EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer (EXPERT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Early Stage Breast Carcinoma
• Intervention / Treatment: Radiation: Omission of radiation therapy

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.

• Study Type: Interventional
• Enrollment (Estimated): 1167
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Heath Badger; Phone Number: +61 2 4925 3022; Email: expert@bctrials.org.au
• Study Contact Backup: Name: Akiko Fong; Phone Number: +61 2 4925 3022; Email: expert@bctrials.org.au

Study Locations

• Argentina
  • Santa Fe, Argentina
    • Recruiting
    • Instituto De Oncologia De Rosario
    • Contact: Luis Fein, Dr
  • Sarmiento, Argentina, R8500ACE
    • Recruiting
    • Clínica Viedma
    • Contact: Ruben Kowalyszsyn, Dr
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000
      • Recruiting
      • Sanatorio Britanico Rosariio
      • Contact: Marcelo Tatangelo, Dr
• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Recruiting
      • The Canberra Hospital
      • Contact: Lisa Sullivan, Dr
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Recruiting
      • Macarthur Cancer Therapy Centre
      • Contact: George Papadatos, Dr
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • The Chris O'Brien Lifehouse
      • Contact: Georgia Harris, Dr
    • Darlinghurst, New South Wales, Australia, 2010
      • Recruiting
      • St Vincent's Hospital, Sydney
      • Contact: Joanne Toohey, Dr
    • Gateshead, New South Wales, Australia, 2290
      • Recruiting
      • Genesis Cancer Care Newcastle
      • Contact: Peter O'Brien, A/Prof
    • Gosford, New South Wales, Australia, 2250
      • Recruiting
      • Gosford Hospital
      • Contact: Hester Lieng, Dr
      • Principal Investigator: Hester Lieng, Dr
    • Liverpool, New South Wales, Australia, 1871
      • Recruiting
      • Liverpool Hospital
      • Contact: Miriam Boxer, Dr
    • Newcastle, New South Wales, Australia, 2298
      • Recruiting
      • Calvary Mater Newcastle
      • Contact: Jane Ludbrook, Dr
    • North Sydney, New South Wales, Australia, 2060
      • Recruiting
      • Mater Hospital Sydney
      • Contact: Andrew Spillane, Prof
    • Port Macquarie, New South Wales, Australia, 2444
      • Recruiting
      • Port Macquarie Base Hospital
      • Contact: Carmen Hansen, Dr
    • Randwick, New South Wales, Australia, 2031
      • Recruiting
      • Prince of Wales Hospital
      • Contact: Boon H Chua, Prof
    • Tamworth;, New South Wales, Australia, 2340
      • Recruiting
      • Tamworth Rural Referral Hospital
      • Contact: Susan Pendlebury, Dr
    • Westmead, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
      • Contact: Verity Ahern, A/Prof
    • Wollongong, New South Wales, Australia, 2500
      • Recruiting
      • Wollongong Hospital
      • Contact: de Leon Jeremiah, Dr
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • Recruiting
      • Genesis Cancer Care Wesley
      • Contact: Marie Burke, Dr
    • Bundaberg, Queensland, Australia, 4670
      • Recruiting
      • Cancer Care Service - Bundaberg
      • Contact: Gerard Adams, Dr
    • Bundaberg, Queensland, Australia, 4670
      • Recruiting
      • Cancer Care Service - Hervey Bay
      • Contact: Bryan Burmeister, Prof
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: Margot Lehman, A/Prof
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Recruiting
      • GenesisCare Tennyson
      • Contact: Phuong Tran, Dr
  • Victoria
    • Ballarat, Victoria, Australia, 3353
      • Recruiting
      • Ballarat Austin Radiation Oncology Centre
      • Contact: Louise Gorman, Dr
    • Bendigo, Victoria, Australia, 3550
      • Recruiting
      • Peter MacCallum Cancer Centre - Bendigo
      • Contact: Solveig Grenfell, Dr
    • Bentleigh East, Victoria, Australia, 3165
      • Recruiting
      • Peter MacCallum Cancer Centre - Moorabin
      • Contact: Steven David, Dr
    • Box Hill, Victoria, Australia, 3128
      • Recruiting
      • Box Hill Hospital
      • Contact: Bianca Devitt, Dr
    • East Melbourne, Victoria, Australia, 3002
      • Recruiting
      • Icon Cancer Centre Richmond
      • Contact: Andrew See, Dr
    • Fitzroy, Victoria, Australia, 3065
      • Recruiting
      • St Vincent's Hospital Melbourne
      • Contact: Melissa Moore, Dr
    • Frankston, Victoria, Australia, 3199
      • Recruiting
      • GenesisCare Radiation Oncology Centre Frankston
      • Contact: David Blakey, Dr
    • Geelong, Victoria, Australia, 3220
      • Recruiting
      • University Hospital Geelong
      • Contact: Michael Francis, Dr
    • Heidelberg, Victoria, Australia, 3084
      • Recruiting
      • Austin Hospital
      • Contact: Michael Chao, Dr
    • Melbourne, Victoria, Australia, 8006
      • Recruiting
      • Peter MacCallum Cancer Centre
      • Contact: Prue Francis, A/Prof
    • Ringwood East, Victoria, Australia, 3135
      • Recruiting
      • Ringwood Radiation Oncology Centre
      • Contact: Michael Chao, Dr
    • Traralgon, Victoria, Australia, 3844
      • Recruiting
      • Latrobe Regional Hospital
      • Contact: Louise Nardone, Dr
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Recruiting
      • Sir Charles Gairdner Hospital
      • Contact: Mandy Taylor, Dr
• Chile
  • Antofagasta, Chile
    • Recruiting
    • Centro Oncologico del Norte
    • Contact: Paves Gonzalo, Dr
  • Puente Alto, Chile
    • Recruiting
    • Hospital Sotero del Rio
    • Contact: Manuel Manzor, Dr
  • San Miguel, Chile
    • Recruiting
    • Hospital Barros Luco Trudeau
    • Contact: Rocio Guerra, Dr
  • Santiago, Chile, 1010
    • Recruiting
    • Instituto Nacional del Cancer
    • Contact: Camila Concha, Dr
  • Region Metropolitana
    • Santiago, Region Metropolitana, Chile
      • Recruiting
      • Hospital Luis Tisne Brousse
      • Contact: Paola Ruiz de Vinaspre, Dr
• Ireland
  • Dublin, Ireland
    • Recruiting
    • St Luke's Radiation Oncology Network
    • Contact: Sinead Brennan, Dr
  • Galway, Ireland
    • Recruiting
    • University Hospital Galway
    • Contact: Joseph Martin, Dr
• Italy
  • Lecco, Italy
    • Recruiting
    • ASST Ospedale A. Manzoni UOS Oncologia
    • Contact: Alessandra Crippa, Dr
  • Milan, Italy
    • Recruiting
    • Istituto Europeo di Oncologia
    • Contact: Marco Colleoni, Prof
• New Zealand
  • Christchurch, New Zealand, 8011
    • Recruiting
    • Christchurch Hospital
    • Contact: Melissa James, Dr
  • Hamilton, New Zealand, 3240
    • Recruiting
    • Waikato Hospital
    • Contact: Ian Campbell, A/Prof
  • Palmerston North, New Zealand, 4414
    • Recruiting
    • Palmerston North Hospital
    • Contact: Claire Hardie, Dr
  • Wellington, New Zealand, 6021
    • Recruiting
    • Wellington Hospital
    • Contact: Anna Nicholson, Dr
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Victoria Reyes, Dr
  • Barcelona, Spain
    • Recruiting
    • Hospital Clinic de Barcelona
    • Contact: Meritxell Molla, Dr
  • Lleida, Spain
    • Recruiting
    • Hospital Universitari Arnoa de Vilanova de Lleida
    • Contact: Serafin Morales, Dr
  • Seville, Spain
    • Recruiting
    • Hospital Universitario Virgen del Rocio
    • Contact: Javier Salvador Bofill, Dr
  • Seville, Spain
    • Recruiting
    • Hospital Universitario Virgen De La Macarena
    • Contact: Eloisa Bayo, Dr
• Switzerland
  • Chêne-Bougeries, Switzerland, 1224
    • Recruiting
    • Hirslanden Clinique des Grangettes
    • Contact: Conny Vrieling, Dr
  • Locarno, Switzerland, 6600
    • Not yet recruiting
    • Fondazione Oncologia Lago Maggiore
    • Contact: Michail Kouros, Dr
  • Winterthur, Switzerland, 8400
    • Recruiting
    • Kantonsspital Winterthur
    • Contact: Daniel Zwahlen, Dr
  • Zurich, Switzerland, 8008
    • Recruiting
    • Brust-Zentrum AG Zürich
    • Contact: Christoph Tausch, Dr
  • Zurich, Switzerland, 8091
    • Recruiting
    • Universitätsspital Zürich
    • Contact: Linsenmeier Claudia, Dr
• Taiwan
  • Changhua, Taiwan, 500
    • Recruiting
    • Changhua Christian Hospital
    • Contact: Shou-Tung Chen, Dr
  • Kaohsiung, Taiwan
    • Recruiting
    • Kaohsiung Medical University Hospital
    • Contact: Fang-Ming Chen, Dr
  • Taichung, Taiwan, 407204
    • Recruiting
    • Taichung Veterans General Hospital
    • Contact: Chih-Chiang Hung, Dr
  • Tainan, Taiwan, 704
    • Recruiting
    • National Cheng Kung University Hospital
    • Contact: Yao-Lung Kuo, Dr
  • Taipei, Taiwan
    • Recruiting
    • Taipei Medical University Hospital
    • Contact: Chin-Sheng Hung, Dr
  • Taipei, Taiwan, 114
    • Recruiting
    • Tri-Service General Hospital
    • Contact: Guo-Hsiou Liao, Dr
  • Taipei, Taiwan, 100
    • Recruiting
    • National Taiwan University Hospital
    • Contact: Chiun-Sheng Huang, Dr
  • Taipei, Taiwan, 10449
    • Recruiting
    • Mackay Memorial Hospital
    • Contact: Yuan-ching Chang, Dr
  • Taipei, Taiwan, 11217
    • Recruiting
    • Taipei Veterans General Hospital
    • Contact: Ling-Ming Tseng, Dr
  • Taoyuan, Taiwan, 10449
    • Recruiting
    • Chang-Gung Memorial Hospital
    • Contact: Wenling Kuo, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: A: Radiation Therapy & endocrine therapy; Patients randomized to Arm A will receive standard radiation therapy and adjuvant endocrine therapy (standard of care).
Experimental: B: No Radiation Therapy (ET only); Patients randomized to Arm B will not receive radiation therapy (omission of radiation therapy) and receive adjuvant endocrine therapy only.	Radiation: Omission of radiation therapy; Omission of radiation therapy (adjuvant endocrine therapy only).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local recurrence rate after breast conserving surgery	The time from randomisation to the date of local recurrence (LR) as a site of first recurrence.	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local-regional recurrence-free interval (LRRFI)	Time from randomisation to the date of local or regional recurrence as a site of first recurrence.	10 years
Distant recurrence-free interval (DRFI)	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.	10 years
Disease free survival including DCIS (DFS-DCIS)	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.	10 years
Invasive disease free survival (iDFS)	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.	10 years
Recurrence-free interval	Time from randomisation to the date of local, regional or distant recurrence as a site of first recurrence.	10 years
Overall survival (OS)	Time from randomisation to date of death from any cause.	10 years
Salvage RT or mastectomy rate	Time from randomisation to the receipt of salvage RT or mastectomy, individually and in combination (one or the other) as a composite endpoint.	10 years
Adverse events for patients	Adverse events during treatment (up to 5 years of endocrine therapy) assessed using NCI CTCAE v4.0.	5 years
Assessment of the impact of endocrine therapy	FACT-ES measure of endocrine symptoms.	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life: Fear of recurrence	Fear of Cancer Recurrence Inventory	5 years
Quality of Life: Convenience of care	Visual Analogue Scales (convenience and impact of treatment)	5 years

Collaborators and Investigators

• Sponsor: Breast Cancer Trials, Australia and New Zealand
• Collaborators: ETOP IBCSG Partners Foundation; Breast International Group
• Investigators: Study Chair: Boon H Chua, Prof, Prince of Wales Hospital; Study Director: Heath Badger, Breast Cancer Trials, Australia and New Zealand

Publications and helpful links

Helpful Links

• Breast Cancer Trials (formerly Australia & New Zealand Breast Cancer Trials Group

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2017
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: August 25, 2016
• First Submitted That Met QC Criteria: August 31, 2016
• First Posted (Estimated): September 7, 2016

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 7, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer; Radiation therapy; non-inferiority; omission
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: ANZ1601/BIG 16-02; 2016-003527-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised Individual Patient Data (IPD) collected during the trial as per BCT Data Sharing Guidelines.
• IPD Sharing Time Frame: Data will be made available for request after publication of the main/final study results; no end date.

IPD Sharing Access Criteria

Subject to approval by Breast Cancer Trials: contact concept@bctrials.org.au for further information.

Note that there may be additional circumstances preventing BCT from sharing requested data as outlined in the BCT Data Sharing Guidelines .

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No