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

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.

Study Overview

• Status: Active, not recruiting
• 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); Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women); Drug: Adjuvant palbociclib (if palbociclib given neoadjuvant); Drug: Adjuvant Epirubicin+ Cyclophosphamide; Drug: Neoadjuvant docetaxel + cyclophosphamide; Drug: Neoadjuvant docetaxel; Drug: Neoadjuvant docetaxel + trastuzumab + pertuzumab; Drug: Adjuvant trastuzumab; Drug: Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab; Drug: Neoadjuvant olaparib; Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Akershus
    • Lørenskog, Akershus, Norway
      • Akershus University Hospital
  • Hordaland
    • Bergen, Hordaland, Norway, 5021
      • Haukeland University Hospital
  • Rogaland
    • Haugesund, Rogaland, Norway
      • Helse Fonna
    • Stavanger, Rogaland, Norway
      • Helse Stavanger
  • Sogn Og Fjordande
    • Førde, Sogn Og Fjordande, Norway
      • Helse Førde
  • Sør Trøndelag
    • Trondheim, Sør Trøndelag, Norway
      • St. Olavs Hospital
  • Troms
    • Tromsø, Troms, Norway
      • Helse Nord/UNN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Collaborators: Pfizer; AstraZeneca; Helse Vest
• Investigators: Principal Investigator: Hans Petter Eikesdal, MD PhD, Consultant Oncologist

Publications and helpful links

General Publications

• Eikesdal HP, Yndestad S, Elzawahry A, Llop-Guevara A, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Vagstad G, Venizelos A, Minsaas L, Leirvaag B, Gudlaugsson EG, Vintermyr OK, Aase HS, Aas T, Balmana J, Serra V, Janssen EAM, Knappskog S, Lonning PE. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol. 2021 Feb;32(2):240-249. doi: 10.1016/j.annonc.2020.11.009. Epub 2020 Nov 24.
• Wang L, Wang D, Sonzogni O, Ke S, Wang Q, Thavamani A, Batalini F, Stopka SA, Regan MS, Vandal S, Tian S, Pinto J, Cyr AM, Bret-Mounet VC, Baquer G, Eikesdal HP, Yuan M, Asara JM, Heng YJ, Bai P, Agar NYR, Wulf GM. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype. Cell Rep. 2022 Oct 11;41(2):111462. doi: 10.1016/j.celrep.2022.111462.
• Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lonning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, Wulf GM. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers. Clin Cancer Res. 2022 Nov 1;28(21):4714-4723. doi: 10.1158/1078-0432.CCR-22-0749.
• Yndestad S, Engebrethsen C, Herencia-Ropero A, Nikolaienko O, Vintermyr OK, Lillestol RK, Minsaas L, Leirvaag B, Iversen GT, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Aase HS, Aas T, Gudlaugsson EG, Llop-Guevara A, Serra V, Janssen EAM, Lonning PE, Knappskog S, Eikesdal HP. Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. JCO Precis Oncol. 2023 Sep;7:e2300338. doi: 10.1200/PO.23.00338.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2016
• Primary Completion (Actual): June 1, 2020
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: November 30, 2015
• First Submitted That Met QC Criteria: December 4, 2015
• First Posted (Estimated): December 9, 2015

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant treatment; personalized medicine
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Surgical Procedures, Operative; Hydrocarbons; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Gonadotropin-Releasing Hormone; Trastuzumab; Cyclophosphamide; Goserelin; Mastectomy, Segmental; pertuzumab; olaparib; palbociclib; Mastectomy
• Other Study ID Numbers: 2015/8463

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Tumor genomic data will be made available after publication.