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

Abstract

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.

Conflict of interest statement

The authors received funding from Lake Imaging, Geelong, VIC, Australia, a commercial company, in the form of salary for author LW. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT flowchart.

Fig 2. Kaplan-Meier estimates for DFS according to breast cancer subtype.

Fig 3. Functional mutations in the ATM signalling pathway.

OncoPrint of variants detected in five genes central to the ATM signalling pathway. The percentage samples affected by variants in each gene are noted and missense (green) and truncating (black) mutations are presented.

Fig 4. Mutational signature analysis.

Signature 17 is highlighted in sample R29. Signature 1 is age-related and is the predominant signature in this sample. Signature 17 contributes to ~13% of the mutation burden.

Fig 5. River plot depicting the clonal structure and evolution of diagnostic and residual disease samples from patient N07.

The plot demonstrates persistence of one dominant subclone and emergence of four new subclones in the residual disease.

Fig 6. River plot depicting the clonal structure and evolution of diagnostic and residual disease samples from patient N27.

The persistence of four subclones (blue, brown, green, orange) and the emergence of a new subclone (pink) despite treatment with neoadjuvant chemotherapy is depicted.