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

Differential effect on different immune subsets of neoadjuvant chemotherapy in patients with TNBC

“…On the contrary, usage of EC before Nab-Pac resulted in 50% of treated patients with BC having neutropenia at the end of treatment, with 18% of them having grade 3 or higher neutropenia. 8 These data suggest that the sequence Nab-Pac plus EC might be better for combination with immunotherapy than the opposite one. However, the stronger effects recorded at surgery might also be explained by long-term consequences of Nab-Pac and/or the sum of the two treatments and not only by an intrinsic stronger immune-depleting effect of EC.…”

Antitumor activity and efficacy of shorter versus longer duration of anthracycline-taxane neoadjuvant chemotherapy in stage II–III HER2-negative breast cancer: a 10-year, retrospective analysis

“…Recent clinical trials have shown that concomitant or sequential administration of the most effective cytotoxic compounds (namely anthracyclines, taxanes, cyclophosphamide and, in some contexts, platinum compounds) in the neoadjuvant treatment setting yields the best clinical results in terms of pCR and reduction of the risk of disease relapses. 25 , 31 – 35 Some of these studies compared neoadjuvant anthracycline-taxane regimens of different duration, and showed that longer ChT duration is associated with a higher percentage of pCR rates. However ChT schedules that were compared in these studies also contained different cytotoxic agents and different combination regimens, thus making it unclear if treatment duration is actually responsible for the observed differences in terms of clinical outcomes.…”

Cytotoxic Effect and Mechanisms from Some Plant-Derived Compounds in Breast Cancer

“…In many cases this disease has become fatal because of its multifactorial origin and also because it has a great number of exogenous and endogenous factors that can stimulate different pathways [3]. In early BrC, gene expression profiles are determined for hormone receptor (HR)-positive disease and human epidermal growth factor type 2 receptor (HER2) status which define if a patient is likely to receive systemic therapy and are therefore used to guide their treatment [4]. Approximately 60-70% of primary BrC cases express positive estrogen receptors (ER+) or positive progesterone receptors (PR+) or both and are hormone responsive.…”

“…However, about 15-20% of BrC cases are in the category of triple-negative phenotype owing to their lack of ER, PR, and amplified HER2. Commonly, ER+ hormone-dependent BrCs have a better prognosis and are often responsive to antihormone therapy [4].…”