EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer
- Conditions
- Early Stage Breast Carcinoma
- Interventions
- Radiation: Omission of radiation therapy
- Registration Number
- NCT02889874
- Lead Sponsor
- Breast Cancer Trials, Australia and New Zealand
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Female
- Target Recruitment
- 1167
for registration in the study:
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Female patients aged ≥ 50 years of any menopausal status.
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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.
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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.
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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).
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No evidence of distant metastasis.
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Eligible for and willing to have adjuvant endocrine therapy.
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ECOG performance status 0-2.
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Availability of FFPE tumour block for Prosigna (PAM50) Assay.
For randomization to the study, patients must fulfill all of the following criteria:
- Primary tumour characteristics as assessed by Prosigna (PAM50) Assay:
- Luminal A intrinsic subtype
- ROR score ≤60
Any one of the following is regarded as a criterion for exclusion from the study:
-
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
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Contra-indication or unwillingness to have adjuvant endocrine therapy.
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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.
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Treated with neoadjuvant endocrine therapy, chemotherapy or biologic therapy prior to breast cancer surgery.
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Prior breast or thoracic RT for any condition.
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Pre-operative breast imaging evidence of disease aside from the primary carcinoma resected by breast conserving surgery.
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Concurrent invasive breast carcinoma or ductal carcinoma in situ (synchronous or metachronous).
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Prior diagnosis of invasive breast carcinoma or ductal carcinoma in situ in either breast irrespective of disease free interval.
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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.
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Significant comorbidity precluding definitive RT for breast cancer (e.g. cardiovascular or pulmonary disease, scleroderma, systemic lupus erythematosus).
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Life expectancy <10 years.
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Documented mutation of BRCA1, BRCA2 or TP53, or at high genetic risk of breast cancer.
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Pregnant or lactating patients.
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Inability to be registered to the study ≤8 weeks after the last surgical procedure for breast cancer.
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Inability to commence RT (if randomised to receive RT) no later than 12 weeks from the last surgical procedure for breast cancer.
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Inability to provide written informed consent.
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Psychiatric, addictive, or any disorder that precludes compliance with protocol requirements.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description B: No Radiation Therapy (ET only) Omission of radiation therapy Patients randomized to Arm B will not receive radiation therapy (omission of radiation therapy) and receive adjuvant endocrine therapy only.
- Primary Outcome Measures
Name Time Method Local recurrence rate after breast conserving surgery 10 years The time from randomisation to the date of local recurrence (LR) as a site of first recurrence.
- Secondary Outcome Measures
Name Time Method Disease free survival including DCIS (DFS-DCIS) 10 years Time from randomisation to date of first evidence of local (invasive breast carcinoma or DCIS), regional or distanct recurrence; contralateral breast cancer (invasive breast carcinoma or DCIS); second (non-breast) primary invasive cancer; or death.
Recurrence-free interval 10 years Time from randomisation to the date of local, regional or distant recurrence as a site of first recurrence.
Overall survival (OS) 10 years Time from randomisation to date of death from any cause.
Local-regional recurrence-free interval (LRRFI) 10 years Time from randomisation to the date of local or regional recurrence as a site of first recurrence.
Invasive disease free survival (iDFS) 10 years Time from randomisation to date of first evidence of local (invasive breast carcinoma), regional or distanct recurrence; contralateral breast cancer (invasive breast carcinoma); second (non-breast) primary invasive cancer; or death.
Distant recurrence-free interval (DRFI) 10 years Time from randomisation to the date of distant recurrence, regardless of occurrence of any intervening local or regional recurrence, contralateral breast cancer or second (non-breast) primary invasive cancer.
Salvage RT or mastectomy rate 10 years Time from randomisation to the receipt of salvage RT or mastectomy, individually and in combination (one or the other) as a composite endpoint.
Adverse events for patients 5 years Adverse events during treatment (up to 5 years of endocrine therapy) assessed using NCI CTCAE v4.0.
Assessment of the impact of endocrine therapy 5 years FACT-ES measure of endocrine symptoms.
Trial Locations
- Locations (68)
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Genesis Cancer Care Wesley
🇦🇺Auchenflower, Queensland, Australia
Icon Cancer Centre Richmond
🇦🇺East Melbourne, Victoria, Australia
Brust-Zentrum AG Zurich
🇨🇭Zurich, Switzerland
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
Hospital Barros Luco Trudeau
🇨🇱San Miguel, Chile
Christchurch Hospital
🇳🇿Christchurch, New Zealand
St Vincent's Hospital Melbourne
🇦🇺Fitzroy, Victoria, Australia
Latrobe Regional Hospital
🇦🇺Traralgon, Victoria, Australia
Taipei Medical University Hospital
🇨🇳Taipei, Taiwan
Hirslanden Clinique des Grangettes
🇨🇭Chêne-Bougeries, Switzerland
GenesisCare Radiation Oncology Centre Frankston
🇦🇺Frankston, Victoria, Australia
Waikato Hospital
🇳🇿Hamilton, New Zealand
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
Wellington Hospital
🇳🇿Wellington, New Zealand
Chang-Gung Memorial Hospital
🇨🇳Taoyuan, Taiwan
Mackay Memorial Hospital
🇨🇳Taipei, Taiwan
Sanatorio Britanico Rosariio
🇦🇷Rosario, Santa Fe, Argentina
Instituto de Oncologia de Rosario
🇦🇷Santa Fe, Argentina
Clinica Viedma
🇦🇷Sarmiento, Argentina
The Canberra Hospital
🇦🇺Canberra, Australian Capital Territory, Australia
St Vincent's Hospital, Sydney
🇦🇺Darlinghurst, New South Wales, Australia
Genesis Cancer Care Newcastle
🇦🇺Gateshead, New South Wales, Australia
Macarthur Cancer Therapy Centre
🇦🇺Campbelltown, New South Wales, Australia
The Chris O'Brien Lifehouse
🇦🇺Camperdown, New South Wales, Australia
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Port Macquarie Base Hospital
🇦🇺Port Macquarie, New South Wales, Australia
Gosford Hospital
🇦🇺Gosford, New South Wales, Australia
Calvary Mater Newcastle
🇦🇺Newcastle, New South Wales, Australia
Mater Hospital Sydney
🇦🇺North Sydney, New South Wales, Australia
Wollongong Hospital
🇦🇺Wollongong, New South Wales, Australia
Prince of Wales Hospital
🇦🇺Randwick, New South Wales, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Tamworth Rural Referral Hospital
🇦🇺Tamworth;, New South Wales, Australia
Cancer Care Service - Hervey Bay
🇦🇺Bundaberg, Queensland, Australia
GenesisCare Tennyson
🇦🇺Kurralta Park, South Australia, Australia
Ballarat Austin Radiation Oncology Centre
🇦🇺Ballarat, Victoria, Australia
Peter MacCallum Cancer Centre - Bendigo
🇦🇺Bendigo, Victoria, Australia
University Hospital Geelong
🇦🇺Geelong, Victoria, Australia
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Ringwood Radiation Oncology Centre
🇦🇺Ringwood East, Victoria, Australia
Centro Oncologico del Norte
🇨🇱Antofagasta, Chile
Hospital Luis Tisne Brousse
🇨🇱Santiago, Region Metropolitana, Chile
Hospital Sotero del Rio
🇨🇱Puente Alto, Chile
Instituto Nacional del Cancer
🇨🇱Santiago, Chile
University Hospital Galway
🇮🇪Galway, Ireland
St Luke's Radiation Oncology Network
🇮🇪Dublin, Ireland
ASST Ospedale A. Manzoni UOS Oncologia
🇮🇹Lecco, Italy
Istituto Europeo di Oncologia
🇮🇹Milan, Italy
Palmerston North Hospital
🇳🇿Palmerston North, New Zealand
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitari Arnoa de Vilanova de Lleida
🇪🇸Lleida, Spain
Hospital Universitario Virgen de la Macarena
🇪🇸Seville, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Fondazione Oncologia Lago Maggiore
🇨🇭Locarno, Switzerland
Hospital Universitario Virgen del Rocio
🇪🇸Seville, Spain
Kantonsspital Winterthur
🇨🇭Winterthur, Switzerland
Universitatsspital Zurich
🇨🇭Zurich, Switzerland
Kaohsiung Medical University Hospital
🇨🇳Kaohsiung, Taiwan
Changhua Christian Hospital
🇨🇳Changhua, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Cancer Care Service - Bundaberg
🇦🇺Bundaberg, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Peter MacCallum Cancer Centre - Moorabin
🇦🇺Bentleigh East, Victoria, Australia
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Tri-Service General Hospital
🇨🇳Taipei, Taiwan