Artificial Intelligence and Machine Learning to Guide CDK4/6 Inhibitor Rechallenge in Breast Cancer.

Inclusion criteria

• Age \>18 years
• Eastern Cooperative Oncology Group performance status 0-2
• Ability to understand and sign the informed consent document
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Advanced breast cancer (defined as unresectable or metastatic) histologically confirmed hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer per American Society of Clinical Oncology/College of American Pathologists (CAP) guidelines.
• Endocrine-sensitive disease per the 7th International Consensus Conference on Advanced Breast Cancer (ABC7) 2023 guideline: no relapse during the first 2 years of adjuvant endocrine therapy or progression within the first 6 months of first-line endocrine therapy in the metastatic setting.
• Progression of disease, radiographically per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or clinically per physician assessment, after a minimum of 6 months of 1 prior line of any CDK4/6 inhibitor therapy plus or minus endocrine therapy in the metastatic setting, or within 6 months of completing adjuvant CDK4/6 inhibitor with endocrine therapy.
• An additional line of therapy with CDK4/6i is possible and available.
• Zero to 1 prior line of chemotherapy or antibody-drug conjugates in the metastatic setting.
• Available next-generation sequencing panel testing results - or possibility to perform next-generation sequencing panel testing - on tumor tissue biopsy collected within 6 months of enrollment but after CDK4/6 inhibitor exposure. Note that If biopsy was performed more than 6 months before enrollment, the patient is not eligible to participate, unless the biopsy is repeated during the prescreening phase. Adequate tissue/testing will be one of these:
• safe non-osseous tumor site for fresh tissue biopsy and subsequent tissue-based next-generation sequencing testing by any Clinical Laboratory Improvement-certified laboratory. Biopsy and next-generation sequencing testing will be performed as standard of care evaluation.
• archival non-osseous tumor tissue adequate for standard of care next-generation sequencing testing by any Clinical Laboratory Improvement Amendments-certified labs.
• prior tissue-based next-generation sequencing testing on tissue that was collected and performed within 6 months of study enrollment.
• Palbociclib sensitive disease as determined by the palbo-VNN model.
• Participants can have non-measurable but evaluable disease or measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
• Participants must have organ and marrow function as defined below:
• Leukocytes \> 3,000/microliter
• Hemoglobin \> 8 g/deciliter
• Absolute neutrophil count \> 1,200/microliter
• Platelets \> 75,000/microliter
• For participants of reproductive potential:
• Females: use of highly effective contraception for at least 1 month before initiation of treatment with study medications (cycle 1 day 1) and agreement to use such a method during study participation and until 3 months after the end of treatment visit. Only non-hormonal contraception (eg., copper intrauterine device, barrier, condoms with spermicidal, sponge with spermicidal, or diaphragm with spermicidal), is allowed.
• Males: use of condoms or other methods to ensure effective contraception with a partner during study participation and until 3 months after the end of treatment visit. For partners, use of hormonal contraception is allowed.
• Palliative radiotherapy is allowed.
• Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate locoregional central nervous system-specific treatment is not required and is unlikely to be required during the first cycle of therapy.
• Human immunodeficiency virus-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible.
• For participants with evidence of chronic hepatitis B virus infection, the viral load must be undetectable on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus infection must have been treated and cured. For participants with hepatitis C virus infection who are currently on treatment, they are eligible if they have an undetectable viral load.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible.

Exclusion criteria

• Life expectancy less than 6 months.
• Any medical or psychiatric condition that would prevent the safe use of a CDK4/6 inhibitor or fulvestrant or treatment of physician's choice or the ability to participate in study procedures.
• Participants who are receiving any other investigational agents within 3 weeks of study enrollment only if there is a known pharmacokinetic interaction with the selected drug. No washout period is otherwise required.
• Uncontrolled intercurrent illness including ongoing or active infection, congestive heart failure, unstable angina pectoris or cardiac arrhythmia, lung disease requiring continuous oxygen supplementation, decompensated cirrhosis, end-stage kidney disease on dialysis, or psychiatric illness that limits the ability to participate in the study.
• Unable to have access to abemaciclib, palbociclib, ribociclib, or fulvestrant as a standard of care treatment.
• Pregnancy or lactation.