PreOperative Endocrine Therapy for Individualised Care With Abemaciclib

Registration Stage Inclusion Criteria:

1. Women determined to be postmenopausal according to established local criteria.

2. Diagnosed operable invasive breast cancer with a clinical/radiological tumour size ≥1.0cm*

3. Grade 2 or 3 tumours

4. Preoperative full assessment completed (including bilateral breast examination andimaging with mammogram +/- ultrasound/MRI as performed locally).

5. Tumour ER positive. ER positivity is defined as >/=1% cells staining positive (orequivalent Allred Score of ER >/=3 out of 8).

6. Tumour HER2 negative or HER2 status unknown. HER2 negativity will be defined as perthe 2018 ASCO/CAP updated guidelines. Patients whose HER2 status is pending/unknownat the time of registration will be allowed to register to the trial. However,please note that only patients who are confirmed to be HER2 negative will beeligible to join the randomised part.

7. Received or planned to receive 10 days to 6 months of anastrozole or letrozole priorto surgery.

8. Written informed consent to enter the registration stage of the trial and todonation of fresh tissue.

9. The patient has given written informed consent prior to any study-specificprocedures and is willing and able to make herself available for the duration of thestudy and amenable and able to follow study schedule during treatment and follow-upand for the use of routinely collected electronic health and related records.

Registration Stage Exclusion Criteria:

1. Men and pre/perimenopausal women.

2. Intended or actual use of HRT or any other oestrogen-containing medication (including vaginal oestrogens) within 4 weeks prior to planned surgery). Note:patient with a Mirena coil in situ at the time of registration are not excluded.

3. Patients who commenced pre-surgical AI therapy >6 months prior to surgery.

4. Prior endocrine therapy for breast cancer or breast cancer prevention.

5. Prior neoadjuvant chemotherapy for breast cancer.

6. Evidence of metastatic disease.

7. Locally advanced breast cancer not amenable to surgery.

8. Bilateral invasive breast cancer (excluding contralateral DCIS/LCIS).

9. Multiple unilateral tumours with different ER and/or HER2 status. SynchronousDCIS/LCIS, as well as multifocal disease with homogenous ER/HER2 status is allowedif at least one lesion is at least 1.0cm; the largest lesion should be used forsample collection and CRF completion. If ER/HER2 status of smaller foci is unknownat time of registration, patients can be registered; however, note that congruity ofreceptor status will need to be confirmed by the time of randomisation, unlesssmaller foci are <10mm and receptor status is unknown.

10. Previous invasive breast cancer except for ipsilateral DCIS or LCIS treated >5 yearspreviously by locoregional therapy alone or contralateral DCIS/LCIS treated bylocoregional therapy at any time.

11. Any invasive malignancy diagnosed within previous 5 years (other than non-melanomaskin cancer or cervical carcinoma in situ).

12. Any other medical condition likely to exclude the patient from subsequentrandomisation stage. (See exclusion criteria: Eligibility for Randomisation).

Randomisation Stage Inclusion Criteria:

1. Patient previously consented and registered for screening component of POETIC-A.

2. Tumour HER2 negative. HER2 negativity will be defined as per the 2018 ASCO/CAPupdated guidelines

3. Centrally confirmed Ki67 >/=8% following 2 weeks of AI.

4. Patient is expected by the time of treatment initiation to have undergone definitivesurgery for the primary breast tumour with clear radial margins as judged by themultidisciplinary team, and will have completed any adjuvant chemotherapy orradiotherapy (if prescribed).

5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy,axillary sampling or dissection.

6. The patient is randomised in time for treatment to start no later than three monthsafter completion of non-endocrine therapy (defined as the final fraction ofradiotherapy, Day 1 of the final cycle of chemotherapy or the date of the finalsurgical procedure).

7. The patient is able to swallow oral medications (excluding transient side effectsfrom adjuvant non-endocrine treatment, if randomised before the end of thistreatment).

8. The patient intends to take adjuvant endocrine therapy for at least 5 years.

9. The patient has given written informed consent prior to any study-specificprocedures (for the randomised intervention part), is willing to donate tissue fromdiagnostic biopsy, and is willing and able to make herself available for theduration of the study and to follow study schedule during treatment and follow-upand for the use of routinely collected electronic health and related records.

Randomisation Stage Exclusion Criteria:

1. Patient has received prior CDK4/6 inhibitor.

2. Patient is planned to receive adjuvant abemaciclib as standard of care.

3. Any patient with a history of VTE (for example, DVT of the leg or arm and/or PE)will be excluded. Patients with a history of venous catheter occlusion by thrombusthat did NOT surround the catheter, and the lumen could be made patent byappropriate measures (for example, saline or thrombolytic agent), are not excluded.

