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Thresholds for therapies: highlights of the St GallenInternational Expert Consensus on the Primary Therapyof Early Breast Cancer 2009 A. Goldhirsch1,2*, J. N. Ingle3, R. D. Gelber4, A. S. Coates5, B. Thu¨rlimann6, H.-J. Senn7& Panel members 1International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 2European Institute of Oncology, Milan, Italy; 3BreastCancer Research Program, Mayo Clinic Cancer Center, Rochester, MN, USA; 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; 5International Breast Cancer Study Group, School of Public Health, University of Sydney, Sydney, New South Wales, Australia; 6Breast Center, Kantonsspital, St Gallen, Switzerland and 7Tumor and Breast Center ZeTuP, St Gallen, Switzerland Received 12 May 2009; accepted 12 May 2009 The 11th St Gallen (Switzerland) expert consensus meeting on the primary treatment of early breast cancer in March 2009 maintained an emphasis on targeting adjuvant systemic therapies according to subgroups defined by predictive markers. Any positive level of estrogen receptor (ER) expression is considered sufficient to justify the use of endocrine adjuvant therapy in almost all patients. Overexpression or amplification of HER2 by standard criteria is an indication for anti-HER2 therapy for all but the very lowest risk invasive tumours. The corollary is that ER and HER2 must be reliably and accurately measured. Indications for cytotoxic adjuvant therapy were refined, acknowledging the role of risk factors with the caveat that risk per se is not a target. Proliferation markers, including those identified in multigene array analyses, were recognised as important in this regard. The threshold for indication of each systemic treatment modality thus depends on different criteria which have been separately listed to clarify the therapeutic decision-making Key words: early breast cancer, St Gallen Consensus, therapies benefit accrues from chemotherapy. Judgements must bemade in the care of individual patients of whether to use or The 11th St Gallen conference held in March 2009, which was withhold each treatment modality. It is the intention of this attended by >4800 participants from 101 countries, report to assist in the rational application of evolving incorporated incremental information but proposed knowledge in reaching these judgements.
a radically different treatment selection algorithm for themanagement of early breast cancer. The more we know aboutthe tumour types underlying the heterogeneity of the disease, the greater the opportunity to refine treatment choice. It was New information was presented in the areas of genetics, recognised that clinical trials are very useful for identifying tumour biology, experimental therapeutics, surgery, effective treatments, but fall short of defining the optimal radiation oncology, and adjuvant systemic therapy. Some of treatment of individual patients. For example, local control is this new information is summarised in Table 1. In the light crucial to improve survival on average and especially in of this information, a Panel of 43 experts from around the patients at low risk, but is overwhelmed by the risk of distant world (see Panel members listed in the appendix) again metastases in patients at high risk. Similarly, while cytotoxic considered specific questions to arrive at recommended chemotherapy improves outcome on average among patients principles for the selection of therapies in early breast cancer.
with endocrine-responsive disease receiving endocrinetherapy, subgroups can be defined by conventional pathologyand by multigene analyses in which little or no additional specific considerations for treatmentchoice *Correspondence to: Prof. A. Goldhirsch, International Breast Cancer Study Group, In distilling patient and tumour features to reach patient European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02- treatment decisions, the Panel has adopted a fundamentally 57489439; Fax: +39-02-94379273; E-mail: [email protected] different approach from that used in previous consensus  See appendix for members of the Panel.
reports [71, 72]. Clinical decisions in systemic adjuvant therapy ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
The online version of this article has been published under an open access model. users are entitle to use, reproduce, disseminate, or display the open access version of this article fornon-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and the European Society for Medical Oncology are attributed as the original place ofpublication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated.
For commercial re-use, please contact [email protected] Table 1. Recent research findings presented at the 11th International Conference on Primary Therapy of Early Breast Cancer and their implications forpatient care Status of research/implications for patient care Decrease in breast cancer incidence in some countries is a result of recent changes in the use of hormone replacement therapy in postmenopausal women [1]. Thus, the increased incidence that might be attributedto the use of estrogen and progestin preparations (induced carcinogenesis? induced progression of subclinicalbreast cancer?) is to be considered at least partly reversible [2].
The well-established high-penetrance BRCA1 and BRCA2 genes continue to demonstrate multiple mutations (roughly 2000 each) which make testing technically difficult. Founder mutations in BRCA in somegeographical areas make the detection of mutations easier.
Genome-wide association studies define an increased number of genes which carry a smaller increase in risk for breast cancer, but are relatively common in the population. These genes are of little value in counsellingindividuals, though they are of biological interest and can potentially identify women at slightly increased riskwhich might justify selective screening policies as public health resources are limited [3].
BRCA1 mutations are associated with triple-negative phenotype, which require clinical evaluation of novel therapeutic approaches including poly (ADP-ribose) polymerase inhibitors and DNA-damagingagents [4, 5].
Five-year results of lasofoxifene [6] involving >8000 postmenopausal women with osteoporosis were presented.
Two doses of lasofoxifene were studied: the higher dose (0.5 mg daily) proving more effective with a significantly reduced incidence of estrogen receptor-positive breast cancer (the primary study end point),overall breast cancer, vertebral fracture, nonvertebral fracture, stroke, and major coronary heart disease [7].
These latter features suggest an improved therapeutic ratio compared with tamoxifen prevention. Inparticular, there was no increase in endometrial cancer, though there was an increased incidence of venousthromboembolism, similar to that seen with tamoxifen.
A cistrome is a concept incorporating the complete set of interacting related factors across the entire genome.
Advancing technology allowing us to take a more comprehensive overview of events, both genetic andepigenetic, which influence particular pathways, such as those involved in steroid receptors. Within the steroid receptor cistrome, these studies have identified FOXA1 as an important component [8, 9].
In experimental models, tamoxifen effectiveness requires HER2 suppression which is in turn regulated by the balance between PAX2 and AIB-1 [10].
Further support for the stem-cell hypothesis in breast cancer arises in preclinical studies in which a subpopulation of cells identified by aldefluor are uniquely capable of transplanting tumours in animalmodels and appear to have the characteristics of self-renewing stem cells [11]. Detection of such cells inclinical tissue microarrays identifies patients with a relatively poor prognosis [12].
MicroRNAs, particularly miR-335 and miR-206, affect metastases by blocking cell migration while miR-126 blocks cell proliferation. These microRNAs may be lost in highly metastatic cancers and this isassociated with an oligogenic signature indicative of poor prognosis. The predictive potential is beinginvestigated. Reintroduction of specific microRNAs has proved to be effective in suppressing metastases inanimal models [13].
Evolution of cell survival mechanisms has required redundant network interactions rather than simple linear systems. This poses a more complex problem when attacking a cancer cell. Success is more likely to occur iftwo or more perturbations can be introduced, preferably at crucial early parts of the network [14]. Anexample is the epidermal growth factor receptor (EGFR) family, including HER2.
Circulating tumour cells have been increasingly studied as poor prognosis markers (though they are not yet ready for routine use). New technology allows the evaluation of phenotypic markers in individual circulatingtumour cells and has demonstrated that these may differ from the gross characteristics of the parent tumour[15]. Thus, for example, HER2 overexpression in circulating tumour cells might justify targeted therapy evenin the absence of conventional HER2 positivity of the primary tumour. This strategy is undergoing clinicalinvestigation [16].
Current studies are examining the possibility that some circulating tumour cells may represent breast cancer Status of research/implications for patient care The benefits of current antiangiogenic treatment in metastatic disease are transitory. Drugs that target angiogenesis might, in the long run, induce angiogenesis as a rebound phenomenon and have been demonstratedin preclinical studies to induce tumour progression and metastases [17–19]. A possible mechanism for thistumour progression may be the release of increasing numbers of circulating endothelial cells following some typesof chemotherapy. Importantly, this effect is not seen with metronomic chemotherapy [20].
Long-term treatment with antiangiogenic drugs together with metronomic chemotherapy was associated with dramatic and profound reduction of vascular endothelial growth factor (VEGF) and substantial clinicalresponse in metastatic breast cancer [21]. The type of cancer vascularisation and the extent of VEGF targetingmight be a crucial strategic issue in the treatment of malignancies [22].
Antiangiogenic treatments are under investigation in the adjuvant setting (but are not recommended for routine The mechanism of estrogen effect in cells resistant to estrogen deprivation is apoptosis, which is mediated by increased calcium influx [23]. Apoptosis is increased by G protein-coupled receptor 30 (GPR30). Which inturn can be induced by its agonist known as G-1 [24].
Antiangiogenic agents enhance the tamoxifen effect [25].
Cells which are resistant to this estrogen effect have high glutathione, and depletion of glutathione using buthionine sulphoximine (BSO) will restore full estrogen sensitivity [26].
Further studies of the crosstalk between estrogen receptor and HER2 pathways show that each can act as resistance mechanism for the other. This logically led to studies combining antiestrogenic therapy with agentstargeting receptors of the EGFR family. Examples included the combination of gefitinib with either tamoxifenor anastrozole and the combination of lapatinib with letrozole [27, 28].
The majority but not all studies have associated abnormalities of CYP2D6 on genetic grounds or as a result of certain antidepressant drugs with poorer outcome among patients treated with tamoxifen [29]. It has beenindicated that increased tamoxifen dosage may overcome less effective metabolic conversion to endoxifen insome of these patients [30].
Functional imaging using targets of the hormone receptor [31] and HER2 is under development [32].
Multigene assays are widely proposed to add to the prognostic information available from classical pathological markers and in some circumstances have been shown to identify groups which do or do notbenefit from the addition of chemotherapy to endocrine adjuvant therapy. Surveys of clinical practiceindicate that the information obtained from genetic assays lead to change in treatment decisions in 30%of cases, mainly to avoid chemotherapy [33]. Trials to further validate this application are currentlyunderway [34, 35]. No data are available regarding the applicability of these assays for patients withestrogen receptor-negative disease.
Studies comparing the various genetic profiles indicate commonality in sampling groups of genes representing activation of the steroid hormone receptor pathway, the epidermal growth factor system, and markers ofproliferation. While the former may be useful for specific treatment selection, the dominant prognosticinformation seems to reside within the proliferative marker set [36, 37].
Clinical, pathological, and molecular data may be integrated in more robust prognostic and predictive models.
The best pathology and the most accurate assessment of established markers are key features for a choice of useful treatment, with appropriate integration of molecular assays [37] which add power to the model [38].
Results of sentinel node biopsy after neoadjuvant chemotherapy are reliable as described in a meta-analysis [39] and supported by experience at a single institution [40].
The definition of adequate surgical margins remains controversial with a majority of North American radiation oncologists willing to accept a margin as negative if the tumour does not extend to the inked specimensurface, while surgeons and European radiation oncologists prefer a clearance of 2–5 mm in addition to this[41]. Invasive tumour found at the inked margin is associated with increased ipsilateral breast tumourrecurrence [42].
Evidence was presented that a more generous margin was required in ductal carcinoma in situ (DCIS), perhaps reflecting the propensity of this disease to discontinuous spread [43]. Lobular carcinoma in situ (LCIS) at themargin is not regarded as an indication for reexcision [44].
Studies to investigate the necessity of axillary dissection for patients whose sentinel node biopsy contains only micrometastatic disease (<2 mm) are underway. Meanwhile, experience from a single institution suggests thatthe rate of axillary recurrence remains <2% at a median follow-up of 39 months [45].
The use of contralateral prophylactic mastectomy is clearly increasing in several series [46] though the rationale remains unclear, and evidence that this procedure improves survival is lacking [47].
Status of research/implications for patient care Partial breast irradiation is being studied in several clinical trials but remains experimental. One application might be the treatment of patients who have already received radiation to part of the breast in the course oftreatment for a previous lymphoma [48].
Recent studies of postmastectomy radiation therapy have attempted to dissect the average survival ratio of one death prevented for every four local recurrences avoided [49]. In patients at very high risk of relapse, distantmetastases predominate and local control is a less critical determinant of survival. Conversely, in low-riskcohorts, the ratio may be more favourable and has been reported to approach one death prevented for eachlocal recurrence avoided [50].
Accelerated partial breast irradiation is being investigated in ongoing trials, but a consensus statement from the American Society for Therapeutic Radiology and Oncology [51] provides guidance on patients who might beconsidered suitable for this technique outside of a study.
Either tamoxifen or tamoxifen plus ovarian function suppression, both for the duration of 5 years, is acceptable standards for premenopausal women with endocrine-responsive disease [52, 53].
Recent results from trials continue to support the benefit of aromatase inhibitors in postmenopausal women with receptor-positive breast cancer [54, 55], though others have questioned the extent of benefit [56]. Benefitmay be particularly marked for women at higher risk of relapse. For the women at very low risk of recurrence,there appears to be little benefit from the use of aromatase inhibitors as compared with tamoxifen during thefirst 5 years [57]. For such patients, it may be wise to choose the best tolerated agent that maximisesadherence and minimises impact on quality of life and health status. The duration of aromatase inhibitor therapy, supported by trial results, is 2–5 years [57].
