Basal-like carcinomas (BLCs) of the breast share discriminatory morphologic features with poorly differentiated high-risk human papilloma virus (HPV)-related squamous cell carcinomas of the oropharynx, penis, and vulva. Because HPV E7 protein inactivates the retinoblastoma (Rb) protein, diffuse p16 expression is a surrogate marker for these high-risk HPV-related carcinomas. HPV E6 protein also inactivates p53, further compromising the G1-S cell cycle checkpoint. The Rb/p16/p53 immunohistochemical profile of BLC of the breast has not been well characterized. Tissue microarrays containing 71 invasive ductal carcinomas (IDCs) of the breast were immunolabeled for p16, Rb, p53, and Ki-67. The cases included 4 distinct groups of IDCs having surrogate immunohistochemical profiles corresponding to categories defined by gene expression profiling (17 luminal A, 7 luminal B, 14 HER-2+, and 21 BLC), along with 12 unclassifiable triple negative carcinomas (UTNCs). Twenty-five of the 71 IDC were Rb negative/p16 diffuse positive (Rb −/p16+). These included 15 of 21 BLC and 9 of 12 UTNC, but only 1 of 14 HER-2 positive cases and none of the 17 luminal A or 7 luminal B cases (P < 0.01, BLC or UTNC vs. others). Six of the Rb − /p16+ IDC also had a significant ductal carcinoma in situ component. The ductal carcinoma in situ in 4 of these 6 cases showed the same Rb − /p16+ phenotype as the associated IDC. BLC and UTNC had the highest Ki-67 indices of the 5 groups, even when matched for grade. The Rb − /p16+ phenotype and the Rb − /p16+/p53 overexpressing phenotype correlated with increased proliferation within the BLC group. In conclusion, BLC and UTNC, but not HER-2, luminal A, or luminal B carcinomas, frequently demonstrate an Rb − /p16+ phenotype, similar to the HPV-related squamous cell carcinomas that BLC resemble morphologically. This subset may represent a more homogenous group than BLC as defined currently.

Approximately 10-15% of human cancers do not show evidence of telomerase activity, and a subset of these maintain telomere lengths by a recombination-based mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in certain sarcomas and germ cell tumors, is very rare in carcinomas. In this study we describe evidence for the ALT phenotype in molecular subclasses of breast carcinoma, specifically a subset of cancers with HER-2 overexpression. Tissue microarrays were created from 71 invasive ductal carcinomas of the breast categorized into subclasses, and telomere lengths were directly assessed using fluorescence in situ hybridization with combined promyelocytic leukemia (PML) protein immunofluorescence. The ALT phenotype was identified in 3 of 21 HER-2-positive cases, but in none of the other 50 cases (P ¼ 0.023). This is the first direct observation of this mechanism of telomere maintenance in breast carcinoma unrelated to Li-Fraumeni syndrome. The correlation of the ALT phenotype with HER-2 positivity, both of which involve abnormal DNA amplification, suggests a possible common underlying mechanism. This telomere phenotype confers a poor prognosis in some cancers; two of the three cases in our study showed rapid tumor progression, possibly suggesting that it may adversely affect outcome in breast carcinoma as well. As cancers using the ALT pathway are predicted to be resistant to therapies based on telomerase inhibition, these results may have therapeutic consequences.

Background-No study has systematically evaluated the significance of involvement of the superficial specimen margin in skin-sparing mastectomies (SSMs).

Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas (n = 103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A (n = 18), luminal B (n = 28), HER-2-positive (n = 20) and triple-negative carcinomas (n = 37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher’s exact tests. ER-negative status (P = 0.022), PR-negative status (P = 0.008), HER-2-positive status (P = 0.023) and p53-positive status (P = 0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases (P = 0.002), HER-2-positive cases (P = 0.011) or triple-negative cases (P = 0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.

Introduction Although lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Global gene expression profiling of LCIS has not been performed.