Ductal carcinoma in-situ (DCIS) accounts for 20–25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.

AbstractPure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

Background Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort. Methods The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models. Results The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR) age < 50 3.2 (95% CI 1.6–6.6); HR age ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HR age<50 2.1 (95% CI 1.4–3.2); HR age ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HR age < 50 0.7 (95% CI 0.3–1.5); HR age ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HR age < 50 0.6 (95% CI 0.4–0.9); HR age ≥ 50 1.2 (95% CI 0.9–1.6)). Conclusion RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

Introduction Ductal carcinoma in situ (DCIS) is considered a potential precursor lesion of invasive breast cancer and is treated to prevent the development of invasive disease. After DCIS treatment, three scenarios emerge: i) the DCIS lesion has been removed completely, ii) a remnant or new DCIS lesion will progress into invasive breast cancer, or iii) a remnant or new DCIS lesion will be diagnosed as a subsequent DCIS lesion. In the latter case a risk of developing invasive breast cancer still or again exists. Therefore, our aim was to investigate risk factors for subsequent DCIS lesions. Material and methods All patients diagnosed with DCIS between 1989 and 2004 in the Netherlands were selected by the Netherlands Cancer Registry (NCR). Pathology reports were made available by the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) with follow-up to 2016. We selected for patients treated by breast conserving surgery with or without radiotherapy, who subsequently presented with a second DCIS lesion according to the pathology report. Afterwards, we linked the datasets of NCR and PALGA to analyse clinical and pathological risk factors for subsequent DCIS lesions. Results and discussions After a median follow-up time of 13 years, 450 of 5584 (8.1%) women with primary DCIS presented with a subsequent DCIS lesion in the ipsilateral breast. The average time to a subsequent ipsilateral DCIS lesion was 4.1 years. Histological factors such as size, grade, margins and clinical factors such as age, radiotherapy yes or no, time of follow-up will be analysed. Results will be compared with the risk factors for developing invasive breast cancer after a primary diagnosis with DCIS (Elshof et al, BCRT 2016). Conclusion According to our results, the risk of a subsequent ipsilateral in situ lesion after primary DCIS is 8.1% after breast conserving surgery. Analysis of clinical variables available from the Netherlands Cancer Registry, histological variables available from the pathology reports, and comparison with risk factors for developing invasive disease is ongoing. Molecular analysis of subsequent in situ lesions will be performed as a follow-up project.