DNA-guided Second Line Adjuvant Therapy for High Residual Risk, Estrogen Receptor Positive, HER-2 Negative Breast Cancer (DARE)

Inclusion Criteria

• Inclusion Criteria for Surveillance/Screening: 1. High risk for recurrence HER-2 negative, ER positive invasive breast cancer. For this study, ER positivity is defined as equal to or greater than 10% ER positivity by immunohistochemistry, regardless of progesterone receptor (PR) status. Patients who are PR positive but ER negative are not eligible. 2. Patients may have completed adjuvant endocrine therapy and are within 7 years since the date of their definitive breast surgery, or may be currently taking an aromatase inhibitor, or tamoxifen, as adjuvant endocrine therapy and have completed at least 6 months (i.e. 24 weeks), but no more than 7 years of endocrine therapy. Prior CDK4/6 therapy in the adjuvant setting, including participation in the PALLAS and PENELOPE trials, is allowed if the last treatment was 12 or more months ago. Adjuvant bisphosphonate therapy is allowed 3. High risk for recurrence is defined as any one of the following (these criteria apply equally to both patients who underwent surgery first and those who received neoadjuvant chemotherapy or endocrine therapy before surgery). (i) Four or more involved ipsilateral axillary lymph nodes or positive ipsilateral supraclavicular, or ipsilateral infraclavicular, or internal mammary lymph nodes at diagnosis or after preoperative systemic therapy, regardless of tumour size. Microscopic positive lymph node (i.e. <2 mm tumor deposit) is not counted as positive for eligibility for patients who underwent surgery first without any preoperative systemic therapy. Microscopic positive lymph nodes (i.e. <2 mm tumor deposit) are considered as positive nodes for eligibility for patients who received preoperative systemic therapy. (ii) Tumor size >5 cm and at least one macroscopically positive lymph node (i.e. >2 mm tumor deposit). (iii) Diagnosis of Inflammatory Breast Cancer. 4. Formalin fixed paraffin embedded tissue from the primary breast cancer available to be sent to Natera to perform ctDNA testing. 5. Signed and dated informed consent, including willingness to be randomized to standard of care versus fulvestrant + palbociclib. Exclusion Criteria for Screening 1. Prior or current treatment with fulvestrant, or current treatment with a CDK4/6 inhibitor, or treatment in the prior 12 months. 2. Patients cannot start participation in another therapeutic clinical trial for breast cancer during participation in this trial unless disease progression occurred, or patient withdrew consent for participation in the current trial. 3. Patients with current or past invasive cancer, other than breast cancer are not eligible, except: Adequately treated basal or squamous cell carcinoma of the skin and cancer survivors of previously diagnosed invasive cancer, who were treated with a curative intent, have no evidence of disease recurrence for 5 years or more, and are considered low risk for future recurrence by the treating physician are also eligible. 4. Patients with a second HER2 positive or triple negative synchronous breast cancer. Inclusion criteria for randomization 1. ctDNA positivity by the Signatera assay, defined as 2 of the 16 cancer specific markers positive in plasma. 2. Patients with positive Signatera results obtained in the context of commercial testing, outside of the screening phase of this trial, are also eligible for randomization if they meet other eligibility criteria. 3. No evidence of metastatic disease on CT scan of the chest, abdomen and pelvis. 1. If imaging, after review with a radiologist, is low probability for metastatic disease, patients may proceed to randomization. 2. Patients with suspicious but inconclusive imaging results should undergo a diagnostic biopsy, if biopsy is negative patients are eligible for randomization. 3. Patients with positive imaging that is conclusive of metastatic disease, or with biopsy proven metastatic disease, are not eligible for randomization. 4. Pre-menopausal women and male patients must be willing to use an adequate method of contraception for the duration of trial treatment and for 4 additional weeks after completion of treatment in the control arm, and for 2 years after the last dose of fulvestrant, if randomized into the experimental arm Post- menopausal status is defined as: 1. Documented bilateral oophorectomy, or 2. Age ≥ 60 years, or 3. Age < 60 years and amenorrhoeic for ≥ 12 consecutive months and FSH and estradiol levels in the post-menopausal range according to the institutional reference range for post- menopausal. Adequate contraception is defined as: 4. ONE highly effective form (i.e. abstinence, surgical sterilization through bilateral tubal ligation, vasectomy), or 5. TWO effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository). 6. Abstinence is to be interpreted as "true abstinence" for heterosexual intercourse and therefore, "periodic abstinence" (e.g. calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus) are not considered highly effective. Exclusion criteria for randomization 1. Patients with known contraindications to receive fulvestrant and palbociclib or those who are unable to tolerate these drugs are not eligible (e.g. absolute neutrophil count less than <1000/mm3) 2. Any concurrent severe and uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks or compromise compliance with the protocol including but not limited to: 1. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medication (e.g. Crohn's disease, ulcerative diseases, uncontrolled chronic nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 2. History of pneumonitis, interstitial lung disease or pulmonary fibrosis 3. Known history of Human Immunodeficiency Virus (HIV) (testing is not mandatory) 4. Known active Hepatitis B or Hepatitis C (testing is not mandatory) 5. Females who are pregnant or breastfeeding 6. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting factor deficiency) that preclude the IM injections of fulvestrant or LHRH agonist as applicable. 3. Patients taking any CYPC3A4 strong inducers and inhibitors, that cannot be changed.