Studying the Effects of Removing Adjuvant Chemotherapy for the Treatment of Estrogen Receptor-Positive, HER2-Negative Breast Cancer in Patients with a Low-Genomic Risk, SELECT Trial
This phase II trial studies whether removing chemotherapy after mastectomy or lumpectomy (adjuvant chemotherapy) affects the length of time treatment is taken (treatment persistence) in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and a recurrence score (RS) ≤ 25 (low-genomic risk). Adjuvant chemotherapy works in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is given to minimize or prevent the cancer from returning following mastectomy or lumpectomy. Adjuvant chemotherapy is often recommended as part of the “standard treatment regimen”, alongside optimized endocrine therapy (ET), with letrozole or anastrozole, and ribociclib. Letrozole or anastrozole blocks the use of estrogen by the tumor cells. They may also be given with goserelin to block hormone production in the ovaries or testicles. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The benefits of adjuvant chemotherapy in patients with a low-genomic risk are controversial. There is ongoing debate about whether chemotherapy benefit arises primarily from endocrine effects or its direct cytotoxic effects. There is also uncertainty regarding the extent to which adjuvant chemotherapy affects the treatment persistence of ribociclib. Removing adjuvant chemotherapy before treatment with ET and ribociclib in patients with ER-positive, HER2-negative breast cancer and a low-genomic risk may help researchers determine it's effects on ribociclib treatment persistence and improve treatment recommendations.
Inclusion Criteria
- Female or male age ≥ 18 years old and have the ability to understand and the willingness to sign a written informed consent document
- Participants may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy
- Participants may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy
- Participants underwent a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy
- For participants who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins * Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection
- For participants who undergo mastectomy, the margins must be free of residual gross tumor * Participants with microscopic positive margins are eligible if post-mastectomy RT of the chest wall will be administered
- Participants must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND)
- The following staging criteria must be met postoperatively according to American Joint Committee on Cancer (AJCC) 8th edition criteria: Men or premenopausal women with T1-3N1-2. Postmenopausal women with T3N1 or T1-3N2 diseases
- The tumor must be ER-positive (≥ 10%), HER2-negative, by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines based on testing results. HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver-enhanced in situ hybridization [SISH]) test is required to confirm the participant’s HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory)
- Oncotype Dx Recurrence Score must be 0 - 25
- Participants with known menopausal status at the time of screen * Postmenopausal status is defined as: ** Participant underwent bilateral oophorectomy, or ** Age ≥ 60 years, or ** Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. Note: All women who do not meet the criteria for postmenopausal status are considered premenopausal for the purpose of this trial
- The interval between the last surgery for breast cancer (including re-excision of margins) and screening must be no more than 16 weeks
- HIV-infected participants with undetectable viral load within 6 months and in long term anti-retroviral therapy that would not have a significant drug-drug interaction with ribociclib are eligible for this trial
- Radiation therapy should be used according to standard guidelines
- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 28 days prior to initiation of the study treatment
- Participant is able to swallow oral medications
- Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (must be obtained within 14 days prior to screening)
- Platelets ≥ 100 × 10^9/L (must be obtained within 14 days prior to screening)
- Hemoglobin ≥ 9.0 g/dL (must be obtained within 14 days prior to screening)
- Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2 according to the Modification of Diet in Renal Disease (MDRD) formula (must be obtained within 14 days prior to screening)
- Alanine transaminase (ALT) < 2.5 × upper limit normal (ULN) (must be obtained within 14 days prior to screening)
- Aspartate transaminase (AST) < 2.5 × ULN (must be obtained within 14 days prior to screening)
- Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert’s Syndrome (must be obtained within 14 days prior to screening)
- International normalized ratio (INR) ≤ 1.5 (must be obtained within 14 days prior to screening) (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 enrollment)
- Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements (the local laboratory value should be documented within normal limits after the correction) before enrollment (must be obtained within 14 days prior to screening): * Potassium * Magnesium * Total calcium (corrected for serum albumin)
- Standard 12-lead electrocardiogram (ECG) values assessed as: corrected QT (QTcF) interval (using Fridericia’s correction) at screening < 450 msec. Resting heart rate 50-90 beats per minute (determined from the ECG)
- Participant must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures
- Participants must adhere to the following reproductive and contraceptive requirements while on study treatment and for the specified duration after the last dose of the treatment drugs * General requirements: ** Participants must not be pregnant or breastfeeding ** Participants must not donate or freeze eggs for future use related to assisted reproduction during the course of this study or within three months after receiving the last dose of the study treatment * For participants of childbearing potential: ** A participant of childbearing potential is defined as an individual who is premenopausal and capable of becoming pregnant. This includes individuals using contraception, those who are sexually inactive, and those with partners who have undergone a vasectomy. A participant is considered of childbearing potential if they have reached menarche, have not yet met the criteria for postmenopause (defined as more than 12 consecutive months of amenorrhea without any other medical cause), and have not undergone surgical sterilization (such as hysterectomy or oophorectomy) ** A negative highly sensitive serum pregnancy test (for beta human choriogonadotropin [β-hCG]) must be obtained within two weeks of starting the treatment drug administration ** Participants must practice at least one highly effective method of contraception * Highly effective methods of contraception include, but are not limited to: ** Total abstinence (no sexual relations), when this is in line with your preferred and usual lifestyle. Periodic abstinence like calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable methods of contraception ** Total hysterectomy (surgical removal of the uterus and cervix) or tubal ligation (getting your “tubes tied”) at least six weeks before taking study treatment ** Your male partner has already been sterilized with the appropriate documentation. The sterilized male partner should be your sole partner ** Placement of an intrauterine device (IUD) ** The use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or intrauterine system (IUS) or any other form of hormonal contraception (e.g., hormone vaginal ring, hormonal-based IUD or transdermal hormone contraception) is not allowed in this study
