Radiotherapy Omission in Low Risk Ductal in Situ Carcinoma Breast (ROMANCE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; DCIS; Low Risk DCIS; Breast Conserving Surgery; Radiotherapy Omission
• Intervention / Treatment: Radiation: Radiotherapy; Other: No Radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Saliha GHANEM, PhD; Phone Number: +33 1 80 50 12 98; Email: s-ghanem@unicancer.fr
• Study Contact Backup: Name: Assia LAMRANI-GHAOUTI, PhD; Email: a-lamrani-ghaouti@unicancer.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • Institut de Cancérologie de l'Ouest -Site Paul Papin
    • Contact: Aurore GOINEAU, MD
  • Avignon, France
    • Recruiting
    • Institut Sainte Catherine
    • Contact: Antoine ARNAUD, MD
  • Bayonne, France
    • Recruiting
    • Clinique Belharra
    • Contact: Raphaël GAUZERE, MD
  • Bayonne, France
    • Active, not recruiting
    • Centre d'oncologie et de radiothérapie du Pays Basque
  • Bordeaux, France
    • Recruiting
    • Institut Bergonie
    • Contact: Adeline PETIT, MD
  • Caen, France
    • Recruiting
    • Centre Francois Baclesse
    • Contact: Julien GEFFRELOT, MD
  • Cherbourg, France
    • Recruiting
    • Centre Hospitalier du Cotentin
    • Contact: Laure KALUZINSKI, MD
  • Clermont-Ferrand, France
    • Recruiting
    • Centre Jean Perrin
    • Contact: Aurélie BELLIERE, MD
  • Créteil, France
    • Not yet recruiting
    • Hôpital Henri Mondor
    • Contact: Yazid BELKACEMI, MD
  • Créteil, France
    • Active, not recruiting
    • CHIC Créteil
  • Dijon, France
    • Recruiting
    • Centre Georges François Leclerc
    • Contact: Karine PEIGNAUX, MD
  • Jossigny, France
    • Active, not recruiting
    • Centre Hospitalier De Lagny Sur Marne
  • La Réunion, France
    • Recruiting
    • CHU Saint-Pierre La Réunion
    • Contact: Shakeel SUMODHEE
  • Le Havre, France
    • Active, not recruiting
    • Centre Guillaume Le Conquerant
  • Lille, France
    • Recruiting
    • Centre OSCAR LAMBRET
    • Contact: David Pasquier, MD
  • Limoges, France
    • Recruiting
    • CHU de Limoges - Hôpital Dupuytren
    • Contact: Pierre CLAVERE, MD
  • Lorient, France
    • Recruiting
    • Centre Hospitalier Bretagne Sud
    • Contact: Guillaume BERA, MD
  • Lyon, France
    • Recruiting
    • Centre LEON BERARD
    • Contact: Jessica SERRAND, MD
  • Lyon, France
    • Recruiting
    • Hôpital La Croix Rousse
    • Contact: Marion CORTET, MD
  • Lyon, France
    • Not yet recruiting
    • Centre de Radiothérapie Mermoz
    • Contact: Séna YOSSI
  • Montpellier, France
    • Recruiting
    • Institut Regional Du Cancer Montpellier Val D Aurelle
    • Contact: Claire LEMANSKI, MD
  • Mougins, France
    • Recruiting
    • Centre Azuréen de Cancérologie
    • Contact: Philippe RONCHIN, MD
  • Nice, France
    • Recruiting
    • Centre Antoine Lacassagne
    • Contact: Marie-Eve CHAND FOUCHE, MD
  • Nice, France
    • Recruiting
    • Centre de Haute Energie
    • Contact: Nathalie PINTO, MD
  • Paris, France
    • Recruiting
    • Hopital Pitie Salpetriere
    • Contact: Philippe MAINGON, MD
  • Paris, France
    • Recruiting
    • Institut Curie
    • Contact: Alain FOURQUET, MD
  • Pierre-Bénite, France
    • Recruiting
    • Centre Hospitalier Lyon Sud
    • Contact: Pierre-Adrien BOLZE, MD
  • Reims, France
    • Recruiting
    • Institut Jean Godinot
    • Contact: Philippe GUILBERT, MD
  • Rennes, France
    • Recruiting
    • Centre Eugene Marquis
    • Contact: Isabelle LECOUILLARD, MD
  • Rouen, France
    • Recruiting
    • Centre Frédéric JOLIOT
    • Contact: Sandrine MEZZANI SAILLARD, MD
  • Rouen, France
    • Withdrawn
    • Centre Henri Becquerel
  • Saint-Cloud, France
    • Recruiting
    • Hôpital René Huguenin - Institut Curie
    • Contact: Alain FOURQUET, MD
  • Saint-Étienne, France
    • Recruiting
    • CHU Saint-Etienne
    • Contact: Omar JMOUR, MD
  • Strasbourg, France
    • Recruiting
    • Centre Paul Strauss
    • Contact: Inès MENOUX, MD
  • Strasbourg, France
    • Not yet recruiting
    • Centre De Radiothérapie De La Robertsau
    • Contact: Anne KARST PROVOT, MD
  • Toulouse, France
    • Recruiting
    • Institut Claudius Regaud
    • Contact: Ciprian CHIRA, MD
  • Vandœuvre-lès-Nancy, France
    • Recruiting
    • Institut de Cancérologie de Lorraine Alexis Vautrin
    • Contact: Claire CHARRA BRUNAUD, MD
  • Villejuif, France
    • Recruiting
    • Gustave Roussy
    • Contact: Sofia RIVERA, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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,

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	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
Experimental: No Radiotherapy; No Irradiation- Active surveillance	Other: No Radiotherapy; No Irradiation- Active surveillance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Rate of in-breast recurrences (IBR).	In-breast recurrence defined as any carcinoma (invasive or in situ) occurring in the treated breast	10 years
Rate of Contralateral breast	Contralateral breast cancer defined as any carcinoma (invasive or in situ) occurring in the contralateral breast.	10 years
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
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
Cosmetics Evaluation	cosmetic results will be evaluated by centralized photographic analysis.	3 years
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.

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: National Cancer Institute, France
• Investigators: Principal Investigator: Alain FOURQUET, MD, Institut Curie

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2019
• Primary Completion (Estimated): November 10, 2029
• Study Completion (Estimated): November 10, 2034

Study Registration Dates

• First Submitted: March 14, 2019
• First Submitted That Met QC Criteria: March 14, 2019
• First Posted (Actual): March 18, 2019

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma
• Other Study ID Numbers: UC-0107/1803

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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