The purpose of this study is to learn if certain drug combinations are effective treatments for patients with advanced ER+/HER2- who have previously been treated with palbociclib, ribociclib, or abemaciclib.

Inclusion Criteria:

1. Post-menopausal women ≥18 years of age with metastatic ER+ breast cancer, or with locally recurrent ER+ disease not amenable to therapy for curative intent.

2. Patient must be post-menopausal per NCCN guidelines.

3. Patient must have been treated with a CDK4/6i (either palbobclib, ribociclib, or abemaciclib) alone or in combination with an endocrine agent in the advanced disease setting.

   • Up to 3 lines of therapy following CDK4/6i are permissible.
   • Any number of prior lines of endocrine-containing therapy is permissible.
   • Up to 1 prior line of chemotherapy is permissible.

4. Histologic documentation of ER+ breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally recurrent disease performed as standard of care.

   • Exceptions: patients with bone-dominant metastatic disease, or non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained, with a history of ER+ breast cancer are eligible, and biopsy is not required, providing their primary cancer is consistent with the ER criteria described below.

5. ER+ status defined as ER staining by immunohistochemistry in ≥1% of malignant cell nuclei.

6. Tumor must be HER2-non-amplified as defined by an immunohistochemistry score of 0-1+, or with a FISH ratio <2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.

7. Genetic profiling of a tumor or plasma specimen acquired after disease progression on a CDK4/6i must have been performed in a CAP-accredited, CLIA-certified laboratory using clinically validated methods. Profiling must minimally include analysis of study-relevant alterations in ERBB2, PIK3CA, AKT1, MTOR, PTEN, and RB1.

   • If not done: Profiling of a tumor (preferable) or plasma specimen will be performed as part of the study in the DHMC Pathology Laboratory. A plasma specimen may be obtained for study-specific genetic profiling to direct treatment assignment. Tumor specimens must be obtained outside of this study (e.g., by biopsy).

8. If available, archived tumor tissue must be accessible for research purposes, sufficient to make ≥10 five-micron sections; more tumor tissue is preferred.

9. Radiographic staging performed as standard of care, including specifically either PET/CT, or contrast CT (CAP) and bone scan.

10. Patient must be capable and willing to provide informed written consent for study participation.

Exclusion Criteria:

1. Treatment with abemaciclib in the most recent or current line of therapy.
2. During the study Treatment Phases, no concurrent anti-cancer therapies are allowed with the following exception: anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
3. Any investigational cancer therapy in the last 3 weeks.
4. Known untreated CNS disease, unless clinically stable for ≥ 3 months.