This is an open-label, multicenter, two-arm Phase II clinical trial that will evaluate the impact of 2nd line chemotherapy (i.e. capecitabine) on survival in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Primary Objective:

- Determine the impact of early chemotherapy (i.e., capecitabine) versus endocrine therapy-based regimen on anti-tumor effect in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer

Secondary Objectives:

• Compare the safety and tolerability of capecitabine versus endocrine therapy in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer
• Determine the impact of early chemotherapy (i.e., capecitabine) versus endocrine therapy-based regimen on anti-tumor effect in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer

Correlatives:

• Determine if the tumor mutations detected in cfDNA are early surrogates of response
• Determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to therapy

Inclusion Criteria:

• Signed and dated written informed consent.

• Subjects ≥ 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is:

  • ER (>/=1%) and/or PR (>/= 1%) by IHC and HER2 negative (by IHC or FISH)

• Previously exposed to an aromatase inhibitor (AI) or a selective estrogenreceptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor.

• Prior radiation permitted (if completed at least 2 weeks prior to study entry. Patients who have received prior radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment (except for alopecia)

• Patients with brain metastasis secondary to breast cancer and clinically stable for more than 4 weeks from completion of radiation treatment and off steroids

• Evaluable disease (measurable or non-measurable)

  • Measurable disease, ie, at least 1 measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation)
  • Patients with bone only disease allowed if possible to evaluate on radiological exams (eg.bone scan, PET/CT, CT, MRI) even if lesions are non-measurable according to RECIST1.1.

• Adequate organ function including:

  • Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L
  • Platelets ≥ 100 × 10^9/L
  • Hemoglobin ≥ 8/g/dL (may have been transfused)
  • Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)
  • Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50mL/min as calculated using the Cockcroft-Gault (CG) equation

• For randomized patients only: tumors must be diagnosed as non-Luminal A using the Blueprint® and Mammaprint® tests

Exclusion Criteria:

• Prior chemotherapy in the metastatic setting
• Previous malignant disease other than breast cancer within the last 2 years with associated competing risk, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment).
• Persisting symptoms related to prior therapy that has not reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; however, menopausal symptoms, alopecia, and sensory neuropathy Grade ≤ 2 is acceptable
• Pregnant or breastfeeding females.