A randomised 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

ELIGIBILTY CRITERIA FOR PATIENT REGISTRATION 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) G. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy H. Lymph node negative and tumour size > 3 cm after chemotherapy 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) A. Patients with bilateral tumours may enrol if both are ER+ and HER2- and if one archival tissue sample can be provided from each tumour B. 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. ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE Please refer to the main protocol for inclusion criteria for treatment phase.

1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate/denosumab. 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: a. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry b. Symptomatic congestive heart failure c. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome. d. 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. ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE Please refer to the main protocol for exclusion criteria for treatment phase.