Ductal carcinoma in situ (DCIS) is a premalignant disease in the breast cancer spectrum, in which cancer cells are confined within the basement membrane of the breast ductal system.1 Because of the enhanced availability of breast imaging and breast cancer awareness, the incidence of DCIS has increased over the past two decades.2 Although the incidence of invasive breast cancer has declined over the past decade, diagnoses of DCIS have continued to rise.3

Although DCIS is the earliest recognised form of breast cancer, its natural history remains largely unknown.4 5 Long-term survival studies have found that mortality of DCIS could be as low as 3% over 10 years of follow-up.6 The current gold standard treatment for DCIS is surgery, with or without radiotherapy, according to the type of surgery performed on a particular patient. To the best of our knowledge, there has been no randomised controlled trial comparing mastectomy and breast-conserving surgery in the context of DCIS treatment; however, a meta-analysis suggested that local recurrence rates were substantially lower among women treated with mastectomy.7

In recent decades, the incidence of DCIS has increased due to the widespread use of breast imaging screenings, on the basis of enhanced breast cancer awareness. As in other screening-detected disorders, there is widespread debate regarding whether DCIS is overdiagnosed and overtreated. Some clinicians have advocated a watchful-waiting strategy for DCIS, with the presumption that not all DCIS will progress to invasive cancer.8

In contrast to many developed countries, a population-based breast cancer screening programme is not available in Hong Kong. A recent study showed that DCIS is more frequently detected and treated in the private sector in Hong Kong, compared with the public health care system. Notably, DCIS is reportedly detected more frequently among patients in higher social classes due to self-initiated breast screening; more than half of these patients undergo successful treatment with breast-conserving surgery.9 Here, we present the results of long-term survival analyses based on a territory-wide breast cancer registry.

This was a retrospective analysis of a territory-wide, prospectively maintained database from the Hong Kong Cancer Registry, concerning patients diagnosed during the period from 1997 to 2006; data were censored in December 2015 for retrieval of long-term survival outcomes. The Hong Kong Cancer Registry is a population-based cancer registry managed by the Hong Kong Hospital Authority; this registry has been responsible for collecting basic demographic data, cancer site information, and cancer histology results for all patients diagnosed with cancer in all public and private medical institutions in Hong Kong since 1963. All raw data were validated by various crosschecking procedures involving the locally designed Cancer Case Audit System; they were scrutinised by multiple quality control processes, commensurate with the recommendations by the International Agency for Research on Cancer, a component of the World Health Organization. Queries and “unusual cases” were referred to a clinical oncologist for re-validation.

Institutional review board approval was not needed for this retrospective review of a breast cancer registry database. This study included all patients with DCIS who were diagnosed from 1997 to 2006. Exclusion criteria were age <30 years or ≥70 years, lobular carcinoma in situ, Paget’s disease, and co-existing invasive carcinoma (ie, diagnosed within 6 months of DCIS onset). Patients were stratified into those diagnosed from 1997 to 2001 and those diagnosed from 2002 to 2006. Five- and 10-year breast cancer–specific survival rates were evaluated; standardised mortality ratios were calculated (with reference to the general population of women in Hong Kong).

From 1997 to 2006, 1391 patients were diagnosed with DCIS and included in the Hong Kong Cancer Registry breast cancer database. In total, 449 patients were diagnosed from 1997 to 2001, while 942 patients were diagnosed from 2002 to 2006. The mean age at diagnosis was 49.2±9.2 years. Most patients (43.5%) were aged 40 to 49 years (Table 1). More than half of the patients (n=712, 51.2%) underwent mastectomy, while 399 (28.7%) underwent breast-conserving surgery. Overall, 410 patients (29.5%) received adjuvant radiotherapy. In addition, 221 patients (15.9%) received risk-reducing hormonal therapy with tamoxifen (Table 1).

The median follow-up interval was 11.6 years; overall breast cancer–specific mortality rates were 0.3% and 0.9% after 5 and 10 years of follow-up, respectively (Table 2). In total, 109 patients (7.8%) developed invasive breast cancer after a considerable delay. Invasive breast cancer rates were comparable between patients diagnosed from 1997 to 2001 and those diagnosed from 2002 to 2006: 37 (8.2%) and 72 (7.6%), respectively (Table 1).

Subgroup analysis revealed higher breast cancer–specific mortality in patients with human epidermal growth factor receptor 2 (HER2)–positive DCIS after 10 years of follow-up, compared with patients who exhibited HER2-negative DCIS (2.9% vs 0%; P=0.0181, Fisher’s exact test). In contrast, 10-year breast cancer–specific mortality rates were comparable between patients with low-/intermediate-grade DCIS and those with high-grade DCIS (0.5% vs 0.8%; P=0.6776).

