Clinical trial NCT02889874: EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer
Official title: A Randomised Phase III Trial of Adjuvant Radiation Therapy Versus Observation Following Breast Conserving Surgery and Endocrine Therapy in Patients With Molecularly Characterised Luminal A Early Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Early Stage Breast Carcinoma
Keywords: Radiation therapy
omission
non-inferiority
breast cancer
Lead sponsor: Breast Cancer Trials, Australia and New Zealand
Sponsor class: OTHER
Collaborators: name: Breast International Group
name: ETOP IBCSG Partners Foundation
First posted: 2016-09-07
Enrollment: 1167
Sex: FEMALE
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised, phase III, non-inferiority trial evaluating radiation therapy versus observation following breast conserving surgery and planned endocrine therapy in patients with stage I breast cancer of luminal A subtype defined using the Prosigna (PAM50) Assay.

Detailed description: Radiation therapy (RT) after breast conserving surgery to improve local control and survival is the current standard of care for patients with early breast cancer. However, breast cancer is a heterogeneous disease, and the absolute benefit of RT in individual patients varies substantially. Thus, a pressing priority in contemporary breast cancer management is to tailor RT utilisation to the individual recurrence risks by identifying patients who are unlikely to benefit from RT, thereby avoiding the morbidity and costs of over-treatment.

It is recognised that selected patients with early breast cancer are unlikely to derive benefits from RT after breast conserving surgery. However, randomised trials have not consistently identified patients who may safely omit RT using conventional clinical-pathologic characteristics.

Breast cancer intrinsic subtypes distinguished by gene expression profiling are shown to be associated with distinct clinical outcomes. There is substantial evidence supporting the clinical validity of multigene assays including the PAM50-based Prosigna Assay that identifies intrinsic subtypes and generates a Risk of Recurrence score (ROR) to quantify individual risks of distant relapse. Multigene assays are increasingly integrated into clinical practice to inform chemotherapy decision, highlighting their substantial practice changing potential in personalising the use of RT for early breast cancer.

A recent analysis of archived tumour specimens of 1,308 patients with early breast cancer has shown significant associations between local recurrence risk and the PAM50-defined intrinsic subtypes and ROR score. EXPERT presents a unique opportunity of clinical and public health importance to optimise personalised local therapy for early breast cancer through precise, individualised quantification of local recurrence risk to identify low-risk patients for whom RT after breast conserving surgery may be safely omitted.

Eligibility criteria: Inclusion Criteria: for registration in the study:

1. Female patients aged ≥ 50 years of any menopausal status.
2. Primary tumour characteristics as assessed by conventional histopathology:

   * Unifocal histologically confirmed invasive breast carcinoma
   * Maximum microscopic size ≤2 cm
   * Grade 1 or 2 histology
   * ER and PR positive in ≥10% of tumour cells in either the biopsy or breast conserving surgical specimen
   * HER2 negative on IHC (score 0 or 1+) or in situ hybridisation (ERBB2-amplification Ratio ERBB2/centromeres \<2.0 or mean gene copy number \<6). Equivocal IHC score (2+) must be assessed by ISH.
3. Primary tumour must be resected by breast conserving surgery with microscopically negative margins for invasive carcinoma and any associated ductal carcinoma in situ (no cancer cells adjacent to any inked edge/surface of specimen) or re-excision showing no residual disease.
4. Histologically confirmed negative nodal status determined by sentinel node biopsy or axillary dissection. Patients with pN0 (i+) disease are eligible for study participation (malignant cells ≤0.2 mm in regional lymph node(s) detected by hematoxylin-eosin (H\&E) stain or IHC, including isolated tumour cells).
5. No evidence of distant metastasis.
6. Eligible for and willing to have adjuvant endocrine therapy.
7. ECOG performance status 0-2.
8. Availability of FFPE tumour block for Prosigna (PAM50) Assay.

For randomization to the study, patients must fulfill all of the following criteria:

1. Primary tumour characteristics as assessed by Prosigna (PAM50) Assay:

* Luminal A intrinsic subtype
* ROR score ≤60

Exclusion Criteria:

Any one of the following is regarded as a criterion for exclusion from the study:

1. Primary tumour characteristics:

   * Presence of multifocal or multicentric invasive carcinoma or ductal carcinoma in situ;
   * Evidence of clinical or pathologic T4 disease (extension to the chest wall, oedema or ulceration of skin, satellite skin nodules, inflammatory carcinoma);
   * The invasive component of the primary tumour is present as micro-invasion only;
   * Grade 3 histology;
   * Presence of lymphovascular invasion
2. Contra-indication or unwillingness to have adjuvant endocrine therapy.
3. Planned to receive adjuvant chemotherapy or biologic therapy after breast cancer surgery, i.e. any systemic therapy other than endocrine therapy is not permitted. Any therapy unrelated to cancer is permitted at the discretion of investigators.
4. Treated with neoadjuvant endocrine therapy, chemotherapy or biologic therapy prior to breast cancer surgery.
5. Prior breast or thoracic RT for any condition.
6. Pre-operative breast imaging evidence of disease aside from the primary carcinoma resected by breast conserving surgery.
7. Concurrent invasive breast carcinoma or ductal carcinoma in situ (synchronous or metachronous).
8. Prior diagnosis of invasive breast carcinoma or ductal carcinoma in situ in either breast irrespective of disease free interval.
9. A diagnosis of non-breast malignancy \<5 years prior to randomisation with the following exceptions:

