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

Patients with locally advanced (stage III) breast cancer (LABC) are characterized by a significantly worse prognosis compared to patients with primarily operable breast cancer. While neoadjuvant chemotherapy has been the first choice in this situation for several decades, recent evidence suggests that some patients may experience an extraordinary effect from neoadjuvant endocrine treatments involving aromatase inhibitors as monotherapy or in modern drug combinations.Selected LABC patients admitted for treatment will be offered combination therapy including letrozole and ribociclib. The overall goal of the project is to improve understanding of tumor responses and resistance in patients suffering from ER-positive/HER-2 negative locally advanced breast cancer, focusing on the role of the immune system including the gut microbiome.

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.

Eligibility Criteria:
Inclusion Criteria:

* Females ≥ 18 years old at the time of the ICF signature
* histologically confirmed locally advanced breast carcinoma, defined as either large T2 (\>3cm in diameter) or T3-T4, and/or N2-3 primary breast cancer
* ER-positive (defined by ER-pos. in ≥ 50% of cancer cells) and HER-2 negative, luminal A/B breast cancer
* postmenopausal status (natural status or induced by treatment with the LHRH-analogue goserelin 3.6mg implant s.c. given every 4 weeks); definition of natural post-menopausal status: age above 55 years or age above 50 years and at least 2 years of amenorrhea in addition to LH-, FSH-, and plasma estradiol levels in the post-menopausal range.
* Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory eligibility): Absolute neutrophil count ≥ 1.0x109/L; platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0g/dL; INR≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug); Estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula; total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN; aspartate transaminase (AST) \< 2.5 x ULN; Alanine transaminase (ALT) \< 2.5 x ULN; patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication: potassium, magnesium, total calcium (corrected for serum albumin).
* Standard 12-lead ECG values defined as the mean of the triplicate ECGs \[QTcF interval at screening \< 450 msec (QT interval using Fridericia's correction), mean resting heart rate 50-90 bpm (determined from the ECG)\]
* Performance status: Eastern Cooperative Oncology Group (ECOG) score 0-1
* Ability and willingness to comply with study visits, treatment, testing and to comply with the protocol.

Exclusion Criteria:

* Any prior treatment for primary invasive breast cancer
* Patient with a known hypersensitivity to any of the excipients of ribociclib or letrozole
* Patient with known hypersensitivity to peanuts or soya-products
* Any evidence of distant metastasis
* Triple-negative breast cancer
* HER-2 positive disease, suitable for neoadjuvant therapy with trastuzumab, pertuzumab and taxanes, etc.
* Other conditions rendering patients in need of other treatment options with immediate effect like chemotherapy
* Concomitant medications that are known strong inducers of CYP3A4/5
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry; documented cardiomyopathy; Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) or Inability to determine the QTcF interval; Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block); Systolic Blood Pressure (SBP) \>160 or \<90 mmHg
* Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (\<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intraarticular).
* Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial
* Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment; Male partner sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient and the success of the vasectomy must be medically confirmed as per local practice; Placement of an intrauterine device (IUD); Note: Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine systems (IUS) or any other hormonal methods of contraception is not allowed in this study
* Autoimmune disorders or significant allergies (i.e. rheumatoid arthritis, asthma, psoriasis, etc.)
* Known HIV infection, Hepatitis B or C infection (testing not mandatory)
* History of autoimmune celiac, inflammatory bowel disease, or other chronic GI disease
* Recent use (within past month) of more than 3 days of antibiotics use
* Current use of probiotic supplements
* Taking proton pump inhibitors, steroids, other non-steroidal antiinflammatory drugs such as ibuprofen or acetyl salicylic acid
* Past bariatric surgery