Management of Low-risk (Grade I and II) DCIS

Inclusion criteria

• Written informed consent according to ICH GCP, and national andlocal regulations

• Women ≥ 45 years old, any menopausal status

• Unilateral DCIS grade I or II of any size

• American Society of Anesthesiologists (ASA) score 1-2 or 3, only if able to undergo surgery and yearly mammography

• Lesions of type 'calcifications only', detected by population-based or opportunistic screening mammography

• Within twelve weeks of detection, stereotactic biopsy has to be performed from the area of the calcifications. Preferably vacuum assisted biopsies. Alternatively, at least six 12 G needle biopsies (or the equivalent of six 12 G needles) may be used. ) . Whatever needle size is applied, it is essential to confirm that the biopsies contain representative calcifications via biopsy radiography, microscopy, or both.

• Estrogen receptor ≥ 80% positive and HER2 negative: 0 or 1+ or 2+ with negative ISH), analysed centrally by pathology at NKI-AVL

• In case of an extended lesion (> 5 cm): biopsies were taken from the center and the periphery of the lesion, or from two peripheral parts of the lesion

• In case of multiple lesions with calcifications biopsies have been taken from two, but not more, groups of calcifications

• Marker placement at biopsy site (s) in the breast

• FFPE tissue blocks from the biopsy and, if applicable, from the resection specimen, are available for translational research purposes. If no FFPE tissue blocks can be submitted, 10 unstained slides of 4-5 micrometer thickness from the lesion(s) are acceptable

• Good correlation between pathological and radiological findings i.e. both findings confirm low-risk DCIS and no suspicion of high- grade DCIS or invasive breast cancer

• The interval between histologic diagnosis of low-risk DCIS on biopsy and inclusion is ≤ 12 weeks

Exclusion criteria

• Estrogen receptor negative: <80% or HER2 positive: 3+, or 2+ with positive ISH

• Presence of either mass, increased focal density or architectural distortion around the calcifications on mammography (suspicious for invasive disease)

• Presence of Paget's disease, invasive breast cancer, or pleomorphic LCIS; Lobular neoplasia, referring to atypical lobular hyperplasia (ALH) and/or classic Lobular Carcinoma In Situ according to the WHO Classification of Tumours of the Breast, is no reason to exclude, whereas pleomorphic LCIS is

• Symptomatic DCIS e.g. DCIS detected by palpation or bloody nipple discharge

• Synchronous invasive carcinoma in the contralateral breast

• Prior history of invasive breast cancer or DCIS, prior surgery because of benign breast lesion (s) is allowed

• Prior history of other malignancy (except non-melanoma skin cancer and carcinoma in situ of the cervix) unless patient is discharged from follow-up for at least five years.

• Serious disease that precludes definitive surgical treatment (e.g cardiovascular/ pulmonary/ renal disease)

• Individual with a family member with a known gene mutation associated with increased risk of breast cancer, unless study participant is a proven non-carrier of mutation

• Pregnancy or breast-feeding. Contraceptive measures during the trial are mandatory for those patients that will participate in standard treatment arm and adequate counseling should be provided by the treating physician. The duration of contraception will be specified by the treating physician according to patient and treatment characteristics, standard clinical practice and national regulations

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial