Triple-Negative Breast Cancer (TNBC)

Introduction

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer. Women with TNBC have significantly reduced survival compared to women with other forms of breast cancer for every tumor stage at presentation (Bauer, Cancer, 2007). Because targeted therapies do not exist for TNBCs, the mainstays of therapy include surgery, radiotherapy, and chemotherapy. Traditional chemotherapy is often met with rapid resistance and consequently poor response rates (Yu, Clin Canc Res, 2013).

Additional therapeutic avenues are desperately needed to combat this aggressive form of breast cancer. Cannabidiol (CBD), with growing evidence to support its role in cancer, is a promising potential adjunctive therapy for the treatment of TNBC.

Image Credit: Bruce Blaus

About Triple-Negative Breast Cancer

Breast cancer is the most frequently diagnosed cancer worldwide, with over a million new cases diagnosed each year in the U.S. alone (Siegel, Cancer statistics, 2018). Although cases of breast cancer are often discussed in aggregate, breast cancer is quite heterogeneous, both at the molecular level and in terms of clinical outcomes. Each individual’s cancer cells express different levels of certain receptors that can impact the responsiveness to therapy and overall prognosis. These receptors include the estrogen receptor (ER), progesterone receptor (PR), and Her2/neu receptor (HER2). Breast cancer subtypes can thus be broken down into hormone receptor positive (ER/PR+), HER2 overexpressing, and triple-negative breast cancers (TNBCs). As the name implies, TNBCs are characterized by the absence of these three receptors.

TNBCs represent roughly 13% of all breast cancers (Parise, Breast J, 2009) and have substantially worse clinical outcomes than other breast cancer subtypes. Specifically, patients with TNBCs have a lower overall and breast cancer specific survival than hormone receptor positive cancers. Strikingly, this increased mortality risk peaks dramatically within the first two years following diagnosis, with TNBC patients possessing approximately six-times greater risk of death compared to hormone receptor positive cancers, even after adjusting for age, race, stage, tumor size, grade, and nodal status (Lin, Cancer, 2012). Additionally, patients with TNBCs have higher rates of both local and distant recurrence over shorter time intervals (Lin, Cancer, 2012; Dent, Clin Cancer Res, 2007). The increased risk of death and recurrence seems to dissipate over time.

U.S. All Breast Cancers Incidence (NIH SEER)

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With the institution of regular breast cancer screening programs, the majority of breast cancers are detected and diagnosed by screening mammography. TNBCs, however, are more likely to be diagnosed by the presence of a palpable breast mass, and typically present with larger tumor sizes (Lin, Cancer, 2012). Furthermore, TNBCs more commonly present in women under 40 years of age, which is a poor prognostic factor independent of tumor subtype (Fredholm, Plos One, 2009).

The poor prognosis of TNBCs may be explained by several biologic factors. First, TNBCs have higher rates of proliferation and typically present at a higher grade than other subtypes (Plasilova, Medicine, 2016; SK, BMC Clin Pathol, 2012). Additionally, almost 20% of patients with TNBCs possess mutations in the breast cancer susceptibility gene, or BRCA, with a predominance of BRCA1 (Gonzalez, Clin Cancer Res, 2011). In healthy cells, functional BRCA promotes DNA repair in order to maintain genetic integrity and stability in response to injury. When BRCA is mutated, as is the case in some TNBCs, the ability to repair DNA by this mechanism is lost, which can result in the accumulation of additional pathologic mutations and ultimately the development of cancer. BRCA mutations can be inherited from a parent or can arise sporadically over the lifespan. These mutations are generally associated with an earlier age at diagnosis and poor overall survival (Litton, Cancer, 2012; Stoppa-Lyonnet, J Clin Onc, 2000).

Stages of Breast Cancer

Management of breast cancer typically involves a combination of surgery, radiation, chemotherapy, and/or targeted therapy. The nature of each therapy and the order in which they are administered largely depends on the stage of the tumor at presentation as well as the molecular subtype.

In hormone receptor positive and HER2 overexpressing breast cancers, excessive signaling through these pathways promotes aberrant cell growth and proliferation. Equipped with a known disease mechanism, researchers have identified targeted therapies, such as tamoxifen and herceptin, to selectively dampen signaling through the ER and HER2 pathway, respectively. These therapies are incredibly effective and represent a critical component of the standard of care in these patient subsets (Burstein, J Clin Oncol, 2016; Moja, Cochrane Database Sys Rev, 2012). Meanwhile, no such targeted therapy exists for TNBCs. Management of TNBCs thus relies on surgery to remove the primary tumor, followed by post-operative radiation and chemotherapy. In cases of more advanced or metastatic disease, chemotherapy may form the mainstay of treatment.

