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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: firstname.lastname@example.org
different approach from that used in previous consensus
See appendix for members of the Panel.
reports [71, 72]. Clinical decisions in systemic adjuvant therapy
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.
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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 . 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 .
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 .
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  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 .
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 .
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 . Detection of such cells inclinical tissue microarrays identifies patients with a relatively poor prognosis .
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 .
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 . 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. 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 .
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 .
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 . The type of cancer vascularisation and the extent of VEGF targetingmight be a crucial strategic issue in the treatment of malignancies .
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 . Apoptosis is increased by G protein-coupled receptor 30 (GPR30). Which inturn can be induced by its agonist known as G-1 .
Antiangiogenic agents enhance the tamoxifen effect .
Cells which are resistant to this estrogen effect have high glutathione, and depletion of glutathione using
buthionine sulphoximine (BSO) will restore full estrogen sensitivity .
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 . It has beenindicated that increased tamoxifen dosage may overcome less effective metabolic conversion to endoxifen insome of these patients .
Functional imaging using targets of the hormone receptor  and HER2 is under development .
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 . 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  which add power to the model .
Results of sentinel node biopsy after neoadjuvant chemotherapy are reliable as described in a meta-analysis 
and supported by experience at a single institution .
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. Invasive tumour found at the inked margin is associated with increased ipsilateral breast tumourrecurrence .
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 . Lobular carcinoma in situ (LCIS) at themargin is not regarded as an indication for reexcision .
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 .
The use of contralateral prophylactic mastectomy is clearly increasing in several series  though the rationale
remains unclear, and evidence that this procedure improves survival is lacking .
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 .
Recent studies of postmastectomy radiation therapy have attempted to dissect the average survival ratio of one
death prevented for every four local recurrences avoided . 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 .
Accelerated partial breast irradiation is being investigated in ongoing trials, but a consensus statement from the
American Society for Therapeutic Radiology and Oncology  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 . 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 . 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 .
There is some evidence that HER2 positivity carries an adverse prognostic significance even in patients with
tumours <1 cm , 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 .
Triple-negative breast cancer is associated with an improved pathological complete response rate with
neoadjuvant chemotherapy , but despite this there is an inferior overall survival in comparison to otherbreast cancer types . New approaches undergoing clinical trial evaluation for treatment of triple-negativedisease include new agents such as ixabepilone  and DNA-damaging agents such as platinum compounds,anthracyclines, and poly (ADP-ribose) polymerase (PARP) inhibitors .
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 .
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 .
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) .
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) .
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 .
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 . 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%)  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 , 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 . 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  as further validation
of findings in this regard was felt to be necessary .
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,
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Sesiones de trabajo: "Espacio europeo de seguridad jurídica" 2ª Sesión de trabajo "Valor para los ciudadanos" La construcción de la Unión Europea, a partir de la Declaración de Robert Schuman de 9 de mayo de 1950, sobre la creación de la Comunidad Europea del Carbón y del Acero se caracteriza por apoyarse fundamentalmente en el derecho. Los anteriores esfuerzos de unific