Mdr304 1736.1747

Strategies for subtypes—dealing with the diversity ofbreast cancer: highlights of the St Gallen InternationalExpert Consensus on the Primary Therapy of EarlyBreast Cancer 2011 A. Goldhirsch1*, W. C. Wood2, A. S. Coates3, R. D. Gelber4, B. Thu¨rlimann5, H.-J. Senn6 & Panelmembers 1International Breast Cancer Study Group, Department of Medicine, European Institute of Oncology, Milan, Italy; 2Department of Surgery, Emory University School ofMedicine, N. E. Atlanta, USA; 3International Breast Cancer Study Group and University of Sydney, Sydney, Australia; 4International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA; 5Breast Center, Kantonsspital St Gallen, St Gallen; 6Tumor and Breast Center ZeTuP, St Gallen, Switzerland Received 21 April 2011; accepted 23 May 2011 The 12th St Gallen International Breast Cancer Conference (2011) Expert Panel adopted a new approach to the classification of patients for therapeutic purposes based on the recognition of intrinsic biological subtypes within the breast cancer spectrum. For practical purposes, these subtypes may be approximated using clinicopathological rather than gene expression array criteria. In general, systemic therapy recommendations follow the subtype classification.
Thus, ‘Luminal A’ disease generally requires only endocrine therapy, which also forms part of the treatment of the ‘Luminal B’ subtype. Chemotherapy is considered indicated for most patients with ‘Luminal B’, ‘Human Epidermal growth factor Receptor 2 (HER2) positive’, and ‘Triple negative (ductal)’ disease, with the addition of trastuzumab in ‘HER2 positive’ disease. Progress was also noted in defining better tolerated local therapies in selected cases without loss of efficacy, such as accelerated radiation therapy and the omission of axillary dissection under defined circumstances. Broad treatment recommendations are presented, recognizing that detailed treatment decisions need to consider disease extent, host factors, patient preferences, and social and economic constraints.
Key words: adjuvant therapies, early breast cancer, St Gallen Consensus, subtypes countries and a worldwide faculty representing all relevantdisciplines. After presentation of recent research findings, It is no longer tenable to consider breast cancer as a single a 51-member Expert Panel (see Appendix 1) considered disease. Subtypes can be defined by genetic array testing [1–3] a number of questions in order to arrive at treatment or approximations to this classification using recommendations for the immediate future. As in previous St immunohistochemistry [4–7]. These subtypes have different Gallen conferences [18], the Panel was charged with assessing epidemiological risk factors [8, 9], different natural histories the evidence, but also advising on the basis of expert opinion [10–12], and different responses to systemic and local therapies on those questions where the evidence was ambiguous or [13–17]. These differences imply that clinicians managing lacking. For the first time, this conference included an explicit breast cancer should consider cases within the various distinct approach to management of conflicts of interest (see subtypes in order to properly assess the relevant evidence and arrive at appropriate therapeutic advice.
Evidence was presented to support a less aggressive approach to axillary surgery in defined circumstances and the use of more convenient equally effective approaches to radiation therapy.
For systemic therapy, the emphasis of this year’s consensus was The 12th International Breast Cancer Conference in March to reach recommendations within each of the biological 2011 brought together some 4300 participants from 96 subtypes, since these already incorporate many of the riskfactors and response predictors previously considered *Correspondence to: Prof. A. Goldhirsch, International Breast Cancer Study Group, separately. Disease extent, host factors, patient preferences, and Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489439; Fax: +39-02-94379273; economic and social factors inevitably impact the choice and delivery of care. In general, the recommendations are intended to guide therapy considerations outside clinical trials in See Appendix 1 for members of the Panel.
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permitsunrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
communities with reasonable levels of available resources, but noting where possible the availability of alternatives, whichmight be only marginally less effective but less expensive.
More than 100 questions were circulated and agreed among This report will first review the new findings presented at the Panel members before the meeting. These were presented meeting (Table 1) and then proceed to summarize the during the final session of the conference. Panel members had deliberations of the Panel, bringing these together to form the opportunity to comment, and then voted electronically either yes or no on each question, with the option to abstainif they felt uninformed or conflicted. The detailed votesare not presented here: Rather, verbal descriptions of the extent of agreement or disagreement are given in the New results from clinical trials supported the safety of omitting axillary dissection not only in patients with a negative sentinelnode biopsy [19] but also in patients with a clinically node- negative axilla but pathological macrometastatic involvementof one or two sentinel nodes in the context of breast-conserving The Panel was clearly of the view that the routine use of surgery with tangential field radiation therapy [20]. This immunohistochemistry to look for low-volume metastatic continues a trend of reduced surgical extent without loss of disease in sentinel nodes was not indicated, since metastases efficacy, which dates back to the breast-conserving approaches shown only by immunohistochemistry would not alter pioneered by Veronesi [74] and Fisher [75].
management. Furthermore, isolated tumor cells, and even Similarly, recent studies in radiation therapy have metastases up to 2 mm (micrometastases) in a single sentinel demonstrated the safety and efficacy of abbreviated schedules node, were not considered to constitute an indication for for improved patient convenience and the use of partial breast axillary dissection regardless of the type of breast surgery irradiation (PBI) under certain defined circumstances. These carried out. The Panel accepted the option of omitting axillary dissection for macrometastases in the context of lumpectomyand radiation therapy for patients with clinically node-negative disease and 1–2 positive sentinel lymph nodes as reported from ACOSOG trial Z0011 with a median follow-up Analysis of gene expression arrays has resulted in the of 6.3 years [20]. The Panel, however, was very clear that this recognition of several fundamentally different subtypes of practice, based on a specific clinical trial setting, should not be breast cancer [1]. Because it is not always feasible to obtain gene extended more generally, such as to patients undergoing expression array information, a simplified classification, closely mastectomy, those who will not receive whole-breast following that proposed by Cheang et al. [7], has been adopted tangential field radiation therapy, those with involvement of as a useful shorthand. Subtypes defined by clinicopathological more than two sentinel nodes, and patients receiving criteria are similar to but not identical to intrinsic subtypes and represent a convenient approximation. As summarized inTable 2, this approach uses immunohistochemical definition ofestrogen and progesterone receptor, the detection of overexpression and/or amplification of the human epidermal The Panel considered accelerated whole-breast radiotherapy to growth factor receptor 2 (HER2) oncogene, and Ki-67 labeling be an acceptable option in select patients: In particular, the index, a marker of cell proliferation, as the means of identifying Panel was divided about the use of this approach in the presence of extensive vascular invasion.
Clearly, this clinicopathological classification requires the Partial breast irradiation (PBI) as definitive treatment in availability of reliable measurements of its individual selected patients was supported by almost half of the Panel and components. Guidelines have been published for estrogen and by a strong majority for patients above the age of 70. There was progesterone receptor determination [76] and for the considerable uncertainty about its use in lymphoma survivors detection of HER2 positivity [77]. For clinical decision who had previously undergone mantle field irradiation, where making, the Panel supported using the US Food and Drug out-of-quadrant second cancers’ risks are considerable and for Administration definition of HER2 positivity based on the any patient groups different from the current eligible population eligibility criteria for HER2 status determination from the in PBI trials. The Panel generally accepted PBI as an alternative to pivotal clinical trials [80, 81]. It was noted that clarifications conventional external beam boost to the tumor bed.
to the ASCO/CAP guidelines were in preparation, and these Post-mastectomy radiation therapy was strongly supported have subsequently been published [82]. Ki-67 labeling index for patients with four or more axillary lymph nodes involved.
presents more substantial challenges, but important guidelines While not in general favoring irradiation for those with lesser for this test are under development [7, 83–85]. In the nodal involvement, the Panel by a slim majority favored proposed classification, Ki-67 labeling index is chiefly post-mastectomy radiation for patients younger than 45 years important in the distinction between ‘Luminal A’ and with 1–3 positive nodes and for patients at any age with ‘Luminal B (HER2 negative)’ subtypes. If reliable Ki-67 extensive vascular invasion in two or more blocks in labeling index assessment is not available, some alternative conjunction with 1–3 positive nodes.
measure of proliferation such as a histological grade may be A majority of the Panel supported radiation after complete excision of ductal carcinoma in situ (DCIS) but was prepared to Table 1. Recent research findings presented at the 12th International Conference on Primary Therapy of Early Breast Cancer and their implications forpatient care Status of research/implications for patient care Several studies have underlined the safety of more conservative approaches to the surgery of the axilla. If sentinel lymph nodes areclear, axillary dissection can be omitted [19]. The ACOSOG trial Z0011for patients with a clinically node-negative axilla who underwentlumpectomy and tangential whole-breast irradiation showed at amedian follow-up of 6.3 years that axillary dissection can be omittedwithout adversely affecting prognosis even in the presence of one ortwo positive sentinel nodes [20].
Radiation therapy—partial breast irradiation A randomized trial of targeted intraoperative radiotherapy yielded results closely similar to conventional whole-breast irradiation [21]. It isnoteworthy that in this study, 14% of the targeted intraoperativeradiotherapy group also received external beam radiotherapy andthe median follow-up in the study is 2.5 years. A single institutionseries of 1822 patients treated with breast-conserving surgery hasdocumented excellent local control with intraoperative electronbeam therapy in selected patients [22].
Radiation therapy—abbreviated (hypofractionated Long-term results of the Canadian randomized trial in pT1,2 N0 patients largely treated without adjuvant chemotherapy at a medianfollow-up of 12 years show similar locoregional control, survival,tolerability, and cosmesis for a 16 fraction regimen compared with a25 fraction conventionally fractionated whole-breast radiotherapydelivered without external beam boost [23]. Similar results have beenreported from the UK START trial at a median follow-up of 6 yearsusing a 15 fraction regimen [24].
