Breast cancer is the second-most common cancer worldwide, with an estimated 2.1 million new cases diagnosed per year (World Health Organization). In Europe, an estimated 523,000 new cases are diagnosed (World Health Organization) and approximately 138,000 women will die of the disease each year (World Health Organization), making it the leading cause of cancer death in women (World Health Organization). In the U.S., an estimated 271,000 new cases are diagnosed and approximately 42,000 women will die of the disease each year, making it the second-leading cause of cancer death in women (American Cancer Society).
Breast cancer typically is staged (Stage 0-IV) based on the size of the tumor, whether or not the tumor is invasive, whether or not the cancer is in the lymph nodes, and whether or not the cancer has spread (metastasized) to other parts of the body beyond the breast. The prognosis for women with metastatic breast cancer (MBC) remains poor; the 5-year survival rate for metastatic disease is about 27% (American Cancer Society), making this an area of continued, high unmet medical need. Therefore, treatment that balances efficacy, tolerability and quality of life is preferred.
Breast cancer is a heterogeneous disease comprised of several molecular subtypes, which are commonly grouped into clinical subtypes based on receptor status (Perou et al., Nature 2000;406:747-752). Receptors that are assessed in standard clinical practice include the estrogen receptor (ER) and progesterone receptor (PgR), collectively the hormone receptors (HRs), and human epidermal growth factor receptor 2 (HER2). Breast cancers generally are categorized by the presence or absence of these receptors. The most common type of breast cancer is HR positive and HER2 negative, accounting for approximately 64% of newly diagnosed cases (Howlader et al., Journal of the National Cancer Institute 2014;106(5):1-8). HER2-positive breast cancer and triple-negative breast cancer (TNBC), the latter of which lacks all three receptors, are less common, accounting for approximately 13% and 11% of breast cancers, respectively (Howlader et al., Journal of the National Cancer Institute 2014;106(5):1-8).
Treatment of HR-Positive,
HR-positive, HER2-negative disease, which represents the majority of all MBC cases, remains an area of high unmet medical need. Over the past two decades, only modest survival benefits have been achieved in this patient population; hence, treatment goals emphasize controlling disease-related symptoms, minimizing toxicity and maximizing quality-of-life: “…therapeutic goals for those with advanced disease include disease control, preservation or improvement in quality of life and prolongation of survival, with symptom palliation…” (Di Leo A et al., The Breast 2015;24:321‑330). Patients with HR-positive, HER2-negative disease are typically treated with endocrine therapy (with or without a CDK 4/6 inhibitor), chemotherapy or both.
Endocrine agents, with or without targeted agents such as a mammalian target of rapamycin inhibitor or a CDK 4/6 inhibitor, are preferred as initial treatment prior to chemotherapy for most patients with HR-positive, HER2-negative MBC (National Comprehensive Cancer Network). These agents, which typically are used sequentially, include aromatase inhibitors (e.g., anastrozole, exemestane and letrozole), selective ER modulators (e.g., tamoxifen) and ER downregulators (e.g., fulvestrant). As initial therapy in post-menopausal women with ER-positive, HER2-negative disease, letrozole plus the recently approved CDK 4/6 inhibitor, palbociclib, resulted in median progression-free survival (PFS) of 24.8 months, compared to 14.5 months with letrozole alone (Finn et al., New England Journal of Medicine 2016;375(20):1925-1936). As second-line endocrine therapy in women with HR-positive, HER2-negative disease, fulvestrant plus palbociclib resulted in median PFS of 9.5 months, compared to 4.6 months with fulvestrant alone (Cristofanilli et al., The Lancet 2016;17(4):425-439). However, despite these recent advances in endocrine therapy, virtually all patients will eventually progress and require subsequent treatment, typically with chemotherapy.
In HR-positive, HER2-negative MBC, chemotherapy generally is used following progression on endocrine therapy or in women for whom endocrine therapy is not indicated. Chemotherapy should be “…continued until progression of disease as tolerated because it modestly improves overall survival and substantially improves PFS, but this has to be balanced against toxicity and quality of life” (Partridge et al., Journal of Clinical Oncology 2014;32:3307‑3329).
While endocrine therapy is most often the first-line treatment for women with HR-positive, HER2-negative MBC, a significant percentage of women receive chemotherapy as their first treatment for advanced disease. In a recent analysis of a large patient record database (n=1,272-1,640 in Europe and n=2,225-2,760 in the U.S.), chemotherapy-only regimens were given as the first therapy following a diagnosis of advanced disease 33%-35% of the time in Europe and 34%-42% of the time in the U.S. (Caldeira et al., Oncology and Therapy 2016;4:189-197). This suggests that a significant percentage of women are not indicated for endocrine therapy in the advanced setting due to: (i) a short relapse-free interval while on adjuvant endocrine therapy (endocrine resistance); (ii) rapidly progressing disease/visceral crisis; or (iii) endocrine intolerance.
There are several approved chemotherapy agents for the treatment of HER2-negative MBC. These include: paclitaxel, nab-paclitaxel and docetaxel (taxanes); capecitabine (a fluoropyrimidine); doxorubicin and epirubicin (anthracyclines); gemcitabine (a nucleoside inhibitor); ixabepilone (an epothilone; approved in the U.S.); and eribulin (a non-taxane microtubule dynamics inhibitor). The taxanes and eribulin are approved as monotherapy, capecitabine is approved as both monotherapy and combination therapy (with docetaxel), gemcitabine is approved as combination therapy only (with paclitaxel) and ixabepilone is approved in the U.S. as both monotherapy and combination therapy (with capecitabine).
No optimal sequence of chemotherapies is known, and choice of individual regimens and agents depends on physician preferences, as well as previous therapies, residual toxic effects, tumor burden and symptoms (Harbeck et al., Breast Cancer Research and Treatment 2017;161:63‑72; Schwartzberg et al., Clinical Breast Cancer 2012;12:87‑93). However, capecitabine, an oral chemotherapy, and taxanes are the preferred first-line chemotherapy agents in HR-positive, HER2-negative MBC (Lin et al., Cancer Medicine 2016;5(2):209-220).
Taxanes are an established class of anticancer agents that are broadly used in various cancers, including breast cancer. Taxanes destroy cancer cells by preventing them from entering mitosis, a process of cell division, and thereby leading to apoptosis, or cell death. Taxanes are one of the most widely used classes of chemotherapy agents in both Europe and the U.S., with more than 2.8 million cycles administered in 2016 (Symphony Health Solutions 2016; IMS Health 2016).
While paclitaxel and docetaxel, the first two taxanes approved for the treatment of breast cancer, possess robust antitumor activity, they have low oral bioavailability and low solubility. Therefore, these pharmaceutical agents must be delivered intravenously, typically at an infusion center, and also are formulated with solubilizing agents that are known to cause hypersensitivity reactions. Nab-paclitaxel, a different formulation of paclitaxel that also is approved for the treatment of breast cancer, has a greatly reduced risk of hypersensitivity reactions, but must still be delivered intravenously.
Therapies that must be given intravenously at an infusion center often are associated withᵃ:
Fear of needles and complications associated with venous access;
Anxiety, including institutional-triggered side effects such as nausea and vomiting;
Heightened awareness of life-threatening disease presence; and
Disruption of daily activities.