Neoadjuvant Response-guided Treatment of Slowly Proliferating Hormone Receptor Positive Tumors

The purpose of this neoadjuvant trial is to evaluate efficacy and toxicity of the cdk 4/6 inhibitor palbociclib when added to standard endocrine treatment. Initially, patients receive endocrine treatment for 4 weeks. In case of decrease of proliferation (Ki67) patients are then randomized between either continuous endocrine therapy (arm A) or the same treatment with addition of palbociclib (arm B). Patients with no change of proliferation are allocated to endocrine treatment + palbociclib without randomization (arm C). During the 12-weekly treatment period, clinical and radiological evaluations are performed repeatedly. Switch between the treatment arms A and B is allowed in case of lack of response or due to toxicity. A translational subprotocol is a mandatory part of the study protocol, except for use of PET-CT evaluations.

Pre- or perimenopausal women are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor.This treatment is given for 4 weeks. In cases with uncertain menopausal status (previous hysterectomy and equivocal gonadotropins), postmenopause age limit is defined as 55 years or older.

Ki67 is determined by FNA or core biopsy before start and after 2 weeks of treatment. After the initial 4-week period, patients with signs of response in terms of decrease of Ki67 by ≥20% are randomized to endocrine treatment either alone or in combination with the cdk 4/6 inhibitor palbociclib (arm A and B). Patients with tumors with stable disease, defined as \<20% decrease or increase of Ki67 and without radiological indication of tumor progression at the 4-week evaluation are offered continuous endocrine treatment with the addition of palbociclib (arm C).

Dose regimen after 4 weeks of endocrine pretreatment:

Arm A: Pre- or perimenopausal women are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor. The preoperative treatment is continued for further 12 weeks, provided that re-evaluation after 6 and 10 weeks of the preoperative treatment does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option.

Arm B: Patients receive the same endocrine treatment as in arm A together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period. The combined treatment is continued for further 12 weeks, if re-evaluation after 6 weeks, week 10 of the preoperative treatment, does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option.

Arm C: Treatment according to the schedule as described for arm B.

Postoperative chemotherapy is recommended to patients with either residual lymph node metastases \>2mm (macro metastases) or primary tumor size \>30mm in combination with Ki67\>15%. Adjuvant endocrine treatment and radiotherapy is offered according to standard guidelines. Structured follow-up visits yearly for five years include reporting of persistent treatment-related toxicity, HRQoL, recurrence and death.

All patients are recommended adjuvant endocrine treatment for at least 5 years.

The trial contains also a translational subprotocol:

1. PET-CT using FDG, confined to the chest, is performed before start of the first treatment period and after 10 weeks, i.e. 6 weeks after treatment allocation (functional imaging, optional).
2. Core biopsies from the tumor are collected before start of the first treatment period and after 10 weeks, i.e. 6 weeks after treatment allocation. Further tissue samples are collected from the surgical specimen.
3. Blood samples are collected repeatedly during the ongoing treatment and yearly follow-up.
4. FNAs from metastases in case of recurrence during follow-up.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent
2. Female patients with non-lobular breast cancer confirmed by histology
3. Tumor and blood samples available. Luminal A type confirmed by immunohistochemistry with ER and PR positive ≥50% and the proliferation marker Ki 67 \<20% and not HER2 amplified
4. Age older than 40 years
5. Primary breast cancer \>20mm without lymph node metastases
6. Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders
7. LVEF \>50%
8. ECOG performance status 0-1

Exclusion Criteria:

1. Metastases, including node metastases in the ipsilateral and/or contralateral thoracic region or in the mediastinum
2. Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix
3. Age ≤40 years
4. Lobular carcinoma
5. Patients in child-bearing age without adequate contraception
6. Pregnancy or lactation
7. Severe medical or psychiatric disorders where the study treatment or study procedures carry increased risk of deterioration of health status