In the presence of tumor defects in homologous recombination DNA repair, inhibition of the PARP enzyme system may result in ‘syntheticlethality’ and increased cell kill [25]. This is particularly well seen in carriersof BRCA1 and BRCA2 mutations. In such patients, single-agent PARP inhibitors,such as olaparib, produce substantial tumor responses. Other cases of triple-negativedisease seldom respond to single-agent PARP inhibition [26]. In such patients,DNA disrupting cytotoxic agents are being investigated in combination with PARP inhibitors.
Double inhibition of HER2 by agents with differing mechanisms of action has been shown to be superior to single-agent therapy in neoadjuvant studies [27, 28],a concept being tested in the postoperative adjuvant setting in the ongoing ALTTOstudy. The further study of the mechanism of action of trastuzumab has clarified arole for antibody-dependent cell-mediated cytotoxicity [29].
Endocrine therapy in postmenopausal patients Direct comparison between 5 years of adjuvant exemestane and anastrozole yielded comparable results, suggesting that exemestane provides an alternativearomatase inhibitor for up-front use [30].
Adjuvant use of zoledronic acid did not improve disease-free survival in a broad population in the AZURE trial [31]. Subset analysis of this study showed anapparent benefit in postmenopausal patients and no benefit in premenopausalwomen. By contrast, the ABCSG 12 trial showed a disease-free survival benefitassociated with the use of zoledronic acid among premenopausal patients, allof whom received GnRH analog [32]. These data raise the hypothesis that anantitumor effect of bisphosphonates might depend upon a low estrogenenvironment. This hypothesis remains to be tested in further clinical trials.
Definition of intrinsic subtypes has proved efficient in defining prognosis for breast cancer patients [33]. Currently, there are no data from phase III trials ontheir role as predictive tools for chemotherapy benefit. Gene expression arraysare reproducible and quantitative, but cost considerations limit their wideavailability. An approximation of gene expression array results is now possibleusing formalin-fixed paraffin-embedded material [7].
Status of research/implications for patient care Proliferative or immune signatures are associated with good chemotherapy response [34–37]. In neoadjuvant therapy, a stromal signature is associatedwith a reduced response, while a lymphocytic infiltrate predicts for a higherresponse rate [38, 39].
Multiple targets for successful treatments The large and growing number of agents targeting specific mutations suggests the eventual need for individual mutational analysis of each tumor to select acombination of agents to block multiple pathways [40].
Overcoming resistance to endocrine therapies An improved understanding of the mechanisms of endocrine therapy resistance includes the role of growth factors, integrins, stress kinases, and molecularpathways including PI3K/AKT and MEK/MAPK [41]. Overcoming endocrinetherapy resistance may, therefore, require inhibition of multiple escape pathwaysselected by biopsy of resistant tumors to confirm the mechanisms of resistance,which are active in each.
Treatment of germline genetic predisposition Of the 394 genes, which have been causally implicated in human cancer, some 10% are transmitted in the germline leading to increased susceptibility [42]. Of these, theBRCA1 and BRCA2 have been best studied, but others include TP53, PTEN, andCDH1, all of which can increase the risk of breast cancer. BRCA1- andBRCA2-associated breast cancer is sensitive to cross-linking agents such as cisplatin[43], but data from randomized comparisons with standard chemotherapy agents are awaited.
Host factors including obesity and hyperinsulinemia are associated with increased risk of breast cancer and recurrence of breast cancer. Retrospective studies indicatethat diabetic patients receiving metformin have a lower incidence of cancercompared with diabetic patients not receiving this agent [44].
Treatment with beta carotene, vitamin A, and vitamin E may increase mortality.
The potential role of vitamin C and selenium on mortality remains inconclusive [45].
Fenretinide showed reduced breast cancer incidence in young women [46].
The relationship between vitamin D levels and breast cancer risk or prognosisis controversial [46].
A recent analysis of the NSABP B-30 [47] confirmed previous observations from IBCSG 13-93 [48] that amenorrhea following chemotherapy was associatedwith substantial benefit in disease-free survival. On reanalysis of the NSABPtrial using the landmark method, as in the IBCSG study, this effect waslimited to the subset of patients with estrogen receptor-positive disease [49].
The early promise of the use of bevacizumab in metastatic breast cancer seen in the E2100 study has not translated into a survival benefit in subsequentstudies: A synthesis of these results suggests no overall survival benefit [50].
This has led the US Food and Drug Administration to reconsider its acceleratedapproval of bevacizumab in breast cancer.
Studies of lipotransfer have demonstrated the potential for a stromal interaction to stimulate vessel formation, raising the possibility that obesity might have an adverseprognostic impact in cancer patients via a similar stromal interaction [51].
Studies of mammary stem cells suggest a synergistic role for progesterone and RANK ligand in tumor formation [52]. This raises the possibility of an additionalmechanism of action of clinically available RANK ligand antagonists such as denosumab [53].
Further studies of mouse mammary stem cells demonstrated that they are highly responsive to steroid hormone signaling though they lack both estrogen and progesterone receptors.
This is thought to be mediated through paracrine signaling involving RANKligand [54].
Micro RNAs are involved in different biopathological features of breast cancer.
MER221 and MER222 are involved in resistance and response to endocrine agents,while MER205 is an oncosuppressor able to interfere with response to tyrosinekinase inhibitors of the HER family [55].
Status of research/implications for patient care Tumor-infiltrating regulatory T cells stimulate mammary cancer metastases through receptor activator (RANKL-RANK) signaling [56]. Tumor FOXP3+ Tregcells are a major source of RANKL, which stimulates the metastatic progressionof HER2-positive RANK-expressing breast cancer cells [52].
The commercial scores from assays such as Oncotype DXÒ [57] and Mamma PrintÒ [58] have been used to determine prognosis. Oncotype DXÒ has been shown topredict chemotherapy benefit among patients with hormone receptor-positive disease.
An interesting STEPP analysis [59] from the adjuvant trastuzumab NSABP B-31 trialexamined the degree of HER2 mRNA expression and corresponding trastuzumab benefit separatelyfor patients with estrogen receptor-positive and estrogen receptor-negative disease. The strikingfinding was that among patients with estrogen receptor-positive disease, trastuzumab benefit interms of 8-year disease-free survival was entirely confined to thosewith the higher levels of HER2 mRNA expression. In contrast, patients withestrogen receptor-negative disease derived some benefit from trastuzumab at alllevels of mRNA expression, though the quantitative benefit was greater amongthose with higher levels of HER2 [60].
The North Central Cancer Treatment Group adjuvant trastuzumab study (N9831) included a randomization between trastuzumab administered either concurrentlywith or following chemotherapy. Analysis presented at the SABCS 2009 suggested asuperior disease-free survival with concurrent administration [61].
Targeted therapy in the neoadjuvant setting The NOAH study [62] showed clear improvement in breast pathological complete remission (bpCR) rate and event-free survival at 3 years with neoadjuvant trastuzumab forpatients with HER2-positive disease.
Studies in metastatic breast cancer and in the neoadjuvant setting have demonstrated activity of trastuzumab and other anti-HER2 agents without chemotherapy[63] albeit usually less than the activity seen for the combination with chemotherapy.
There are no corresponding data in the adjuvant setting. However, it may be logical topropose that anti-HER2 therapy, alone or with endocrine therapy if appropriate,may be effective in patients who for various reasons cannot receive cytotoxic therapy [64, 65].
Triple-negative breast cancer includes cases susceptible to DNA-damaging agents such as cisplatin. Neoadjuvant studies including cisplatin have produced pCR ratesbetween 22% and 40% among unselected triple-negative cases [66, 67], while 10 of 12cases with BRCA1 mutations achieved pCR with single agent cisplatin [68].
Failure to achieve pCR among patients with rapidly proliferating tumors identifies a group with a poor prognosis, which may be suitable for early trials of investigational agents [11].
A historical cohort of patients, who did not receive adjuvant systemic therapy in the Danish Breast Cancer Group, were compared with the general Danishpopulation to ascertain mortality ratios associated with the diagnosis of breastcancer. In the absence of other risk factors, patients aged 50 years and older withsmall (1–10 mm) breast cancers had a risk of death comparable to thebackground population. By contrast, younger patients with similar tumorshad a significantly higher risk of death than the unaffected population [69].
Young patients with endocrine-responsive disease The ABCSG Trial 12 shows that premenopausal women with endocrine-responsive disease who receive ovarian function suppression plus either tamoxifen oranastrozole continue to experience a low risk of relapse [32].
The EBCTCG reported similar benefit to systemic chemotherapy in all age groups with estrogen receptor poor disease [70]. The CALGB 49907 study showed inferiorresults for single-agent chemotherapy compared with standard first generationcombination regimens [71]. The SWOG 8814 trial demonstrated an overall benefit toCAF followed by tamoxifen versus tamoxifen alone in postmenopausal patients withendocrine-responsive disease [72], though this was seen primarily among those withadverse biologic features such as quantitatively lower estrogen receptor levels,involvement of four or more lymph nodes, or high 21 gene RS [14].
Status of research/implications for patient care Special histological types of breast cancer Review of special histological types in a large institutional series suggested that endocrine-responsive types such as tubular and cribriform carcinomas may besuitable for observation without therapy or for endocrine therapy alone. Rarevariants of lobular carcinomas (e.g. pleomorphic) and apocrine carcinomas requiretreatment according to their biological features in a manner analogous to that usedfor ductal carcinoma. The heterogeneous ‘Triple negative’ subtype includes adenoidcystic, juvenile secretory (good prognosis), medullary (intermediate prognosis), andmetaplastic (either low grade, with good prognosis; or high grade, with poor prognosis)carcinomas, for which no generalizations can be proposed [73].
countenance its omission for some elderly patients and those postmenopausal patients (<55 years of age). The Panel was almost unanimous in rejecting CYP2D6 testing to dictatechoice of endocrine therapy type.
The Panel strongly supported the clinicopathologicaldetermination of estrogen receptor, progesterone receptor, The Panel agreed that factors arguing for the inclusion of HER2, and Ki-67 as useful for defining subtypes, but did not chemotherapy were high histological grade, high proliferation support the incorporation of tests for cytokeratin 5/6 or as measured by Ki-67, low hormone receptor status, positive epidermal growth factor receptor/HER1 for the determination HER2 status, and ‘Triple negative’ status in invasive ductal of ‘basal-like’ tumors for clinical decision making. The carcinoma of usual forms. These factors are largely captured in endorsed clinicopathological criteria define a convenient the tumor subtype definitions summarized in Table 2. There alternative to formal subtyping and are likely to be refined in was a lack of complete consensus on the threshold indication the future. The Panel did not require multigene array definition for inclusion of chemotherapy for patients with ‘Luminal A’ or of tumor subtype, although there was acceptance of such ‘Luminal B (HER2 negative)’ disease. In terms of disease extent, assays for certain indications (see below). However, the Panel the Panel did not believe that node positivity per se was an did recommend that the clinicopathological markers described indication for use of chemotherapy, though a strong majority above were generally sufficient to guide therapeutic choices.
would use it if more than three lymph nodes were involved.
Several tests are available which define prognosis [57, 58, 86].
selection of endocrine therapy in premenopausal These may indicate a prognosis so good that the doctor andpatient decide that chemotherapy is not required. A strong majority of the Panel agreed that the 21-gene signature The Panel accepted tamoxifen alone or ovarian function (Oncotype DXÒ) [57] may also be used where available to suppression plus tamoxifen as reasonable, though expressing predict chemotherapy responsiveness in an endocrine- a preference for tamoxifen alone. In patients with responsive cohort where uncertainty remains after a contraindication to tamoxifen, ovarian function suppression consideration of other tests, but the majority agreed that the alone was accepted as a treatment, while the combination of chemopredictive properties of the 70-gene signature ovarian function suppression plus an aromatase inhibitor was (MammaPrintÒ) [58] were not yet sufficiently established.
Trials are ongoing to clarify this role for both tests. Themajority of the Panel did not support lymphovascular invasion selection of endocrine therapy in postmenopausal as a sufficient indication for chemotherapy, and less than a quarter of the Panel supported uPA/PAI1 [86] as a predictive The Panel was exactly equally divided about whether all postmenopausal patients should receive an aromatase inhibitor(if available and not contraindicated) at some point in treatment, but was more supportive of aromatase inhibitors in The Panel strongly agreed that the ‘Luminal A’ subtype was less the presence of involved lymph nodes. A large majority felt that responsive to chemotherapy; that chemotherapy was less useful selected patients could be treated with tamoxifen alone, and in such patients; and that no preferred chemotherapy regimen that patients could be switched to tamoxifen if intolerant to could be defined for treatment of ‘Luminal A’ disease.
aromatase inhibitors. The Panel stressed the need to ensure that For ‘Luminal B’ disease, the Panel considered that both patients receiving an aromatase inhibitor were indeed anthracyclines and taxanes should be included in the postmenopausal, whether by clinical or biochemical criteria.
chemotherapy regimen. While the Panel could not define a single The Panel considered that 5 years of an aromatase inhibitor preferred chemotherapy regimen for ‘HER2 positive’ disease, the was a sufficient duration and a majority opposed extension majority again favored the inclusion of both anthracyclines and even in the presence of node-positive disease or among younger taxanes. For ‘Triple negative’ disease of the usual ductal type, the Table 2. Surrogate definitions of intrinsic subtypes of breast cancer (4, 7) This cut-point for Ki-67 labelling index was established by comparison with PAM50 intrinsic subtyping (7). Local quality control of Ki-67 Genes indicative of higher proliferation are markers of poor prognosis in multiple genetic assays (78). If reliable Ki-67 measurement is not available, some alternative assessment of tumor proliferation such as grade may be used to distinguish between ‘Luminal A’ and ‘Luminal B (HER2 negative)’.
Both endocrine and anti-HER2 therapy may be indicated.
ER and/or PgR positiveAny Ki-67HER2 over-expressed or amplified HER2 over-expressed or amplifiedER and PgR absent Approximately 80% overlap between ‘triple negative’ and intrinsic ‘basal-like’ subtype but ‘triple negative’ also includes some special histological types such as (typical) medullary and adenoid cystic carcinoma with low risks of distant recurrence.
Staining for basal keratins (79) although shown to aid selection of true basal-like tumors, is considered insufficiently reproducible for general use.
*This cut-point is derived from comparison with gene array data as a prognostic factor [7]. Optimal cut-points in Ki-67 labelling index for prediction ofefficacy of endocrine or cytotoxic therapy may vary.
**Some cases over-express both luminal and HER2 genes.
Panel again supported the inclusion of anthracyclines and associated with pathological complete response to such therapy, taxanes and an alkylating agent (typically cyclophosphamide), particularly in patients with ‘HER2 positive’ and ‘Triple but did not support the routine use of cisplatin or carboplatin. A negative (ductal)’ tumors [89], which may allow earlier change slim majority agreed that dose-dense chemotherapy [87] should be considered for such patients, and the Panel was strongly The Panel considered that the choice of neoadjuvant opposed to the inclusion of antiangiogenic therapies at this time, chemotherapy should be made on the same basis as applied in while noting that further trials are ongoing.
the selection of postoperative adjuvant treatments. The Panelsupported the incorporation of an anti-HER2 drug in the neoadjuvant therapy for patients with ‘HER2 positive’ disease, The Panel unanimously supported the use of 1 year of but did not support dual HER2 targeting at this point in time.
trastuzumab as standard adjuvant treatment for patients with The Panel did not support cytotoxic neoadjuvant therapy for ‘HER2 positive’ disease, and the majority were willing to extend tumors with low proliferation or high endocrine responsiveness.
this to patients with pT1b, but not pT1a pN0 disease.
Trastuzumab administered for <1 year [88] was regarded as suboptimal if 1 year of therapy was feasible, but better than no The Panel was almost unanimous in supporting the use of trastuzumab if limited resources prevented its full duration use.
neoadjuvant endocrine therapy as an option for postmenopausal While awaiting data from the ongoing HERA trial, the Panel did patients with highly endocrine-responsive disease. If given, the not support continuation of adjuvant trastuzumab beyond 1 Panel considered that such treatment should be continued until year. While preferring that trastuzumab be initiated concurrently maximal response or for a minimum of 4–8 months.
with chemotherapy, the Panel also accepted its sequential use.
The Panel did not support the use of trastuzumab withoutchemotherapy if chemotherapy could be given, but was prepared to countenance such treatment in circumstances where The Panel did not support the use of bisphosphonates for chemotherapy could not be delivered.
antitumor effect in either pre- [32] or postmenopausal [90]patients.
A majority of the Panel considered that neoadjuvant cytotoxic therapy was of value beyond its role in facilitating conservative Adjuvant tamoxifen was strongly supported, but only a slim surgery and noted the improved prognostic information majority would consider aromatase inhibitors in patients with Table 3. Systemic treatment recommendations for subtypes Few require cytotoxics (e.g. high nodal status or Inclusion and type of cytotoxics may depend on level of endocrine receptor expression,perceived risk and patient preference.
Cytotoxics + anti-HER2 + endocrine therapy No data are available to support the omission of Patients at very low risk (e.g. pT1a and node negative) may be observed withoutsystemic adjuvant treatment.
Medullary and adenoid cystic carcinomas may not require any adjuvant cytotoxics (if nodenegative).
*Special histological types: Endocrine responsive (cribriform, tubular, and mucinous); Endocrine nonresponsive (apocrine, medullary, adenoid cystic andmetaplastic).
contraindications to tamoxifen, such as thrombosis. The Panel Grant No. CA75362 from the United States National Cancer did not support extended endocrine treatment beyond 5 years for male breast cancer. The lack of any evidence on these lattertwo points was acknowledged.
summary of systemic treatment recommendations Aapro M., Roche (Speakers Bureau, Consultant), Novartis The approach to treatment within breast cancer subtypes (Speakers Bureau, Consultant), Pfizer (Speakers Bureau, greatly simplifies the definition of therapy indications, since the Consultant), Amgen (Speakers Bureau, Consultant), Genomic subtypes themselves incorporate many of the risk and Health (Speakers Bureau, Consultant), GSK (Consultant, predictive factors used in previous consensus Research), Genomic Health (Speakers Bureau, Consultant); recommendations. The broad recommendations are Albain K., Genomic Health (Speakers Bureau), Roche/ summarized in Table 3 and essentially indicate endocrine Genentech (Speakers Bureau); Baselga J., Merck (Consultant); therapy alone for patients with clinicopathologically classified Bergh J., Onyx/Bayer (Consultant), AstraZeneca (Speakers ‘Luminal A’ disease (except in defined high-risk cases), chemo- Bureau), Roche (Speakers Bureau), Novartis (Speakers endocrine therapy for ‘Luminal B’, the addition of anti-HER2 Bureau), Pfizer (Speakers Bureau), Amgen (Speakers Bureau), therapy in the presence of ‘HER2 positivity’, and a reliance on TRM (Speakers Bureau), Merck (Research), Tapestry Network chemotherapy for most patients with ‘Triple negative’ disease (Consultant); Bertolini F., Pfizer (Research), Molmed (e.g. those with invasive ductal carcinoma).
(Research); Bonnefoi H., Sanofi-aventis (Speakers Bureau,Consultant), Roche (Consultant), Novartis (Speakers Bureau);Brisken C., None; Burstein H., None; Castiglione M.; None; Coates A., None; Coleman R., Novartis (Speakers Bureau), The authors thank the participants in the 12th International Amgen (Speakers Bureau, Consultant), Roche (Speakers Conference on Primary Therapy of Early Breast Cancer for Bureau, Consultant, Travel), Pfizer (Speakers Bureau); Colleoni many useful remarks and for substantial contributions to the M., None; Costa A., None; Curigliano G., None; Davidson N., process. We acknowledge the substantial contributions of Mrs.
None; DeCensi A., None; DiLeo A., AstraZeneca (Speakers Shari Gelber and Mrs. Sabina Briner. We also thank Prof.
Bureau), GSK (Speakers Bureau), Pfizer (Speakers Bureau), Umberto Veronesi for his guidance and Dr Franco Nole` for his Roche (Speakers Bureau), Sanofi-aventis (Speakers Bureau), Cephalon (Speakers Bureau); Dowsett M., AstraZeneca(Speakers Bureau, Consultant, royalties), Roche (SpeakersBureau, Consultant), GSK (Consultant), Ipsen (Consultant), Cayar (Speakers Bureau, Consultant); Ejlertsen B., None;Forbes J., AstraZeneca (Speakers Bureau); Galimberti V., None; Support for the conference was provided by SONK from Garber J., Novartis (Spouse Consults); Gelber R., None; Glaus registration fees paid by the conference attendees and by A., None; Glick J., None; Gnant M., AstraZeneca (Speakers Bureau, Consult, Travel), Novartis (Speakers Bureau, Consult, Sanofi-aventis (Consultant), Novartis (Consultant), Specialize Travel), Roche (Consult, Research, Travel), Sanofi-aventis Thera/Abraxis (Consultant); Winer E., Genentech (Research); (Research), GSK (Speakers Bureau); Goldhirsch A., Pfizer (Travel), GSK (Speakers Bureau, Travel), Roche (SpeakersBureau, Travel), Ferring (Speakers Bureau); Gomis R., None; Goodwin P., Amgen (Speakers Bureau), Novartis(Employment), Pfizer (Travel); Goss P., Novartis (Speakers 1. Perou CM, Sorlie T, Eisen MB et al. Molecular portraits of human breast tumours.
Bureau), GSK (Speakers Bureau), Novartis (Research); Harris 2. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol J., None; Hayes D., DNAR (Speakers Bureau), Compendia (Speakers Bureau), Chugai (Speakers Bureau), GSK (Research), 3. Parker JS, Mullins M, Cheang MCU et al. Supervised risk predictor of breast Pfizer (Research), Novartis (Research), Veridex/J&J (Research), cancer based on intrinsic subtypes. J Clin Oncol 2009; 27: 1160–1167.
OncImmune (Stock), Halcyon Diagnostics (Stock); Ingle J., 4. Nielsen TO, Hsu FD, Jensen K et al. Immunohistochemical and clinical Pfizer (Consultant uncompensated); Intra M., None; Iorio M., characterization of the basal-like subtype of invasive breast carcinoma. Clin None; Jassem J., None; Jiang Z., None; Jordan V.C., None; Karlsson P., Sanofi-aventis (Travel), AstraZeneca (Travel), 5. Blows FM, Driver KE, Schmidt MK et al. Subtyping of breast cancer by Amgen (Travel); Kaufmann M., AstraZeneca (Consultant, immunohistochemistry to investigate a relationship between subtype and short Travel), Pfizer (Consultant, Travel), Novartis (Consultant, and long term survival: a collaborative analysis of data for 10,159 cases from 12 Travel), Roche (Travel), GSK (Consultant, Travel), Amgen studies. PLoS Med 2010; 7: e1000279.
(Consultant, Travel), Sanofi-aventis (Consultant, Travel); 6. Hugh J, Hanson J, Cheang MC et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical Kerbel R., Taiho (Consultant), GSK (Consultant, Research), definition in the BCIRG 001 Trial. J Clin Oncol 2009; 27: 1168–1176.
MetronomiX (Consultant), Pfizer (Research); Kuhl C., None; 7. Cheang MCU, Chia SK, Voduc D et al. Ki67 index, HER2 status, and prognosis of Lindemann G., Sanofi-aventis (Consultant); Mandelblatt J., patients with luminal B breast cancer. J Natl Cancer Inst 2009; 101: 736–750.
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European Insitute of Oncology, Via Ripamonti 435, 20141 83. Viale G, Regan MM, Mastropasqua MG et al. Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for  Nancy E. Davidson, University of Pittsburgh Cancer Institute, node-negative breast cancer. J Natl Cancer Inst 2008; 100: 207–212.
5150 Centre Avenue, UPMC Cancer Pavilion, 84. Viale G, Giobbie-Hurder A, Regan MM et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with 5th Floor, Suite 500, Pittsburgh, PA 15232, USA endocrine-responsive breast cancer: results from Breast International Group trial  Angelo Di Leo, ‘Sandro Pitigliani’ Medical Oncology Unit, 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 2008; 26: Department of Oncology, Hospital of Prato, Piazza  Bent Ejlertsen, Department of Oncology, Bldg 4262  C. Kent Osborne, Dan L. Duncan Cancer Center, Baylor College Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen, of Medicine, One Baylor Plaza, Houston, TX 77030, USA  Fre´de´rique Penault-Llorca, Service d’Anatomie Pathologie  John F. Forbes, Department of Surgical Oncology, University Mole´culaire, De´pt. RIO, Centre Jean Perrin, 58 rue of Newcastle, Calvary Mater Hospital, ANZ BCTG, Edith Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 1, Street Waratah, Newcastle 2298 NSW Australia  Richard D. Gelber, Department of Biostatistics and  Charles M. Perou, Lineberger Comprehensive Cancer Center, Computational Biology, Dana-Farber Cancer Institute, 450 Departments of Genetics and Pathology, The University of North Carolina, Chapel Hill, NC 27599, USA  Agnes Glaus, ZeTuP, Center for Tumor Detection, Treatment  Martine J. Piccart-Gebhart, Internal Medicine, Oncology, and Prevention, Rorschacher Strasse 150, 9006 St Gallen, Institut Jules Bordet, Rue He´ger-Bordet 1, 1000 Brussels,  John H. Glick, University of Pennsylvania, Abramson Cancer  Kurt Possinger, Universita¨tsklinikum Charite´ Campus Mitte, Center, Perelman Center, 3400 Civic Center Blvd, Centrum 14, M.S. Onkologie/Ha¨matologie, Charite´platz 1,  Michael Gnant, Medical University of Vienna, Department of  Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre, Surgery, Comprehensive Cancer Center Vienna, Wa¨hringer Ontario Clinical Oncology Group (OCOG), 2075 Bayview  Aron Goldhirsch, International Breast Cancer Study Group,  Emiel J.T. Rutgers, The Netherlands Cancer Institute, Department of Medicine, European Institute of Oncology, Department of Surgery, Plesmanlaan 121, 1066 CX Via Ripamonti 435, 20141 Milan, Italy, and Swiss Center for Breast Health, Sant’Anna Clinics, 6924 Lugano-Sorengo,  Vladimir Semiglazov, N.N. Petrov Research Institute of Oncology, 68 Leningradskaya Street, Pesochny-2, 197758 St  Pamela Goodwin, Department of Medicine, Division of Clinical Epidemiology, Samuel Lunenfeld Research Institute,  Ian Smith, Breast Unit, Royal Marsden Hospital and Institute Mount Sinai Hospital and Princess Margaret Hospital, of Cancer Research, Fulham Road, London, SW3 6JJ, UK University of Toronto, 1284-600 University Avenue, Toronto, ¨rlimann, Breast Center, Kantonsspital St Gallen,  Paul E. Goss, MGH Cancer Center, 55 Fruit Street, Boston,  Masakazu Toi, Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin-Kawahara cho, Sakyo-ku,  Jay R. Harris, Department of Radiation Oncology, Dana- Farber Cancer Institute, Brigham and Women’s Hospital,  Andrew Tutt, Breast Oncology Unit, Guy’s Hospital, King’s Room 1622, 44 Binney Street, Boston, MA 02115, USA  Dan F. Hayes, Breast Care Center, University of Michigan,  Michael Untch, Department of Gynecology and Obstetrics, Comprehensive Cancer Center, 1500 East Medical Center Multidisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Academic Hospital of the University of  James N. Ingle, Mayo Clinic Cancer Center, Women’s Cancer Go¨ttingen, Schwanebecker Chaussee 50, 13125 Berlin, Program, 200 First Street S.W., Rochester, MN 55905, USA  Jacek Jassem, Medical University of Gdansk, Deptartment of  Giuseppe Viale, Department of Pathology, European Institute Oncology & Radiotherapy, Debinki Street 7, 80-211 Gdansk, of Oncology and University of Milan, Via Ripamonti 435,  Zefei Jiang, 307 Hospital, Academy of Military Medical  Toru Watanabe, Department of Medicine, Hamamatsu Sciences, 8 Fengtai East Avenue, 100071 Beijing, China Oncology Center, 3-6-13 Chuo Naka-Ku , 430-0929  Per Karlsson, Department of Oncology, Institute of Selected Clinical Sciences, Sahlgrenska Academy, Sahlgrenska  Nicholas Wilcken, Department of Medical Oncology, University Hospital, 413 45 Go¨teborg, Sweden University of Sydney, Westmead Hospital, Westmead 2145,  Manfred Kaufmann, Department of Gynecology, Obstetrics, Breast Unit, J.W. Goethe University, Theodor Stern Kai 7,  Eric P. Winer, Breast Oncology Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02115, USA  Gunter von Minckwitz, GBG Forschungs GmbH, Martin  William C. Wood, Department of Surgery, Winship Cancer Behaim Strasse 12, 63263 Neu-Isenburg, Germany Institute, 1365C Clifton Road, Atlanta, GA 30322, USA  Monica Morrow, Memorial Sloan-Kettering Cancer Center, Evelyn Lauder Breast Center, 300 East 66 Street, New York,NY 10065, USA  Moise Namer, Medical Oncology, Centre Antoine Lacassagne, 33 Av. de Valombrose, 06189 Nice Cedex 2, France  Larry Norton, Memorial Sloan-Kettering Cancer Center, Room H 901, 205 East 64th Street, Concourse Level, New Note: details of the declared conflicts of interest are available at

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