EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer

Early Stage Breast Carcinoma Clinical Trial

— EXPERT  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02889874
• Other study ID #: ANZ1601/BIG 16-02
• Secondary ID: 2016-003527-33
• Status: Recruiting
• Phase: N/A
• Start date: August 21, 2017
• Est. completion date: April 2026

Study information

• Verified date: April 2024
• Source: Breast Cancer Trials, Australia and New Zealand
• Contact: Heath Badger
• Phone: +61 2 4925 3022
• Email: expert[@]bctrials.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 1167
• Est. completion date: April 2026
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 50 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Early Stage Breast Carcinoma

Intervention

Radiation:
• Omission of radiation therapy
Omission of radiation therapy (adjuvant endocrine therapy only).

Locations

Country	Name	City	State
Argentina	Sanatorio Britanico Rosariio	Rosario	Santa Fe
Argentina	Instituto de Oncologia de Rosario	Santa Fe
Argentina	Clinica Viedma	Sarmiento
Australia	Genesis Cancer Care Wesley	Auchenflower	Queensland
Australia	Ballarat Austin Radiation Oncology Centre	Ballarat	Victoria
Australia	Peter MacCallum Cancer Centre - Bendigo	Bendigo	Victoria
Australia	Peter MacCallum Cancer Centre - Moorabin	Bentleigh East	Victoria
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Cancer Care Service - Bundaberg	Bundaberg	Queensland
Australia	Cancer Care Service - Hervey Bay	Bundaberg	Queensland
Australia	Macarthur Cancer Therapy Centre	Campbelltown	New South Wales
Australia	The Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	The Canberra Hospital	Canberra	Australian Capital Territory
Australia	St Vincent's Hospital, Sydney	Darlinghurst	New South Wales
Australia	Icon Cancer Centre Richmond	East Melbourne	Victoria
Australia	St Vincent's Hospital Melbourne	Fitzroy	Victoria
Australia	GenesisCare Radiation Oncology Centre Frankston	Frankston	Victoria
Australia	Genesis Cancer Care Newcastle	Gateshead	New South Wales
Australia	University Hospital Geelong	Geelong	Victoria
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	GenesisCare Tennyson	Kurralta Park	South Australia
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Newcastle	New South Wales
Australia	Mater Hospital Sydney	North Sydney	New South Wales
Australia	Port Macquarie Base Hospital	Port Macquarie	New South Wales
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Ringwood Radiation Oncology Centre	Ringwood East	Victoria
Australia	Tamworth Rural Referral Hospital	Tamworth;	New South Wales
Australia	Latrobe Regional Hospital	Traralgon	Victoria
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Chile	Centro Oncologico del Norte	Antofagasta
Chile	Hospital Sotero del Rio	Puente Alto
Chile	Hospital Barros Luco Trudeau	San Miguel
Chile	Hospital Luis Tisne Brousse	Santiago	Region Metropolitana
Chile	Instituto Nacional del Cancer	Santiago
Ireland	St Luke's Radiation Oncology Network	Dublin
Ireland	University Hospital Galway	Galway
Italy	ASST Ospedale A. Manzoni UOS Oncologia	Lecco
Italy	Istituto Europeo di Oncologia	Milan
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Waikato Hospital	Hamilton
New Zealand	Palmerston North Hospital	Palmerston North
New Zealand	Wellington Hospital	Wellington
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	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 Universitario Virgen del Rocio	Seville
Switzerland	Hirslanden Clinique des Grangettes	Chêne-Bougeries
Switzerland	Fondazione Oncologia Lago Maggiore	Locarno
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Brust-Zentrum AG Zurich	Zurich
Switzerland	Universitatsspital Zurich	Zurich
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Medical University Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	Chang-Gung Memorial Hospital	Taoyuan

Sponsors (3)

Lead Sponsor	Collaborator
Breast Cancer Trials, Australia and New Zealand	Breast International Group, ETOP IBCSG Partners Foundation

Countries where clinical trial is conducted

Argentina,  Australia,  Chile,  Ireland,  Italy,  New Zealand,  Spain,  Switzerland,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life: Fear of recurrence	Fear of Cancer Recurrence Inventory	5 years
Other	Quality of Life: Convenience of care	Visual Analogue Scales (convenience and impact of treatment)	5 years
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Recurrence-free interval	Time from randomisation to the date of local, regional or distant recurrence as a site of first recurrence.	10 years
Secondary	Overall survival (OS)	Time from randomisation to date of death from any cause.	10 years
Secondary	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
Secondary	Adverse events for patients	Adverse events during treatment (up to 5 years of endocrine therapy) assessed using NCI CTCAE v4.0.	5 years
Secondary	Assessment of the impact of endocrine therapy	FACT-ES measure of endocrine symptoms.	5 years

External Links

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