4. The patient has a serious/or uncontrolled pre-existing medical condition(s) that, inthe judgment of the investigator, is likely to preclude study treatment (such assevere renal impairment, [for example, estimated creatinine clearance <30 mL/min],interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy,history of major surgical resection involving the stomach or small bowel, orpre-existing Crohn's disease or ulcerative colitis or a pre-existing chroniccondition resulting in baseline Grade 2 diarrhoea).

5. The patient has a personal history of any of the following conditions: syncope ofcardiovascular aetiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest. Exception: patients with controlled atrial fibrillation diagnosedmore than 30 days prior to randomisation are not excluded.

6. The patient has received an experimental treatment in a clinical trial within thelast 30 days or 5 half-lives, whichever is longer, prior to randomisation, or iscurrently enrolled in any other type of medical research (for example: medicaldevice) judged by the Chief Investigator not to be scientifically or medicallycompatible with this study.

7. The patient has any known active systemic bacterial infections (that would beexpected to require IV antibiotics at time of initiating study treatment), systemicfungal infection or detectable viral infection (such as known HIV positivity or withknown active hepatitis B or C, e.g. hepatitis B surface antigen positive) whichwould be expected to preclude study treatment. Screening is not required forenrolment.

8. Evidence of metastatic disease or local recurrence.

9. Multiple unilateral tumours with different ER and/or HER2 status (DCIS/LCIS arepermitted, and confirmation of congruent ER/HER2 status is not necessary for lesionsless than 10mm).

Week 1 Day 1 Inclusion Criteria:

1. Patient must have undergone definitive surgery for the primary breast tumour withclear radial margins as judged by the multidisciplinary team.

2. Adjuvant chemotherapy, if prescribed, must have been completed prior to Week 1 Day 1, and patients must have recovered (Common Terminology Criteria for Adverse Events,version 5 [CTCAE v5] Grade ≤1) from the acute effects of chemotherapy except forresidual alopecia or Grade 2 peripheral neuropathy prior to Week 1 Day 1. A washoutperiod of a minimum of 28 days from day 1 of the last cycle of treatment isrequired.

3. Adjuvant radiotherapy, if prescribed, must have been completed prior to Week 1 Day 1, and patients must have recovered (Grade </=1) from the acute effects ofradiotherapy. A washout period of at least 14 days is required between end ofradiotherapy and Week 1 Day 1.

4. Week 1 Day 1 is scheduled to take place no later than three months after completionof non-endocrine therapy (defined as the final fraction of radiotherapy, Day 1 ofthe final cycle of chemotherapy or the date of the final surgical procedure,whichever is latest).

5. The patient is able to swallow oral medications.

6. The patient has adequate organ function for all of the following criteria definedas: ANC >/= 1.5 × 10e9/L (G-CSF cannot be administered to meet this ANC eligibilitycriterion); Platelets >/= 100 × 10e9/L; Haemoglobin >/= 8g/dL; Total bilirubin </= 1.5 × ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULNand direct bilirubin within normal limits are permitted); ALT and AST </= 3 × ULN

Week 1 Day 1 Exclusion Criteria:

1. Patient has received any CDK4/6 inhibitor therapy since randomisation.

2. Any newly occurring or diagnosed VTE since randomisation (for example, DVT of theleg or arm and/or PE). Note: patients with a history of venous catheter occlusion bythrombus that did NOT surround the catheter, and the lumen could be made patent byappropriate measures (for example, saline or thrombolytic agent), are not excluded.

3. Any newly occurring or diagnosed medical conditions since randomisation that, in thejudgment of the investigator, would preclude participation in this study (such assevere renal impairment, [for example, estimated creatinine clearance <30 mL/min],interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy,major surgical resection involving the stomach or small bowel, or conditionresulting in baseline Grade 2 diarrhoea).

4. Any newly occurring or diagnosed cardiovascular conditions since randomisation suchas: syncope of cardiovascular aetiology, ventricular arrhythmia of pathologicalorigin (including, but not limited to, ventricular tachycardia and ventricularfibrillation), or sudden cardiac arrest.

5. Major surgery within 14 days prior to Week 1 Day 1.

6. The patient has received an experimental treatment in a clinical trial within thelast 30 days or 5 half-lives, whichever is longer, prior to Week 1 Day 1, or iscurrently enrolled in any other type of medical research (for example: medicaldevice) judged by the Chief Investigator not to be scientifically or medicallycompatible with this study.

7. Any active systemic bacterial infections (requiring IV antibiotics at time of Week 1Day 1), systemic fungal infection or detectable viral infection (such as known HIVpositivity or active hepatitis B or C, e.g. hepatitis B surface antigen positive).Screening is not required for initiation of treatment.

8. Evidence of metastatic disease or local recurrence