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

Publication ,  Journal Article
Murphy, C; Muscat, A; Ashley, D; Mukaro, V; West, L; Liao, Y; Chisanga, D; Shi, W; Collins, I; Baron-Hay, S; Patil, S; Lindeman, G; Khasraw, M
Published in: PLoS One
2019

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.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2019

Volume

14

Issue

2

Start / End Page

e0210891

Location

United States

Related Subject Headings

  • Triple Negative Breast Neoplasms
  • Trastuzumab
  • Serum Albumin, Human
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Paclitaxel
  • Neoadjuvant Therapy
  • Nanoparticles
  • Middle Aged
  • Humans
 

Citation

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Murphy, C., Muscat, A., Ashley, D., Mukaro, V., West, L., Liao, Y., … Khasraw, M. (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, 14(2), e0210891. https://doi.org/10.1371/journal.pone.0210891
Murphy, Caitlin, Andrea Muscat, David Ashley, Violet Mukaro, Linda West, Yang Liao, David Chisanga, et al. “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 14, no. 2 (2019): e0210891. https://doi.org/10.1371/journal.pone.0210891.
Murphy C, Muscat A, Ashley D, Mukaro V, West L, Liao Y, Chisanga D, Shi W, Collins I, Baron-Hay S, Patil S, Lindeman G, Khasraw M. 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. 2019;14(2):e0210891.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2019

Volume

14

Issue

2

Start / End Page

e0210891

Location

United States

Related Subject Headings

  • Triple Negative Breast Neoplasms
  • Trastuzumab
  • Serum Albumin, Human
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Paclitaxel
  • Neoadjuvant Therapy
  • Nanoparticles
  • Middle Aged
  • Humans