There is some evidence that HER2 positivity carries an adverse prognostic significance even in patients with tumours <1 cm [58], but the relationship to steroid hormone receptor status and adjuvant endocrine orcytotoxic therapies remains unclear in this group [59, 60].
There is a lack of specific predictive markers for response to individual chemotherapeutic agents. Many different regimens are used and no clear indications for a particular regimen exist. Low estrogen receptor, HER2overexpression, and increased proliferation predict response to chemotherapy in general, rather than being Preoperative cytotoxic therapy is less effective for tumours with higher levels of estrogen receptor expression [62].
Triple-negative breast cancer is associated with an improved pathological complete response rate with neoadjuvant chemotherapy [63], but despite this there is an inferior overall survival in comparison to otherbreast cancer types [64]. New approaches undergoing clinical trial evaluation for treatment of triple-negativedisease include new agents such as ixabepilone [65] and DNA-damaging agents such as platinum compounds,anthracyclines, and poly (ADP-ribose) polymerase (PARP) inhibitors [66].
Early clinical investigations are underway to evaluate several promising compounds including new anti-HER2 therapies, HSP-90 inhibitors, mTor inhibitors, anti-IGF1R mAbs, PI3K inhibitors, and antiangiogenesis drugs [67].
All the randomized trials on follow-up were conducted before availability of targeted therapies and molecular markers. A revisiting of early diagnosis of metastases to permit earlier application of targeted therapies iswarranted. Intensive follow-up does not have clinical relevance. Beyond the randomized trials, newtechnologies including positron emission tomography scans and the detection of circulating tumour cellsrequire further evaluation [68].
BIG 1-98: Neither the conventional sequence of tamoxifen followed by letrozole nor the reverse sequence of letrozole followed by tamoxifen proved superior to 5 years of letrozole monotherapy. Early relapses were morefrequent among patients commencing treatment with tamoxifen, particularly in those at higher risk for suchevents. Despite substantial crossover among patients assigned tamoxifen monotherapy, the updatedcomparison suggested that letrozole monotherapy produced superior survival, though this did not attainconventional significance in the intent-to-treat analysis (P = 0.08) [55].
FinHER update: Updated results of the HER2-positive component in the FinHER study confirmed the benefit of a 9-week duration treatment with trastuzumab especially if given with docetaxel (at reduced dose).
Exploratory analyses suggested that the trastuzumab benefit was particularly seen among patients receivingdocetaxel rather than vinorelbine during trastuzumab therapy. A prospective study is comparing this shortregimen with a conventional 1-year trastuzumab regimen (SOLD trial) [69].
HERA: Updated analyses to 4-years median follow-up confirmed the value of one year of trastuzumab in improving disease-free survival, but the overall survival analysis on an intent-to-treat basis has beencomplicated by substantial crossover to late use of trastuzumab in the control arm after publication in 2005 ofinitial study results. The 2-year treatment group remains blinded [70].
Table 2. Thresholdsa for treatment modalities ER negative and PgR positive are probably and complete staining (IHC) or FISH>2.2+]b Trial evidence for trastuzumab is limited to therapy without chemotherapy instrongly ER-positive, HER2-positive islogical but unproven No proven alternative; most at elevated risk aMost factors are continuous but a binary decision needs to be made at some level.
bPatients with tumours of <1 cm in size without axillary nodal involvement and without other features indicating increased metastatic potential (e.g. vascularinvasion) might not need adjuvant systemic therapy. If the tumour is, however, endocrine responsive, endocrine therapy should be considered.
cMedullary carcinoma, apocrine carcinoma, and adenoid cystic carcinoma do not require chemotherapy due to low risk despite being triple negative(provided that, as is usually the case, they have no axillary node involvement and no other signs of increased metastatic risk).
ER, estrogen receptor; PgR, progesterone receptor; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; IHC,immunohistochemistry.
of early breast cancer must address three distinct questions: (i) Oncology and the College of American Pathologists (ASCO/ what justifies the use of endocrine therapy, (ii) what justifies CAP) guidelines [74]. The Panel noted that the existing trials the use of anti-HER2 therapy, and (iii) what justifies the use of used a slightly less restrictive definition of HER2 positivity chemotherapy. Because these decisions are based on quite and acknowledged that patients satisfying the inclusion separate criteria, the previous attempt to produce a single-risk criteria used in the trials might also be considered for anti- categorization and a separate therapy recommendation are no longer considered appropriate. The new algorithm issummarised in Table 2. As before, the Panel recognised that adherence to therapeutic guidelines is affected by affordabilityof certain genetic and imaging tests and the costs of some The threshold for use of cytotoxic chemotherapy is the most systemic therapies in various geographic settings.
difficult to define. Patients receiving anti-HER2 therapyconventionally also receive chemotherapy either preceding orconcurrent with the anti-HER2 treatment. Although considered logical by some of the Panel members, the use of adjuvant anti-HER2 therapy without chemotherapy remains unsupported by The Panel recommends the inclusion of adjuvant endocrine evidence. Chemotherapy is the mainstay of adjuvant treatment therapy in almost all patients whose tumours show evidence of patients with triple-negative disease who are at sufficient risk of endocrine responsiveness, now defined as the presence of of relapse to justify its utilisation. Some rare histological types any detectable estrogen receptor (ER). It questioned the of breast cancer that fall into the category of triple negative and validity of reports of positive progesterone receptor (PgR) in are diagnosed neither with axillary node involvement nor with the absence of ER and suggested that such cases be submitted other signs of increased metastatic potential do not require for further pathological review. Whereas previous categories adjuvant treatment (e.g. medullary, apocrine, and adenoid of highly endocrine responsive and incompletely endocrine cystic breast cancers). Patients with small primary tumours responsive are not relevant to the decision to use or withhold (pT1a pN0 and ER negative) might be spared adjuvant systemic endocrine therapy, such consideration remains important for the selection of patients with ER-positive disease to receive The threshold for recommending chemotherapy for patients with ER-positive, HER2-negative disease is particularly difficultto define. These patients include a spectrum from those at low risk [75, 76] for whom there is little evidence supporting theaddition of chemotherapy to endocrine therapy and to those Anti-HER2 therapy is indicated in patients with HER2- with high risk disease and limited ER expression where positive disease as defined by the American Society of Clinical chemotherapy appears clearly justified. Table 3 summarises the Table 3. Chemoendocrine therapy in patients with ER-positive, HER2-negative disease aConventional measures of proliferation include assessment of Ki67-labelling index (e.g. low, £15%; intermediate, 16%–30%; high, >30%) [77] andpathological description of the frequency of mitoses. The reliability of these measures will vary in different geographic settings. First-generation genetic signatures contain genes sampling the ER, HER2, and proliferative pathways [78, 79]. Meta-analysis indicates that much of the prognostic information inthese signatures resides in their sampling of proliferative genes [80], but their respective total scores may be the only form in which information is provided atpresent and could be used in this component of assessment of relative indications for chemotherapy.
bThe Panel agreed that validated multigene tests, if readily available, could assist in deciding whether to add chemotherapy in cases where its use wasuncertain after consideration of conventional markers.
ER, estrogen receptor; PgR, progesterone receptor; pT, pathological tumour size (i.e. size of the invasive component); PVI, peritumoral vascular invasion.
characteristics which favour the use of chemotherapy, those pathology phenotyping if doubt about the indication for that might justify endocrine therapy alone, and those which are chemotherapy persists after consideration of other factors.
not useful for making this decision. Features indicating Considerations of availability and cost determine the current increased risk of recurrence and thus indirectly supporting the usefulness of multigene assays. The Panel noted that patients value of adding chemotherapy to endocrine therapy in such with pT1a pN0 and ER-positive disease should be offered patients include lower expression of steroid hormone receptors, endocrine therapy alone even if features which usually indicate grade 3 tumours, high proliferation as measured by conventional or multigene assays, and the risk factors of four ormore axillary lymph nodes involved, extensive peritumoral vascular invasion, and tumour size >5 cm. Emerging datapresented but not published indicate that the overall scores Based on the philosophy of defining categories according to from multigene assays may identify patients in these high-risk their implications for treatment selection, the previous categories who do not gain benefit from the addition of three categories of endocrine responsiveness have been chemotherapy to endocrine therapy. This represents an simplified so that endocrine therapy is considered indicated important area of research that will likely be clarified over the if any ER staining is present in the tumour. The majority of next several years. Patients with high expression of ERs and Panellists were in favour of indicating the percentage of PgRs (e.g. >50%), grade 1 tumours, low proliferation, negative stained cells on pathology reports rather than merely using axillary lymph nodes, no peritumoral vascular invasion, and scores. Staining for hormone receptors of ‡50% of tumour tumour size £2 cm may be considered for endocrine therapy cells was viewed as indicating highly endocrine-responsive alone. We note that some features individually provide little guidance in reaching a decision to use chemotherapy. Inparticular, histological grade 2, intermediate scores on multigene assays, tumour size between 2 and 5 cm, and lownumbers of involved lymph nodes (one to three) do not Two technologies are recognised for the determination of provide definitive indications to either give or withhold HER2 positivity. These have recently been addressed by a joint chemotherapy. However, if all these intermediate criteria are working party of the ASCO/CAP [74]. Either present, it usually tips the balance towards the use of immunohistochemical analysis showing uniform, intense chemotherapy. The Panel considered the available multigene membrane staining of >30% of the tumour cells or, assays in this context and concluded that a validated assay alternatively, determination of gene amplification by should be taken into account as an adjunct to high-quality fluorescence in situ hybridisation (FISH) (ratio of HER2 gene copies to chromosome 17 centromers >2.2) or chromogenic in increasing use of prophylactic contralateral mastectomy was situ hybridisation (CISH) (more than six HER2 signals per reported, though it was acknowledged that this procedure was nucleus) is sufficient to define HER2 positivity. Although the not associated with any proven survival advantage.
definitions used in the pivotal trials of trastuzumab were less Radiation therapy after local excision of DCIS was restrictive [81–84], a substantial minority of the Panellists considered to be standard by the Panel members, though most preferred to use 30% intense and complete staining as members considered that it could be avoided in elderly patients a threshold for recommendation of anti-HER2 therapy.
and those with low-grade DCIS and clearly negative margins.
For patients with invasive cancer, postmastectomy radiation therapy was indicated for those with four or more involved axillary lymph nodes, but indications for its use in patients withone to three nodes were considered more restricted and In addition to reporting the presence and type of tumour, the particularly applicable for young patients and those with other Panel considered various additional pathological parameters.
poor prognostic features. The majority of the Panel considered Markers of proliferation, and specifically Ki-67-labelling index, that accelerated whole-breast radiation after conservative were considered important for the determination of prognosis surgery was an acceptable option for patients aged ‡60 with and, importantly, to indicate the potential value of the addition cancers with favourable patterns, but that partial breast of chemotherapy to patients with receptor-positive disease.
radiation should still be considered experimental. The Panel Ki-67 specifically was not accepted as the basis for choosing considered that endocrine therapy without radiation might be aromatase inhibitors rather than tamoxifen in postmenopausal considered in elderly patients with small tumours, clinically patients with receptor-positive disease [85] as further validation of findings in this regard was felt to be necessary [86].
Reporting of ER generated considerable discussion. The Panelstrongly endorsed the reporting of percentage of stained cells but was evenly divided on whether other scoring methods The Panel considered targeted therapies against the steroid should also be reported. PgR was considered valuable for hormone receptors and overexpressed HER2 as of prime prognosis, but less important for predicting response to importance. In patients whose tumours lack these targets or in those at higher risk despite the presence of steroid hormone The majority of the Panel considered that high grade was receptors, the use of chemotherapy requires consideration as set a sufficient indication for chemotherapy and that genomic grade could be considered as an adjunct to histological grade if readilyavailable. Gene expression signatures are likely to indicate endocrine therapy for premenopausal patients a prognostically relevant dichotomy (low grade versus highgrade), though the implications of this observation for therapy The Panel accepted either tamoxifen or tamoxifen plus ovarian require further study [87, 88]. uPA/PAI-1 was not accepted by function suppression as standard endocrine therapies in this a majority of the Panel as a useful prognostic factor.
group. Ovarian function suppression alone or ovarian ablation In an important change from the previous St Gallen conference was considered a possibility only in extraordinary and after a long debate, the Panel supported the use of a validated circumstances. Aromatase inhibitors alone are contraindicated multigene-profiling assay, if readily available, as an adjunct to in premenopausal patients. In case tamoxifen is high-quality phenotyping of breast cancer in cases in which the contraindicated, aromatase inhibitors may be administered to indication for adjuvant chemotherapy remained uncertain.
premenopausal women together with ovarian functionsuppression. Verification of ovarian function suppression topostmenopausal levels is important also in patients under the age of 60 who are receiving aromatase inhibitors.
The aspects considered by the Panel included surgical margins, Pharmacogenetic determination of tamoxifen metabolism indications for sentinel node biopsy, and the role of status as influenced by CYP2D6 was not considered ready for prophylactic mastectomy. Re-excision was considered routine application in selecting patients for tamoxifen therapy mandatory if invasive cancer or DCIS is present at the inked surgical margin, but is not required for lobular carcinoma insitu (LCIS). The Panel was divided about the need for surgical endocrine therapy in postmenopausal patients margins greater than ‘‘not on ink’’ in DCIS, although no A majority of the Panel considered that an aromatase inhibitor detailed specific recommendation was given beside avoiding the should form part of standard endocrine therapy for need to insist on a large (e.g. 1 cm) free margin. The use of postmenopausal women with receptor-positive breast cancer, surgical procedures developed to allow a wide excision with though acknowledging that there were certain patients for satisfactory results (oncoplastic surgery) was also endorsed. The whom tamoxifen alone can be considered adequate. There was Panel considered that sentinel node biopsy is the standard of division about the proper duration of treatment with aromatase care for patients with a clinically negative axilla and that axillary inhibitors, though it was pointed out that safety data beyond 5 node dissection could be avoided in all patients with a negative years are not yet available. The majority of the Panel preferred sentinel node and in selected patients with micrometastatic aromatase inhibitors as up-front endocrine treatment disease or isolated tumour cells in the sentinel node. A trend to particularly in patients at higher risk of early relapse.
about options for preserving fertility. The Panel did not Updated results from two of the trastuzumab trials were consider that any currently available methods for preservation presented continuing to demonstrate the value of this therapy for of fertility following chemotherapy were of proven value, patients with HER2-positive disease. The FinHER trial evaluated though gonadotropin-releasing hormone agonists are used a short course of trastuzumab, which is currently being occasionally. These are being tested in an ongoing clinical trial compared with a conventional 1-year duration. Meanwhile, the for women with endocrine nonresponsive disease who are standard duration of trastuzumab therapy remains 1 year. The receiving alkylating agents. Cryoconservation and Panel noted that no results are yet available from the 2-year retransplantation of ovarian tissue are also experimental.
trastuzumab group in the HERA trial. Interestingly, a majority ofthe Panel was prepared, for selected women, to contemplate trastuzumab with endocrine therapy but without chemotherapydespite the absence of clinical trial evidence to support this Emerging information on bone protection from approach. Finally, the limited evidence of increased risk among demineralisation and tumour by bisphosphonates was viewed patients with HER2-positive tumours <1 cm in size without as interesting, but the Panel did not consider that routine use of axillary nodal involvement does not allow definitive bisphosphonates was indicated for women with normal bone recommendation regarding anti-HER2 therapy in this group.
health receiving adjuvant endocrine therapy.
Two situations were recognised in which the decision to use The Panel considered that adjuvant tamoxifen was standard adjuvant chemotherapy was relatively clear-cut. First, adjuvant therapy and did not endorse the use of adjuvant aromatase systemic therapy for patients with triple-negative disease is inhibitors in men with breast cancer.
essentially limited to chemotherapy, and most such patients areat sufficient risk to justify this treatment. Secondly, as notedabove, chemotherapy is conventionally given with or preceding trastuzumab for patients with HER2-positive invasive breast The present report proposes a new approach to the separate cancer. The remaining patients—those with ER-positive, selection of each treatment modality according to its most HER2-negative disease—are the group in whom decisions relevant indications. We look forward to future studies more about adjuvant chemotherapy are most difficult (Table 3). The accurately defining the value of various high-throughput Panel recognised that patients whose tumours contained high technologies in assessing the level of risk and likelihood of levels of ER derived less benefit from addition of chemotherapy response to specific therapies. Meanwhile, careful application of to endocrine therapy. There was no agreement about the the presently available therapies described in this report offers definition of a standard chemotherapy regimen for any disease great value to women with early breast cancer.
subset. Taxane-containing regimens were discussed andcombinations containing docetaxel and cyclophosphamide aswell as dose-dense doxorubicin and cyclophosphamide followed by paclitaxel were viewed as standard therapies amongseveral other regimens.
Members of the Panel are listed below. All had a significantinput to the discussion and manuscript. John Forbes and StellaKyriakides were unable to attend the Panel session, but provided input for the planning of the meeting and reviewed Neoadjuvant systemic therapy was considered justified primarily to enhance the possibility of breast-conserving Matti Aapro, Clinique de Genolier, 1 Route du Muids, surgery. If indicated, the majority of the Panel considered that 1245 Genolier, Switzerland; Kathy S. Albain, Loyola the neoadjuvant chemotherapy regimen should include both University Medical Center, Cardinal Bernardin Cancer a taxane and an anthracycline and (for HER2-positive disease) Center, 2160 S First Avenue, Room 109, Maywood, IL 60153, an anti-HER2 drug. Thus, the choice of a regimen for adjuvant USA; Jonas Bergh, Department of Oncology, Karolinska or neoadjuvant chemotherapy might be made using similar Institute and University Hospital, 17176 Stockholm, Sweden; criteria. Neoadjuvant endocrine therapy without chemotherapy Harold Burstein, Department of Medical Oncology/Solid was considered reasonable for postmenopausal patients with Tumor Oncology, Dana-Farber Cancer Institute, 44 Binney strongly receptor-positive disease. If used, such treatment Street, Boston, MA 02115, USA; Robert Carlson, Medical should be considered for a duration of 5–8 months or until Oncology, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA; Monica Castiglione-Gertsch,MHA ISPM/RGT University of Geneva, Boulevard de la Cluse55, 1205 Geneva, Switzerland; Alan S. Coates, International Breast Cancer Study Group and University of Sydney, Sydney,40 Cook Road, Centennial Park NSW 2021, Australia; Marco Pregnancy after diagnosis of breast cancer has not been shown Colleoni, Research Unit Medical Senology, European to negatively impact prognosis. Women should be counselled Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; Alberto Costa, European School of Oncology, Via del Bollo 4, Oncology, Institut Jules Bordet, Rue He´ger-Bordet 1, 1000 20123 Milan, Italy; Jack Cuzick, Cancer Research, UK Centre Brussels, Belgium; Kurt Possinger, Universita¨tsklinikum for Epidemiology, Mathematics and Statistics, Wolfson Charite´ Campus Mitte, Centrum 14, M.S. Onkologie/ Institute of Preventive Medicine, Queen Mary College, Ha¨matologie, Charite´platz 1, 10117 Berlin, Germany; University of London, Charterhouse Square, London EC1M Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre, 6BQ, UK; Nancy Davidson, Director, University of Ontario Clinical Oncology Group, 2075 Bayview Avenue, Pittsburgh Cancer Institute, 5150 Centre Avenue, UPMC Toronto, Ontario M4N 1H6, Canada; Emiel J.T. Rutgers, Cancer Pavilion, 5th Floor, Suite 500, Pittsburgh, PA 15232, The Netherlands Cancer Institute, Department of Surgery, USA; Angelo Di Leo, Sandro Pitigliani Medical Oncology Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Unit, Department of Oncology, Hospital of Prato, Piazza Vladimir F. Semiglazov, N.N. Petrov Research Institute of dell’Ospedale, 59100 Prato, Italy; John F. Forbes, ANZ Breast Oncology, 68 Leningradskaya Street, Pesochny-2, 197758 St.
Cancer Trials Group, University of Newcastle, Locked Bag 7, Petersburg, Russia; Ian Smith, Department of Medicine, Hunter Region Mail Centre, NSW 2310, Newcastle, Australia Royal Marsden Hospital and Institute of Cancer Research, (Absent); Richard D. Gelber, Department of Biostatistics and Fulham Road, London, SW3 6JJ, UK; Beat Thu¨rlimann, Computational Biology, Dana-Farber Cancer Institute, 44 Breast Center, Kantonsspital St Gallen, 9007 St Gallen, Binney Street, Boston, MA 02115, USA; John H. Glick, Switzerland; Giuseppe Viale, Department of Pathology, University of Pennsylvania, Abramson Cancer Center, 16 European Institute of Oncology and University of Milan, Via Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104- Ripamonti 435, 20141 Milan, Italy; Toru Watanabe, 4283, USA; Joseph Gligorov, APHP Tenon, Cancer Est, 4 Rue Department of Medicine, Hamamatsu Oncology Center, 3-6- de la Chine, 75020 Paris, France; Michael Gnant, Department 13 Chuo Naka-Ku, 430-0929 Hamamatsu, Japan; Eric P.
of Surgery, Medical University of Vienna, Wa¨hringer Gu¨rtel Winer, Breast Oncology Center, Dana-Farber Cancer 18-20, 1090 Wien, Austria; Aron Goldhirsch, International Institute, 44 Binney Street, Boston, MA, 02115, USA; William Breast Cancer Study Group, Oncology Institute of Southern C. Wood, Department of Surgery, Suite B 206, Emory Switzerland, 6500 Bellinzona, Switzerland and European University Hospital, 1364 Clifton Road, Atlanta, GA 30322, Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy (Chairman); Paul E. Goss, Director, Breast Cancer Research, The authors thank the Participants in the 11th International MGH Cancer Center, 55 Fruit Street, Boston, MA 02114, Conference on Primary Therapy of Early Breast Cancer for USA; Jay Harris, Department of Radiation Oncology, Dana- many useful remarks and for substantial contributions to the Farber Cancer Institute, Brigham and Women’s Hospital, process. We acknowledge the substantial contributions of Room 1622, 44 Binney Street, Boston, MA 02115, USA; James Giuseppe Curigliano, Shari Gelber, and Sabina Briner. We also N. Ingle, Mayo Clinic Cancer Center, Breast Cancer Research thank Professor Umberto Veronesi for his guidance and Franco Program, 200 First Street, S.W., Rochester, MN 55905, USA (Chairman); Jacek Jassem, Department of Oncology &Radiotherapy, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; Per Karlsson, Department ofOncology, Sahlgrenska University Hospital, 41345 Go¨teborg, 1. Chlebowski RT, Kuller LH, Prentice RL et al. Breast cancer after use of Sweden; Manfred Kaufmann, Director, Department estrogen plus progestin in postmenopausal women. N Engl J Med 2009; 360: Gynecology, Obstetrics and Breast Unit, J.W. Goethe University Hospital, Theodor Stern Kai 7, 60596 Frankfurt a.
2. Ravdin PM. The changes in breast cancer incidence: a result of recent changes M., Germany; Stella Kyriakides, Europa Donna Cyprus, 28 in hormone use by postmenopausal women? Breast 2009; 18 (Suppl 1): S1(Abstr S3).
Prodromou Street, 2406 Nicosia, Cyprus (Absent); LouisMauriac, Institute Bergonie´, Regional Cancer Center, 229 3. Brody LC. Current knowledge on genetic predispositions for breast cancer.
Breast 2009; 18 (Suppl 1): S4 (Abstr S9).
Cours d’Argonne, 33076 Bordeaux, France; Gunter von 4. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA Minckwitz, GBG Forschungs GmbH, Schleussnerstrasse 42, mutant cells as a therapeutic strategy. Nature 2005; 434: 917–921.
63263 Neu Isenburg, Germany; Monica Morrow, Breast 5. Rottenberg S, Jaspers JE, Kersbergen A et al. High sensitivity of BRCA1- Surgery Service, Anne Burnett Windfohr Chair of Clinical deficient mammary tumors to the PARP inhibitor AZD2281 alone and in Oncology, Memorial Sloan-Kettering Cancer Center, combination with platinum drugs. Proc Natl Acad Sci U S A 2008; 105: Department of Surgery, 1275 York Avenue MRI 1026, New York, NY 10065, USA; Henning T. Mouridsen, Department 6. Powles T, Neven P, Osborne C et al. Five year results of a randomised placebo of Oncology, Finsen Center 5074, Rigshospitalet, Blegdamsvej controlled trial of lasofoxifene (PEARL) on the incidence of ER positive breast 9, 2100 Copenhagen, Denmark; Moise Namer, Head, Medical cancer in postmenopausal women with osteoporosis. Breast 2009; 18 (Suppl 1): Oncology, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France; Larry Norton, 7. Powles T, Neven P, Osborne C et al. Effects of 5 years of treatment with lasofoxifene on incidence of breast cancer in older women by baseline estradiol Director of Breast Cancer Program, Memorial Sloan- levels. Breast 2009; 18 (Suppl 1): S26 (Abstr 0033).
Kettering Cancer Center, Room H 901, 205 East 64th Street, 8. Krum SA, Miranda-Carboni GA, Lupien M et al. Unique ERalpha cistromes Concourse Level, New York, NY 10021-6007, USA; control cell type-specific gene regulation. Mol Endocrinol 2008; 22: Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project, 4929 Bayard Street, Pittsburgh, PA 15213, 9. Lupien M, Eeckhoute J, Meyer CA et al. FoxA1 translates epigenetic signatures USA; Martine J. Piccart-Gebhart, Internal Medicine, into enhancer-driven lineage-specific transcription. Cell 2008; 132: 958–970.
10. Brown M. Mining the steroid receptor cistrome for novel targets, biomarkers and 35. Sparano JA. TAILORx: trial assigning individualized options for treatment (Rx).
risk alleles. Breast 2009; 18 (Suppl 1): S3 (Abstr S6).
Clin Breast Cancer 2006; 7: 347–350.
11. Charafe-Jauffret E, Ginestier C, Iovino F et al. Breast cancer cell lines contain 36. Wirapati P, Sotiriou C, Kunkel S et al. Meta-analysis of gene expression profiles functional cancer stem cells with metastatic capacity and a distinct molecular in breast cancer: toward a unified understanding of breast cancer subtyping and signature. Cancer Res 2009; 69: 1302–1313.
prognosis signatures. Breast Cancer Res 2008; 10: R65.
12. Wicha MS, Ginestier C, Dontu G et al. Breast cancer stem cells: getting to treat 37. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med the core. Breast 2009; 18 (Suppl 1): S7 (Abstr S17).
13. Tavazoie SF, Alarco´n C, Oskarsson T et al. Endogenous human microRNAs that 38. Viale G. Integrating molecular profiling, histologic type and other variables: suppress breast cancer metastasis. Nature 2008; 451: 147–152.
defining the fingerprint of responsiveness to treatment. Breast 2009; 18 (Suppl 14. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol 39. Xing Y, Foy M, Cox DD et al. Meta-analysis of sentinel lymph node biopsy after 15. Ignatiadis M, Kallergi G, Ntoulia M et al. Prognostic value of the molecular preoperative chemotherapy in patients with breast cancer. Br J Surg 2006; 93: detection of circulating tumor cells using a multimarker reverse transcription- PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer.
40. Veronesi P, Rodriguez J. Breast conservation and sentinel lymph node biopsy Clin Cancer Res 2008; 14: 2593–2600.
after neoadjuvant systemic therapy. Breast 2009; 18 (Suppl 1): S11 (Abstr S27).
16. Cristofanilli M. The biological information obtainable from circulating tumor cells.
41. Morrow M, Wu S. Breast conservation and clear margins: invasive or in situ Breast 2009; 18 (Suppl 1): S6 (Abstr S13).
involvement. Breast 2009; 18 (Suppl 1): S12 (Abstr S28).
17. Ebos JM, Lee CR, Cruz-Munoz W et al. Accelerated metastasis after short-term 42. Kreike B, Hart AA, van de Velde T et al. Continuing risk of ipsilateral breast treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009; 15: relapse after breast-conserving therapy at long-term follow-up. Int J Radiat Oncol Biol Phys 2008; 71: 1014–1021.
18. Loges S, Mazzone M, Hohensinner P et al. Silencing or fueling metastasis 43. Dunne C, Burke JP, Morrow M et al. Effect of margin status on local recurrence with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15: after breast conservation and radiation therapy for ductal carcinoma in situ. J 19. Pa`ez-Ribes M, Allen E, Hudock J et al. Antiangiogenic therapy elicits malignant 44. Ciocca RM, Li T, Freedman GM et al. Presence of lobular carcinoma in situ does progression of tumors to increased local invasion and distant metastasis. Cancer not increase local recurrence in patients treated with breast-conserving therapy.
Ann Surg Oncol 2008; 15: 2263–2271.
20. Kerbel RS. Modulation of angiogenesis: clinical impact (in breast cancer). Breast 45. Galimberti V. Axillary sentinel lymph node: how low can you go? Breast 2009; 18 21. Dellapasqua S, Bertolini F, Bagnardi V et al. Metronomic cyclophosphamide and 46. Tuttle TM, Jarosek S, Habermann EB et al. Increasing rates of contralateral capecitabine combined with bevacizumab in advanced breast cancer. J Clin prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin 22. Bertolini F, Mancuso P, Curigliano G et al. The (last?) word about biomarkers for angiogenesis. Breast 2009; 18 (Suppl 1): S6 (Abstr S15).
47. Brekelmans CT, Seynaeve C, Menke-Pluymers M et al. Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol 2006; 17: 391–400.
23. Prossnitz ER, Arterburn JB, Smith HO et al. Estrogen signalling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol 2008; 70: 48. Kraus-Tiefenbacher U, Bauer L, Scheda A et al. Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previousexternal-beam radiotherapy. BMC Cancer 2007; 7: 178.
24. Bologa CG, Revankar CM, Young SM et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2006; 2: 207–212.
49. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in 25. Aesoy R, Sanchez BC, Norum JH et al. An autocrine VEGF/VEGFR2 and p38 the extent of surgery for early breast cancer on local recurrence and 15-year signaling loop confers resistance to 4-hydroxytamoxifen in MCF-7 breast cancer survival: an overview of the randomised trials. Lancet 2005; 366: 2087–2106.
cells. Mol Cancer Res 2008; 6: 1630–1638.
50. Kyndi M, Overgaard M, Nielsen HM et al. High local recurrence risk is not 26. Lewis-Wambi JS, Kim HR, Wambi C et al. Buthionine sulfoximine sensitizes associated with large survival reduction after postmastectomy radiotherapy in antihormone-resistant human breast cancer cells to estrogen-induced apoptosis.
high-risk breast cancer: a subgroup analysis of DBCG 82 b&c. Radiother Oncol 27. Arpino G, Wiechmann L, Osborne CK et al. Crosstalk between the estrogen 51. Smith BD, Arthur DW, Buchholz TA et al. Accelerated partial breast irradiation receptor and the HER tyrosine kinase receptor family: molecular mechanism and consensus statement from the American Society of Therapeutic Radiology and clinical implications for endocrine therapy resistance. Endocr Rev 2008; 29: Oncology. Int J Radiat Oncol Biol Phys 2009; doi:10.1016/j.ijrobp.2009.02.031.
52. Higgins MJ, Davidson NE. What is the current status of ovarian suppression/ 28. Osborne K, Schiff R. Combined ER and HER-targeted therapy in breast cancer ablation in women with premenopausal early-stage breast cancer? Curr Oncol treatment. Breast 2009; 18 (Suppl 1): S8 (Abstr S20).
29. Ntukidem NI, Nguyen AT, Stearns V et al. Estrogen receptor genotypes, 53. Davidson NE. Adjuvant therapies for premenopausal women with endocrine- menopausal status, and the lipid effects of tamoxifen. Clin Pharmacol Ther 2008; responsive disease. Breast 2009; 18 (Suppl 1): S15 (Abstr S35).
54. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Forbes JF, 30. McLeod HL. Pharmacogenetics to drive breast cancer treatments. The Breast Cuzick J et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 31. Hospers GA, Helmond FA, de Vries EG et al. PET imaging of steroid receptor expression in breast and prostate cancer, Curr Pharm Des 2008; 14: 55. Mouridsen HT, Giobbie-Hurder A, Mauriac L et al. BIG 1–98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence 32. de Vries E, Oude Munnink T, Nagengast W et al. Molecular imaging of breast as adjuvant endocrine therapy for postmenopausal women with receptor-positive cancer. Breast 2009; 18 (Suppl 1): S8 (Abstr S21).
breast cancer. In San Antonio Breast Cancer Symposium, San Antonio, TX.
33. Albain KS. Should genomic profiles be used to determine who should receive adjuvant chemotherapy? Breast 2009; 18 (Suppl 1): S17 (Abstr S40).
56. Seruga B, Tannock IF. Up-front use of aromatase inhibitors as adjuvant therapy 34. Bogaerts J, Cardoso F, Buyse M et al. Gene signature evaluation as a prognostic for breast cancer: the emperor has no clothes. J Clin Oncol 2009; 27: 840–842.
tool: challenges in the design of the MINDACT trial. Nat Clin Pract Oncol 2006; 3: 57. Winer E. Treatment of postmenopausal women with hormone responsive breast cancer. Breast 2009; 18 (Suppl 1): S16 (Abstr S39).
58. Chia S, Norris B, Speers C et al. Human epidermal growth factor receptor 2 epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; overexpression as a prognostic factor in a large tissue microarray series of node- negative breast cancers. J Clin Oncol 2008; 26: 5697–5704.
75. Gnant M, Mlineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic 59. Curigliano G, Viale G, Bagnardi V et al. Clinical relevance of HER-2 acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–691.
overexpression/amplification in patients with small tumor size (pT1a-b) and 76. Thu¨rlimann B, Price KN, Gelber RD et al. Is chemotherapy necessary for node-negative breast cancer. J Clin Oncol 2009 in press.
premenopausal women with lower-risk node positive, endocrine responsive 60. Smith IE. Targeting HER2 in the adjuvant setting: dealing with new standards and breast cancer? 10-year update of International Breast Cancer Study Group Trial open questions. Breast 2009; 18 (Suppl 1): S17 (Abstr S41).
11–93. Breast Cancer Res Treat 2009; 113: 137–144.
61. Hayes D. Is there a standard type and duration of adjuvant chemotherapy? 77. Jalava P, Kuopio T, Juntti-Patinen L et al. Ki67 immunohistochemistry: Breast 2009; 18 (Suppl 1): S15 (Abstr S37).
a valuable marker in prognostication but with a risk of misclassification: 62. Colleoni M, Viale G, Zahrieh D et al. Expression of ER, PgR, HER1, HER2, and proliferation subgroups formed based on Ki67 immunoreactivity and response: a study of preoperative chemotherapy. Ann Oncol 2008; 19: standardized mitotic index. Histopathology 2006; 48: 674–682.
78. Paik S, Tang G, Shak S et al. Gene expression and benefit of chemotherapy in 63. von Minckwitz G, Kaufmann M, Ku¨mmel S. Integrated meta-analysis on 6402 women with node-negative, estrogen receptor-positive breast cancer. J Clin patients with early breast cancer receiving neoadjuvant anthracycline-taxane +/2 trastuzumab containing chemotherapy. In San Antonio Breast Cancer 79. van de Vijver MJ, He YD, van’t Veer LJ et al. A gene-expression signature as Symposium, San Antonio, TX. 2008; (Abstr 79).
a predictor of survival in breast cancer. N Engl J Med 2002; 347: 1999–2009.
64. Liedtke C, Mazouni C, Hess KR et al. Response to neoadjuvant therapy and long- 80. Wirapati P, Sotiriou C, Kunkel S et al. Meta-analysis of gene expression profiles term survival in patients with triple-negative breast cancer. J Clin Oncol 2008; in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures. Breast Cancer Res 2008; 10: R65.
65. Baselga J, Zambetti M, Llombart-Cussac A et al. Phase II genomics study of 81. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol 2009; 27: for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 82. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after 66. Perez EA. Adjuvant therapy of triple negative breast cancer. Breast 2009; 18 adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 67. Baselga J. Review of new targeted drugs: crawling towards the adjuvant setting.
83. Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or Breast 2009; 18 (Suppl 1): S17 (Abstr S43).
vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 68. Smith IE. The follow-up of women at high risk for breast cancer relapse. Breast 84. Slamon D, Eiermann W, Robert NJ. BCIRG 006: 2nd interim analysis phase III 69. Joensuu H, Bono P, Kataja V et al. Update of the FINHER trial based on 5 years of randomized trial comparing doxorubicin and cyclophosphamide followed by follow-up. Breast 2009; 18 (Suppl 1): S10 (Abstr S24).
docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and 70. Gianni L, Goldhirsch A, Gelber RD et al. Update of the HERA trial and the role of trastuzumab with docetaxel, carboplatin and trastuzumab in Her2neu positive 1 year trastuzumab as adjuvant therapy for breast cancer. Breast 2009; 18 early breast cancer patients. In Presented at the 2006 San Antonio Breast Cancer Symposium. San Antonio: Texas, 14–17 December 2006.
71. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: international expert 85. Dowsett M, Dunbier AK. Emerging biomarkers and new understanding of consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; traditional markers in personalized therapy for breast cancer. Clin Cancer Res 72. Goldhirsch A, Wood WC, Gelber RD et al. Progress and promise: highlights of the 86. Viale G, Giobbie-Hurder A, Regan MM et al. Prognostic and predictive value of international expert consensus on the primary therapy of early breast cancer centrally reviewed Ki-67 labeling index in postmenopausal women with 2007. Ann Oncol 2007; 18: 1133–1144.
endocrine responsive breast cancer. Results from Breast International Group Trial 73. Ibrahim M, Dodson A, Barnett S et al. Potential for false-positive staining with 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 2008; 26: a rabbit monoclonal antibody to progesterone receptor (SP2): findings of the UK National External Quality Assessment Scheme for Immunocytochemistry and 87. Ivshina AV, George J, Senko O et al. Genetic reclassification of histologic grade FISH highlight the need for correct validation of antibodies on introduction to delineates new clinical subtypes of breast cancer. Cancer Res 2006; 66: the laboratory. Am J Clin Pathol 2008; 129: 398–409.
74. Wolff A, Hammond ME, Schwartz JN et al. American Society of Clinical Oncology/ 88. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med College of American Pathologists guideline recommendations for human

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