   * Patients who are diagnosed with carcinoma in situ of cervix, endometrium or colon; melanoma in situ; and basal or squamous cell carcinoma of the skin at any time prior to randomisation are not excluded from study participation.
   * Patients who are diagnosed with other non-breast malignancy ≥5 years prior to randomisation and without evidence of disease recurrence are not excluded from study participation.
10. Significant comorbidity precluding definitive RT for breast cancer (e.g. cardiovascular or pulmonary disease, scleroderma, systemic lupus erythematosus).
11. Life expectancy \<10 years.
12. Documented mutation of BRCA1, BRCA2 or TP53, or at high genetic risk of breast cancer.
13. Pregnant or lactating patients.
14. Inability to be registered to the study ≤8 weeks after the last surgical procedure for breast cancer.
15. Inability to commence RT (if randomised to receive RT) no later than 12 weeks from the last surgical procedure for breast cancer.
16. Inability to provide written informed consent.
17. Psychiatric, addictive, or any disorder that precludes compliance with protocol requirements.

Primary outcomes:
measure: Local recurrence rate after breast conserving surgery
timeFrame: 10 years
Secondary outcomes:
measure: Local-regional recurrence-free interval (LRRFI)
timeFrame: 10 years
measure: Distant recurrence-free interval (DRFI)
timeFrame: 10 years
measure: Disease free survival including DCIS (DFS-DCIS)
timeFrame: 10 years
measure: Invasive disease free survival (iDFS)
timeFrame: 10 years
measure: Recurrence-free interval
timeFrame: 10 years
measure: Overall survival (OS)
timeFrame: 10 years
measure: Salvage RT or mastectomy rate
timeFrame: 10 years
measure: Adverse events for patients
timeFrame: 5 years
measure: Assessment of the impact of endocrine therapy
timeFrame: 5 years
Other outcomes:
measure: Quality of Life: Fear of recurrence
timeFrame: 5 years
measure: Quality of Life: Convenience of care
timeFrame: 5 years
Locations:
city: Rosario
country: Argentina
facility: Sanatorio Britanico Rosariio
state: Santa Fe
city: Santa Fe
country: Argentina
facility: Instituto de Oncologia de Rosario
city: Sarmiento
country: Argentina
facility: Clinica Viedma
city: Canberra
country: Australia
facility: The Canberra Hospital
state: Australian Capital Territory
city: Campbelltown
country: Australia
facility: Macarthur Cancer Therapy Centre
state: New South Wales
city: Camperdown
country: Australia
facility: The Chris O'Brien Lifehouse
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital, Sydney
state: New South Wales
city: Gateshead
country: Australia
facility: Genesis Cancer Care Newcastle
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: North Sydney
country: Australia
facility: Mater Hospital Sydney
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Tamworth;
country: Australia
facility: Tamworth Rural Referral Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: Genesis Cancer Care Wesley
state: Queensland
city: Bundaberg
country: Australia
facility: Cancer Care Service - Bundaberg
state: Queensland
city: Bundaberg
country: Australia
facility: Cancer Care Service - Hervey Bay
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Kurralta Park
country: Australia
facility: GenesisCare Tennyson
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Austin Radiation Oncology Centre
state: Victoria
city: Bendigo
country: Australia
facility: Peter MacCallum Cancer Centre - Bendigo
state: Victoria
city: Bentleigh East
country: Australia
facility: Peter MacCallum Cancer Centre - Moorabin
state: Victoria
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: East Melbourne
country: Australia
facility: Icon Cancer Centre Richmond
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Frankston
country: Australia
facility: GenesisCare Radiation Oncology Centre Frankston
state: Victoria
city: Geelong
country: Australia
facility: University Hospital Geelong
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Ringwood East
country: Australia
facility: Ringwood Radiation Oncology Centre
state: Victoria
city: Traralgon
country: Australia
facility: Latrobe Regional Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Santiago
country: Chile
facility: Hospital Luis Tisne Brousse
state: Region Metropolitana
city: Antofagasta
country: Chile
facility: Centro Oncologico del Norte
city: Puente Alto
country: Chile
facility: Hospital Sotero del Rio
city: San Miguel
country: Chile
facility: Hospital Barros Luco Trudeau
city: Santiago
country: Chile
facility: Instituto Nacional del Cancer
city: Dublin
country: Ireland
facility: St Luke's Radiation Oncology Network
city: Galway
country: Ireland
facility: University Hospital Galway
city: Lecco
country: Italy
facility: ASST Ospedale A. Manzoni UOS Oncologia
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Lleida
country: Spain
facility: Hospital Universitari Arnoa de Vilanova de Lleida
city: Seville
country: Spain
facility: Hospital Universitario Virgen de la Macarena
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Chêne-Bougeries
country: Switzerland
facility: Hirslanden Clinique des Grangettes
city: Locarno
country: Switzerland
facility: Fondazione Oncologia Lago Maggiore
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Brust-Zentrum AG Zurich
city: Zurich
country: Switzerland
facility: Universitatsspital Zurich
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Taoyuan
country: Taiwan
facility: Chang-Gung Memorial Hospital
Study officials:
affiliation: Breast Cancer Trials, Australia and New Zealand
name: Heath Badger
role: STUDY_DIRECTOR
affiliation: Prince of Wales Hospital
name: Boon H Chua, Prof
role: STUDY_CHAIR
References: