A subset of patients with
ductal carcinoma in situ (
DCIS) will develop invasive
breast cancer (IBC). To date, there are no effective predictive
biomarkers for identifying this subset with worse prognosis whose lesions are essentially indistinguishable histologically from those with favorable outcomes. We hypothesized that measurable parameters that discriminate
DCIS from
DCIS with concurrent invasion may serve as diagnostic
biomarkers (BM) of progressive
cancer in situ (CIS).
RESULTS: Using a novel imaging-based method of tissue testing, we measured the relative expression levels of three candidate BM
proteins specifically implicated in IBC progression - the
insulin-like growth factor I receptor (IGF-IR), Ras-related
protein 1 (Rap1), and Vav2
oncoprotein.
Protein profiles were compared in 42 histologically normal mammary epithelial samples, 71 CIS (35 without/36 with invasion either on diagnostic biopsy or final surgical excision), and 98 IBC of known
estrogen receptor (ER),
progesterone receptor (PR) and
human epidermal growth factor receptor 2 (HER2) status. The levels of the IGF-IR and Rap1
protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 -)
DCIS relative to normal epithelium (P <0.0001). The IGF-IR
protein expression was also significantly up regulated in HER2-positive (ER+/-/PR+/-/HER2+)
DCIS relative to normal epithelium (P = 0.0002). IGF-IR and Rap1
protein expression levels were similar among
DCIS patients without or with concurrent invasion. Vav2 upregulation in
DCIS relative to normal group was not associated with
steroid hormone receptor and HER2 status, but was associated with the presence of concurrent invasion, including microinvasion (invasive foci of less than 1 mm).
DCIS with high Vav2 were more than twice as likely to progress to invasive
cancers as
DCIS with low Vav2 (odds ratio, 2.42; 95% CI, 1.26-4-65; P =0.008). Furthermore, a receiver operating characteristic curve analysis revealed moderate ability of Vav2
protein expression measurements in
DCIS to predict the existence of invasion concurrent with
DCIS (area under the curve, 0.71; 95% CI, 0.59- 0.84).
CONCLUSIONS: