Lotte E. Elshof

Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ - The LORD study

BACKGROUND The current debate on overdiagnosis and overtreatment of screen-detected ductal carcinoma in situ (DCIS) urges the need for prospective studies to address this issue. A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns non- to slow-growing low-grade DCIS. The LORD study aims to evaluate the safety of active surveillance in women with low-risk DCIS. DESIGN This is a randomised, international multicentre, open-label, phase III non-inferiority trial, led by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organization for Research and Treatment of Cancer (EORTC-BCG 1401). Standard treatment will be compared to active surveillance in 1240 women aged ⩾ 45 years with asymptomatic, screen-detected, pure low-grade DCIS based on vacuum-assisted biopsies of microcalcifications only. Both study arms will be monitored with annual digital mammography for a period of 10 years. The primary end-point is 10-year ipsilateral invasive breast cancer free percentage. Secondary end-points include patient reported outcomes, diagnostic biopsy rate during follow-up, ipsilateral mastectomy rate and translational research. FEASIBILITY To explore interest in and feasibility of the LORD study we conducted a survey among EORTC and BOOG centres. A vast majority of EORTC and BOOG responding centres expressed interest in participation in the LORD study. The proposed study design is endorsed by nearly all centres.

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.

Does the pretreatment tumor sampling location correspond with metabolic activity on 18F-FDG PET/CT in breast cancer patients scheduled for neoadjuvant chemotherapy?

PURPOSE To define the correlation between the core biopsy location and the area with highest metabolic activity on 18F-FDG PET/CT in stage II-III breast cancer patients before neoadjuvant chemotherapy. Also, we would like to select a subgroup of patients in which PET/CT information may optimize tumor sampling. METHODS A PET/CT in prone position was acquired in 199 patients with 203 tumors. The distance and relative difference in standardized uptake value (SUV) between core biopsy localization (indicated by a marker) and area with highest degree of FDG uptake were evaluated. A distance ≥ 2 cm and a relative difference in SUV ≥ 25% were considered clinically relevant and a combination of both was defined as non-correspondence. Non-correspondence for different tumor characteristics (TNM stage, lesion morphology on MRI and PET/CT, histology, subtype, grade, and Ki-67) was assessed. RESULTS Non-correspondence was found in 28 (14%) of 203 tumors. Non-correspondence was significantly associated with T-stage, lesion morphology on MRI and PET/CT, tumor diameter, and histologic type. It was more often seen in tumors with a higher T-stage (p = 0.028), diffuse (non-mass) and multifocal tumors on MRI (p = 0.001), diffuse and multifocal tumors on PET/CT (p<0.001), tumors >3 cm (p<0.001), and lobular carcinomas (p<0.001). No association was found with other features. CONCLUSION Non-correspondence between the core biopsy location and area with highest FDG uptake is regularly seen in stage II-III breast cancer patients. PET/CT information and possibly FDG-guided biopsies are most likely to improve pretreatment tumor sampling in tumors >3 cm, lobular carcinomas, and diffuse and multifocal tumors.

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.

PO-070 Identification of risk factors for subsequent invasive breast cancer after primary DCIS by transcriptomic profiling

Introduction Ductal carcinoma in situ (DCIS) is a pre-invasive breast lesion, frequently detected by breast cancer screening, with thousands of new cases each year. While DCIS is not life threatening, it does increase a women’s risk of developing invasive breast cancer; this in turn can lead to breast-cancer specific mortality. Therefore, almost all DCIS lesions are treated to prevent progression to invasive disease. However, many DCIS lesion will never develop into invasive breast cancer if left untreated, indicating that many women are overtreated. In this study, we performed RNA sequencing (RNAseq) on a large set of primary DCIS lesions, comparing lesions with a subsequent invasive breast cancer recurrence (IBCR) to those without, to identify factors distinguishing harmless from potentially hazardous DCIS. Material and methods We made use of a DCIS case-control series, nested in a nation-wide population-based cohort of Dutch women diagnosed with primary DCIS and treated with breast conserving surgery alone (standard clinical practice) between 1989–2005. Mean follow up time was 12.0 years. RNA was extracted from FFPE laser-microdissected tissue fragments of 183 primary DCIS lesions: 100 associated with subsequent IBCR and 83 which remained free of invasive recurrence. RNAseq was performed to identify differentially expressed genes between DCIS with and without IBCR. Subsequently, gene set enrichment analysis (GSEA) was performed. Finally, findings were correlated with patients’ clinical and histopathological characteristics. Results and discussions DCIS lesions were categorised into PAM50 intrinsic subtypes: Luminal A 25%, Luminal B 38%, Her2 22%, Basal 10%, Normal 5%. Within each PAM50 subtype, 1 to 64 genes were statistically significant (p<0.05) differentially expressed between DCIS lesions with and without IBCR. GSEA revealed these genes were enriched in immune-related pathways. In Luminal A DCIS the pathways interferon alpha response and interferon gamma response and were associated with subsequent IBCR. Correlation of these findings with clinical and histopathological characteristics is ongoing. Conclusion To our knowledge, we performed the first large-scale transcriptome analysis of primary DCIS lesions with and without subsequent IBCR and long-term follow-up. Our data suggest that immune-related pathways are involved in DCIS progression. The results of our study add to the current understanding of DCIS and to risk stratification of DCIS in the near future.

Abstract CT137: Standard therapy versus active surveillance for low grade DCIS: the LORD trial

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-grade DCIS can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be low-grade 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-grade DCIS patients from intensive treatment. We will compare active surveillance with conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy for primary low-grade DCIS, detected by calcifications only, in a phase III, open-label, non-inferiority, multi-center, randomized clinical trial legally supported by the Breast Cancer Group of the European Organisation for the Research and Treatment of Cancer (EORTC-1401-BCG). The Dutch Centers are coordinated by the BOOG Study Center (BOOG 2014-04). Randomization will be 1:1 in to one of the following arms: active surveillance or standard treatment per local policy. In total, 1240 women (≥ 45 years) with asymptomatic, pure, low-grade DCIS, based on vacuum-assisted biopsies of calcifications as detected by population-based or opportunistic screening, without prior breast cancer, will be included. Assuming 25% of randomized women qualified to enroll in the study will drop out or will be excluded from per protocol population, at least 1,240 women need to be randomized to obtain the 930 patients required for the evaluation of the primary endpoint. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of 10 years. 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. Accrual has started in January 2017. Acknowledgements: This trial is funded by Pink Ribbon Netherlands, the Dutch Cancer Society and Dutch Cancer Society/Alpe d’HuZes. Citation Format: Jelle Wesseling, Frederieke van Duijnhoven, Konstantinos Tryfonidis, Aleksandra Peric, Elise van Leeuwen-Stok, Nina Bijker, Lotte Elshof, Emiel Rutgers. Standard therapy versus active surveillance for low grade DCIS: the LORD trial [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 CT137. doi:10.1158/1538-7445.AM2017-CT137

Abstract P5-16-02: Risk of subsequent ipsilateral invasive breast cancer after a primary diagnosis of ductal carcinoma in situ

Background Since the introduction of population-based mammography screening the incidence of ductal carcinoma in situ of the breast (DCIS) has increased dramatically and concerns about overdiagnosis and overtreatment have been raised. DCIS is considered to be a precursor lesion of most invasive breast cancer, but the challenge remains to distinguish the progressive from the clinically indolent, i.e. harmless lesions. Therefore, we aim to assess the risk of developing a subsequent ipsilateral invasive breast cancer after a first cancer diagnosis of primary DCIS in a large cohort as a first step to solve this clinical dilemma. Methods We conducted a retrospective study using a nationwide cohort comprising 12,721 women with a first cancer diagnosis of breast carcinoma in situ in the Netherlands between 1 January 1989 and 31 December 2004 and follow-up data up to 31 December 2010, extracted from the Netherlands Cancer Registry (NCR). Women who had bilateral breast disease, a diagnosis other than pure DCIS, and patients who received chemo- or hormonal therapy for their DCIS were excluded, as well as patients who had any other previous cancer diagnosis except for non-melanoma skin carcinoma. Using data from NCR and PALGA, the Dutch Pathology Registry, information about treatment and outcomes was collected and analysed. Outcome was defined as a subsequent ipsilateral invasive breast cancer as first invasive recurrence. Women who had a contralateral invasive breast cancer first, were censored at this diagnosis date. Invasive recurrence rates were compared by age and treatment groups using Cox regression. Women were divided into three age groups: women who were within the age group eligible for participation in the Dutch screening programme, and women who were either younger or older. Results A total number of 10,276 women with pure DCIS were included. After a median follow-up of 11.6 years, 520 first ipsilateral invasive recurrences were identified. Preliminary results show that approximately half of the women were treated with breast-conserving surgery (BCS), and the other half underwent a mastectomy. Of the patients who underwent BCS, about half received additional radiotherapy (RT). The age-adjusted hazard ratio for ipsilateral invasive breast cancer in BCS only versus BCS + RT was 2.49 (95% CI: 1.99 – 3.12) and in mastectomy versus BCS + RT 0.32 (95% CI: 0.24 - 0.43). After adjusting for treatment, risk of subsequent ipsilateral invasive breast cancer was higher for women who were younger than the invitation age range for screening when diagnosed compared to women within the age group eligible for the Dutch screening programme (HR = 1.86; 95% CI: 1.51 – 2.29). Conclusion This unique nationwide DCIS cohort shows that young women and women treated with BCS only have an increased risk of developing a subsequent ipsilateral invasive breast cancer after a first cancer diagnosis of primary DCIS. Using this cohort with a large number of women with subsequent ipsilateral invasive breast cancer, we will subsequently evaluate the concordance of features of the primary DCIS and the subsequent invasive breast cancer, and the association of characteristics of the DCIS with the risk of developing invasive ipsilateral breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-02.