We thank Van Bockstal et al.1 for their important focus on one of the many observations of our paper;2 that the risk of subsequent invasive carcinoma increased over time and certainly beyond the first 5 years of follow-up, whereas DCIS recurrence risk plateaued after 5 years. We agree that the length of the follow-up impacts on the ratio of subsequent DCIS to invasive events; studies with shorter follow-up report an almost equal proportion of DCIS to invasive lesions whereas higher proportions of invasive carcinomas are seen in the (fewer) studies with long follow-up. It is thus important that studies not only require sufficient length of follow-up to be clinically and biologically meaningful but that they should report separately the median time to recurrent DCIS versus invasive recurrence, as suggested by Van Bockstal et al.
Differentiation between short-term (<5 years) versus long-term (>5 years) recurrence risk has implications for clinical patterns of follow-up of patients, as well as patient outcome. The hypothesis that most lesions developing in the first 5 years after diagnosis are more likely to be true recurrence of the primary DCIS is important, potentially arising from overtly incompletely excised DCIS or from nearby cells with the same genetic changes but without yet the same cytomorphological features. In our cohort, events that arose within the first 6 months of DCIS diagnosis were excluded, as these were deemed to be representative of incomplete excision. We are, however, undertaking research on a sub-set of patient- and disease-matched recurrent and non-recurrent DCIS cases within the Sloane Project to decipher the molecular profile of the primary DCIS and its paired ipsilateral DCIS and/or invasive recurrence and to determine if the primary and subsequent lesions are clonally and genetically related. To date, Shah et al. have presented analysis of primary DCIS from 40 patients and their subsequent recurrences to assess clonal relatedness by copy number analysis and targeted sequencing. The vast majority (11/12) of DCIS and most invasive carcinoma 16/24 that developed during the first 5 years (mean follow-up 5.2 years) were clonally related to the primary DCIS.3 If Van Bockstal et al.’s hypothesis is correct; the analysis of samples recurring after longer follow-up should reveal a smaller proportion of clonally related lesions. It is, conversely, plausible that some invasive carcinomas simply develop over a longer period necessary for them to acquire further molecular alterations that enable invasion.
Our data showed no significant difference in the time to ipsilateral recurrence (in situ or invasive) by primary DCIS grade. This is also supportive of the concept of later invasive ‘recurrences’ actually being new primary lesions; one would anticipate the high grade invasive carcinomas that typically arise from high grade DCIS presenting sooner, with low grade invasive disease arising more slowly from low grade DCIS over many more years.4 We found a higher concordance of the grade of primary compared with recurrent DCIS than with the invasive grade, although we have been unable to compare cytonuclear grade of DCIS with the equivalent nuclear ‘pleomorphism’ score component of invasive grade, as this is not collected in the Sloane database.
The relevance of subsequent contralateral events is also intriguing. While these would logically be interpreted as independent of the primary DCIS lesion, Stout et al.5 from SEER data proposed that oestrogen receptor (ER) positive DCIS may represent a field-effect; contralateral events may therefore also be relevant. Of 46,007 DCIS cases with known ER status, and median follow-up of 14 years 2 months, 2347 patients developed contralateral invasive breast cancer versus 1119 DCIS. In a multivariate model, 5.3% of women with ER positive DCIS would develop a contralateral breast event compared to 3.3% in the ER negative group. It thus seems that not only should one consider time to recurrence of ipsilateral DCIS versus invasive disease and the factors which are prognostically important in these two situations, but also, potentially, the time to contralateral breast malignancy.
For these detailed analyses, from our Sloane Project experience, it is clear that high quality, comprehensive and verified data is essential. Obtaining this is not without its challenges and requires the collaboration, willingness and continued input of the multidisciplinary teams. The Sloane Project team is in the process of updating the outcome data of all DCIS patients and the primary DCIS and subsequent DCIS and invasive carcinoma tissue collection is being expanded for extensive molecular analysis. This will shed further light on the relationship between those lesions, including in relation to the time for development of subsequent events.
Van Bockstal, M. R. Libbrecht, L. Galanta, C. Comment on: Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project. Br. J. Cancer.
Shaaban, A. M., Hilton, B., Clements, K., Provenzano, E., Cheung, S., Wallis, M. G. et al. Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project. Br. J. Cancer. https://doi.org/10.1038/s41416-020-01152-5 (2020).
Shah, V., Megalios, A., Shami, R., Sridharan, M., Salinas de Souza, C., Kumar, T. et al. Genomic analysis of paired DCIS and subsequent recurrence to assess clonal relatedness in screen detected DCIS [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium. 2019; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-04.
Sanders, M. E., Schuyler, P. A., Dupont, W. D. & Page, D. L. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer 103, 2481–2484 (2005).
Stout, N. K., Cronin, A. M., Uno, H., Ozanne, E. M., Hassett, M. J., Frank, E. S. et al. Estrogen-receptor status and risk of contralateral breast cancer following DCIS. Breast Cancer Res. Treatment 171, 777–781 (2018).
The Sloane Project uses data provided by patients and collected by the UK NHS BSP as part of their care and support. We thank all patients and all breast units who have participated in the Sloane Project Audit.
Ethical approval and consent to participate
Ethics Committee approval was not required for this study, originally conducted under the NHS Cancer Screening Programme’s application to the Patient Information Advisory Group (PIAG). More recently, the study has been permitted to process personally identifiable data without consent under Regulation 5 of Statutory Instrument 2002 No. 1438: The Health Service (Control of Patient Information) Regulations 2002 (15/CAG/0207) in line with the following clause: “quality assuring screening services to ensure they are effective and safe, and that any incidents are investigated and managed appropriately”. This statutory exemption to common law permits Public Health England to process personally identifiable data for activities it is ‘responsible and accountable to the Secretary of State for Health for’, as part of its core remit for population screening.
Consent to publish
Data is held by Public Health England. Access to the Sloane Project data from external parties is governed by consultation with the Sloane Project Steering Group and application to Public Health England’s breast screening research advisory committee (RAC) and Public Health England’s office for data release (ODR). Data will subsequently only be released by Public Health England to researchers under approval and in an anonymised or depersonalised format, with a data sharing contract in place.
The authors declare no competing interests.
The Sloane Project was supported by Public Health England and, in part, by Cancer Research UK and by KWF Kankerbestrijding (ref. C38317/A24043).
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Shaaban, A.M., Hilton, B., Clements, K. et al. Reply to “Comment on: Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project”. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01281-5