Breast Cancer
Conditions
Keywords
neoadjuvant treatment, personalized medicine
Brief summary
Breast cancer is an optimal "model disease" for studying personalized medicine. Breast cancer was the first malignancy for which a predictive factor forecasting response to therapy was identified nearly 50 years ago; the expression of the estrogen receptor (ER). Furthermore, breast cancer is by far the malignancy in which prognostic and predictive factors have been most extensively studied. Primary medical treatment (pre-surgical medical therapy) offers a unique setting to explore predictive factors due to the fact that primary breast cancers are easily accessible to repeated tissue sampling and evaluation of therapy response both clinically and radiologically. For many years, the investigators have studied predictive factors in primary medical treatment of breast cancer. In the present project, the investigators will implement a new trial concept where the current knowledge from previous trials with respect to predictive markers (hormone receptors, HER2; TP53, CHEK2 and RB1), will be combined with massive parallel sequencing (MPS). Thereby, the investigators aim to design the "next-generation" primary medical treatment where 1) therapy regimens are individualized based on a limited number of known predictive factors and, 2) MPS is used to explore additional predictive factors and their co-regulators in order to fully identify the mechanisms of drug sensitivity / resistance across individual tumours and pave the way for further personalized breast cancer therapy in the future. As for the new era of "genomic medicine", the current trial concept will allow individual tumours to be characterized by their unique gene mutation / epigenetic modification profile upfront, to allocate patients to their optimal personalized medicine as compared to "classical" drug testing through phase II/III trials.
Interventions
DRUGNeoadjuvant docetaxel + trastuzumab + pertuzumab
DRUGNeoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab
DRUGNeoadjuvant olaparib
DRUGNeoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)
PROCEDUREBreast conserving surgery or mastectomy + SNB/axillary dissection
After response to neoadjuvant treatment
RADIATIONPostoperative radiotherapy breast/chest wall + regional lymph nodes
DRUGAdjuvant trastuzumab
DRUGAdjuvant letrozole (postmenopausal women)
DRUGAdjuvant tamoxifen + goserelin (premenopausal women)
DRUGAdjuvant palbociclib (if palbociclib given neoadjuvant)
DRUGAdjuvant Epirubicin+ Cyclophosphamide
DRUGNeoadjuvant docetaxel + cyclophosphamide
DRUGNeoadjuvant docetaxel
DRUGNeoadjuvant tamoxifen + goserelin (premenopausal women)
DRUGNeoadjuvant letrozole (postmenopausal women)
DRUGNeoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone)
Sponsors
Haukeland University Hospital
Helse Vest
Pfizer
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Previously untreated, histologically confirmed non-inflammatory breast cancer, \>4 cm in diameter and /or metastatic ipsilateral axillary deposits for which the smallest diameter of the largest node \>2 cm by CT or ultrasound scan. * WHO performance status 0-1 * Known tumor ER, PGR, HER2 and TP53 status. * Known tumor Ki67 percentage (if ER/PGR\>50% and TP53 wt status). * Distant metastasis not suspected. Patients will undergo radiology exams during screening phase, after signing the informed consent. * Age \>18 years * Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST. * Radiology studies (CT thorax/abdomen and bone scintigraphy/bone scan) must be performed within 28 days prior to registration. * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial * Before patient registration/randomization, written informed consent must be given according to national and local regulations. * For arms B-H: * Neutrophils \> 1.5 x 109/L * Platelets \> 100 x 109/L * Bilirubin \< 2 x upper limit normal (ULN). For patients with Gilbert´s syndrome bilirubin \>2 x ULN is accepted if there is no evidence of biliary obstruction. * Serum creatinine \< 1.5 x ULN * ALT and Alk Phos (ALP) \<2.5 x ULN * INR \< 1.5
Exclusion criteria
* Unstable angina pectoris or heart failure * Other co-morbidity that, based on the assessment of the treating physician, may preclude the use of chemotherapy at actual doses. * Pregnant or lactating patients can not be included. * Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist. * Patient not able to give an informed consent or comply with study regulations as deemed by study investigator. * Active cystitis (to be treated upfront) * Active bacterial infections * Urinary obstruction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Predictive and prognostic value of mutations in 300 cancer-related genes assessed in breast cancer tissue by next generation sequencing before starting neoadjuvant therapy. | Ten years | Primary endpoint |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess genetic/epigenetic changes within the tumor tissue during therapy | Before vs. 16-24 wks after treatment start. Four years: summary of all patients treated. | Secondary endpoint |
| The objective response rate (ORR) of personalized medicine, compared to ORR for best standard-of-care using historical data for comparison | Four years | Secondary endpoint |
| Tumor Ki67 reduction after 2 and 5 weeks of treatment in Arm A | Assessment for each patient after 2 and 5 weeks of treatment. Four years - summary of all patients in arm A. | Secondary endpoint |
| To estimate recurrence-free and overall survival when patients are treated with the optimal personalized treatment available as of 2015, using historical data for comparison | Ten years | Secondary endpoint |
| To evaluate the percentage of patients completing neoadjuvant treatment and completing surgery | Four years | Secondary endpoint |
| Breast conserving surgery rate (potential to avoid mastectomy) | Four years | Secondary endpoint |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Ten years | Secondary endpoint |
Countries
Norway
Contacts
PRINCIPAL_INVESTIGATORHans Petter Eikesdal, MD PhD
Consultant oncologist
Outcome results
None listed