Aromatase Inhibitor Therapy With or Without Fulvestrant for the Treatment of HR Positive Metastatic Breast Cancer With an ERS1 Activating Mutation, the INTERACT Study

This phase II trial studies how well letrozole, anastrozole, or fulvestrant work when given together with ribociclib, palbociclib, and/or abemaciclib in treating patients with hormone receptor (HR) positive breast cancer that has spread to other places in the body (metastatic) and has an ERS1 activating mutation. Letrozole, anastrozole, ribociclib, palbociclib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known if giving letrozole, anastrozole, or fulvestrant with ribociclib, palbociclib, and/or abemaciclib will work better in treating patients with breast cancer.

PRIMARY OBJECTIVE:

I. To assess progression free survival (PFS) with transition to fulvestrant compared with continuing aromatase inhibitor (AI) therapy in patients with emergence of estrogen receptor 1 (ESR1) mutations in plasma.

SECONDARY OBJECTIVES:

I. To assess circulating tumor deoxyribonucleic acid (ctDNA) ESR1 mutant allele fraction (MAF) and kinetics with fulvestrant compared with AI.

II. To assess the prevalence of ESR1 mutations in patients with secondary resistance to endocrine therapy.

III. To correlate ctDNA with cancer antigens (CA) 15-3 tumor marker changes. IV. To assess overall survival (OS) with transition to fulvestrant compared with continuing AI therapy in patients with emergence of ESR1 mutations.

V. To assess PFS and time to next treatment (TTNT) on next line of therapy after progression on fulvestrant versus (vs.) AI in combination with CDKI.

EXPLORATORY OBJECTIVES:

I. Characterize other co-existing actionable genomic alterations of interest in relation to ESR1 and clinical outcomes.

II. To determine frequency of other actionable genomic alterations and frequency of enrollment on genotype-matched therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ribociclib orally (PO) once daily (QD), palbociclib PO QD on days 1-21, and/or abemaciclib PO twice daily (BID) on days 1-28. Patients also receive fulvestrant intramuscularly (IM) for 2 injections over 1-2 minutes each on days 1 and 15 of cycle 1 and day 2 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ribociclib orally PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive letrozole PO QD or anastrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
* Platelets \>= 50 x 10\^9/L
* Hemoglobin (Hb) \>= 9 g/dL
* Total serum bilirubin =\< 2.0 mg/dL
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x upper limit of normal (ULN) (=\< 5 x ULN in patients with liver metastases)
* Serum creatinine =\< 1.5 x ULN
* Activating ESR1 mutation (e.g. D538G, Y537S/N, S463P) identified on ctDNA. Novel ESR1 alterations allowed as per discretion of principal investigator (PI)
* On AI with CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) as first line therapy for metastatic breast cancer (MBC) for at least 12 months without evidence of clinical progression
* Patients with histologically confirmed HR positive (estrogen receptor \[ER\] positive \[+\] and/or progesterone receptor \[PR\]+ \[\> 10%\]), MBC

Exclusion Criteria:

* Pregnant or lactating women
* Received prior therapy for MBC (except for AI use for up to 4 weeks prior to initiation of CDK4/6 inhibitor)
* Prior therapy with fulvestrant in the metastatic setting
* Corrected QT (QTc) interval \> 480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes
* Psychiatric illness which would limit informed consent
* Patients with de novo metastatic disease
* Patients who have any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =\< 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease, active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable hepatitis B virus \[HBV\]-DNA and/or positive hepatitis B surface antigen \[HbsAg\], quantifiable hepatitis C virus \[HCV\]-ribonucleic acid \[RNA\]), severe hepatic impairment (Child-Pugh C)
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
* Expected survival \< 6 months
* Any serious medical illness, other than that treated by this study, which would limit survival to less than 1 month
* Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
* Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
* Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after the end of treatment. Highly effective contraception methods include combination of any two of the following: placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository; total abstinence or; male/female sterilization
* Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment