S2 Session 1. News since St.Gallen 2009 Wednesday, 16 March 2011

relapse, and this drug is now the standard of care in the management ofHER2-amplified breast cancer. However, a significant proportion of HER2positive breast cancers display either primary or secondary resistance totrastuzumab. The basis of resistance is multi-factorial and not fully under-stood, but probably involves impaired receptor-antibody binding, truncatedHER2 protein, gene mutations, or signaling via alternate pathways. Recentin-vivo preclinical work has suggested a possible important role of thehost (i.e. the patient) immunity in clinical outcome of trastuzumab-basedtherapy, leading to a revised mechanism of action of trastuzumab [1,2]:1. trastuzumab recruits Fc receptor expressing cells such as monocytesand NK cells

2. antibody-dependent cellular cytotoxicity and/or HER2 signaling block-ade causes cell death and the release of “death signals” such asHMGB-1, which triggers the activation of antigen presenting cells

3. as a result, CD8-dependent adaptive anti-tumor immunity is generatedIt will be therefore important to investigate whether or not the ability

to generate such an immune response might help selecting patients forantibody-based therapies rather than newer, alternative anti-HER2 strate-gies.Lapatinib is a small molecule with dual-specificity tyrosine kinase in-

hibitor (TKI) activity against HER2 and EGFR/HER1, and has alreadygained regulatory approval for use in the metastatic setting after failureof trastuzumab. Many other novel agents are in the pipeline, includingirreversible inhibitors of HER2 tyrosine-kinase (neratinib and afatinib), in-hibitors of PI3K, mTOR or both, AKT or MEK inhibitors, HSP90 and HDACinhibitors. HER2 signalling occurs via the PI3K/AKT/mTOR pathway butalso via the Raf/MEK/ERK pathway, and dual inhibition of both cascadesis an interesting concept that deserves testing in clinical trials. We andother think that this dual cascade inhibition might be more relevant to ER-HER2+ breast cancers than ER+HER2+ ones.Newer anti-HER2 antibodies in trials include pertuzumab, a bispecific

monoclonal antibody directed against HER2 and HER3 receptors, anda first-in-class HER2 antibody-drug conjugate T-DM1, which combinesthe anti-HER2 antibody trastuzumab with targeted delivery of the anti-microtubule agent DM1. The first results of a randomized phase II trial(n = 137) in advanced disease comparing T-DM1 with docetaxel andtrastuzumab were released in 2010 [3]. While antitumor activity was verysimilar in both arms with a clinical benefit rate of 56%, the overall safetyprofile of T-DM1 was clearly superior with far less Grade 3−4 events andminimal alopecia. The results of several phase III trials involving neratinib,pertuzumab and T-DM1 are expected in 2011.A great deal of interest has been generated by recent data from the

randomized neo-adjuvant studies NeoALTTO (trastuzumab versus lapa-tinib versus the combination) [4] and NeoSphere [5] (trastuzumab versuspertuzumab versus the combination) which has shown that combining twoanti-HER2 agents is markedly superior to one agent alone in early breastcancer. Large adjuvant trials, such as ALTTO, will hopefully provide thedefinitive validation of this concept. If all the above results are indepen-dently confirmed, they could lead to a paradigm shift in treatment strategy,but also have a significant negative impact on healthcare costs. Thereforeit is critical to intensify the search for biomarkers that can indeed identifypatients likely to benefit from such combinations of targeted therapies.Finally, has the time come to start thinking about curing HER2 positive

breast cancer without chemotherapy?

References

[1] Park S, Jiang Z, Mortenson ED, et al: The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. CancerCell 18:160−70, 2010.

[2] Smyth MJ, Stagg J: Her 2 in 1. Cancer Cell 18:101−2, 2010.[3] Perez E, Dirix L, Kocsis L, et al: Efficacy and Safety of trastuzumab-DM1

versus trastuzumab plus docetaxel in HER2-positive metastatic breast can-cer patients with no prior chemotherapy for metastatic disease: Preliminaryresults of a randomized, multicenter, open-label phase II study (TDM4450G).Ann Oncol 21 (Supplement 8):Abstract LBA3, 2010.

[4] Baselga J, Bradbury I, Eidtmann H, et al: First Results of the NeoALTTOTrial (BIG 01-06/EGF 106903): A Phase III, Randomized, Open Label,Neoadjuvant Study of Lapatinib, Trastuzumab, and Their Combination PlusPaclitaxel in Women with HER2-Positive Primary Breast Cancer. CancerRes 70(24 Suppl.): Abstract S3−3, 2010.

[5] Gianni L, Pienkowski T, Im Y-H, et al: Neoadjuvant Pertuzumab (P) andTrastuzumab (H): Antitumor and Safety Analysis of a Randomized Phase IIStudy (‘NeoSphere’). Cancer Res 70(24 Suppl.): Abstract S3−2, 2010.

Disclosure of Interest: None Declared

S03 Is caring for the bone also fighting the breast cancer?

R. Coleman1. 1Academic Unit of Clinical Oncology, Weston Park Hospital,Sheffield, United Kingdom

Bisphosphonates and denosumab (an antibody to RANK-ligand) are potentinhibitors of bone resorption that reduce the risk of skeletal complicationsand prevent treatment induced bone loss. Additionally, they may modifythe course of the disease and disrupt the metastatic process via indirectinhibitory effects on the “vicious cycle” of growth factor and cytokineexpression between tumour and bone cells within the bone marrow mi-croenvironment. Effects on the stem cell niche, directs effects on thecancer and immune modulation may also contribute. In vivo animal studieshave shown that bone targeted therapies can prevent establishment ofbone metastases. Bisphosphonates also appear to enhance the anti-tumour activity of cytotoxic drugs in a sequence dependent manner.In early breast cancer, improvements in disease free survival (DFS)

have been seen in several clinical trials of adjuvant bisphosphonates,notably in premenopausal women with endocrine responsive diseasetreated with goserelin. AZURE is an academic study designed to determinewhether treatment with zoledronic acid (ZOL) added to standard adjuvanttherapy improves DFS across a broad range of patients with stage II/IIIbreast cancer. 3360 patients were randomized to receive (neo) adjuvantchemotherapy (CT) and/or endocrine therapy (ET) +/− ZOL 4mg iv every3−4 weeks for 6 doses, then 3 monthly ×8 and 6 monthly ×5 to complete5 years treatment. With a median follow up of 59 months and 752 DFSevents, no difference in overall DFS was seen (ZOL 377; control 375 – H.R.0.98, 95%CI 0.85–1.13; p = 0.79). However, pre-planned subset analysisdid reveal significant improvements in both DFS (HR: 0.76, 95%CI 0.60–0.98) and overall survival (HR: 0.71, 95%CI 0.54–0.94) in postmenopausalwomen.The results from AZURE indicate that adjuvant bisphosphonates are

not broadly applicable and cannot be routinely recommended. However,AZURE and other adjuvant bisphsophonate studies suggest that ZOL mayhave significant, clinically important activity in the context of an oestrogendeprived environment. Further study to explain the biological basis of thisobservation is ongoing.Disclosure of Interest: R. Coleman Consultant for: Amgen, Novartis,Honoraria from: Amgen, Novartis, Paid Instruction for Novartis, Fundingsfrom: Novartis

S04 Molecular classification of breast cancer and its emergingclinical relevance

C. Perou1. 1Lineberger Comprehensive Cancer Center, Chapel Hill,United States

It is thought that breast cancer is not a single disease, but instead is aspectrum of tumor subtypes with distinct cellular origins, somatic changesand etiologies. Prognostic factors such as stage and grade, and predictivefactors such as hormone receptors and HER2 status are the main featuresupon which clinical decision-making has traditionally been based. Geneexpression data coming from DNA microarrays has provided additionalinsights into the biology of breast cancer, and has been developed into anumber of clinically useful assays. Our work on breast tumors using DNAmicroarrays has led to a new molecular taxonomy that identifies at least fivesubtypes of breast cancers (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) and a normal breast group. Known as the “intrinsicsubtypes”, these groups have revealed critical differences in incidence, sur-vival, and response to treatment. Importantly, the information provided bythe intrinsic subtypes complements and expands the information providedby classical clinical-pathological markers, and adds value beyond ER andHER2 status.In addition to the intrinsic subtypes, many other important prognostic and

predictive gene expression profiles have been identified, including the twomost widely used clinical assays that are OncotypeDX and Mammaprint.Comparative analyses have shown a good level of concordance betweenthe intrinsic subtypes, OncotypeDX RS, and Mammaprint, especially withinER-positive patients. These tests and data have lead to the identificationof a subset of ER-positive patients that have an extremely good outcome,and thus, for which endocrine therapy alone appears to be all that may beneeded. Alternatively, the remaining patients/subtypes including Luminal B,HER2-enriched, and Basal-like, show significantly worse outcomes; thesepatients are given the appropriate targeted agent (endocrine therapy for