Citations

Abstract Abstract #4033 Background: Aromatase activity within the breast is a source of estrogen that may cause breast cancer. Mammographic density (MD) is a risk factor for breast cancer whose biologic basis is unknown. Our study compared aromatase expression in tissue from dense and non-dense areas of the breasts of healthy volunteers.
 Methods: Participants were 40+ yrs, had a screening mammogram with visible MD, no history of cancer and were not on endocrine therapy. Ultrasound-guided core biopsies were done within 6 months of mammography to obtain three paired cores from mammographically dense and non-dense regions of the breast. Immunostaining for aromatase expression employed the streptavidin-biotin amplification method using the recently developed 677 mouse monoclonal antibody. Immunoreactivity (IR) was scored in terms of proportion of cells staining positive for aromatase (PPC) (0=<1%, 1=1-25%, 2=26-50%, 3=51+% (and 4=75%+ for adipocytes)) and relative immunointensity (0=none, 1=weak, 2=moderate, 3=intense) for each cell type (stroma, normal ductal epithelium, adipocytes). A composite score weighting the PPC by their relative intensity (range 0-9; 0-12 for adipocytes) was also calculated. The sum of the composite score across the three cell types provided a global assessment of aromatase IR. Repeated measures analyses evaluated differences in aromatase IR for dense compared to non-dense tissue within and across cell types. Parameter estimates (β) indicated the average difference between dense and non-dense IR.
 Results: 18 (37%) of the 49 participants were premenopausal (median age 46 yrs). Summing across cell types, the global composite score showed increased aromatase IR on sections sampled from dense vs. non-dense regions (β=5.3,p<0.001). This global difference reflected increased aromatase IR in the stroma and normal ductal epithelium from dense sections (vs. non-dense). For 42 women with >1% stromal cells on each section, there was evidence for increased IR on dense sections as indicated by the greater PPCs (β=0.9), relative intensity (β=0.7) and composite score (β=2.7)(p's<0.001). Similarly, for 20 women with >1% normal ductal epithelium in both dense and non-dense sections, there was a greater composite score (β=1.4,p=0.004) for cells on dense sections although differences for PPC (β=0.3,p=0.11) and relative intensity (β=0.3,p=0.09) did not reach statistical significance. No differences were seen in IR for adipocytes from the two density regions (46 women). Findings were unchanged with adjustment for covariates, including proportions of each cell type per section.
 Conclusions: There is strong evidence for increased aromatase expression in the stromal and normal ductal epithelium of dense vs. non-dense tissue. These results support ongoing research into mammographic density as a biomarker of effect of aromatase inhibitors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4033.

Purpose Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. Patients and Methods The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Results Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. Conclusion The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.

The authors describe the case of a 36-year-old man with gynecomastia who was previously treated with liposuction of the breast for cosmetic purposes. Histologic examination of a subsequent excisional biopsy revealed nests of displaced epithelial cells in adipose tissue. Epithelial cell displacement is a well-known risk of core needle biopsies and fine-needle aspirations of breast lesions. However, to the authors’ knowledge, epithelial displacement in gynecomastia after liposuction, mimicking invasive ductal carcinoma, has not previously been reported.

Purpose Mammographic density and lobular involution are both significant risk factors for breast cancer, but whether these reflect the same biology is unknown. We examined the involution and density association in a large benign breast disease (BBD) cohort. Patients and Methods Women in the Mayo Clinic BBD cohort who had a mammogram within 6 months of BBD diagnosis were eligible. The proportion of normal lobules that were involuted was categorized by an expert pathologist as no (0%), partial (1% to 74%), or complete involution (≥ 75%). Mammographic density was estimated as the four-category parenchymal pattern. Statistical analyses adjusted for potential confounders and evaluated modification by parity and age. We corroborated findings in a sample of women with BBD from the Mayo Mammography Health Study (MMHS) with quantitative percent density (PD) and absolute dense and nondense area estimates. Results Women in the Mayo BBD cohort (n = 2,667) with no (odds ratio, 1.7; 95% CI, 1.2 to 2.3) or partial (odds ratio, 1.3; 95% CI, 1.0 to 1.6) involution had greater odds of high density (DY pattern) than those with complete involution (P trend < .01). There was no evidence for effect modification by age or parity. Among 317 women with BBD in the MMHS study, there was an inverse association between involution and PD (mean PD, 22.4%, 21.6%, 17.2%, for no, partial, and complete, respectively; P trend = .04) and a strong positive association of involution with nondense area (P trend < .01). No association was seen between involution and dense area (P trend = .56). Conclusion We present evidence of an inverse association between involution and mammographic density.

Occult breast cancer has frequently been described as presenting as axillary lymph node metastases but rarely as gastrointestinal metastases, Varadarajan et al. (2007). In extremely rare situations, cancerous lesions identified in the gastrointestinal tract have been determined to be metastatic lesions from primary breast cancers, Taal et al. (2000). We report a case of an occult lobular adenocarcinoma presenting as gastrointestinal metastases. It is essential that the possibility of lesions found in the gastrointestinal tract originating from distant or occult cancers be considered in order that appropriate therapeutic options may be discussed and considered early after diagnosis.

Purpose Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women. Methods We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women. Results There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic. Conclusion Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.