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

             D. At least a 15% predicted residual risk of death within 10 years using NHS PREDICT
             (see appendix A3 on calculating predicted residual risk of death with PREDICT)

             Neoadjuvant chemotherapy (chemotherapy prior to surgery) E. At least one lymph node
             positive (micrometastasis or macrometastasis) after chemotherapy F. 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)

             i) Patients with bilateral tumours may enrol if both are ER+ and HER2- and if one
             archival tissue sample can be provided from each tumour

             ii) Patients with multifocal breast cancer whose histopathologically examined tumours
             all meet pathologic criteria for ER+ and HER2- breast cancer, and two archival tissue
             samples can be provided.

          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 urine or serum pregnancy test
             within 72 hours prior to receiving the first dose of treatment. If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test will be required.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required

          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 suppression with the GnRH analogue goserelin or similar
             GnRH analogue. Patients must have commenced goserelin or an alternative GnRH analogue
             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 fulvestrant is not permitted.

          4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5
             years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ

          5. Patients previously entered into a therapeutic trial where experimental therapy is
             continued post-surgery. Patients who have entered a clinical trial of a CDK4/6
             inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6
             inhibitor only before an operation, with no post-operative adjuvant use, are eligible.

          6. Treatment with an unlicensed or investigational product within 4 weeks prior
             registration to trial

          7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
             which in the opinion of the Investigator should not exclude the patient) from related
             side effects of any prior antineoplastic therapy, not including side-effects of
             endocrine therapy

          8. Patient with 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 nausea, vomiting, diarrhoea, malabsorption syndrome,
             or small bowel resection)

          9. Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
             patient participation in the clinical trial or compromise compliance with the
             protocol.

         10. Clinically significant uncontrolled heart disease including any of the following:

               1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis,
                  or coronary artery bypass graft (CABG) within 6 months prior to trial entry

               2. Symptomatic congestive heart failure

               3. Long QT syndrome or family history of idiopathic sudden death or congenital long
                  QT syndrome.

               4. Cardiac arrhythmia.

         11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis

         12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of
             study screening)

         13. Known active Hepatitis B or Hepatitis C (testing not required as part of study
             screening)

         14. Females who are known to be pregnant or breastfeeding

         15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
             factor deficiency), other known abnormalities in coagulation or treatment with
             anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
             are permitted.

         16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min.

        Exclusion Criteria for Interventional phase:

          1. Evidence of recurrent disease (metastatic or local, see section 6.6 for management of
             patients with potentially curable local recurrences) on staging scans conducted since
             positive ctDNA result

          2. Known hypersensitivity to the excipients of palbociclib plus fulvestrant

          3. Any anti-cancer treatment since enrolling in the TRAK-ER study other than hormonal
             therapy or a bisphosphonate. Prior exposure to fulvestrant is not permitted.

          4. Diagnosis of an alternative cancer since enrolment in the trial other than
             non-melanoma cancer of the skin or cervical carcinoma in situ

          5. Patient has had major surgery within 4 weeks prior to starting trial treatment or has
             not recovered from major side effects of such procedure

          6. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for
             treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
             heparin (LMWH), rivoroxiban or fondaparinux is allowed

          7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities,
             which in the opinion of the Investigator should not exclude the patient) from related
             side effects of any prior antineoplastic therapy, not including side-effects of
             endocrine therapy

          8. Patient with 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 nausea, vomiting, diarrhoea, malabsorption syndrome,
             or small bowel resection)

          9. Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the Investigator' opinion cause unacceptable safety risks, contraindicate
             patient participation in the clinical trial or compromise compliance with the
             protocol.

         10. Clinically significant uncontrolled heart disease including any of the following:

               1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis,
                  or coronary artery bypass graft (CABG) within 6 months prior to trial entry

               2. Symptomatic congestive heart failure

               3. Long QT syndrome or family history of idiopathic sudden death or congenital long
                  QT syndrome.

               4. Cardiac arrhythmia.

         11. Patient is currently receiving any of the following substances and cannot be
             discontinued 7 days prior to Cycle 1 Day 1:

               -  Medications that are strong inducers or inhibitors of CYP3A4 (section 8.5.2)

               -  Herbal preparations/medications, dietary supplements, fruits (e.g grapefruit,
                  pomelos, starfruit, Seville oranges) and their juice

         12. History of pneumonitis, interstitial lung disease or pulmonary fibrosis

         13. Known history of HIV (testing not required as part of study screening)

         14. Known active Hepatitis B or Hepatitis C (testing not required as part of study
             screening)

         15. Patient has a history of non-compliance to medical regimen

         16. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
             factor deficiency), other known abnormalities in coagulation or treatment with
             anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel
             are permitted.