Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer

Inclusion Criteria:

1. Men or women age ≥ 18 years.

2. Patients with a diagnosis of ER+, HER2- metastatic (Stage IV) breast cancer.Positivity status is defined as >10% staining for ER and immunohistochemistry (IHC) 0+ or IHC 1 or 2+ staining for HER-2, and fluorescence in situ hybridization (FISH)negative with standard pathology staining methods.

3. Archived tumor tissue available.

4. Women and men with proven locally advanced, locoregionally recurrent or metastaticdisease adenocarcinoma of the breast not amenable to curative therapy. Note:patients relapsing while on adjuvant tamoxifen or AI are eligible for this study.

5. No prior systemic anticancer therapy for metastatic or advanced disease (chemotherapy targeted therapy or ET). Note 1: prior endocrine therapy in the metastatic setting is not allowed unlessinitiated <30 days from study initiation or Cycle 1, Day 1 (C1D1) (Section 3.2). Note 2: prior initiation of LHRH agonist or bone-directed agents, however, isallowed.

6. No visceral crisis. Visceral crisis is defined as advanced, symptomatic, visceralspread that is at risk of life-threatening complication in the short term and thatrequires chemotherapy.

7. Adequate organ and marrow function as defined below:

• Hematological

• Absolute neutrophil count (ANC) ≥1,500 cells/mm³

• Platelets ≥100,000 cells/mm³

• Hemoglobin ≥9.0 g/dL

• Renal

• Serum creatinine or Measured or calculated creatinine clearance (glomerular filtration rate (GFR) can also be used in place of creatinineor creatinine clearance (CrCl)) ≤ 1.5 x upper limit of normal (ULN) orCrCl ≥ 40 mL/min. CrCl should be calculated per institutional standard.

• Hepatic

• Serum total bilirubin < 1.0 ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine transaminase (ALT) (serum glutamic-pyruvictransaminase (SGPT)). Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 XULN for patients with liver metastases

• Albumin ≥ 2.5 mg/dL

8. Measurable disease as defined by Response Evaluation Criteria in Solid Tumorsversion 1.1 (RECIST V.1.1) or non- measurable disease that is evaluable (EisenhauerEA, Therasse P, Bogaerts J et al, 2009).

9. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or

10. (See APPENDIX A for more information.)

11. Ability to understand and the willingness to sign a written informed consentdocument.

12. Life expectancy >3 months.

13. Postmenopausal women, women with suppressed ovarian function, or premenopausalwomen, provided they are being treated with monthly LHRH analogues (first injectionperformed ≥ 7 days before treatment initiation) and are willing to continue toreceive LHRH agonist therapy for the duration of the trial. Menopausal patients orpatients with suppressed ovarian function are defined as follows:

• Women with bilateral oophorectomy

• Postmenopausal women, as defined by any of the following criteria:

• Age 60 or over

• Age 50-59 years and meets the following criterion:

• Amenorrhea for ≥12 months and follicle-stimulating hormone and estradiollevels within the postmenopausal range

• Women with hysterectomy or chemotherapy-induced amenorrhea. Note: Patientswith hysterectomy or chemotherapy-induced amenorrhea must display folliclestimulating hormone and estradiol levels within the postmenopausal range.

13. Resolution of all acute toxic effects from prior anticancer therapy or surgicalprocedures as defined by the National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) V 5.0 to grade 1 (except alopecia or othertoxicities not considered a safety risk for the patient at Investigator'sdiscretion) (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_ Reference_8.5x11.pdf).

Exclusion Criteria:

1. Patients who are currently receiving or have received treatment for a secondarycancer other than resected non-melanoma skin cancer lesions or in situ cancer withinthe past 24 months.

2. Prior exposure to CDK4/6i ≤12 months prior to enrollment.

3. Use of investigational drugs ≤28 days prior to study enrollment and during thestudy.

4. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the patient'sparticipation for the full duration of the trial, or that makes participation in thetrial to be not in the best interest of the patient in the opinion of theInvestigator.

5. Locally advanced breast cancer or locoregional relapse amenable for any treatmentwith curative intent.

6. HER2+ or equivocal tumor status either on the primary or on the recurrent tumordefined as IHC3+, FISH/CISH (chromogenic in situ hybridization) amplified orFISH/CISH equivocal according to the American Society of Clinical Oncologists (ASCO) 2015 criteria (Wolff AC, Hammond MEH, Allison KH et al, 2018).

7. Prior endocrine therapy in the metastatic setting is not allowed unless initiated < 30 days from study initiation or Cycle 1, Day 1 (C1D1).

8. Prior treatment with any CDK 4/6 inhibitor in the metastatic setting is not allowed.

9. Patients who are ctDNA negative or with undetectable levels of ctDNA at study entry.

10. Any major surgery (defined as requiring general anesthesia) or significant traumaticinjury within 4 weeks of treatment; however, surgical diagnostic procedure isallowed (even if under general anesthesia).

11. Known active, bleeding diathesis.

12. Any serious known concomitant systemic disorder incompatible with the study (at thediscretion of the Investigator).

13. Patients unable to swallow tablets.

14. History of malabsorption syndrome or other condition that would interfere withenteral absorption.

15. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,carcinomatous meningitis, or leptomeningeal disease as indicated by clinicalsymptoms, cerebral edema and/or progressive growth. Patients with a history of CNSmetastases or cord compression are eligible if they have been definitively treatedwith local therapy (e.g., radiotherapy, stereotactic surgery) and are clinicallystable and off anticonvulsants and steroids for at least 4 weeks before treatmentinitiation.

16. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, orCDK4/6i or any of their excipients.

17. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolongingdrug (eg, hypocalcemia, hypokalemia, hypomagnesaemia).

18. Patients treated within the last 7 days prior to treatment start in the study withmedications that are known to be cytochrome (CYP) 3A4 inhibitors or drugs that areknown to be CYP3A4 inducers.

19. Patients requiring palliative radiation within the Screening Period (Section 7.1) orwithin the 60 days following C1D1 in Step 1 (Section 4.3.1).

20. Patients already included in another therapeutic trial evaluating an investigationalmedicinal product or having received an investigational medicinal product within 3months.

21. Any stage II, III, or IV cancer within 5 years preceding patient enrollment in thetrial; however, multiple breast cancers (contralateral/ipsilateral cancers/localrelapses) are allowed pending all tumor masses were ER+.

22. Any history of hematologic malignancy.

23. Pregnancy or lactation period. Women of childbearing potential must implementadequate nonhormonal contraceptive measures (barrier methods, intrauterinecontraceptive devices, sterilization; LHRH agonist cannot be considered as anefficient contraceptive measure) during study treatment and for 90 days afterdiscontinuation. A serum pregnancy test must be negative in premenopausal women orwomen with amenorrhea of less than 12 months.