The breast cancer–specific mortality rate (per 100 000) was 2.2 among patients aged 30 to 34 years; this rate slowly increased and peaked at 34.8 among patients aged 60 to 64 years (Table 3). Patients with DCIS were more likely to die of breast cancer, compared with the general population of women in Hong Kong (standardised mortality ratio=5.7; 95% confidence interval=3.1-8.3).

Breast cancer is the most common cancer among women in Hong Kong, such that it constituted 26.1% of all newly diagnosed cancers among women in Hong Kong in 2015.10 Notably, a population-wide breast cancer screening programme is not available in Hong Kong. However, because of improved patient-level and population-level education regarding breast cancer awareness, rates of self-initiated breast cancer screening by ultrasonography and mammography have increased over the past decade.9 This might well explain the doubling of DCIS incidence from 449 patients (1997-2001) to 942 patients (2002-2006).

The mortality rate of patients with DCIS has substantially declined over the past few decades in the United States: the 10-year breast cancer mortality rate was 3.4% for women who received a diagnosis from 1978 to 1983, then decreased to 1.9% for women who received a diagnosis from 1984 to 198911 and 1.1% for women who received a diagnosis from 1988 to 2011.2 The mortality rate of patients with DCIS in Hong Kong has remained stable during this same period, despite improved detection through selfinitiated breast screening. Nevertheless, the 10-year breast cancer–specific mortality rate of 0.9% in the current study is comparable with the findings from Western nations; in particular, the 10-year breast cancer–specific mortality rate was reportedly 1.8% in a randomised trial of 1046 Swedish patients with DCIS, who were diagnosed from 1987 to 1999.12 The underlying reason for such an improvement in survival is beyond the scope of this study, but we presume that it is multifactorial (eg, earlier detection and improved surgical oncologic treatment for DCIS).13 However, reports on the improved survival of patients with DCIS (including the current cohort) should be interpreted with care, because this improvement may be the result of overdiagnosis of DCIS.

Overdiagnosis and overtreatment for DCIS have been a major focus of debate over the past decade.12 Several randomised controlled trials, such as the COMET (NCT02926911) and LORIS trials, are currently investigating the feasibility and non-inferiority of active surveillance with or without endocrine therapy for management of low-risk DCIS.

Biological markers such as HER2 receptor and oestrogen receptor statuses have been used for assessment of prognosis and tumour behaviour in patients with invasive breast cancers,14 but their roles in the context of DCIS may have been previously underestimated. Human epidermal growth factor receptor 2–positive DCIS is considered the most unstable precursor among all molecular subtypes, because of its high invasion rate and frequent association with a discordant phenotype.15 Our results may provide clinical validation of this postulation, because they demonstrated that the 10-year breast cancer–specific mortality is significantly worse in patients with HER2-positive disease. However, because of the relatively small number of events included in the subgroup analysis, it may be premature to conclude that positive HER2 findings are associated with adverse survival outcome. Oestrogen receptor–positive DCIS was associated with slightly lower 10-year breast cancer–specific mortality (Table 2). Indeed, the use of systemic hormonal therapy with tamoxifen in patients with oestrogen receptor–positive DCIS has been shown to reduce the risk of future invasive cancer.16

We acknowledge that this study was limited by its retrospective in nature, because all pathological diagnoses were supplied by the breast cancer database from The Hong Kong Cancer Registry. A formal pathology review might have identified patients whose diagnoses were modified from DCIS (in core biopsy) to invasive cancers (in final pathology); other diagnoses might have been modified from invasive cancers to DCIS. While some researchers reported a 17% exclusion rate after a central pathology review,17 others reported a much lower exclusion rate of 2% after secondary pathological review of patients with DCIS.18 19 20 Nevertheless, our analysis was based on a large territory-wide cancer registry. All data were maintained and validated in a consistent manner. In addition, the extended follow-up period enabled detailed long-term survival analysis for patients with DCIS.

Data from the Hong Kong Cancer Registry revealed that the incidence of DCIS doubled from the late 1990s to the early 2000s. The estimated standardised mortality ratio of patients with DCIS in Hong Kong was 5.7, compared with the general population of women in Hong Kong. Our cohort represents one of the largest DCIS cohorts in the published literature. For locations where population-wide breast cancer screening is not available, as in Hong Kong, we believe that the results of our study support further investigation of the cost-effectiveness of population-wide breast cancer screening implementation.

Concept or design: M Co, A Kwong.
Acquisition of data: A Kwong, OWK Mang, RKC Ngan, AHP Tam, KH Wong.
Analysis or interpretation of data: M Co, A Kwong, OWK Mang, AHP Tam.
Drafting of the manuscript: M Co, A Kwong.
Critical revision of the manuscript for important intellectual content: A Kwong, RKC Ngan, KH Wong.

The authors have no conflicts of interest to disclose.

We thank the Dr Ellen Li Charitable Foundation and the Kuok Foundation for their continual support in providing the staff for collection of the data to make this possible. We also thank members of the Hong Kong Breast Cancer Research group for their advice on the research during the period of data collection.

This research was funded by the Dr Ellen Li Charitable Foundation and the Kuok Foundation. The funders had no role in the design of this study, the analysis and interpretation of the data, or the decision to submit the results for publication.

This study was approved by the Hong Kong Hospital Authority West Cluster Research Ethics Committee (Ref UW 09-045). Patient consent was obtained for data collection and analysis.

1. Silverstein MJ, Baril NB. In situ carcinoma of the breast. In: Donegan WL, Spratt JS, editors. Cancer of the Breast. 5th ed. Saunders: Philadelphia; 2002.

2. Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 1996;275:913-8. Crossref

3. Surveillance, epidemiology and end results program, National Cancer Institute. USA government. Previous version: SEER cancer statistics review, 1975-2009. Available from: https://seer.cancer.gov/archive/csr/1975_2009_pops09/. Accessed 10 Jan 2019.

4. Sprague BL, Trentham-Dietz A. In situ breast cancer. In: Li CI, editor. Breast Cancer Epidemiology. New York: Springer; 2010: 47-72. Crossref

5. Allegra CJ, Aberle DR, Ganschow P, et al. National Institutes of Health State-of-the-Science Conference Statement: Diagnosis and Management of Ductal Carcinoma in Situ September 22-24, 2009. J Natl Cancer Inst 2010;102:161-9. Crossref

6. Co M, Kwong A. Ductal carcinoma in situ of the breast—long term results from a twenty-year cohort. Cancer Treat Res Commun 2018;14:17-20. Crossref

7. Boyages J, Delaney G, Taylor R. Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. Cancer 1999;85:616-28. Crossref

8. Merrill AL, Esserman L, Morrow M. Clinical decisions. Ductal carcinoma in situ. N Engl J Med 2016;374:390-2. Crossref

9. Yau TK, Chan A, Cheung PS. Ductal carcinoma in situ of breast: detection and treatment pattern in Hong Kong. Hong Kong Med J 2017;23:19-27. Crossref

10. Centre for Health Protection, Department of Health, Hong Kong SAR Government. Breast Cancer. Available from: https://www.chp.gov.hk/en/healthtopics/content/25/53.html. Accessed 7 Jul 2018.

11. Ernster VL, Barclay J, Kerlikowske K, Wilkie H, Ballard-Barbash R. Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program. Arch Intern Med 2000;160:953-8. Crossref

12. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Correa C, McGale P, et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010;2010:162-77. Crossref

13. Co M, Kwong A, Shek T. Factors affecting the underdiagnosis of atypical ductal hyperplasia diagnosed by core needle biopsies—a 10-year retrospective study and review of the literature. Intl J Surg 2018;49:27-31. Crossref

14. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52. Crossref

15. Harada S, Mick R, Roses RE, et al. The significance of HER-2/neu receptor positivity and immunophenotype in ductal carcinoma in situ with early invasive disease. J Surg Oncol 2011;104:458-65. Crossref

16. Boughey JC, Gonzalez RJ, Bonner E, Kuerer HM. Current treatment and clinical trial developments for ductal carcinoma in situ of the breast. Oncologist 2007;12:1276-87. Crossref

17. Collins LC, Achacoso N, Haque R, et al. Risk factors for non-invasive and invasive local recurrence in patients with ductal carcinoma in situ. Breast Cancer Res Treat 2013;139:453-60. Crossref

18. Bijker N, Peterse JL, Duchateau L, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001;19:2263-71. Crossref

19. Fisher ER, Costantino J, Fisher B, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Five-year observations concerning lobular carcinoma in situ. Cancer 1996;78:1403-16. Crossref

20. Rakovitch E, Mihai A, Pignol JP, et al. Is expert breast pathology assessment necessary for the management of ductal carcinoma in situ? Breast Cancer Res Treat 2004;87:265-72. Crossref