Subsequent Invasive Breast Cancer Research Articles

S4-4: Clarifying the Risk of Breast Cancer in Women with Atypical Breast Lesions.

Abstract Background: Women diagnosed with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and borderline ADH/DCIS are at increased risk for breast cancer, but the precise degree of risk varies widely in the literature. Information from prior studies is limited by grouping ADH and ALH together and by small cohort sizes. Objectives: To identify women with a pathologic diagnosis of ADH, ALH, LCIS, and borderline ADH/DCIS using Natural Language Processing. To evaluate breast cancer risk based on atypia type. Methods: Using Natural Language Processing, we reviewed all electronically available pathology reports from Massachusetts General Hospital, Brigham and Women's Hospital, and Newton-Wellesley Hospital (members of Partners HealthCare System) from 1987–2010. We identified all women with a diagnosis of ADH, ALH, LCIS, and borderline ADH/DCIS with no prior or concurrent diagnosis of breast cancer. We determined the incidence of subsequent invasive and noninvasive breast cancer, the side of cancer diagnosis compared to original atypia side, and the time to cancer diagnosis for each atypia type. Results: We reviewed 76,333 path reports in 42,950 unique individuals and identified 3049 women who were diagnosed with atypical breast lesions over this 14-year period; 1233 (40.4%) had ADH, 851 (27.9%) had ALH, 595 (19.5%) had LCIS, and 370 (12.1%) had borderline ADH/DCIS. The mean age for atypia diagnosis was 51 years (range: 18–93). At a mean follow-up of 66 months, cancer occurred in 7.0% of women with ADH, 11.3% of women with ALH, 11.1% of women with LCIS, and 8.4% of women with borderline ADH/DCIS. The median time to breast cancer diagnosis was 48 months with ADH, 50 months with ALH, 47 months with LCIS, and 60 months with borderline ADH/DCIS. Significantly more ipsilateral cancers developed than contralateral cancers for all types of atypia combined (p=0.027). The development of invasive versus noninvasive breast cancer was not significantly affected by atypia type. Subsequent cancers were DCIS in 121 patients (43.4%) and invasive in 158 patients (56.6%). Kaplan Meier curves for time to cancer diagnosis based on atypia type were created. The curves for ADH and borderline ADH/DCIS were similar and significantly different than the curves for ALH and LCIS (p<0.001). The estimated 5 and 10-year breast cancer risks for each atypia type are presented in Table 1. Conclusion: A diagnosis of ADH, ALH, LCIS, or borderline ADH/DCIS increases a woman's risk of invasive and noninvasive breast cancer in either breast. The breast cancer risk at 5 and 10 years is significantly higher in those with ALH or LCIS compared to those with ADH or borderline ADH/DCIS, but there is little difference in risk between ADH and borderline ADH/DCIS or between LCIS and ALH. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-4.

Variation in the risk of radiation-related contralateral breast cancer by histology and estrogen receptor expression in SEER

Radiation exposure, particularly at a young age, is an established cause of breast cancer. It is not known whether radiation-related breast cancer risk varies by molecular subtype. We characterized the relative risk (RR) of contralateral breast cancer (CBC) related to radiotherapy by histology and estrogen receptor (ER) status of the CBC in five-year survivors in the Surveillance, Epidemiology, and End Results database using Poisson regression models adjusted for attained age and calendar year, age at and year of treatment, ER status of the first breast cancer, and disease stage. 205,316 female breast cancer survivors were followed for an average of 10years from 1973 until 2007, during which time 6924 women developed a subsequent primary invasive breast cancer in the contralateral breast. The overall RR (and 95% confidence interval (CI)) of radiotherapy-related CBC was 1.11 (1.05-1.16). There was no heterogeneity in risk according to histology of the CBC (P>0.50) for all ages or young age at exposure, but case numbers were small for subtypes other than ductal and lobular carcinomas. Information on ER status was available from 1990 onwards for 3546 CBC cases, of which 2597 (73%) were ER+and 949 (27%) were ER-. The RRs were 1.10 (1.02-1.19) for ER+CBC and 1.19 (1.04-1.35) for ER-CBC (P (difference)=0.33). Among women treated age<35years, radiation-related risk of CBC was non-significantly elevated for ER- (RR=1.38, 95% CI: 0.96-1.97) but not for ER+tumors (RR=0.80, 95% CI: 0.47-1.35) (P (difference)=0.09). We did not find clear evidence that radiation-related risk varies by histology or ER status, but our findings, which were the first to examine this question, were suggestive of possible differences by ER status that may merit further investigation.

Is There a Low-Grade Precursor Pathway in Breast Cancer?

