Background. Researchers question whether estrogen receptorα-negative (ERN) and -positive (ERP) represent different stages of one disease or different breast cancer types. 
Objective. To further examine ERα phenotypes, we stratified incident tumor characteristics in the Surveillance, Epidemiology, and End Results (SEER) Database (n = 82,488) by ERN and ERP. 
Methods. Study variables included black–white race, age-at-diagnosis, and standard incident tumor characteristics. These characteristics were arbitrarily dichotomized into good versus poor prognostic factor groups, for example, good (tumor size ≤ 2.0 cm, negative axillary lymph nodes, and good histologic grade) versus poor (tumor size > 2.0 cm, positive nodes, and poor grade). Age frequency density plots were generated from the corresponding age-at-diagnosis frequency histograms. Average annual age-specific incidence rates (or risks) were adjusted to the 1970 United States standard female population. 
Results. Age frequency density plots demonstrated bimodal premenopausal and postmenopausal breast cancer populations. ERN was correlated with premenopausal disease, black race, and poor prognostic factor groups, whereas ERP was associated with postmenopausal disease, white race, and favorable tumor characteristics. ERN rates increased premenopausally and then flattened to a nearly constant level after 50 years of age. ERP risk rose for most of a woman's lifetime with the greatest risk occurring between 75 and 79 years. 
Conclusions. ERα exhibited bimodal age frequency distribution with a dichotomous pattern for age-specific rates, racial, and prognostic factor profiles. Menopause had a greater effect on ERN than ERP. Possible implications for breast carcinogenesis and cancer prevention are discussed in the text.

Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database.

An attempt has been made to put forward a unifying hypothesis explaining the role hormones play in the genesis of mammary cancers of different phenotypes and genotypes in mice, rats, and humans. Most mammary cancers in these species originate in luminal mammary epithelial cells lining the mammary ducts and alveoli. These cancers are histopathologically diverse and are classified on the basis of growth requirements as hormone-dependent or hormone-independent tumors. In most strains of mice, mammary cancers at the time of detection are largely of the hormone-independent type; in rats, almost all mammary cancers are hormone-dependent, while humans have both phenotypes. In spite of these differences, in vivo studies show that hormones (ovarian and pituitary) are essential for luminal mammary epithelial cell proliferation and also for the development of mammary cancers of both hormone-independent and hormone-dependent types. This article, based on our extensive in vivo and in vivo studies and on current literature, proposes a model to explain the central role of hormones in the genesis of all types of mammary cancers. The model attempts to address the following questions: (i) how hormones regulate luminal mammary epithelial cell proliferation, (ii) why hormones are required for the genesis of mammary cancers of all phenotypes and genotypes, including those which are always classified as hormone-independent tumors, and (iii) why the three species (mouse, rat, and human) have consistently different ratios of hormone-dependent to hormone-independent tumors.

https://www.pnas.org/content/pnas/92/9/3650.full.pdf

Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis.

Background. Ductal carcinoma in situ (DCIS) of the breast has been diagnosed increasingly since the advent of mammography. However, the natural history of these lesions remains uncertain. Ductal carcinoma in situ of the breast does not represent a single entity but a heterogeneous group with histologic and clinical differences. The histologic subtype of DCIS seems to have an influence on its biologic behavior, but there are few studies correlating subtype with biologic markers. Methods. The authors studied a consecutive series of 40 cases of DCIS and after its histologic categorization verified its relationship with ploidy using image analysis and analyzing estrogen receptor (ER), progesterone receptor (PR), p53 and c-erbB-2 expression using immunohistochemistry. Results. The three groups proposed according to the grade of malignancy were correlated significantly with some of the additional parameters studied, including aneuploidy and c-erbB-2 expression. Aneuploidy was detected in 77.5% of cases of DCIS mainly in high and intermediate grade subtypes (100% and 80% vs. 35.7% in low grade) whereas immunoreactivity for c-erbB-2 was detected in 45% of cases of DCIS mainly in the high grade group. Expression of ER and PR were observed frequently in this study (63.9% and 65.7% respectively), but without correlation with the histologic subtype of DCIS, although we found a somewhat significant association between high grade DCIS and lack of ER. p53 protein expression was detected in 36.8% of these cases, but no relationship between this expression and histologic subtype or grading of DCIS was found. Conclusions. These results provide further evidence for the morphologic and biologic heterogeneity of DCIS. Besides histologic classification and nuclear grading, some biologic markers such as aneuploidy and c-erbB-2 expression constitute additional criteria of high grade of malignancy. Cancer 1995 ; 75 :2123-31.

/pdf/ductal-carcinoma-in-situ-of-the-breast-histologic-2hyr67o0it.pdf

Ductal carcinoma in situ of the breast. Histologic categorization and its relationship to ploidy and immunohistochemical expression of hormone receptors, p53, and c-erbB-2 protein.

Angiogenesis, the formation of new blood vessels from the existing vascular network, has been demonstrated to be an important prognostic factor in invasive breast carcinoma. The switch to an angiogenic phenotype represents a growth-limiting step during carcinogenesis and might, in pre-invasive lesions, indicate the risk for developing an invasive phenotype. The discrepancy between modern therapy options for invasive breast carcinomas and the relatively aggressive treatment of in situ lesions underlines the need for such prognostic factors for ductal in situ breast carcinomas (DCIS). Patterns of vascularity were examined in 75 formalin-fixed, paraffin-embedded DCIS by immunohistochemical staining of vessels using antibodies against Factor VIII-related antigen. Histological classification was performed according to four different systems, based on architectural or cytonuclear features, or a combination of both. Two distinct vascular patterns were observed: a diffuse increase of stromal vascularity between duct lesions (pattern I), which was present alone in 8/75 (11 per cent), and a dense rim of microvessels adjacent to the basement membrane of individual ducts (pattern II), present alone in 12/75 (16 per cent). In total, 57 per cent (43/75) showed pattern 1 and 62 per cent (47/75) showed pattern II. There was a significant correlation between these patterns (P = 0.0001; chi 2 = 15.1), such that both were present in 35 (47 per cent). These different vascular patterns imply two angiogenic pathways: one pathway mediated by angiogenic factors released directly by tumour cells resulting in the rim of vessels and another generated indirectly via recruitment of accessory cells such as macrophage and endothelial cells, which themselves release other angiogenic factors, causing the increase of stromal vascularity. A significant increase in both stromal vascularity (pattern I) and the presence of a rim (pattern II) was observed in high-grade DCIS lesions (P = 0.005 and P = 0.037). Indeed, all the patient relapses occurred in these high-grade lesions, but due to the small number of patient events, no significant correlation of vascular pattern to survival was observed (P > 0.05). This study suggests that distinct patterns of vascularity in DCIS might be useful for identifying patients who are at risk of relapse.

Distinct angiogenic patterns are associated with high-grade in situ ductal carcinomas of the breast.

