E. Groen

Finding the balance between over- and under-treatment of ductal carcinoma in situ (DCIS)

With the widespread adoption of population-based breast cancer screening, ductal carcinoma in situ (DCIS) has come to represent 20-25% of all breast neoplastic lesions diagnosed. Current treatment aims at preventing invasive breast cancer, but the majority of DCIS lesions will never progress to invasive disease. Still, DCIS is treated by surgical excision, followed by radiotherapy as part of breast conserving treatment, and/or endocrine therapy. This implies over-treatment of the majority of DCIS, as less than 1% of DCIS patients will go on to develop invasive breast cancer annually. If we are able to identify which DCIS is likely to progress or recur as invasive breast cancer and which DCIS would remain indolent, we can treat the first group intensively, while sparing the second group from such unnecessary treatment (surgery, radiotherapy, endocrine therapy) preserving the quality of life of these women. This review summarizes our current knowledge on DCIS and the risks involved regarding progression into invasive breast cancer. It also shows current knowledge gaps, areas where profound research is highly necessary for women with DCIS to prevent their over-treatment in case of a harmless DCIS, but provide optimal treatment for potentially hazardous DCIS.

The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: A comparison with the radioguided occult lesion localization with 99m technetium

BACKGROUNDnRadioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL.nnnMETHODSnWe retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen.nnnRESULTSnPre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21).nnnCONCLUSIONnMargin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy.

Clinicopathological Risk Factors for an Invasive Breast Cancer Recurrence after Ductal Carcinoma In Situ—A Nested Case–Control Study

Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case–control study. Experimental Design: We conducted a case–control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (N = 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0–15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS. Results: High COX-2 protein expression showed the strongest association with subsequent iIBC [OR = 2.97; 95% confidence interval (95% CI), 1.72–5.10]. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05–2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01–2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2−/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years. Conclusions: With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS. Clin Cancer Res; 24(15); 3593–601. ©2018 AACR.

Breast conserving surgery for extensive DCIS using multiple radioactive seeds

BACKGROUND AND OBJECTIVESnBreast conserving surgery (BCS) can be challenging for large regions of ductal carcinoma in situ (DCIS), resulting in high rates of positive resection margins. Radioactive seed localization (RSL) using multiple radioactive iodine (125I) seeds can be used to bracket extensive DCIS (eDCIS). The goal of this study was to retrospectively compare the use of a single or multiple 125I seeds in RSL to enable BCS in patients with eDCIS.nnnMETHODSnAll patients with eDCIS (area of ≥3.0xa0cm) who underwent either single or multiple-seed RSL between January 2008 and December 2016 were included. Patient, tumor and surgery characteristics were compared between both groups. Primary outcome measures were positive resection margin and re-operation rates.nnnRESULTSnRespectively 48 and 58 patients with eDCIS underwent single- and multiple-seed RSL and subsequent BCS. The rate of positive resection margin (focal and more than focal) with single-seed RSL was 47.9%, compared to 29.3% with multiple-seed RSL (pxa0=xa00.06). Thexa0re-operation rate was 39.6% with single-seed RSL and 20.7% in the multiple-seed RSL group (pxa0=xa00.05).nnnCONCLUSIONnMultiple-seed RSL enables bracketing of large areas of DCIS, with the potential to decrease the high rate of positive resection margins in this patient group.

Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure

BackgroundAxillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positronxa0emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy.MethodsAll breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node.ResultsThe data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment.ConclusionCombining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cNu2009+u2009breast cancer patients.

Abstract 4738: Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis

INTRODUCTION. The wide spread adoption of population-based breast cancer screening has led to a substantial increase in diagnosis of ductal carcinoma in situ (DCIS). When detected, almost all DCIS is treated to prevent progression to invasive disease, even though the majority of DCIS will never progress. Yet, we are unable to discriminate harmless from potentially hazardous DCIS. Hence, there is an urgent need to find characteristics of DCIS and biomarkers that predict subsequent invasive tumor development. In this study, we compared primary DCIS lesions with their subsequent ipsilateral invasive breast cancer (iIBC), to explore how the initial DCIS lesion and its subsequent iIBC are related. PATIENTS AND METHODS. We used a population-based, nation-wide cohort consisting of 2,654 women who were treated for primary DCIS by breast conserving surgery (BCS) only. Within a median follow-up time of 10.7 years, 316 women developed a subsequent iIBC (12%). FFPE tissue blocks of both DCIS and subsequent iIBC could be collected for 158 of these 316 women. We assessed histology characteristics, tumor location, estrogen and progesterone receptor status, p16 expression, and HER2 and p53 overexpression. Additionally, DNA and RNA were simultaneously isolated from 100 DCIS and 100 matched subsequent iIBC specimens for extensive molecular profiling. RESULTS. More than 95% of the invasive recurrences were located at or near the site of the primary DCIS. Concordant histological grade was found in 94% of the matched pairs and identical immunohistochemical (IHC) marker expression in 58%. Of the 44 patients with HER2 positive DCIS, 36% developed HER2 negative iIBC. Furthermore, this change in HER2 status was also a main cause of a change in surrogate intrinsic subtype (based on ER, PR, HER2) between DCIS and iIBC, which was observed in 16% of the patients. These dissimilarities were not found when we compared invasive disease with synchronous DCIS (present in 83 of 158 patients). Molecular analyses is still ongoing. CONCLUSION. This is the first time that an unbiased comparison could be made between primary DCIS and its subsequent iIBC within such a large patient group, integrating clinical, histological and IHC data. Our results suggest that the majority of invasive breast cancers in our cohort reflect outgrowth of residual disease based on tumor location and histological grade. DCIS and iIBC are very similar when comparing histological grade, but frequently show differences on the IHC level. Remarkably, the dissimilarities in HER2 status and surrogate intrinsic subtype as seen in primary DCIS vs. iIBC are missing when comparing IBC with synchronous DCIS. As a next step, we will analyse the lesions on the molecular level, to verify these findings and to look for molecular characteristics of DCIS that could be associated with progression to invasive disease. Citation Format: Lindy L. Visser, Lotte L. Elshof, Koen van de Vijver, Emma J. Groen, Mathilde Almekinders, Marjanka K. Schmidt, Flora van Leeuwen, Emiel J. Rutgers, Michael Schaapveld, Esther H. Lips, Jelle Wesseling. Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2017-4738

Abstract P2-01-07: Selective elimination of axillary surgery after primary systemic treatment in clinically node-positive breast cancer patients by combining PET/CT and the MARI procedure (marking the axilla with radioactive iodine seeds)

Background The increasing use of primary systemic treatment (PST) for patients with breast cancer enables more breast conserving surgery. In addition, PST converts node-positive into node-negative disease in 20-40% of patients. However, the current guidelines still recommend axillary lymph node dissection (ALND) for clinical node-positive disease (cN+), even if it became node-negative after PST, since false-negative rates of sentinel lymph node biopsy after PST range from 5-30%. Recently, an alternative technique has been introduced to stage the axilla after PST: the MARI-procedure (sensitivity 97%; FNR 7%), in which a tumour-positive lymph node is marked with a radioactive iodine seed before the start of PST and selectively removed after PST. In the present study, we propose a new strategy for treatment of the axilla in cN+ patients by combining results of the pre-PST PET/CT with the post-PST MARI-procedure. Material and methods All patients who received a MARI-procedure from July 2014 until May 2016 were included. Before the start of PST a PET/CT was performed for axillary staging and the detection of distant metastasis. A radioactive iodine seed was placed in a proven tumour-positive axillary lymph node (MARI-node), after which PST was given according to Dutch national guidelines. At our institute, we have implemented a protocol in which results of the pre-PST PET/CT and the post-PST MARI-procedure determine the type of axillary treatment. Patients with 1-3 positive axillary lymph nodes (ALNs) on PET/CT and a tumour-negative MARI-node receive no further axillary treatment. Patients with ≤3 positive ALNs on PET/CT and a tumour-positive MARI-node receive axillary radiotherapy, as well as patients with >3 positive ALNs on PET/CT and a tumour-negative MARI-node. An ALND is only performed in patients with >3 positive ALNs on PET/CT and a tumour-positive MARI-node. Results In total 168 patients received a PET/CT and a MARI procedure, of whom 43% were hormone receptor positive, 28% triple negative and 29% Her2-positive. One hundred and eight patients (64%) showed ≤ 3 and 60 patients (36%) >3 suspected ALNs on PET/CT before the start of PST. The axillary pathologic complete response was 39%. In 134 patients (80%) an ALND was omitted; of these patients 94 (56%) were treated with axillary radiotherapy and 40 patients (24%) received no further axillary treatment. In 34 patients (20%) an ALND was performed (Table 1). The median number of positive additional nodes at ALND was 5 (range 0-16). During a median follow-up of 6 months there were no local recurrences. Conclusion Combining pre-PST axillary staging with PET/CT and post-PST staging with use of the MARI-procedure results in a reduction of 80% of axillary lymph node dissections in breast cancer patients with clinical node-positive disease. Citation Format: van der Noordaa MEM, Straver M, van Duijnhoven FH, Groen E, Stokkel M, Vrancken Peeters M-JTFD. Selective elimination of axillary surgery after primary systemic treatment in clinically node-positive breast cancer patients by combining PET/CT and the MARI procedure (marking the axilla with radioactive iodine seeds) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-07.

