Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast

https://doi.org/10.1016/S0959-8049(02)00666-4Get rights and content

Abstract

The optimal management of ductal carcinoma in situ (DCIS) is controversial, due in part to our poor understanding of its natural history. We undertook to identify subgroups of DCIS based on the expression of biomarkers, which were related to the likelihood of clinical recurrence. Biomarker expression of a total of 95 DCIS lesions in a nested case–control study within a population-based cohort with up to 135 months follow-up data (median 101 months) was analysed using immunohistochemistry. ERBB2-positivity and bcl-2-, oestrogen receptor (ER)- and progesterone receptor (PR)-negativity were individually associated with the risk of clinical recurrence. The predictive value of these biomarkers was independent of cytonuclear grade. ERBB2, bcl-2, ER and PR expression were conserved in the recurrent lesions, including subsequent invasive cancers. p21-positive DCIS was also associated with clinical recurrence, independently of the associations with ERBB2/bcl-2/ER/PR expression. These data identify clinically and biologically relevant subcategories of DCIS lesions, an essential basis for improving management.

Introduction

Ductal carcinoma in situ (DCIS) of the breast is the proliferation of epithelial cells with all the morphological features of malignancy, but without stromal invasion [1]. Previously a rare entity accounting for <5% of breast cancers, DCIS has dramatically increased in incidence since the advent of screening mammography, now representing 15–20% of all breast cancers and up to 40% of screen-detected cancers [2].

Historically, DCIS was treated with mastectomy, leading to prevention of recurrence of DCIS and invasive cancer in almost all cases [3]. However, with the increased utilisation of local therapy for invasive cancer, it has become difficult to justify mastectomy for a pre-invasive condition that should be curable with adequate local excision. Notwithstanding, long-term series show that up to 40% of women treated with local therapy (excision±radiotherapy) will develop recurrent disease in the ipsilateral breast 3, 4. Approximately half of these recurrences will be as invasive cancer, with the concomitant risk of metastasis and death 3, 5. Several morphological factors have been shown to predict recurrence 6, 7, 8, 9. However, many of these factors, including high morphological grade, are not sensitive markers of recurrence and inter-observer variability affects the reproducibility of a purely morphological approach to disease stratification 10, 11, 12. Furthermore, morphological analysis alone does not take into account the key molecular drivers of the neoplastic process. Currently therefore, we have no way of reliably identifying those patients at increased risk of developing recurrent disease and there is a need to identify biological markers which predict disease progression.

In contrast to invasive cancer, there are few publications on the role of biological markers in predicting prognosis in DCIS 13, 14, 15, 16. Two of the four published studies showed no relationship between expression of biological markers detected by immunohistochemistry and disease recurrence 13, 14, but these studies had very limited power since there were only small numbers of recurrences (8 out of 36 patients [13], and 3 out of 81 patients [14]). The third study showed bcl-2, p53 and Ki-67 immunostaining were predictive of a shorter time interval to ipsilateral recurrence, with no effect attributable to ERBB2 expression status [15]. A fourth study showed strong p53 staining was common in DCIS cases which recurred, but again only small numbers of DCIS lesions with known recurrence were examined (five DCIS lesions of 8 cases with recurrence were p53-positive) and the ERBB2 status was not assessed [16].

We have evaluated the potential role of biological markers in predicting disease outcome in DCIS, using a nested case–control study taken from a population-based cohort with long-term follow-up.

Section snippets

Subject selection

The In Situ and Small Invasive Breast Cancer Register (ISSIBCR) was established to examine the natural history of DCIS and invasive breast cancers less than 1 cm in size [17]. Reporting of all in situ and invasive cancers to the Victorian Cancer Registry is mandatory. The registry contains 457 women with DCIS reported from 1988 to 1992, 62% of which were known to have had breast conserving surgery. These subjects were followed-up for a maximum of 135 months (range 35–135 months; median 101

Results

A total of 95 subjects with DCIS were used for this study; 53 cases and 42 controls. The median length of follow-up was 101 months (range 35–135 months). 28 of the cases (53%) had an ipsilateral recurrence as DCIS and 23 (43%) had ipsilateral recurrence as invasive cancer, while a further two had recurrent disease diagnosed clinically, with no pathology to confirm type of recurrence. A further case had ipsilateral recurrent DCIS followed by ipsilateral invasive cancer. The status of lymph node

Discussion

In an effort to improve our understanding of the fundamental molecular drivers of DCIS, with a view to thereby improving stratification as a prelude to advancing management of this disease, we have evaluated biomarkers in primary DCIS lesions and recurrent disease. Only four previous studies have directly examined expression of biomarkers in DCIS and recurrence 13, 14, 15, 16 and in all but one study [15] the numbers of recurrent cases analysed have been very few. In contrast to our own study,

Acknowledgements

We would like to thank Dr Gino Somers for his careful reading of the manuscript. The study would not have been possible without the collaboration and long-term support of members of the Breast Committee of the Victorian Cooperative Oncology Group. This work was supported by The Cancer Council Victoria, The Victorian Breast Cancer Research Consortium and the National Health and Medical Research Council, Australia.

References (34)

  • E.R Frykberg et al.

    Overview of the biology and management of ductal carcinoma in situ of the breast

    Cancer

    (1994)
  • E.R Fisher et al.

    Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17intraductal carcinoma [see comments]

    Cancer

    (1999)
  • M.J Silverstein et al.

    A prognostic index for ductal carcinoma in situ of the breast [see comments]

    Cancer

    (1996)
  • M.J Silverstein et al.

    The influence of margin width on local control of ductal carcinoma in situ of the breast [see comments]

    N. Engl. J. Med.

    (1999)
  • N Bijker et al.

    Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situanalysis of European Organization for Research and Treatment of Cancer Trial 10853

    J. Clin. Oncol.

    (2001)
  • W.A Wells et al.

    Pathologists’ agreement with experts and reproducibility of breast ductal carcinoma-in-situ classification schemes

    Am. J. Surg. Pathol.

    (2000)
  • A.G Douglas-Jones et al.

    Consistency in the observation of features used to classify ductal carcinoma in situ (DCIS) of the breast

    J. Clin. Pathol.

    (2000)
  • Cited by (114)

    • Breast Carcinoma: Updates in Molecular Profiling 2018

      2018, Clinics in Laboratory Medicine
    • Radiotherapy and ductal carcinoma in situ

      2017, The Breast: Comprehensive Management of Benign and Malignant Diseases
    View all citing articles on Scopus
    View full text