Invasive ductal carcinoma breast cancer with and without a ductal carcinoma in situ component; implications for prevention, prognosis and treatment
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Cancer of the breast is a heterogeneous disease, with each tumor having its own history of development. The classical model of breast cancer development describes the steps of tumor progression, starting with the transformation of an epithelial cell of the duct. The transformation leads to proliferation of cells within the lumen, resulting in ductal carcinoma in situ, or DCIS. DCIS, which is contained within the lumen of the duct, is a nonobligatory precursor to invasive breast cancer. Once tumor cells break through the basement membrane of the duct and invade the stroma of the breast, it is considered invasive carcinoma. Invasive ductal carcinoma (IDC) is presented in clinic, both with and without concomitant DCIS. There is limited information on the reasons behind, or the implications for preventative measures and/or treatment for different presentations of the most common type of breast cancer. We examined mixed IDC with DCIS (mixed IDC/DCIS) vs. pure IDC in relation to risk factors, tumor characteristics, survival outcomes and expressions of proteins associated with tumor progression. Using data from the Women's Circle of Health Study (WCHS), a multi-centered case-control study of breast cancer we examined the association between well-known risk factors for breast cancer and mixed IDC/DCIS and pure IDC. Odds ratios were estimated adjusting for other known risk factors, with additional stratification for race and estrogen receptor status. Using both the WCHS, and data from the medical records of women treated at Roswell Park Cancer Institute (RPCI), we compared tumor characteristics associated with mixed IDC/DCIS vs. pure IDC. In addition, we created Kaplan-Meier curves and built models adjusted for other clinical factors using Cox proportional hazard regression to look at recurrence and survival for women with mixed IDC/DCIS and pure IDC, with stratification for treatment. Finally, we used immunohistochemistry to evaluate the expression of a panel of proteins known for their role in tumor progression, in tumor samples from the primary surgery of women treated at RPCI for breast cancer. The associations observed with mixed IDC/DCIS and pure IDC were consistent with traditional risk factors. However, associations observed with lower BMI in postmenopausal women, younger age at last birth and breastfeeding were significantly associated with pure IDC. Pure IDC was associated with larger tumor size, higher grade and were more likely to have negative ER and PR statuses in both the WCHS and among breast cancer patients treated at RPCI. The number of recurrences was greater among mixed IDC/DCIS than pure IDC overall and among women who received breast conservation therapy. The significant difference resulted from an increased number of local recurrences in women with mixed IDC/DCIS. In contrast, the largest increased risk of breast cancer specific mortality was observed for pure IDC, among women who were treated with mastectomies. Finally, we observed a significantly higher expression of FLT1/VEGFR1, a receptor for VEGF and PlGF, known inducers of angiogenesis, among pure IDC tumors. The evidence found supports our hypothesis that mixed IDC/DCIS and pure IDC evolve via different pathways of tumor development, and that pure IDC is associated with more aggressive tumor characteristics.