Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole

Neoadjuvant endocrine therapy (NET) offers a good treatment option to reduce the size of large (inoperable) primary breast tumors and/or advanced axillary lymph node metastasis prior to definite surgery. For selected patients (postmenopausal women with ER-positive breast cancer), primary endocrine therapy has been shown to be as effective as standard neoadjuvant chemotherapy. It is the general opinion that aromatase inhibitors of the "third-generation" (letrozole, anastrozole, exemestane) are the preferable drugs for neoadjuvant endocrine therapy in ER-positive, postmenopausal breast cancer patients. Anastrozole, letrozole and exemestane have been shown to suppress total body aromatisation as well as plasma and tissue estrogen levels by \> 90% in vivo. All three drugs are currently used as standard care in the neoadjuvant, adjuvant and metastatic setting worldwide, including in Norway. In 2015, a new class of anti-cancer drugs was introduced known as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. Following pivotal trials showing dramatic effects when combined with aromatase inhibitors or steroidal antiestrogens like fulvestrant, these compounds are now well established in distinct combinations during therapy for metastatic breast cancer. All in all, the addition of a CDK4/6 inhibitor to standard anti-hormone therapy for breast cancer doubled the time to disease progression and caused significant improvements in overall survival. Based on these findings, CDK4/6 inhibitors have also been tested in the neoadjuvant setting in clinical trials with very promising results. However, the combination of an aromatase inhibitor and a CDK4/6-inhibitor is not currently approved as standard neoadjuvant treatment for patients with locally advanced breast cancer (LABC) in Norway. Thus, the study described here will make this highly promising drug combination available for all patients who participate in this study. At the same time, the protocol will allow investigators to optimize the selection of patients benefitting from this treatment, highlight relevant biomarkers for personalized medicine and treatment, evaluate predictive markers and study the basic biology underlying treatment effects and resistance. In recent years researchers have noted a growing body of evidence concerning the involvement of the immune system in the onset and prognosis of breast cancer both locally (in the tumor or connected tissues) and through the involvement of the immune system as a whole. Interestingly, the gastrointestinal (gut) microbiota seems to play an important role in determining whether the immune system is able to fight against several cancer types. Pre-clinical studies have shown that the microbes in the gut may influence the repertoire and activity of immune cells, such as T cells, potentially priming the immune system for cancer cell recognition and destruction. This hypothesis is supported by the finding that treatment responses to immune checkpoint inhibitors (ICIs) in a variety of cancer types is dependent on the distinct gut microbiome of an individual patient as the efficacy of the ICIs relies on the presence of cancer-recognizing T cells. In addition, recent findings indicate that an emerging group of small molecules / targeting cancer therapies have immune altering properties. The MAPK kinase (MEK) inhibitors exemplify this by contributing to anti-tumor immunity through increasing the levels of cytotoxic T lymphocytes in preclinical model systems. Similar findings have recently been reported for both CDK4/6 inhibitors and PI3K-inhibitors. Thus, CDK4/6 inhibitors are believed to increase the antigen presentation of cancer cells, increase the activity of tumor infiltration by CD45+ cells and effector T cell activation, as well as decreasing Treg cell proliferation. While these mechanisms have been well described in in vitro and animal models, they need to be studied in humans as soon as possible to understand them and allow investigators to take advantage of these novel aspects in clinical decision making. These findings may also pave the way for microbiome and immune-related data to be used as potential biomarkers for patient selection and response evaluations during therapy. In addition to the clinical effects of being the standard care for breast cancer patients suffering from locally advanced breast cancer, neoadjuvant therapy is widely used to study the endocrinology of breast cancer in general and is recognized as one of the best model systems to predict responses in other clinical settings (early breast cancer or metastatic breast cancer). Tumor biopsies obtained before initiation of treatment and following six months of therapy will allow correlations to the individual type of clinical response (partial responses vs complete responses etc.). The research will focus on intratumoral mechanisms of adaption through tumor characterization using single cell technology which will allow investigators to follow both the different cancer clones as well as the evolution of different immune cells during therapy. Investigators will use novel approaches to evaluate liquid biopsies (measurement of cytokines levels, metabolites and cell free DNA-fragments etc.) during letrozole and ribociclib therapy using state of the art laboratory methods available at the host hospital and in the laboratories of the listed collaborators. Thus, all in all, the planned study will be able to contribute to the basic understanding of this very potent new drug combination that may be used in large groups of breast cancer patients in the future, including locally advanced breast cancer, hopefully reducing the use of traditional chemotherapy in this setting.