Reliance on traditional chemotherapy predisposes to treatment resistance and ultimately detrimental outcomes (Yu, Clin Canc Res, 2013). This may be best reflected in the disparity in five-year survival rates among breast cancer patients presenting in later stages. TNBC patients presenting at Stage III had a five-year survival of only 35% compared to 58% in women with other cancer subtypes at the same stage (Bauer, Cancer, 2007). There is a clear unmet need for novel therapeutic strategies to improve survival in these patients.

Cannabidiol (CBD) as an Adjunct to Standard of Care Treatment

Accumulating evidence suggests a role for cannabidiol (“CBD”) in the management of certain cancers. CBD is an attractive candidate for translation into clinical practice due the absence of psychoactive effects. Furthermore, it has been suggested that of several naturally occurring cannabinoids, including THC, CBD is the most potent inhibitor of cancer cell growth with minimal effects in healthy cells (Ligresti, J Pharm Exp Ther, 2006). In some rare instances, THC has also been demonstrated to increase tumor size, growth, and metastases for unclear reasons (McKallip, J Immunol, 2005).

The mechanism by which CBD exerts its anti-tumor effects is not fully understood, although results from preclinical studies suggest they may be multifactorial. In the case of TNBC, CBD was shown to reduce cell viability of TNBC cell lines by dampening signaling pathways implicated in the development of cancer and through induction of programmed cell death (Shrivastava, Mol Cancer Ther, 2011; Elbaz, Mol Onc, 2015). CBD substantially reduced tumor growth in mouse models of TNBC (Elbaz, Mol Onc, 2015; McAlister, Mol Canc Ther, 2011; Murase, Br J Pharmacol, 2014). Furthermore, CBD may incite damage in cells through the overproduction of unstable oxygen molecules, termed reactive oxygen species, that can damage other nearby molecules, such as nucleic acids, proteins, and lipids (Shrivastava, Mol Cancer Ther, 2011).

CBD was also shown to impact other critical aspects of cancer. In mouse models of TNBC, CBD substantially reduced metastases, perhaps due to the downregulation of a key regulator of tumor metastasis, ID-1 (McAlister, Mol Cancer Ther, 2007; McAlister, Mol Canc Ther, 2011; Murase, Br J Pharmacol, 2014). Additionally, in order for tumors to persist, grow, and invade locally, tumor cells must degrade the surrounding extracellular matrix and develop new blood vessels to support the growth. In CBD-treated mice with TNBC, there was significant downregulation of enzymes known to degrade the extracellular matrix and decreased recruitment of tumor-associated macrophages (TAMs) (Elbaz, Mol Onc, 2015), which are known to secrete growth factors that support the development of new blood vessels and secrete enzymes that support local tissue invasion (Condeelis, Cell, 2006). Taken together, CBD was shown to influence several key processes in cancer pathogenesis– tumor growth, local invasion, and metastasis.

Jay Pharma advisor Dr. Wai Liu discusses the potential merits of cannabinoids in breast cancer.

Merits of a Cannabinoid Combination Therapy

While CBD may be effective as an anti-tumor agent alone, some preclinical evidence suggests that its use in combination with standard chemotherapies and the cholesterol epoxide hydrolase (ChEH)/antiestrogen-binding site (AEBS) inhibitors clomiphene citrate and DPPE may be beneficial (WO2017072773A1; Scott, Int J Oncol, 2017). Clomiphene citrate and DPPE both inhibit the activity of the antiestrogen-binding site (AEBS), which can regulate cell growth, with a demonstrated effect in multiple cancer cell lines. Of note, the AEBS is an intracellular receptor whose actions occur independently of the estrogen receptor. This is particularly relevant to TNBC given its estrogen receptor-negative status (Payre, Mol Cancer Ther, 2008).

Adding traditional chemotherapies to these regimens may further improve outcomes. CBD in combination with specific chemotherapies reduced cell viability and promoted programmed cell death in certain cancer cell lines (WO2017072773A1). Furthermore, a Phase 3 clinical trial in patients with metastatic breast cancer demonstrated that DPPE in combination with the traditional chemotherapeutic agent doxorubicin prolonged survival by 50% compared to those who received doxorubicin alone (Brandes, Human Exper Toxicol, 2008). It may be advantageous to employ these combination therapies both for the added benefit and for the possibility of reducing the effective dose of each agent.

Preliminary work with small sample sizes of several forms of cancer, including breast, has demonstrated that the clinical impact of CBD may recapitulate many of the effects observed in preclinical studies (Kenyon, Anti Cancer Res, 2018). With accumulating evidence supporting the use of combination therapies in the treatment of TNBC (Scott, Int J Onc, 2017; Scott, Anticancer Res, 2013), researchers seek to replicate findings in large scale clinical trials.

Clinical Program

Jay Pharma researchers have proposed an open label Phase 2 prospective cohort study to evaluate the efficacy of CBD and clomiphene citrate and DPPE in patients with locally advanced TNBC. CBD and clomiphene citrate or DPPE will be administered with traditional chemotherapy prior to surgical intervention.