Radiotherapy Omission in Low Risk Ductal in Situ Carcinoma Breast

Breast Cancer Clinical Trial

— ROMANCE  

Official title:

Prospective Study of Omission of Whole-breast Radiotherapy Following Breast-conserving Surgery in Patients With Very Low Risk Ductal Carcinoma in Situ of the Breast

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03878342
• Other study ID #: UC-0107/1803
• Status: Recruiting
• Phase: N/A
• Start date: May 10, 2019
• Est. completion date: November 10, 2034

Study information

• Verified date: December 2023
• Source: UNICANCER
• Contact: Saliha GHANEM, PhD
• Phone: +33 1 80 50 12 98
• Email: s-ghanem[@]unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Following breast-conserving surgery (BCS) for localized ductal carcinoma in situ (DCIS) of the breast, whole-breast irradiation (WBRT) is a standard of care, reducing the absolute rate of in-breast recurrences (IBR) by more than 15% at 10 years, from 28% without radiotherapy to 13 % with radiotherapy. Half of the recurrences occurred as invasive disease. Whereas in the comparative trials, WBRT did not impact on overall survival, survival of patients who recurred with invasive cancers was impaired in comparison to patients who did not recur, or to patients with DCIS-only recurrences.

Using criteria based on age, tumor size, nuclear grade, and margins status, several trials and cohort studies failed to identify subgroups of patients at low risk, who could be safely spared the need for WBRT. The Radiation Therapy Oncology Group (RTOG) DCIS trial included patients treated with BCS for low- or intermediate grade DCIS revealed by unifocal microcalcifications, size ≤25 mm, margins ≥3 mm, and no residual microcalcifications after surgery. The 5-year rates of IBR were 3.5 % without radiotherapy, versus 0.4 % with radiotherapy, and 6.7 % and 0.9 % at 7 years, respectively (p <0.001). Sixty percent of the patients received tamoxifen in both groups.

Several studies showed that the same molecular classes were identified in DCIS as in invasive cancers. Studies suggested that low proliferation, hormone receptors expression, and lack of ERBB2 amplification were associated with a low risk of IBR in patients not receiving radiotherapy. A combined signature was tested in the Eastern Cooperative Oncology Group (ECOG) trial, showing a 10% IBR rate at ten years in patients with a low-risk.

Identifying very low-risk DCIS, using biological markers in addition to the clinical and histological markers of low-risk DCIS, could help to select patients who could be safely avoided WBRT following BCS. It would avoid over-treatment in these women and could decrease the cost of management.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: November 10, 2034
• Est. primary completion date: November 10, 2029
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

1. Woman aged =50 years,

2. ECOG performance status =2

3. Microcalcifications on pre-biopsy mammography, unifocal, =25 mm or opacity without microcalcifications and no clinical palpable tumour

4. Absence of suspicious residual microcalcifications either on post-biopsy/ preoperative localization mammography, or on post-operative mammography Note: if absence of residual microcalcifications on post-biopsy/pre-operative mammography, post-operative mammography is not mandatory;

5. Breast-conserving surgical excision;

6. Histologically proven DCIS of the breast without an invasive component; Note Incidental histological finding of DCIS lesions developed within a benign breast lesion as well as an association with classical lobular carcinoma in situ (LCIS) associated with the DCIS are accepted.

7. Free margins (=2 mm), or free margins following re-excision;

8. Low or Intermediate nuclear grade; Note: In case of nuclear grade heterogeneity within the same sample or between the biopsy or the surgical specimen, the highest nuclear grade score will prevail.

9. Tumour tissue sample availability; Note: Surgical specimen is mandatory unless no residual disease on the surgical specimen. In this instance, the initial diagnosis biopsy is required.

10. Absence of extensive necrosis (=30% of the lumen diameter);

11. Immunohistochemical characteristics of luminal A subtype: ER=10 %, PR =20 %, HER2 negative (0/1+) or 2+ not amplified (confirmed by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)), Ki67 <15%.

12. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations and including follow-up;

13. Written informed consent.

14. Affiliation to the French social security.

Exclusion Criteria:

1. Endocrine treatment for breast cancer.

2. Previous invasive breast cancer including contralateral breast cancer, either metachronous or synchronous

3. Previous DCIS except contralateral DCIS in complete and continuous remission for more than 5 years

4. Previous other cancers (except basal-cell, carcinoma in situ of the cervix or endometrium), not in complete and continuous remission for more than 10 years

5. Known breast-cancer predisposing germ-cell mutation;

6. Palpable tumour with a diagnosis of DCIS on biopsy

7. Bloody nipple discharge;

8. Histological size >25 mm in one or multiple foci

9. High nuclear grade, including high nuclear grade in heterogeneous tumours;either on biopsy or on surgical specimen

10. Associated microinvasive or invasive component;

11. Presence of tumour cells in lymph nodes detected using H&E or immunohistochemical examination (if lymph node sentinel biopsy or dissection has been performed);

12. Absolute contra-indication to whole-breast irradiation as determined by the referring physician;

13. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study.

14. Pregnant women or breast feeding mothers,

Related Conditions & MeSH terms

• Breast Cancer
• Breast Conserving Surgery
• Carcinoma
• DCIS
• Low Risk DCIS
• Radiotherapy Omission

Intervention

Radiation:
• Radiotherapy
two fractionation regimens will be allowed for whole-breast irradiation: 50 Gy in 25 fractions over 5 weeks or 40 Gy in 15 fractions over 3 weeks. The delivery of an additional dose to the tumour bed (boost) will be at the referring physician discretion, according to the guidelines

Other:
• No Radiotherapy
No Irradiation- Active surveillance

Locations

Country	Name	City	State
France	Institut de Cancérologie de l'Ouest -Site Paul Papin	Angers
France	Institut Sainte Catherine	Avignon
France	Centre d'Oncologie et de Radiothérapie du Pays Basque	Bayonne
France	Clinique Belharra	Bayonne
France	Institut Bergonie	Bordeaux
France	Centre Francois Baclesse	Caen
France	Centre Hospitalier du Cotentin	Cherbourg
France	Centre Jean Perrin	Clermont-Ferrand
France	CHIC Créteil	Créteil
France	Hôpital Henri Mondor	Créteil
France	Centre Georges Francois Leclerc	Dijon
France	Centre Hospitalier De Lagny Sur Marne	Jossigny
France	CHU Saint-Pierre La Réunion	La Réunion
France	Centre Guillaume le Conquérant	Le Havre
France	Centre Oscar Lambret	Lille
France	Chu De Limoges - Hopital Dupuytren	Limoges
France	Centre Hospitalier Bretagne Sud	Lorient
France	Centre de Radiothérapie Mermoz	Lyon
France	Centre Léon Berard	Lyon
France	Hôpital La Croix Rousse	Lyon
France	Institut Regional Du Cancer Montpellier Val D Aurelle	Montpellier
France	Centre Azuréen De Cancérologie	Mougins
France	Centre Antoine Lacassagne	Nice
France	Centre de Haute Energie	Nice
France	Hopital Pitie Salpetriere	Paris
France	Institut CURIE	Paris
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Institut Jean Godinot	Reims
France	Centre Eugène Marquis	Rennes
France	Centre Frédéric Joliot	Rouen
France	Centre Henri Becquerel	Rouen
France	Hôpital René Huguenin - Institut Curie	Saint-Cloud
France	CHU Saint-Etienne	Saint-Étienne
France	Centre De Radiothérapie De La Robertsau	Strasbourg
France	Centre Paul Strauss	Strasbourg
France	Institut Claudius Regaud	Toulouse
France	Institut De Cancerologie De Lorraine Alexis Vautrin	Vandœuvre-lès-Nancy
France	Gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
UNICANCER	National Cancer Institute, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	5-year cumulative incidence of in-breast cancer recurrences	Incidence of breast recurrence is determined from the date of last surgery to the date of breast recurrence.	5 years
Secondary	Overall survival (OS)	OS is defined as the interval between the date of last surgery and the date of death from any cause;	10 years
Secondary	Breast cancer-specific survival (BCSS)	BCSS is defined as the interval between the date of last surgery and the date of death from breast cancer	10 years
Secondary	Relapse-free survival (RFS)	RFS is defined as the interval between the date of last surgery and the date of ipsilateral breast recurrence, regional nodes recurrence, distant metastases, of death from breast cancer, whichever occurs first	10 years
Secondary	Rate of in-breast recurrences (IBR).	In-breast recurrence defined as any carcinoma (invasive or in situ) occurring in the treated breast	10 years
Secondary	Rate of Contralateral breast	Contralateral breast cancer defined as any carcinoma (invasive or in situ) occurring in the contralateral breast.	10 years
Secondary	Quality of life of the patients using EORTC-QLQ-C 30	Quality of life will be assessed using QLQ-C 30 questionnaire from the European Organization for Research and Treatment of Cancer (EORTC). It is a 30-item self-reporting questionnaire developed to assess the quality of life of cancer patients. It is grouped into five functional subscales (role, physical, cognitive, emotional and social functioning). In addition, there are three multi-item symptom scales (fatigue, pain, and nausea and vomiting), individual questions concerning common symptoms in cancer patients,and two questions assessing overall Quality of Life	3 years
Secondary	Quality of life of the patients using EORTC-QLQ-BR23	Quality of Life of Patients will be assessed using a EORTC-QLQ BR23.It is a 23-item self-reporting specific questionnaire developed to assess the quality of life of breast cancer patients. It permits to evaluate the symptoms of breast cancer and the side effects of treatment.	3 years
Secondary	Cosmetics Evaluation	cosmetic results will be evaluated by centralized photographic analysis.	3 years
Secondary	Long term toxicities	The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders and so the late effects and sequelea regarding the whole-breast radiotherapy.	Throughout study completion, up to 10 years.