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

Background of the study:

The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-risk DCIS (grade I and II DCIS) can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be lowgrade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. It also may save many low-risk DCIS patients from intensive treatment.

Objective of the study:

The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years.

Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate and patient reported outcomes. To determine whether low- risk DCIS can safely (measured by ipsilateral invasive breast cancer rate at 10 years) be managed by an active surveillance strategy or if the conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy, will remain the standard of care.

Study design:

Phase III, open-label, non-inferiority, multi-center, non-randomized clinical trial. By patient's preference, women will be included into one of the following arms: active surveillance or standard treatment according to local policy, being either WLE alone, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of five years and an additional two mammograms at year seven and ten.

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