Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: the phase II NEONAB trial—clinical outcomes and molecular determinants of response

Murphy, Caitlin, Muscat, Andrea, Ashley, David, Mukaro, Violet, West, Linda, Liao, Yang, Chisanga, David, Shi, Wei, Collins, Ian, Baron-Hay, Sally, Patil, Sujata, Lindeman, Geoffrey and Khasraw, Mustafa 2019, Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: the phase II NEONAB trial—clinical outcomes and molecular determinants of response, PLoS one, vol. 14, no. 2, pp. 1-20, doi: 10.1371/journal.pone.0210891.

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Title Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: the phase II NEONAB trial—clinical outcomes and molecular determinants of response
Author(s) Murphy, Caitlin
Muscat, AndreaORCID iD for Muscat, Andrea orcid.org/0000-0003-1666-7961
Ashley, David
Mukaro, Violet
West, Linda
Liao, Yang
Chisanga, David
Shi, Wei
Collins, IanORCID iD for Collins, Ian orcid.org/0000-0001-6936-0942
Baron-Hay, Sally
Patil, Sujata
Lindeman, Geoffrey
Khasraw, MustafaORCID iD for Khasraw, Mustafa orcid.org/0000-0003-3249-9849
Journal name PLoS one
Volume number 14
Issue number 2
Article ID e0210891
Start page 1
End page 20
Total pages 20
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2019
ISSN 1932-6203
Keyword(s) NEOadjuvant epirubicin
cyclophosphamide
Nanoparticle Albumin-Bound paclitaxel
breast cancer
phase II NEONAB trial
Clinical outcomes
treatment
Science & Technology
Multidisciplinary Sciences
Summary BACKGROUND: This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored. PATIENTS AND OUTCOME MEASURES: Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses. RESULTS: The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones. CONCLUSIONS: This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT01830244.
Language eng
DOI 10.1371/journal.pone.0210891
Field of Research MD Multidisciplinary
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2019, Murphy et al
Persistent URL http://hdl.handle.net/10536/DRO/DU:30118526

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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