Neoadjuvant Chemotherapeutic and Targeted Therapies for Early-stage, High-risk Breast Cancer

European Oncology & Haematology, 2014;10(1):28–34

Abstract:

Neoadjuvant or preoperative chemotherapy is the preferred treatment for locally advanced, inflammatory and early-stage high-risk breast cancers. Patients with locally advanced breast cancers are candidates for neoadjuvant therapy because their tumours are often not amenable to resection. On the other hand, patients are candidates for neoadjuvant chemotherapy if the breast-conserving surgery is not possible. At present, anthracycline- and taxane-based chemotherapy regimens remain as the cornerstone for neoadjuvant therapy in early breast cancer, but there is a clear need for effective therapies in high-risk, early-stage patients. A number of chemotherapeutic and targeted therapies have been evaluated in clinical trials with varying results. The US Food and Drug Administration (FDA) has recently approved pertuzumab in combination with trastuzumab and cytotoxic chemotherapy as a neoadjuvant therapy option for HER2-positive breast cancer. This article reviews the neoadjuvant chemotherapeutic and targeted therapies options for early-stage, high-risk breast cancer. Possible role of molecular subtyping in triple-negative breast cancer is also described.

Keywords: Neoadjuvant, triple-negative, locally advanced, inflammatory, breast cancer, HER2, molecular subtyping
Disclosure: Clement Chung and Rosetta Lee have no conflicts of interest to declare. No funding was received for the publication of this article.
Received: March 20, 2014 Accepted June 03, 2014 Citation European Oncology & Haematology, 2014;10(1):28–34
Correspondence: Clement Chung, Pharmacist, Lyndon B Johnson General Hospital, 5656 Kelley St, Houston, TX 77026, US. E: clement_t_chung@yahoo.com

According to the World Health Organization (WHO), cancer-related mortalities reach 7.9 million worldwide each year.1 Among women, breast cancer is one of the most common cancers globally. Despite advances in early detection and understanding on the molecular pathogenesis of breast cancer, approximately 30 % of patients with early-stage breast cancer experience recurrent disease.2 Systemic treatment of breast cancer includes cytotoxic chemotherapy, endocrine (or hormonal) therapy and targeted therapy. These therapeutic agents are used in the adjuvant (post-surgical), neoadjuvant (pre-surgical) and metastatic settings.

Neoadjuvant therapy (also referred to as preoperative, pre-surgical, induction or primary systemic therapy) is the systemic treatment of breast cancer in the preoperative setting with curative intent. It was first evaluated more than 30 years ago for the treatment of locally advanced, inflammatory (a subtype of locally advanced breast cancer) and inoperable breast cancers.3 It is now increasingly used in patients with operable disease.3 The primary objective of the neoadjuvant therapy is to improve surgical outcomes3–5 in patients for whom a primary surgical approach is technically not feasible and in patients with operable breast cancer who desire breast conservation. Second, neoadjuvant therapy decreases the need for complete axillary lymph node dissection.6–8 It also allows an early evaluation of the systemic therapy. Third, neoadjuvant therapy gives clinicians an opportunity to obtain tumour specimens prior to and during the preoperative treatment, thus enabling researchers to investigate emerging drug therapies and predictive biomarkers.7,8 Recently, following the announcement by the US Food and Drug Administration (FDA)9 that it will consider neoadjuvant randomised trials for accelerated drug approval in early breast cancer, there has been a marked increase in clinical trials with novel agents in the neoadjuvant setting. This review focuses on the current and emerging neoadjuvant chemotherapies and targeted therapies for early-stage, high-risk9 (defined as 20–25 % risk of recurrence or death at 5 years) breast cancer.

Patient Selection
Neoadjuvant chemotherapy is the preferred treatment for locally advanced and inflammatory breast cancer. According to the American Joint Committee on Cancer,10 locally advanced breast cancer is a stage III disease. Clinically, locally advanced breast cancer includes tumours that are localised to the breast tissue without regional nodal involvement, and may also include tumour sizes greater than 5 cm in diameter, or tumours of any size with overlying oedema, chest-wall fixation, skin infiltration or inflammatory features. Among these forms of locally advanced breast cancer, only clinical stage IIIA (T0N2M0; T1-3N2M0) is considered surgically resectable; whereas clinical stage IIIB (T4N0-2M0) and stage IIIC (any TN3M0) are considered unresectable or inoperable.11 Patients with locally advanced breast cancer IIIB-C are candidates for neoadjuvant therapy. Moreover, patients with high-risk, early-stage breast cancer (clinical stage I or II) are candidates for neoadjuvant therapy if breast-conserving surgery is not possible or if the tumour subtype is associated with a higher likelihood of response (e.g. human epidermal growth factor receptor type-2 [HER2]- positive or triple-negative [oestrogen receptor [OR]-negative, progesterone receptor [PR]-negative, HER2-negative), regardless of tumour size.12,13

The histologically proved complete response following neoadjuvant therapy, i.e. the absence of invasive and non-invasive tumour in the breast tissue and lymph nodes (ypT0ypN0), confirmed by pathology, is known as the pathological complete response (pCR).10 It has been widely used as a surrogate marker for disease response and is an indication for complete eradication of distant micrometastasis or residual disease.11 It was first observed in patients with locally advanced breast cancer14 and was subsequently confirmed in randomised trials in patients with operable disease.14 However, the definition of pCR and the methods of assessment varied across clinical trials.15–22 Therefore, pCR alone cannot be applied as a predictor for long-term disease outcome. It is important to consider tumour involvement in both breast tissue and lymph nodes for pCR since the presence of residual disease in lymph nodes after neoadjuvant therapy may affect disease-free survival (DFS) and overall survival (OS).23,24 Of note, ductal carcinoma in situ (DCIS) does not require pCR since the presence of residual disease in DCIS does not affect DFS or OS.25,26

Neoadjuvant chemotherapy for locally advanced breast cancer is generally anthracycline- or taxane-based (see Table 1). At present, approximately 20 % of patients14–17,23 achieve pCR after an appropriate neoadjuvant regimen. Randomised trials20,27 showed that non-anthracycline and anthracycline-containing regimens are considered equally efficacious regardless of whether they are given pre- or postoperatively. Equally, long-term efficacy had been demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial in which docetaxel was administered either pre- or postoperatively.28 An important caveat is, if the goal of therapy is to treat operable breast cancer, then any patient who is indicated for adjuvant therapy should also be offered neoadjuvant therapy.14 Current US National Comprehensive Cancer Network (NCCN) guidelines29 state that preoperative chemotherapy is not indicated unless invasive breast cancer is confirmed.

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Keywords: Neoadjuvant, triple-negative, locally advanced, inflammatory, breast cancer, HER2, molecular subtyping