- Participant has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for five years or more
Exclusion Criteria
- Definitive clinical or radiologic evidence of distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery
- T4 tumors, including inflammatory breast cancer
- N3 tumors
- Participants that have received neoadjuvant chemotherapy or biotherapy
- Participant has received prior treatment with tamoxifen, raloxifene or aromatase inhibitors (AIs) for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last two years prior to randomization. Participant is concurrently using hormone replacement therapy
- Participants with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy)
- History of ipsilateral or contralateral invasive breast cancer: Participants with synchronous and/or previous ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are eligible. If prior ipsilateral DCIS was treated with lumpectomy and radiation therapy, a mastectomy must have been performed for the current cancer
- Participant has received any CDK4/6 inhibitor
- Participant has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within two years before randomization. Note: Participants with adequately treated basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ are eligible
- Participant has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation)
- Life expectancy of < 10 years due to co-morbid conditions in the opinion of the treating investigator
- Non-epithelial breast malignancies such as sarcoma or lymphoma
- Hormonally based contraceptive measures must be discontinued prior to registration (including progestin/progesterone IUDs)
- Pregnancy or lactating women or women who plan to become pregnant or breast-feed during the trial * Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed at screening
- 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 within six months prior to screening * Documented cardiomyopathy * Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) within six months prior to screening * 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 Pointes (TdP) including uncorrected 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 TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within five half-lives or seven days prior to starting trial treatment) ** Inability to determine the QTcF interval * Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II- and third-degree AV block) * Uncontrolled arterial hypertension with systolic blood pressure > 160 mmHg
- Participant is currently receiving any of the following substances within 7 days before registration: * Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummelos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5 * Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
- Participant is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment or has 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)
- Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection)
- Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the principal investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ≤ 5 years
- Participation in other studies involving investigational drug(s) within 30 days prior to registration or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial. If the participant is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the sponsor-investigator is required to establish eligibility
Additional locations may be listed on ClinicalTrials.gov for NCT06953882.
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PRIMARY OBJECTIVES:
I. To assess the one-year discontinuation rate of ribociclib in participants with resected moderate to high-anatomical risk (men or premenopausal women T1-3N1-2, and postmenopausal women T3N1 or T1-3N2), low-genomic risk (RS ≤ 25), ER-positive, HER2-negative breast cancer who choose to forgo adjuvant chemotherapy in their treatment regimen (arm 1).
II. To assess the one-year discontinuation rate of ribociclib in participants with resected moderate to high-anatomical risk (men or premenopausal women T1-3N1-2, and postmenopausal women T3N1 or T1-3N2), low-genomic risk (RS ≤ 25), ER-positive, HER2-negative breast cancer who choose to include adjuvant chemotherapy in their treatment regimen (arm 2).
SECONDARY OBJECTIVES:
I. To evaluate the three-year invasive disease-free survival (iDFS) in participants in arm 1 and arm 2.
II. To describe patient reported outcomes (PRO) for symptoms, anxiety and depression in participants in arm 1 and arm 2.
III. To describe PRO health-related quality-of-life (QoL) in participants in arm 1 and arm 2.
IV. To explore the factors that impact decision on whether to include or omit adjuvant treatment in participants in arm 1 and arm 2.
V. To evaluate the change in fear of cancer recurrence and decision regret in participants in arm 1 and arm 2.
EXPLORATORY OBJECTIVES:
I. To evaluate the one-year discontinuation rates of ribociclib between participants in arm 1 and arm 2, documenting and analyzing these metrics within each group before conducting a comparative evaluation.
II. To evaluate the change in willingness to join a randomized clinical trial for adjuvant treatment in participants in arm 1 and arm 2.
III. To assess adherence to ribociclib in participants in arm 1 and arm 2.
IV. To characterize the clinical and biological profile of disease recurrence in participants in arms 1 and arm 2.
V. Offer enrollment for circulating tumor deoxyribonucleic acid (DNA) (ctDNA) analyses.
OUTLINE: Patients choose between 1 of 2 arms.
ARM 1: Patients receive ET consisting of either letrozole orally (PO) once daily (QD) or anastrozole PO QD continuously with or without gonadal suppression consisting of goserelin subcutaneously (SC) on day 1 of each cycle. Treatment with letrozole or anastrozole continues for up to 3 years and cycles of goserelin repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. Four to eight weeks after initiation of ET with or without gonadal suppression, patients also receive ribociclib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.
ARM 2: Patients receive adjuvant chemotherapy as per National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or European Society for Medical Oncology (ESMO) guidelines in the absence of disease progression or unacceptable toxicity. Four weeks following the completion of chemotherapy or radiation therapy (RT), if given, patients receive ET with or without gonadal suppression and ribociclib as in Arm 1.
Additionally, all patients undergo blood sample collection throughout the trial. Patients may also undergo mammography, computed tomography (CT), magnetic resonance imaging (MRI), bone scan, positron emission tomography (PET), and/or biopsy as clinically indicated throughout the trial.
After completion of study treatment, patients are followed up at 30 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationYale University
Principal InvestigatorJing Du
- Primary ID2000038734
- Secondary IDsNCI-2025-05716
- ClinicalTrials.gov IDNCT06953882