In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as
endocrine therapy) for at least five years after surgery is very effective at reducing the
risk of the cancer returning. However, for some women their cancer may eventually become
resistant to these drugs. POETIC-A Registration part will identify those who have a higher
risk of developing resistance to standard endocrine therapy (ET). 5000 - 6000 women diagnosed
with early stage breast cancer and have not yet had surgery to remove the cancer will enter
the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a
type of ET, to treat the cancer for 2 weeks before surgery. A sample will be taken from the
cancer during surgery and the study laboratory will measure a biological marker called Ki67.
If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be
less sensitive to endocrine therapy, and the study doctor will explore additional treatments
after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage
(2500 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or
Group2: ET plus a new drug called abemaciclib. The first aim of the Treatment stage is to
confirm whether abemaciclib given in combination with ET is more effective than giving ET
alone in preventing the cancer coming back. The study laboratory will perform a second test
on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups
of patients based on their tumour biology are more suitable for treatment with abemaciclib.
Patients in Group 2 will receive ET plus abemaciclib for 2 years. Patients in both groups
will have regular study visits during this period.
Registration Stage Inclusion Criteria:
1. Postmenopausal women defined as:
1a. A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range
may be used to confirm a post-menopausal state in women not using hormonal contraception or
hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient.
or
1b. Documented bilateral oophorectomy.
2. Diagnosed operable invasive breast cancer with a palpable tumour of any size or an
estimated invasive tumour size >/=1.5cm by imaging (ultrasound/MRI/mammogram) excluding
those who are grade 1 and /or lobular histological type on diagnostic biopsy.
3. Tumour ER positive and HER2 negative. ER positivity is defined as >/=1% cells staining
positive (or equivalent Allred Score of ER >/=3 out of 8). HER2 negativity will be defined
as per the 2018 ASCO/CAP updated guidelines.
4. Baseline Ki67 and/or clinical pathological factors which predict for a high (20%) 5-year
risk of relapse with AI alone (see Appendix 2) 4a. Baseline Ki67 >/=20% measured at the
local site or 4b. Presence of clinicopathologic factors that have been previously shown to
predict (>50% chance) patients with Ki67 >/=8% after 2 weeks' AI, defined as one or more of
the following: grade 3; clinical/radiological tumour size > 5cm; PgR negative; PgR unknown
AND evidence of Vascular Invasion.
5. No evidence of metastatic spread by standard assessment according to local guidelines.
6. Written informed consent to enter the registration stage of the trial and to donation of
fresh tissue.
7. No medical condition or other factor likely to preclude entry to randomised stage of the
study if eligible e.g. patient would not be suitable to receive abemaciclib due to
concomitant medications or medical history.
8. The patient has given written informed consent prior to any study-specific procedures
and is willing and able to make herself available for the duration of the study and
amenable and able to follow study schedule during treatment and follow-up and for the use
of routinely collected electronic health and related records.
Registration Stage Exclusion Criteria:
1. Men and pre/perimenopausal women.
2. Grade 1 tumours
3. Invasive lobular carcinoma.
4. Concurrent use (defined as use within 4 weeks prior to diagnostic tissue sample being
taken) of HRT or any other oestrogen-containing medication (including vaginal
oestrogens).
5. Prior endocrine therapy for breast cancer or breast cancer prevention.
6. Evidence of metastatic disease.
7. Locally advanced breast cancer not amenable to surgery.
8. Bilateral breast cancer.
9. Multiple unilateral tumours with different ER/PgR/HER2 status, grade or type (e.g.
ductal vs lobular) i.e. anything that suggests two or more different cancers.
Multifocal disease with homogenous ER/PgR/HER2 status, grade and type is allowed if at
least one lesion is palpable or at least 1.5cm on ultrasound; the largest lesion
should be used for sample collection and CRF completion.
10. Previous invasive breast cancer except for ipsilateral DCIS or LCIS treated >5 years
previously by locoregional therapy alone or contralateral DCIS/LCIS treated by
locoregional therapy at any time.
11. Any invasive malignancy diagnosed within previous 5 years (other than non-melanoma
skin cancer or cervical carcinoma in situ).
12. Any other medical condition likely to exclude the patient from subsequent
randomisation stage. (See exclusion criteria: Eligibility for Randomisation).
Randomisation stage Inclusion Criteria
1. Patient previously consented and registered for screening component of POETIC A.
2. Centrally confirmed Ki67 >/=8% following 2 weeks of AI.
3. Aromatase Inhibitor Resistant-CDK4/6 Inhibitor Sensitive (AIR-CIS) signature has been
derived in the central laboratory and confirmed to ICR-CTSU.
4. Patient must have undergone definitive surgery for the primary breast tumour with
clear radial margins as judged by the multidisciplinary team.
5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy,
axillary sampling or dissection.
6. Adjuvant chemotherapy, if prescribed, must have been completed prior to randomisation
and patients must have recovered (Common Terminology Criteria for Adverse Events,
version 5 [CTCAEv5] Grade </=1) from the acute effects of chemotherapy except for
residual alopecia or Grade 2 peripheral neuropathy prior to randomisation. A washout
period of a minimum of 28 days from day 1 of last cycle of treatment is required.
7. Adjuvant radiotherapy, if prescribed, must have been completed prior to randomisation,
and patients must have recovered (Grade </=1) from the acute effects of radiotherapy.
A washout period of at least 14 days is required between end of radiotherapy and
randomisation.
8. The patient should be randomised within 6 months of commencement of adjuvant endocrine
therapy.
9. The patient is able to swallow oral medications.
10. The patient has adequate organ function for all of the following criteria defined as;
ANC >/= 1.5 × 109/L (G-CSF cannot be administered to meet this ANC eligibility
criterion) Platelets >/= 100 × 109/L Haemoglobin >/= 8g/dL (Blood transfusions cannot
be administered to meet this haemoglobin eligibility criterion) Total bilirubin </=
1.5 × ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and
direct bilirubin within normal limits are permitted.) ALT and AST </= 3 × ULN
11. The patient intends to take adjuvant endocrine therapy for at least 5 years.
12. The patient has given written informed consent prior to any study-specific procedures
(for the randomised intervention stage), willing to donate tissue from diagnostic
biopsy, and is willing and able to make herself available for the duration of the
study and to follow study schedule during treatment and follow-up and for the use of
routinely collected electronic health and related records.
Randomisation stage Exclusion Criteria
1. Patient has received prior CDK4/6 inhibitor.
2. 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 thrombus that did
NOT surround the catheter, and the lumen could be made patent by appropriate measures
(for example, saline or thrombolytic agent), are not excluded.
3. The patient has a serious/or uncontrolled pre-existing medical condition(s) that, in
the judgment of the investigator, would preclude participation in this study (such as
severe 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, or
pre-existing Crohn's disease or ulcerative colitis or a pre-existing chronic condition
resulting in baseline Grade 2 diarrhoea).
4. The patient has a personal history of any of the following conditions: syncope of
cardiovascular aetiology, ventricular arrhythmia of pathological origin (including,
but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest. Exception: patients with controlled atrial fibrillation diagnosed more
than 30 days prior to randomisation are eligible.
5. The patient has active systemic bacterial infections (requiring IV antibiotics at time
of initiating study treatment), systemic fungal infection or detectable viral
infection (such as known HIV positivity or with known active hepatitis B or C (e.g.
hepatitis B surface antigen positive). Screening is not required for enrolment.
