A Trial of Early Detection of Molecular Relapse With Circulating Tumour DNA Tracking and Treatment With Palbociclib Plus Fulvestrant Versus Standard Endocrine Therapy in Patients With ER Positive HER2 Negative Breast Cancer

Inclusion Criteria for ctDNA Surveillance: 1. Written informed consent to participate in the trial and to donation of tissue and blood samples 2. Male or female patients aged 18 years or older 3. ECOG performance status 0, 1 or 2 (see https://ecog-acrin.org/resources/ecog-performance-status) 4. Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in ≥10% of cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ hybridization) breast cancer as determined by local laboratory 5. Patients with high risk early stage breast cancer according to at least one of the following criteria: Primary surgery (no other treatment prior to surgery) A. Four or more involved axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or B. Tumour size \> 5 cm, regardless of lymph node status, or C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour size \> 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx Recurrence Score \>=26, Prosigna score \>=60, EPclin risk score \>=4.0, or Mammaprint high risk category, or Neoadjuvant chemotherapy (chemotherapy prior to surgery) D. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy E. Lymph node negative and tumour size \> 3 cm after chemotherapy Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) Use the primary surgery criteria - staging tumour size and lymph node status may be either the pathological staging after endocrine therapy or on the initial clinical staging prior to neoadjuvant therapy 6. Available tissue from one archival tumour tissue sample (either from diagnostic biopsy, primary surgery or where available residual disease post-neoadjuvant chemotherapy) 7. No evidence of macroscopic distant metastatic disease or incurable locally advanced disease on staging scans conducted at any time since initial diagnosis. 8. Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole, anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6 months\* and maximum of 7 years duration with an additional three years of endocrine therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues. \* patients may enrol during the first 6 months of standard endocrine therapy, and wait until at least 6 months of endocrine therapy has been received prior to starting ctDNA surveillance 9. Patients must have had surgery achieving clear margins (as per local guidelines) 10. Female and male patients of reproductive potential must be willing to use an adequate method of contraception for the first three years of the trial, if randomised to standard endocrine therapy for the duration of trial treatment through to at least 4 weeks after the last dose of trial treatment, and if randomised to fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 11. Patients willing to have frequent blood tests. Inclusion Criteria for Interventional phase: 1. Signed informed consent for treatment 2. ECOG performance status 0, 1 or 2 3. Women of childbearing potential should have a negative serum pregnancy test prior to randomisation. If randomisation occurs more than 72 hours prior to receiving the first dose of treatment the test must be repeated before treatment. 4. Female and male patients of childbearing potential must be willing to use an adequate method of contraception (section 4.6), starting with the first dose of treatment through 4 weeks after the last dose of treatment if randomised to standard endocrine therapy and 2 years after the last dose of fulvestrant if randomised to fulvestrant and palbociclib. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Female patients will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilisation 5. Patient has adequate bone marrow and organ function as defined by the following laboratory values: 1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L 2. Platelets ≥ 100 × 109/L 3. Haemoglobin ≥ 100 g/L 4. INR ≤1.5 5. Creatinine \<1.5 x ULN and creatinine clearance ≥30ml/min 6. Total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN. 7. Alanine aminotransferase (ALT) \< 2.5 x ULN 8. Aspartate aminotransferase (AST) \< 2.5 × ULN 6. Patients must be post-menopausal OR Pre- or peri-menopausal patients or men may be enrolled if they have ovarian/gonadal suppression with licensed GnRH analogues. Patients must have commenced licensed GnRH analogues at least 2 weeks prior to Cycle 1 Day 1 and continue throughout the study if randomised to fulvestrant and palbociclib. Post-menopausal female patients, as defined by at least one of the following: * Age ≥60 years; * Age \<60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and serum estradiol and FSH levels within the institutional laboratory's reference range for post-menopausal females; * Documented bilateral oophorectomy; Exclusion Criteria for ctDNA Surveillance: 1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate. 2. Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may enrol only after at least 12 months from completing CDK4/6 therapy. 3. Prior exposure to therapeutic dose of fulvestrant is not permitted. One subtherapeutic dose of fulvestrant is permitted. 4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for non-melanoma carci