Inclusion Criteria:

1. Written (signed and dated) informed consent and be capable of co-operating with
treatment and follow-up

2. Aged ≥ 25 years of age (N.B. in line with other studies with AZD4574 and due to
concerns of possible effects on the immature skeleton)

3. Post menopausal women. Women will be considered postmenopausal if they have had a
bilateral oophorectomy or the following specific requirements apply:

- Women under 50 years old would be considered post-menopausal if they have been
amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and
oestradiol levels in the post-menopausal range. Patients with prior exposure to
depot LHRH analogues must be 24 months or more following the last administration

- Women aged 50 years and older would be considered post-menopausal if they have
been amenorrhoeic for 12 months and patients with prior exposure to depot LHRH
analogues must be 12 months or more following the last administration

- Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or
perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least
24 months

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no
deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

5. Histological confirmation of breast cancer with documented positive oestrogen
receptor status (ER+) of primary or metastatic tumour tissue according to local
laboratory parameters

6. Randomised phase IIa: Mandatory provision of tumour biopsy for AZ central laboratory
confirmation of FGFR1 status by FISH

7. Fulfils criteria for previous treatment of breast cancer:

- Relapse during a single regimen of adjuvant endocrine therapy with either
anastrozole or letrozole or

- Progression during first line endocrine therapy with a non-steroidal AI for
advanced breast cancer*. Co-administration of a targeted agent with the
non-steroidal AI is permitted providing all toxicities have recovered to CTCAE
Grade 1 or below Safety run-in: 1 prior regimen of chemotherapy in the advanced
setting is permitted. Chemotherapy administered in the adjuvant setting is
permitted Randomised phase IIa: Chemotherapy administered in the adjuvant
setting is permitted * Advanced breast cancer: metastatic disease or locally
advanced disease which is not amenable to treatment with curative intent

8. Safety run-in: At least one lesion (measurable and/or non-measurable) that can be
accurately assessed by CT/MRI/plain x-ray at baseline and follow up visits Randomised
phase IIa: At least one lesion ≥ 10mm in the longest diameter at baseline that can be
accurately measured with CT/MRI at baseline and is suitable for accurate repeated
measurements

Exclusion Criteria

1. Treatment with any of the following:

1. more than 1 regimen of endocrine therapy for advanced breast cancer

2. previous exposure to any FGFR inhibitor

3. Safety run in: more than 1 prior regimen of chemotherapy for advanced breast
cancer.

Randomised phase IIa: any prior chemotherapy for advanced breast cancer

4. potent inhibitors or inducers of CYP3A4 or CYP2D6, or substrates of CYP3A4
within 2 weeks prior to first dose of study treatment (3 weeks for St John's
Wort)

5. major surgery within 4 weeks prior to first dose of study treatment

6. radiotherapy with a wide field of radiation within 4 weeks prior to first dose
of study treatment; or radiotherapy with a limited field of radiation for
palliation within 2 weeks before the first dose of study treatment

2. With the exception of alopecia, any unresolved toxicities from prior therapy greater
than CTCAE grade 1 at time of starting study

3. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment

4. Any evidence of severe or uncontrolled systemic diseases or active infection

5. Any of the following cardiac criteria:

1. Mean resting corrected QT interval (QTc) >470 ms obtained from 3
electrocardiograms (ECGs)

2. Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block

3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age or
any concomitant medication known to prolong the QT interval

6. Inadequate bone marrow reserve or organ function as defined by any one of the
following parameters:

Haemoglobin < 9.0 g/dL

- Absolute neutrophil count (ANC) < 1.5 x 109 /L

- Platelet count > 100 x 109 /L

- Alanine aminotransferase > 2.5 x ULN if no demonstrable liver metastases or > 5
x ULN in the presence of liver metastases

- Aspartate aminotransferase 2.5 x ULN if no demonstrable liver metastases or > 5
x ULN in the presence of liver metastases

- Total bilirubin > 1.5 x ULN if no demonstrable liver metastases or > 3 x ULN in
the presence of liver metastases

- Creatinine > 1.5 times ULN or creatinine clearance <50ml/min

- Corrected calcium > ULN

- Phosphate > ULN

7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated IMP or previous significant bowel resection that would
preclude absorption of AZD4547 or exemestane or anastrozole or letrozole

8. History of hypersensitivity to AZD4547 or exemestane or anastrozole or letrozole

9. History of another malignancy within 5 yrs prior to starting study treatment, except
adequately treated basal or squamous cell carcinoma of the skin, carcinoma of the
cervix and the disease under study

10. Any of the following ophthalmological criteria:

- Current evidence or previous history of retinal pigmented epithelium detachment
(RPED)

- Previous laser treatment or intra-ocular injection for treatment of macular
degeneration

- Current evidence or previous history of dry or wet age-related macular
degeneration

- Current evidence or previous history of retinal vein occlusion (RVO)

- Current evidence or previous history of retinal degenerative diseases (e.g.
hereditary)

- Current evidence or previous history of any other clinically relevant
chorioretinal defect

11. Concurrent treatment with another investigational agent or use of another
investigational agent within 30 days or 5 half lives, whichever is longer, preceding
the first dose of study treatment

12. Patients taking prohibited medications who will not have completed the stated washout
period for that drug before starting the study medication