastectomy there was little evidence to suggest that radiotherapy provided any benefit for women with node-negative disease who have had mastectomy and full axillary dissection [45]. Radiotherapy may, however, provide some benefit in terms of a reduced 10-year recurrence risk for women with an incomplete axillary dissection. Radiotherapy for breast cancer inevitably involves some incidental exposure of normal tissues, including the heart and the lung, which can lead to considerable side effects. In the past, irradiated breast cancer patients have been at increased risk of mortality from both lung cancer and heart disease [46]. In recent years, improved radiotherapy techniques have resulted in lower doses to normal tissues [47]. It seems likely, therefore, that the risk of fatal side effects has also reduced, although some risks may still remain especially for women with additional diagnosis of lung or heart diseases or unfavourable anatomy. To avoid the side effects of radiotherapy, intraoperative radiotherapy (IORT) using different techniques has been developed and shown to be of some benefit for certain subgroups [48]. It is likely that in the next 10 years these new techniques will be further developed. Also increased knowledge on appropriate selection of patients for IORT rather than conventional radiotherapy or even no
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radiotherapy for certain subgroups will improved treatment outcome.
Adjuvant chemotherapy Schabel first investigated adjuvant chemotherapy in the 1970s [49]. The first clinical trials with adjuvant chemotherapy in operable breast cancer were started in the USA by the NSABP (L-phenylalanine mustard; L-PAM) and in Europe in Milano/Italy (cyclophosphamide, methotrexate, and 5-fluorouracil; CMF) and by the OSAKO-Group in St. Gallen/Switzerland. All three demonstrated an improvement in disease-free and/or overall survival. These first results were validated in more than 100 clinical trials by over 40 study groups worldwide, periodically collated and analysed by the EBCTCG in Oxford/UK, supplemented by tri- and then bi-annually published breast cancer treatment consensus recommendations by the St. Gallen international consensus panel since 1988. The inclusion of anthracyclines in the 80s and of taxanes in the 90s improved disease-free and overall survival independent of nodal involvement. Numerous trials investigated chemo-endocrine adjuvant therapy of different designs in postmenopausal patients between 1980 and 90 [50]. The 2011 St. Gallen recommendations suggest tailoring the use of chemotherapy according to subtypes defined by ER/PR, HER2 and Ki67. The recently published EBCTCG overview on polychemotherapy clearly demonstrates that chemotherapy adds value of about a 30 % relative risk reduction independently of ER/PR and HER2 status and endocrine treatment [51]. It also demonstrated clearly that anthracycline-/taxane-based therapies are at present the most effective adjuvant chemotherapies even though some data suggest that anthracycline-free regimen might be of similar effect. High dose chemotherapy with stem cell support as opposed to conventionally dosed chemotherapy has been shown to increase progression free, but not overall survival [52]. However, the idea of giving more chemotherapy in a shorter time was transferred into the dose-dense, doseintensified concept, which proved to increase disease-free and overall survival especially in ER-negative tumours [53–55].
Neoadjuvant therapy Neoadjuvant therapy was first used in inoperable breast cancer patients and then transferred to primary operable breast cancer patients. This was first investigated in the NSABP-B18 study. Those first generation trials had DFS and overall survival (OS) as primary endpoints and
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compared the neoadjuvant with the adjuvant approach, demonstrating no difference in overall survival [56]. The second generation looked primarily at the pathological complete response rate (pCR) [57]. Current third generation trials with pCR as primary endpoint were focusing in addition on predictive biomarkers. Meanwhile, pCR is an acknowledged surrogate endpoint because it correlates with disease-free and overall survival, at least in certain subtypes [58, 59]. The patients who do not achieve a pCR have a worse prognosis especially in the group with TNBC (triple negative breast cancer) or HER2-positive tumours [60–62]. The pCR rate, depending on definition, in an unselected patients’ population with an anthracycline/taxane is below 20 % and can rise to around 30 % by adding trastuzumab in the HER2-positive group, depending on the duration of chemotherapy and trastuzumab. The rate of pCR varies between biological subgroups (Luminal A: 5 %; Luminal B: HER2- 10–20 %; HER2 ? 30 % and TNBC up to 50 %). New agents and treatment strategies, i.e. the double anti-HER2 blockade might further improve the pCR rate and eventually the long-term outcome [63– 66] (Table 4). The future of neoadjuvant therapy lies in selecting the most promising drugs to move forward to early breast cancer.
Endocrine therapy In 1983 survival advantage was shown in early breast cancer using tamoxifen and later confirmed by the Oxford overview data [67]. AIs were introduced about 30 years ago. Aminogluthetimide, was originally used as an antiepileptic drug [68]. In search of better tolerated aromatase inhibitors two classes of AIs could be identified, the steroidal such as formestane and exemestane and the nonsteroidal such as the triazoles (e.g. letrozole and anastrozole). Third generation AIs (exemestane, letrozole, anastrozole) are far better tolerated and highly efficient and have been shown to reduce the risk of recurrence, but not the risk of dying of breast cancer in postmenopausal breast cancer patients. After treating more than 40,000 women in adjuvant aromatase inhibitor studies many questions are still open, e.g. optimal duration, sequence and defining the subgroup of patients who derive the largest benefit [69–72]. Extended endocrine therapy seems to be of some advantage for node-positive breast cancer, but it is not absolutely clear who will need this long-term treatment [73–76]. These open questions emphasise the importance to further define the group of patients who benefits most of endocrine therapy. Therefore, it is of great importance to phrase biomarker questions prior to study start and link them to translational research questions.
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Table 4 Overview of most recent neoadjuvant trials in HER2-positive breast cancer investigating double anti-HER2 treatment Trial
Treatment
pCR ypT0/Tis (breast) %
pCR ypT0/Tis/ypN0 (%)
pCR breast HR? (%)
pCR breast HR- (%)
Neosphere (63), n = 417
TH
29
21.5
20
36.8
THP
45.8
39.3
26
63.2
HP
16.8
11.2
5.9
29.1
TP
24
17.7
17.4
30
PL
24.7
20
16.2
33.8
PH
29.5
27.6
22.7
36.5
PHL
51.3
46.9
41.6
61.3
Neo-ALTTO (64), n = 450
pCR (ypT0, ypN0) Geparquinto (62), n = 620
Trial Cherlob (65), n = 131
Holmes (62), n = 78
Chang (62), n = 61
ECH-TH
50.4
45
31.3
ECL-TL
35.2
29.9
21.7
Treatment
pCR ypT0/Tis (breast) %
ypT0/Tis/ypN0 (%)
pCR HR? (%)
pCR HR- (%)
PwH-FEC-H
26
25
26.6
PwL-FEC-L
28
22.7
35.7
PwHL-FEC-HL
43
35.7
56.2
FEC-H-PwH
54
FEC-L-PwL
45
FEC-HL-PwHL
74
HL(?EH)
30
21
46
T docetaxel, H trastuzumab, P paclitaxel, E eprirubicin, C cyclophosphamide, w weekly, F 5-fluorouracil, L lapatinib
Several trials have shown that LHRH analogues are effective in treating breast cancer in premenopausal patients [77]. Due to the trials limitations, it is still not clear if the addition of an LHRH agonist adds an independent effect to chemotherapy and tamoxifen in young women. The SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) trials will hopefully answer this question [78].
Biological treatment Trastuzumab was the leading breakthrough for the treatment of early breast cancer. Approximately 20 % of breast cancers overexpress HER2, which is a negative prognostic factor in early breast cancer [79]. Slamon et al. demonstrated that the addition of trastuzumab to either paclitaxel or AC improved progression-free survival and overall survival in first-line metastatic HER2-positive breast cancer [80]. The dogma of changing the treatment at the time of progression could be overcome by a trial that demonstrated that the treatment beyond progression is possible with trastuzumab in combination with capecitabine [81]. But also changing the antiHER2 agent as well as the chemotherapy is superior to continuing with chemotherapy alone [82]. In 2005, an interim analysis of the HERA (HERceptin Adjuvant) trial was destined to change clinical practice in
early HER2-positive breast cancer therapy [83]. DFS advantages were evident for all subgroups analysed. Data were validated by the combined analyses of NSABP B-31 and NCCTG trial N9831 as well as the BCIRG 006 trial [84, 85]. There is consistent evidence that early concurrent use of trastuzumab with chemotherapy may result in OS benefits which could not be proven in trials that begin with trastuzumab sequentially after chemotherapy. However, the data should be interpreted carefully as the cross-over effect of the standard arm in HERA might have damned the results. Despite the large amount of randomised evidence for early breast cancer it is still questionable in how far patients with pT1a,b tumours should receive trastuzumab as these patients have not been included in the trials. The potential risk of developing cardiac toxicity may jeopardize the long-term survival especially in these patients. Indeed, the potential risk of surviving from breast cancer, but developing heart failure for women undergoing targeted therapies had been raised [86, 87]. Patients at higher risk for cardiac failure were never included in trastuzumab trials. New anti-HER2 agents (lapatinib, pertuzumab, neratinib) have been introduced and the double/triple blockade with or without chemotherapy will focus on research in the next decade. Due to the high costs of these combined therapies, future clinical studies should include translational research to better select those patients with a clear OS benefit and reduce side effects.
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Bevacizumab, an antibody targeting vascular endothelial growth factor receptor (VEGF) was demonstrated in the neoadjuvant setting to increase the pCR in early breast cancer [88, 89]. The adjuvant trials investigating bevacizumab have completed recruitment and results will be available shortly. The potential of bisphosphonates to improve DFS and OS has been investigated in the adjuvant setting showing a benefit only for clearly postmenopausal women or women with ovarian function suppression [90, 91].
10.
Conclusion
13.
The paradigm shift in understanding breast cancer has been of major importance. Breast cancer is a heterogeneous disease with early haematological micrometastatic spread. The greatly improved outcome is due to a multidisciplinary concept, not least driven by new therapies, drugs and better insight into breast cancer biology and early diagnosis. Acknowledgments We thank the independent, non-profit BANSS Foundation, Biedenkopf/Lahn, Germany, for financial support, and the GBG Forschungs-GmbH, Neu-Isenberg, Germany for logistical support of the meeting. All members of the panel had input in the discussion and formulation of the article. The symposium as well as the manuscript preparation was conducted independent of the pharmaceutical industry. The report was drafted entirely by the meeting participants without any paid assistance. Conflict of interest interest to declare.
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17.
None of the co-authors has any conflict of 18.
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