The purpose of this neoadjuvant trial is to evaluate efficacy and toxicity of chemotherapy using weekly paclitaxel (arm A) versus the combination of the cdk 4/6 inhibitor palbociclib and standard endocrine treatment (arm B). After 12 weeks treatment is switched crossover. During the 24-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. Postoperatively, patients receive three 3-weekly courses of chemotherapy with a combination of epirubicin and cyclophosphamide.
Patients are randomized to either weekly treatment with paclitaxel (arm A) or endocrine treatment in combination with palbociclib (arm B) for 12 weeks. Choice of endocrine treatment is for pre- and perimenopausal women and all men tamoxifen 20 mg daily, alternatively for women in this age cohort, an LHRH analogue in combination with an aromatase inhibitor, for all postmenopausal women treatment with an aromatase inhibitor. The aromatase inhibitors to be used according to local practice are anastrozole 1 mg daily, exemestane 25 mg daily, or letrozole 2.5 mg daily. Pre- or perimenopausal women and all men are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor. After 12 weeks, patients without signs of disease progression (PD) are switched to either endocrine treatment in combination with palbociclib (arm A) or weekly treatment with paclitaxel (arm B) for 12 weeks. Postoperatively, patients receive three 3-weekly courses of chemotherapy with a combination of epirubicin and cyclophosphamide. Before start, after 6, 12, 18 and 24 weeks of treatment, radiological assessments of tumor size are performed using mammography and ultrasound alt. MRI breast; PET-CT, confined to the breast and regional lymph nodes, before start, after 12 and 24 weeks, blood tests before start, after 1 week, 12, 18 and 24 weeks. Physical examinations are performed before start and then four-weekly after weeks 4, 8, 12, 16, 20 and 24 weeks of treatment. In case of disease progression during ongoing study treatment, individualized management in the patient's best interest must be considered, in which case surgery is the primary option.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
181
Any brand of paclitaxel may be used, excluding nab-paclitaxel
Any brand of tamoxifen may be used
Any brand of letrozole, anastrozole or exemestane may be used
Any brand of letrozole, anastrozole or exemestane may be used
Södersjukhuset
Stockholm, Sweden
Karolinska University Hospital
Stockholm, Sweden
Capio S:t Göran Hospital
Stockholm, Sweden
Radiological Objective Response Rate after Completion of the First 12-week Period of Primary Medical Treatment
Radiological response by use of mammography and ultrasound, alternatively MRI of the breast, if mammography/ultrasound does not allow for objective measurements of the primary tumor. Clinical measurements using calliper, if the tumor is palpable and tumor size cannot be estimated by radiological methods
Time frame: Start of treatment until 12 weeks of treatment
Pathological Objective Response Rate
Presence/abscense of residual tumor in mm, fibrosis and other signs of response by histology
Time frame: From the date of surgery up to 4 weeks after surgery
Sequencing of Chemotherapy versus Endocrine Treatment plus Palbociclib in relation to Radiological Objective Response Rate after Completion of the 24-week Period of Primary Medical Treatment
Radiological response by use of mammography and ultrasound, alternatively MRI of the breast, if mammography/ultrasound does not allow for objective measurements of the primary tumor. Clinical measurements using calliper, if the tumor is palpable and tumor size cannot be estimated by radiological methods
Time frame: From start of treatment until termination of the preoperative treatment after 24 weeks
Disease-Free Survival
Disease-free survival includes all events related to breast cancer, and death from any cause during the follow-up period
Time frame: From date of surgery until 10 years past surgery
Breast Cancer-Specific Survival
Breast cancer-specific survival includes all events related to breast cancer and death caused by breast cancer during the follow-up period
Time frame: From date of surgery until 10 years past surgery
Overall Survival
Overall survival relates to death from any cause during the follow-up period
Time frame: From date of surgery until 10 years past surgery
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Safety will be assessed using NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) for reporting laboratory and non-laboratory toxicities
Time frame: From start of treatment until 28 days after termination of 24 weeks of treatment. Delayed toxicity is reported until 60 months follow-up
Health-Related Quality of Life
Time frame: From start of study treatment until termination after 24 weeks, and then annually during 5 years of postoperative follow-up period
Frequency of Breast-Conserving Surgery
Refers to the rate of patients who are operated with breast-conserving surgery compared with mastectomy
Time frame: At surgery after neoadjuvant therapy
Characteristics of the Genome of Previously Untreated Tumors Before and After Exposition to Treatment
New Generation Sequencing (NGS) is performed on biopsies from the tumors with the aim to classify the tumors according to PAM50. Repeated analyses of tumor tissue during the treatment process will be performed to identify heterogeneity and mutations which might be responsible for resistance to study treatment. Blood samples are collected to identify tumor DNA sequences which might predict recurrence during the follow-up period. Tissue and blood samples are also analyzed in case of recurrence. The results are descriptive and expressed as clustering. Units of measure are lacking
Time frame: Before start and during treatment, at surgery, and then annually during the 60 months of postoperative follow-up period
Changes of the Proteome of Previously Untreated Tumors Before and After Exposition to Treatment
Proteome analyses with the intention to identify tumor-specific pathways are performed on repeated biopsies from the tumors. The results are descriptive, defined units of measure are lacking
Time frame: Before start, during treatment and at surgery
Quantification of Hormone Receptors Before and After Treatment
Immunohistochemistry on core biopsies before start, after 10 weeks of treatment, and tumor samples from the surgical specimen. Presence of estrogen receptor (ER) and progesterone receptor (PR), described as percentage in relation to the total count of tumor cells
Time frame: Before start, during treatment and at surgery
Quantification of Proliferation Before and After Treatment
Immunohistochemistry on core biopsies before start, after 10 weeks of treatment, and tumor samples from the surgical specimen. Presence of cells indicating proliferation by use of Ki67, described as percentage in relation to the total count of tumor cells
Time frame: Before start, during treatment and at surgery
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