Human solid tumors develop multiple genetic evolutionary abnormalities as they evolve. Studies that have focused primarily on early colorectal cancer have suggested that genetic instability is a prominent feature of preinvasive disease. At least two separate mechanisms for the generation of genetic instability have been identified. The first, which involves widespread microsatellite instability in near-diploid cells, affects less than one-fifth of colon cancers. The second form of genetic instability is characterized by the development of p53 gene abnormalities that result in gross aneuploidy and multiple structural chromosomal changes. p53/aneuploidy affects most colon cancers, breast cancers, and many other solid tumors. This genetic evolutionary change commonly occurs at the interface between severe dysplasia and invasive disease. Specific post-aneuploid sequences of genetic changes that are relevant to tumor progression often involve the accumulation of multiple gain-of-function abnormalities in individual cells. The co-occurrence of Her-2/neu overexpression and EGF receptor overexpression in the same aneuploid cells defines an adeno/squamous genetic evolutionary sequence that is common to ductal breast cancers, non-small cell lung cancers, and other solid tumors. Later steps in this sequence include ras and c-myc overexpression. The neuroendocrine genetic evolutionary sequence is a separate branch of the p53/aneuploidy sequence with distinctive features that include loss of Rb and raf1 overexpression. Her-2/neu overexpression is not characteristic of this sequence; c-myc amplification/overexpression is common to both p53-associated sequences. The neuroendocrine sequence is found in small cell carcinoma of the lung and in minor proportions of other solid tumors, including breast cancer. Mutiparameter cell-based methods are especially well suited for elucidation in human solid tumors of the genetic evolutionary sequences that could provide a rational scientific basis for determining prognosis and for optimizing therapy in individual cancer patients. Cytometry 29:1–27, 1997. © 1997 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0320%2819970901%2929%3A1%3C1%3A%3AAID-CYTO1%3E3.0.CO%3B2-J

Common patterns of genetic evolution in human solid tumors

Immunohistochemical c-erbB-2 proto-oncogene expression and nuclear DNA distribution patterns were assessed in 119 formalin-fixed paraffin-embedded surgical specimens of human mammary carcinomas in situ (CIS). The series consisted of 107 ductal carcinomas in situ (DCIS), 9 lobular carcinomas in situ, and 3 cases of Paget's disease of the nipple. Nuclear DNA distribution patterns were assessed by image cytometric analysis of histopathologically identified cell nuclei. Fifty-one of 107 (48%) DCIS were immunoreactive for c-erbB-2, whereas specific cell membrane staining was absent in lobular carcinomas in situ. The neoplastic cell nuclei of 46 CIS (39%) were of DNA diploid type, and 73 CIS (61%) contained aneuploid nuclear DNA. Among various histopathologic subtypes of DCIS, significant differences in c-erbB-2 immunoreactivity and nuclear ploidy were observed. DCIS of the comedo type most often were c-erbB-2 positive and exhibited aneuploid nuclear DNA histograms. DCIS of micropapillary type was the second most frequently reactive c-erbB-2 expression, and aneuploidy were less common in solid, cribriform, and papillary DCIS. The results of the current study indicate that immunohistochemical expression of the c-erbB-2 proto-oncogene product is closely related to the histopathologic subtype and the nuclear DNA content of mammary CIS. Examples of CIS that are c-erbB-2 immunoreactive and DNA aneuploid seem to have a significantly higher risk for the subsequent development of infiltrating mammary carcinoma.

Immunohistochemical c-erbB-2 protooncogene expression and nuclear DNA content in human mammary carcinoma in situ.

The nuclear DNA content of 46 mammary adenocarcinomas in situ was measured by means of image cytometry in 4-microns-thick Feulgen-stained histological sections. Aneuploidy was found in 23 cases (50%), whereas the other 23 cases exhibited a diploid DNA distribution pattern. Intraductal carcinoma, the most common subtype in the present study, was found to be aneuploid in 19 cases (63%), with the comedo variant showing aneuploidy in as many as 10 of 11 cases (91%). In contrast, lobular and papillary carcinoma in situ exhibited only 17% and 0% aneuploidy, respectively. The percentages of aneuploid and diploid DNA profiles of the in situ lesions in the present study are almost identical to those observed in invasive breast adenocarcinoma. This indicates that the DNA distribution pattern characteristic for an individual breast adenocarcinoma is already established at the in situ stage, i.e., it occurs before invasiveness and does not progress from a euploid to an aneuploid pattern. In clinical routines DNA ploidy measurements may be of help to distinguish between e.g., hyperplasias and in situ lesions and may also indicate in which direction the malignancy potential of in situ lesions will develop.

The DNA profile of breast cancer in situ.

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Immunohistochemical c-erbB-2 protooncogene expression and nuclear DNA content in human mammary carcinoma in situ.

The DNA profile of breast cancer in situ.