Tailored Neoadjuvant Epirubicin and Cyclophosphamide (EC) and Nanoparticle Albumin Bound (Nab) Paclitaxel for Newly Diagnosed Breast Cancer

The prognosis and survival rate of breast cancer varies depending on the extent of the disease, performance status of patients and the type of tumour including the status of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Expression of ER and PR generally indicates better prognosis than the overexpression of HER2 and triple negative breast cancer generally indicates more aggressive cancers with a high growth rate [1].

Preoperative or neoadjuvant therapy which is also known as primary systemic therapy followed by surgery and adjuvant radiation therapy is recommended for patients with locally advanced breast cancer [2]. Studies using primary systemic therapy have demonstrated useful rates of clinical response and pathological complete response(pCR) rates in the breast alone and pathological complete response rates in the axillary notes. The response rates vary considerably, however response rates to cytotoxic chemotherapy have been uniformally higher in ER negative tumors. There is additional improvement in the pathological complete response rates of about 10 % with the addition of a taxane [4]. For operable breast cancer, primary systemic therapy can be considered as an alternative to adjuvant systemic therapy for patients who require a mastectomy but who desire breast conservation surgery. In patients with large tumours who can technically have a lumpectomy, primary systemic therapy may permit less extensive surgery and may result in a better cosmetic result. Primary systemic therapy may also be advisable in patients who have medical contraindications to surgery or where delayed surgery is required.

Nanoparticle albumin bound paclitaxel is reported to achieve a higher intracellular tumour paclitaxel concentration via the albumin mediated transendothelial transport system [5]. Better tolerability and efficacy has been demonstrated when compared to paclitaxel or docetaxel in the treatment of metastatic breast cancer [6, 7]. Nab paclitaxel is being evaluated in the adjuvant treatment of patients with breast cancer [8, 9] and in the neoadjuvant setting [10.] The preoperative setting provides an opportunity to study the early molecular changes that may occur in response to treatment. Alteration of biomarkers between pre and post chemotherapy including hormone receptors, the Human Epidermal growth factor receptor (HER2)and Ki67 [11, 12] as well as gene pathways [13] are areas of possible exploration in neoadjuvant studies whereby tissue is available for analysis before and after the chemotherapy treatment. Particular patterns of reduction in tumour size on MRI can be predictive of successful response, detecting residual tumour not apparent on mammogram or U/S and in accurate evaluation of tumour volume [14.] Functional imaging biomarkers of response also have potential utility in assessing treatment response [15.] A recent study reported that 4 cycles of adjuvant therapy with the combination of nab Paclitaxel and cyclophosphamide, with or without trastuzumab, is feasible and well tolerated in patients with early stage breast cancer. Another small study demonstrated feasibility of nab Paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (FEC) [16.] An anthracycline containing regimen followed by conventional paclitaxel is amongst the most commonly prescribed adjuvant chemotherapy regime for early breast cancer. Cyclophosphamide is given in combination with doxorubicin or its epimer epirubicin. Epirubicin achieves similar efficacy results to doxorubicin but causes less cardiotoxicity [17 19].

Although standards of care are varied, adjuvant chemotherapy in 2011 is generally recommended in women with triple negative breast cancer (TNBC) and HER amplified tumors. In women with hormone receptor positive tumors without HER2 amplification, chemotherapy is reserved for tumors that are large or with extensive nodal involvement and/ or high risk biology. The latter includes young age, presence of lymphovascular space invasion, a high proliferative index (Ki67 expression), lower ER/PR expression, higher Oncotype Dx score and luminal B tumors[20]. Thus there are evolving trends to tailor therapy based on the tumor characteristics indicating perceived risk, patient factors, particularly comorbid illness and patient preferences as well as prediction of response.

In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become a widely used method for comparing proliferation between tumour samples[21]. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy[21, 22]. Ki67 labeling Index has been incorporated as one of the means of identifying tumor subtypes by the 2011 St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer[20]. Analysis of gene expression arrays has resulted in the recognition of several fundamentally different subtypes of breast cancer[23]. Using gene expression profile distinction can be made between luminal A and luminal B tumors. While both subtypes could be ER positive but luminal A tumours are unlikely to benefit from cytotoxic chemotherapy. Because it is not always feasible to obtain gene expression array information, a simplified classification, closely following that proposed by Cheang et al whereby a cutpoint for Ki67 labeling index of <15% was established by comparison with PAM50 intrinsic subtyping to differentiate between luminal A and luminal B tumours[24]. Local quality control of Ki67 staining is important[20].