Abstract P5-17-09: Biomarkers to distinguish hazardous from harmless ductal carcinoma in situ (DCIS) of the breast

Background . The incidence of DCIS has increased since the introduction of population-based screening. This has not resulted in a decrease in invasive breast cancer incidence, implying overdiagnosis exists. All women with DCIS are still intensively treated, by surgery, radiotherapy, and/or hormonal treatment, although only a minority will develop a subsequent invasive breast cancer. As we cannot discriminate such hazardous from harmless DCIS lesions, accurate prognostic biomarkers are urgently needed. In the current study we aim to identify molecular markers for DCIS aggressiveness, using a large population-based cohort. Patients and methods . We used a population-based, nation-wide cohort consisting of 10,090 women treated for primary DCIS between 1989 and 2004 with a median follow-up time of 10.7 years. Within this cohort, a case-control study was set up to analyse which markers are associated with progression to invasive breast cancer. Formalin-fixed paraffin embedded (FFPE) tissue blocks were retrieved from 1580 DCIS patients who were treated by breast conserving surgery without radiotherapy (316 DCIS patients with a subsequent ipsilateral invasive breast cancer (iiBC): i.e. the cases; and 1264 DCIS patients without subsequent invasive breast cancer: i.e. the controls). A first study using this population-based cohort will involve immunohistochemistry (IHC) on 200 cases and 500 controls for an 8-marker IHC panel (ER, PR, HER2, Ki67, p16, p53, COX-2, and Annexin A1). Molecular subtypes of the DCIS and invasive breast cancer lesions will be determined and intra-individual heterogeneity will be assessed. IHC marker expression will be both compared between cases and controls as well as between DCIS lesions and its subsequent invasive breast cancer. In a second study, DNA and RNA will be isolated from these specimens, using laser microdissection, and extensive molecular profiling will be performed. Results . We have collected FFPE tissue blocks of 287 cases and 1149 controls (86% of requested material) from 56 participating hospitals. At present, the specimens of 223 cases (matched DCIS and iiBC specimen) and 103 controls have been centrally revised for extensive morphological characteristics. Only a small part (14%) of the specimens had to be excluded from the study population. IHC staining of the tissue specimens, using the 8-marker IHC panel is ongoing. Conclusion . Within a nation-wide cohort of 10,090 patients diagnosed with primary DCIS, we were able to collect tissue material of a representative case-control series of 200 cases with subsequent invasive breast cancer and 500 invasive breast cancer-free controls. This is the first time such a large unique, unbiased DCIS series, with long-term follow-up is analysed integrating clinical, histological, and immunohistochemical data. The results will be presented at SABCS 2015. Citation Format: Visser L, Elshof L, Groen E, van de Vijver K, Lips E, de Maaker M, Nieboer F, Schaapveld M, Rutgers E, Wesseling J. Biomarkers to distinguish hazardous from harmless ductal carcinoma in situ (DCIS) of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-17-09.