Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial

Untch, Michael; Gelber, Richard D.; Jackisch, Christian; Procter, Marion; Baselga, José; Bell, Richard H.; Cameron, David; Bari, M.; Smith, Ian; Leyland‐Jones, Brian; Azambuja, Evandro de; Wermuth, Peter J.; Хасанов, Р Ш; Feng-yi, F.; Constantin, Carolina; Mayordomo, J. I.; Su, Cheng-Hsi; Yu, Shiying; Lluch, Aña; Senkus, Elżbieta; Price, C. H. G.; Haslbauer, Ferdinand; Sahui, T. Suarez; Srimuninnimit, Vichien; Colleoni, Marco; Coates, Alan S.; Piccart‐Gebhart, Martine; Goldhirsch, Aron

doi:10.1093/annonc/mdn005

Cited by 177 publications

(91 citation statements)

References 8 publications

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“…Our results are in keeping with those from the HERA trial, which suggested that patients with the best prognosis tumours (node negative and size 1 -2 cm) had benefit from herceptin, similar to the overall cohort (Untch et al, 2008). The 29% of patients in the BCIRG 006 trial who were node negative (Slamon et al, 2006) also derived benefits similar to those derived by the whole cohort using trastuzamab, although they were included only if they had another high-risk feature (grade, ER negative over 2 cm).…”

Section: Discussionsupporting

confidence: 89%

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours

et al. 2009

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We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab. Human epidermal growth factor receptor 2 (HER2) amplification has become the prototype biomarker for translation of a laboratory discovery through to development of a highly successful individualised biological therapy agent. Slamon et al (1987) established HER2 as a poor prognostic marker for survival in breast cancer and developed a monoclonal antibody, trastuzumab, targeted to HER2, as a novel therapy for breast cancer patients. More recently, randomised trials in early breast cancer have shown the clinical benefit of trastuzumab after chemotherapy with significant overall survival benefit over chemotherapy alone (Romond et al, 2005;Slamon et al, 2006;Smith et al, 2007). As a result, trastuzumab has been introduced into routine clinical practice in the UK for HER2-positive patients who have completed their standard adjuvant treatment. Current Scottish and National Institute for Health and Clinical Excellence (NICE) guidelines parallel the herceptin adjuvant (HERA) trial entry criteria, according to which trastuzumab is offered only to those patients who have already received standard chemotherapy regimes as part of their treatment regime.However, there remains a small subset of HER2-positive patients who are low grade and node negative and who are currently ineligible for trastuzumab treatment as clinically they have been deemed to have no requirement for standard adjuvant chemotherapy. In our region, approximately 25% of HER2 patients are not offered herceptin as they are deemed to be at 'low risk' (personal communication). Our study analyses a retrospective cohort of lowgrade and node-negative tumours, traditionally classified by Nottingham Prognostic Index (NPI) and Adjuvant! Online as 'low risk' to assess whether HER2 positivity affects survival in this otherwise very good prognostic group. METHODS PatientsWe have a large cohort (n ¼ 1351) of breast cancers diagnosed between 1980 -2002 with full clinical follow-up (median 6.5 years) and pathological details taken from pathology reports. Tissue specimens from these cancers had been used to create tissue microarray technology (TMA) for research purposes (ethical approval was obtained). The grades of tumours from the cohorts diagnosed in the 1980 -90s were reviewed for accuracy by a consultant pathologist (EAM). From this database, we wished to identify a group of patients who would classically be identified as 'low risk'. We selected all node-negative, grade 1 or 2 cancers (n ¼ 362) for further analysis. Human epidermal growth factor receptor 2 status assessmentHuman epider...

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Section: Discussionsupporting

confidence: 89%

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours

et al. 2009

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“…Prior to the advent of anti-HER2 agents such as trastuzumab, patients with HER2C disease had a poorer 5-year overall survival (Nguyen et al 2008, Park et al 2012. Interestingly, although the recent HERA trial points to a similar trastuzumab response irrespective of hormone receptor status (Untch et al 2008), there is evidence that noeadjuvant trastuzumab may be less effective in ERC/ HER2C vs ERK/HER2C tumours (Bhargava et al 2011), suggesting that the presence of the ER in HER2C tumours may be an important consideration. Conversely, the presence of HER2 in ERC tumours may also be a limiting factor for endocrine therapy, particularly since ERC/ HER2C tumours are likely to be treated with both endocrine and trastuzumab treatments.…”

Section: Discussionmentioning

confidence: 99%

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro¹,

Smith

Goddard

et al. 2013

Endocrine-Related Cancer

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The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ERC)/HER2C breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ERC/HER2K (MCF7 and T47D) and ERC/HER2C (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878Gtrastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ERC/HER2C cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ERC/HER2C cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ERC/HER2C breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ERC/HER2C, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

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“…Subgroup analyses from several of the randomized trials have shown a consistent benefit with trastuzumab irrespective of tumor size or nodal status. 154,287,288 The panel recommends AC followed by paclitaxel with trastuzumab, commencing with the first dose of paclitaxel, for 1 year as a preferred HER2-targeting adjuvant regimen. The TCH regimen is also a preferred regimen, especially in those with risk factors for cardiac toxicity, given the results of the BCIRG 006 study that showed superior disease-free survival in patients receiving either TCH or AC followed by docetaxel plus trastuzumab both compared with AC followed by docetaxel alone.…”

mentioning

confidence: 99%

Breast Cancer Version 3.2014

Gradishar¹,

Anderson²,

Blair³

et al. 2014

J Natl Compr Canc Netw

175

117

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Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial

Abstract: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Cited by 177 publications

References 8 publications

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Breast Cancer Version 3.2014

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