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

Study Overview
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Brief Summary
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A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing low-risk DCIS (grade I and II). This implies that many women might be unnecessarily going through intensive treatment resulting in a decrease in quality of life and an increase in health care costs, without any survival benefit. The LORD (LOw Risk DCIS) study is a non-randomized, international, multicenter, phase III non-inferiority trial, and aims to determine whether screen-detected low-risk DCIS can safely be managed by an active surveillance strategy or that the conventional treatment, being either WLE alone, WLE + RT, or mastectomy, and possibly HT, should remain the standard of care.

Detailed Description
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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.

Official Title
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Management of Low Risk Ductal Carcinoma in Situ (Low-risk DCIS): a Non-randomized, Multicenter, Non-inferiority Trial, Between Standard Therapy Approach Versus Active Surveillance

Conditions
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DCIS

Intervention / Treatment
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* Other: Standard treatment
* Device: digital mammography
* Radiation: radiotherapy


Participation Criteria
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Eligibility Criteria
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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 or 2 (see Appendix E) 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: <20% 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

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard treatment<br>Standard treatment according to local policy. This can be either wide local excision only, wide local excision and radiotherapy, or mastectomy. Hormonal therapy is also allowed. Follow-up:by annual digital mammography for a period of 5 years and a digital mammography at 7 and 10 years. | Other: Standard treatment<br>* wide local excision only or wide local excision and radiotherapy or mastectomy. +/- hormonal therapy<br>Radiation: radiotherapy<br>* according local policy<br>|
| Experimental: Active surveillance<br>Active surveillance : monitoring by annual digital mammography for a period of 5 years and a digital mammography at 7 and 10 years. | Device: digital mammography<br>* annual mammography<br>* Other names: Active surveillance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ipsilateral invasive breast cancer-free rate at 10 years | Ipsilateral invasive breast cancer-free rate at 10 years (both therapeutic policies | 10 years from inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ipsilateral grade III DCIS | Time to ipsilateral grade III DCIS, both therapeutic policies | from inclusion to the development of a new ipsilateral DCIS, up to 10 years | 
| Time to contralateral DCIS | Time to contralateral DCIS, both therapeutic policies | from inclusion to the development of a new contralateral DCIS, up to 10 years | 
| Time to contralateral invasive breast cancer | Time to contralateral invasive breast cancer,, both therapeutic policies | from inclusion to the development of a contralateral invasive breast cancer, up to 10 years | 
| Time to failure of active surveillance strategy | Time to failure of active surveillance strategy, i.e. time to crossover to standard treatment, due to any cause | from inclusion to the time to patients received standard treatment, up to 10 years | 
| Distant metastases free interval | Distant metastases free interval,both therapeutic policies | from inclusion to the time of invasive distant metastases or death due to breast cancer, up to 10 years | 
| Overall survival | Overall survival,both therapeutic policies | from inclusion to the time of death, during 10 years at minimum | 
| Rate of invasive disease at the final pathology specimen (standard arm only) | Rate of invasive disease at the final pathology specimen (standard arm only) | from inclusion till time of invasive disease during 10 years at minimum | 
| Rate of grade III DCIS at the final pathology specimen (standard arm only) | Rate of grade III DCIS at the final pathology specimen (standard arm only) | from inclusion till time of invasive disease during 10 years at minimum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Women, DCIS grade I and II, Active surveillance, Standard treatment