Clinical trial NCT03878342: Radiotherapy Omission in Low Risk Ductal in Situ Carcinoma Breast
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: DCIS
Breast Cancer
Low Risk DCIS
Breast Conserving Surgery
Radiotherapy Omission
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: The French National Cancer Institute
First posted: 2019-03-18
Enrollment: 295
Sex: FEMALE
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.


Eligibility criteria: 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,

Primary outcomes:
measure: 5-year cumulative incidence of in-breast cancer recurrences
timeFrame: 5 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 10 years
measure: Breast cancer-specific survival (BCSS)
timeFrame: 10 years
measure: Relapse-free survival (RFS)
timeFrame: 10 years
measure: Rate of in-breast recurrences (IBR).
timeFrame: 10 years
measure: Rate of Contralateral breast
timeFrame: 10 years
measure: Quality of life of the patients using EORTC-QLQ-C 30
timeFrame: 3 years
measure: Quality of life of the patients using EORTC-QLQ-BR23
timeFrame: 3 years
measure: Cosmetics Evaluation
timeFrame: 3 years
measure: Long term toxicities
timeFrame: Throughout study completion, up to 10 years.
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest -Site Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bayonne
country: France
facility: Centre d'Oncologie et de Radiothérapie du Pays Basque
city: Bayonne
country: France
facility: Clinique Belharra
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre Francois Baclesse
city: Cherbourg
country: France
facility: Centre Hospitalier du Cotentin
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: CHIC Créteil
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Jossigny
country: France
facility: Centre Hospitalier De Lagny Sur Marne
city: La Réunion
country: France
facility: CHU Saint-Pierre La Réunion
city: Le Havre
country: France
facility: Centre Guillaume le Conquérant
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Chu De Limoges - Hopital Dupuytren
city: Lorient
country: France
facility: Centre Hospitalier Bretagne Sud
city: Lyon
country: France
facility: Centre de Radiothérapie Mermoz
city: Lyon
country: France
facility: Centre Léon Berard
city: Lyon
country: France
facility: Hôpital La Croix Rousse
city: Montpellier
country: France
facility: Institut Regional Du Cancer Montpellier Val D Aurelle
city: Mougins
country: France
facility: Centre Azuréen De Cancérologie
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nice
country: France
facility: Centre de Haute Energie
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Paris
country: France
facility: Institut CURIE
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Centre Frédéric Joliot
city: Saint-Cloud
country: France
facility: Hôpital René Huguenin - Institut Curie
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
city: Strasbourg
country: France
facility: Centre De Radiothérapie De La Robertsau
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandœuvre-lès-Nancy
country: France
facility: Institut De Cancerologie De Lorraine Alexis Vautrin
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Institut Curie
name: Alain FOURQUET, MD
role: PRINCIPAL_INVESTIGATOR
References: