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

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

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

The goal is to use the best combination, sequence and duration of therapy together with
predicting and monitoring response with high fidelity in the individual patient. Further
studies are needed to optimize treatment regimens so as to increase pathologic response
rates and ultimately survival, with a further goal of reducing risk and adverse events.

This study uses a tailored approach to select treatment involving the choice of nab
Paclitaxel and EC based on the individual patient and tumour characteristics Translational

Breast Cancer Stem Cells

It is now widely accepted that our inability to cure cancer is largely due to the presence
of a subset of cells within a cancer that constitutes a reservoir of self sustaining [25].
Current radiation and cytotoxic chemotherapies more effectively destroy the proliferating
cells that form the bulk of the tumour, but are largely ineffective against the cancer stem
cells (CSC)[26, 27]. Breast cancer was the first solid malignancy from which CSCs were
identified[28], via specific cell surface marker proteins CD44 and epithelial cell adhesion
molecules (EpCAM)[29, 30]. EpCAM and CD44v6 are among best available, clinically relevant
breast cancer stem cell markers for the proof of principle work in this project [30] .


Aptamers are short, singlestranded RNA or DNA that fold into specific 3D structures and bind
to their target molecules with high affinity and specificity[31]. Unlike antibodies,
aptamers remain structurally stable across a wide range of temperature and storage
conditions. They are generally nonimmunogenic, nontoxic and are 20 to 25 times smaller than
monoclonal antibodies. Thus aptamers offer several advantages for tissue penetration and
have shorter circulation time and faster body clearance resulting in a low background noise
during imaging and lower radiation dose. In addition, aptamers can be produced rapidly,
relatively inexpensively, and with high homogeneity [32, 33].


Histone deacetylases (HDACs) play an important role in gene regulation. Inhibitors of HDACs
(HDACi) are novel anticancer drugs, which induce histone (hyper) acetylation and counteract
aberrant gene repression[34]. HDACi also evoke nonhistone protein acetylation, which can
alter signalling networks relevant for tumorigenesis and these agents can also promote the
degradation of (proto) oncoproteins. Adult stem cells are maintained in a quiescent state
but are able to exit quiescence and rapidly expand and differentiate in response to stress.
The quiescence of cancer stem cells (CSCs) is highly relevant to cancer therapy since the
quiescent CSC is often resistant to both conventional therapy and targeted therapies. The
p53 gene plays a critical role in regulating stem cell quiescence [35]. CSCs promote
chemotherapy and radiation resistance through an increase in DNA repair capacity and in
histone H3 deacetylation[35]. Recently the role of HDACi in moving latent or quiescent cells
to an activated state and sensitizing them to other treatments has become a focus of
investigation in both HIV and cancer. The HDAC inhibitors have been studied in many
hematologic and solid malignancies but little work has focused on breast cancer and
particularly CSC[36, 37]. A study of HDACi on quiescent CSCs in breast tumours and their
radiation and chemotherapy responses would be of great interest in developing new
therapeutic paradigms using this class of agents.

NAD(P)H:quinone oxidoreductase 1 and NQO1*2 genotype (P187S)

Nicotinamide adenine dinucleotide, (NAD+), is a coenzyme found in all cells. In metabolism,
NAD+ is involved in reduction oxidation (redox) reactions, carrying electrons from one
reaction to another. The coenzyme is found as NAD+, which is an oxidizing agent and forms
NADH. This can then be used as a reducing agent. Electron transfer reactions are the main
function of NAD+. However, it is also used in other cellular processes, the most notable one
being a substrate of enzymes that add or remove chemical groups from proteins, in
posttranslational modifications. There is evidence that genetic variants in oxidative stress
related genes predict resistance to chemotherapy in primary breast cancer and that germline
polymorphisms can affect chemotherapy sensitivity in patients with breastcancer[38].

