Biomarker Expression and Risk of Subsequent Tumors After Initial Ductal Carcinoma In Situ Diagnosis

University of California, San Francisco, CA 94121, USA. [corrected]
Journal of the National Cancer Institute (Impact Factor: 12.58). 05/2010; 102(9):627-37. DOI: 10.1093/jnci/djq101
Source: PubMed


Studies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.
We conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.
Factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).
Biomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.

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Available from: Karla Kerlikowske
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    • "In 21PT, this was associated with a significant increase in AP-1 activity, whereas AP-1 activity, already higher in 21NT cells, showed no change in response to WNT5A. Increased COX-2 expression has been previously associated with increased propensity of DCIS (or ADH) to progress to invasion, particularly when seen in association with increased proliferation (Ki-67 index), and in the case of DCIS, with high p16404142. This has been suggested to be a reflection of an altered stress response in cells more likely to progress. "
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    ABSTRACT: Planar cell polarity (PCP) signaling has been shown in different studies to either promote or inhibit the malignancy of breast cancer. Using the 21T cell lines, which were derived from an individual patient and represent distinct stages of progression, we show that the prototypical PCP ligand, WNT5A, is expressed highest in 21MT-1 cells (invasive mammary carcinoma) and lowest in 21PT (atypical ductal hyperplasia) and 21NT (ductal carcinoma in situ) cells. Overexpression of WNT5A decreased spherical colony formation and increased invasion and in vivo extravasation only in 21NT cells; whereas overexpression increased migration of both 21PT and 21NT cells. WNT5A overexpression also increased RHOA expression of both cell lines and subsequent RHOA knockdown blocked WNT5A-induced migration, but only partially blocked WNT5A-induced invasion of 21NT cells. PCP can signal through VANGL1 to modulate AP-1 target genes (e.g. MMP3) and induce invasion. VANGL1 knockdown inhibited WNT5A-induced invasion of 21NT cells, but had no effect on WNT5A-induced migration of either 21PT or 21NT cells. WNT5A-induced MMP3 expression was seen only in 21NT cells, an effect that was VANGL1 dependent, but independent of AP-1. We thus provide evidence that PCP signaling can act in a context dependent manner to promote breast cancer progression.
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    • "An evaluation of 132 patients with DCIS treated with BCS without (n = 33) or with (n = 99) whole-breast RT found an absolute difference of about 8.5% in rates of local recurrence in patients with ER-negative and ER-positive DCIS (Roka et al. 2004; Provenzano et al. 2003). Indeed, several studies have revealed an association between ER-negative DCIS and risk of recurrence (Ringberg et al. 2001; Provenzano et al. 2003; Kerlikowske et al. 2010). "
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    • "With the increasing occurrence of very small, radiologically detected subclinical lesions, several teams started considering, in the nineties, most DCIS as a possibly ''indolent disease'' and claimed that lumpectomy alone could be the treatment of choice in patients presenting with small size unifocal DCIS [17] [18] [19] [20] [21] [22] [23] [24]. After the turn of the century, a number of reports strongly challenged this policy, eliciting, after 5 and 10-year median follow-ups, local recurrence (LR) rates ranging from 17 to 32%, 40–45% of them having progressed to invasive carcinoma (Table 1) [23] [24] [25]. Even in cohorts including only radiologically detected DCIS with complete excision, 10-year LR rates varied between 19% and 28%, 35% of which being invasive carcinomas [18] [22]. "
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