PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

Study Overview
=================
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.

Official Title
-----------------
PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Neoadjuvant tamoxifen + goserelin (premenopausal women)
* Drug: Neoadjuvant letrozole (postmenopausal women)
* Drug: Neoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone)
* Drug: Neoadjuvant docetaxel + cyclophosphamide
* Drug: Neoadjuvant docetaxel
* Drug: Neoadjuvant docetaxel + trastuzumab + pertuzumab
* Drug: Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab
* Drug: Neoadjuvant olaparib
* Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)
* Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection
* Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes
* Drug: Adjuvant trastuzumab
* Drug: Adjuvant letrozole (postmenopausal women)
* Drug: Adjuvant tamoxifen + goserelin (premenopausal women)
* Drug: Adjuvant palbociclib (if palbociclib given neoadjuvant)
* Drug: Adjuvant Epirubicin+ Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>ER/PGR>50% TP53 wt | Drug: Neoadjuvant tamoxifen + goserelin (premenopausal women)<br> <br> Drug: Neoadjuvant letrozole (postmenopausal women)<br> <br> Drug: Neoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone)<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> Drug: Adjuvant palbociclib (if palbociclib given neoadjuvant)<br> <br> Drug: Adjuvant Epirubicin+ Cyclophosphamide<br> <br> |
| Experimental: B<br>ER/PGR>50% TP53 mutated | Drug: Neoadjuvant docetaxel + cyclophosphamide<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> |
| Experimental: C<br>ER/PGR<50% TP53 wt | Drug: Neoadjuvant docetaxel<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> |
| Experimental: D<br>ER/PGR<50% TP53 mutated | Drug: Neoadjuvant docetaxel + cyclophosphamide<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> |
| Experimental: E<br>HER2+ TP53 wt | Drug: Neoadjuvant docetaxel + trastuzumab + pertuzumab<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant trastuzumab<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> |
| Experimental: F<br>HER2+ TP53 mutated | Drug: Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> Drug: Adjuvant trastuzumab<br> <br> Drug: Adjuvant letrozole (postmenopausal women)<br> <br> Drug: Adjuvant tamoxifen + goserelin (premenopausal women)<br> <br> |
| Experimental: G<br>Triple negative breast cancer TP53 wt | Drug: Neoadjuvant olaparib<br> <br> Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> |
| Experimental: H<br>Triple negative breast cancer TP53 mutated | Drug: Neoadjuvant olaparib<br> <br> Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)<br> <br> Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection<br>* After response to neoadjuvant treatment<br>Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive and prognostic value of mutations in 300 cancer-related genes assessed in breast cancer tissue by next generation sequencing before starting neoadjuvant therapy. | Primary endpoint | Ten years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess genetic/epigenetic changes within the tumor tissue during therapy | Secondary endpoint | Before vs. 16-24 wks after treatment start. Four years: summary of all patients treated. | 
| The objective response rate (ORR) of personalized medicine, compared to ORR for best standard-of-care using historical data for comparison | Secondary endpoint | Four years | 
| Tumor Ki67 reduction after 2 and 5 weeks of treatment in Arm A | Secondary endpoint | Assessment for each patient after 2 and 5 weeks of treatment. Four years - summary of all patients in arm A. | 
| 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 | Secondary endpoint | Ten years | 
| To evaluate the percentage of patients completing neoadjuvant treatment and completing surgery | Secondary endpoint | Four years | 
| Breast conserving surgery rate (potential to avoid mastectomy) | Secondary endpoint | Four years | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Secondary endpoint | Ten years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neoadjuvant treatment, personalized medicine