The status of superoxide dismutases and NAD (P) H quinone oxidoreductases have prognostic
significance in breast carcinomas[39]. The NQO1 enzyme guards against oxidative stress and
carcinogenesis and stabilizes p53 tumor suppressor[40, 41]. NQO1 deficient mice show reduced
p53 induction and apoptosis. NQO1*2 is a missense variant (NP_000894:p.187P4S) that is
homozygous in 4-20% of human population[42]. Cells with the homozygous NQO1*2 genotype have
no measurable NQO1 activity, reflecting the very low levels of the NQO1 P187S protein, which
undergoes rapid turnover via the ubiquitin proteasome pathway[43]. Response to epirubicin is
impaired in NQO1*2homozygous breast carcinoma cells in vitro, reflecting both p53linked and
p53independentroles of NQO1. A potential defective anthracycline response in NQO1deficient
breast tumors may confer increased genomic instability promoted by elevated reactive oxygen
species, and suggest that the NQO1 genotype is a prognostic and predictive marker for breast
cancer. A homozygous common missense variant (NQO1*2, rs1800566(T), NM_000903.2:c.558C4T)
that disables NQO1 strongly has been shown to predicts poor survival among two independent
series of women with breast cancer, an effect particularly evident after anthracycline based
adjuvant chemotherapy with epirubicin[44]. As part of this study the NQO1*2 genotype status
of all patients will be assessed. A correlation can be explored between NQO1*2 genotype
status and response rate in this setting. The study will evaluate the feasibility and safety
of tailored primary systemic therapy in the study population.

Inclusion Criteria:

- The patient must have consented to participate and must have signed and dated an
appropriate approved consent form.

- Female 18 Years and older

- The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1

- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy or limited incisional biopsy.

- Patients must have tumor diameter >2 cm measurable at least clinically; by physical
exam, unless the patient has inflammatory breast cancer, in which case measurable
disease by physical exam is not required or ultrasonographic staging (T2, T3 or T4 a,
b, c tumours with any clinical node status N0-N2).

- Left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or Multi
Gated Acquisition Scan (MUGA scan) performed within 3 months prior to study entry
must be greater or equal to 50%.

- Adequate haematological, renal and hepatic function (neutrophils >=2 × 109/L,
platelets ≥100 × 109/L, hemoglobin >=100g/L, total bilirubin ≤ 1.5 upper limit of
normal (ULN), aspartate aminotransferase and alanine aminotransferase ≤1.5 × ULN,
alkaline phosphatases ≤2.5 ULN, creatinine ≤ 1.5 ULN).

- Negative pregnancy test

Exclusion Criteria:

- Severe cardiovascular, hepatic, neurologic or renal comorbid conditions

- Primary surgical treatment of the tumor or excisional biopsy or lumpectomy performed
prior to study entry.

- Surgical axillary staging procedure prior to study entry.

- Definitive clinical or radiologic evidence of metastatic disease.

- History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
ductal carcinoma in situ (DCIS) treated with radiotherapy (RT).

- Non-breast malignancies unless the patient is considered to be disease-free for 5 or
more years prior to study entry and is deemed by her physician to be at low risk for
recurrence. Patients with the following cancers are eligible if diagnosed and treated
within the past 5 years: carcinoma in situ of the cervix, melanoma in situ, and basal
cell and squamous cell carcinoma of the skin.

- Previous therapy with anthracyclines or taxanes for any malignancy.

- Treatment including RT, chemotherapy, and/or targeted therapy, administered for the
currently diagnosed breast cancer prior to study entry.

- Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other
Selective estrogen receptor modulator (SERM).

- Any sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement

- History of hepatitis B or C.

- Sensory/motor neuropathy greater or equal to grade 2, as defined by the current
version of the NCI's CTCAE.

- Pregnancy or continuing lactation at the time of study entry.

- Use of any investigational agent within 4 weeks prior to enrollment in the study.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathological complete response in the breast

Outcome Description:

Pathological complete response defined as breast only, ypT0/ ypTis regardless of nodal status

Outcome Time Frame:

24 weeks (time window + 4 weeks)

Safety Issue:


Principal Investigator

Mustafa Khasraw, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barwon Health


Australia: Department of Health and Ageing Therapeutic Goods Administration

Study ID:




Start Date:

April 2013

Completion Date:

January 2015

Related Keywords:

  • Breast Cancer
  • chemotherapy
  • nab paclitaxel
  • neoadjuvant therapy
  • breast cancer
  • pathologic complete response
  • Breast Neoplasms