Newly proposed models of breast tumorigenesis suggest that low- and high-grade lesions have distinct tumor progression pathways. Our objective was to examine the relationship between histologic grade and molecular subtype in women with lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) who developed subsequent ipsilateral invasive breast cancers. Patients who underwent surveillance for classical LCIS (1994-2007) and those followed after lumpectomy±radiation for DCIS (1991-2004) who developed subsequent ipsilateral invasive cancers and had available tissue blocks were included. ER/PR/HER2 surrogates were used for molecular subtype. Material was available for 27 patients with classical LCIS who developed ipsilateral invasive cancer (12 invasive ductal cancer [IDC], 14 invasive lobular, 1 mixed), and 26 patients with DCIS (12 low-grade [LG], 14 high-grade [HG]) who developed ipsilateral IDC. No difference in age at diagnosis or median time to invasive cancer existed between groups with LCIS and DCIS. When stratified by grade, 0 of 12 LG-DCIS developed LG-IDC (3 grade II; 9 grade III), and only 1 of 12 LCIS patients who developed IDC had LG-IDC. Thirteen (93%) patients with HG-DCIS developed HG-IDC. In contrast, molecular subtype was maintained in 23 of 27 (85%) cases of LCIS and in 18 of 26 (69%) cases of DCIS. These data do not support a low-grade precursor pathway characterized by LCIS and LG-DCIS. ER/PR and HER2 status have a high rate of concordance between in situ and subsequent invasive lesions. Additional studies of metachronous in situ and invasive lesions are needed to better understand pathways of breast tumorigenesis.

Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias

It has been reported that approximately a million women are diagnosed with benign breast lesions that include ductal hyperplasias per year in the United States. Recent studies that followed women with benign lesions have established that about 8% to 9% of them will subsequently develop invasive breast cancer (IBC). However, currently, there are no means of identifying a subclass of "true precancerous tissues" in women with ductal hyperplasias who will subsequently develop cancer. The purpose of this study is to investigate whether expression of hyaluronoglucosaminidase 1 (HYAL1), a known tumor promoter, in hyperplastic tissues identifies a "true precancerous stage" and predicts subsequent IBC development. A retrospective study was conducted with archival benign tissues of various histologic types and clinical information on development/nondevelopment of IBC. The control group was hyperplastic tissues from women who had no prior history of IBC and did not develop cancer in 5 to 7 years after diagnosis (n = 81). The test group was hyperplastic tissues from patients who developed cancer (n = 82). HYAL1 expression was studied by immunohistochemistry, and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value. Statistical analysis of HYAL1 expression data showed very highly significant association between its expression and subsequent cancer development (P = 0) and very high sensitivity (0.83), specificity (0.84), positive predictive value (0.84), and negative predictive value (0.83). The expression of HYAL1 in ductal hyperplastic tissues is a strong predictor of subsequent development of IBC; therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to screen benign tissues to predict subsequent development of IBC. Detection at the precancerous stage and treatment could drastically cut down breast cancer incidence and deaths from it.

The Sea of Uncertainty Surrounding Ductal Carcinoma In Situ--The Price of Screening Mammography

Wouldn’t it be easier if we lived in a binary world? Everything would be either black or white, yes or no, 1 or 0. And biopsy results would be either normal or cancer. Unfortunately, in the world of cancer, our efforts to detect the disease early have made this a fantasy. We are increasingly faced with the reality of a big gray zone — a broad spectrum of pathologic fi ndings between normal tissue and invasive cancer. And our nosology refl ects the associated ambiguity — dysplasia, intraepithelial neoplasia, hyperplasia with atypia, and even abnormalities of “unknown signifi cance.” The unifying theme for these fi ndings is that they may progress to invasive cancer. Or they may not. Despite the presence of the word “carcinoma,” ductal carcinoma in situ (DCIS) is the poster child for this problem (a senior pathologist involved in developing classifi cation systems confi ded to one of us that he regretted the use of the term carcinoma in DCIS). No one believes that DCIS always progresses to invasive cancer, and no one believes it never does. Although no one is sure what the probability of progression is, studies of DCIS that were missed at biopsy ( 1 , 2 ) and the autopsy reservoir ( 3 ) suggest that the lifetime risk of progression must be considerably less than 50%. There is an added complexity: DCIS is associated with not just one risk but two. In addition to the specifi c risk that the lesion might progress to invasive cancer, DCIS confers a general risk. It is a marker for an increased chance of developing invasive cancer elsewhere in the ipsi- or contralateral breast. Again, although no one is sure what this probability is, a recent prospective study of a cohort of patients with DCIS who were treated largely by excision alone suggested that the 5-year risk of subsequent invasive breast cancer elsewhere is less than 10% ( 4 ). In short, there is a sea of uncertainty surrounding DCIS. Some lesions will progress to cancer, others will not. Some women with DCIS will develop cancer elsewhere in their breasts, whereas others will not. And we’re not sure what the chances are. It isn’t surprising that among women with DCIS the uncertainty of being in this gray zone leads to anxiety. In this issue of the Journal, Partridge et al. ( 5 ) report that many women with DCIS are anxious — even months after the diagnosis. The authors also report that anxiety is associated with exaggerated risk perceptions — many women with DCIS estimate their risk of developing invasive cancer 5 years following treatment to be greater than 50%. Although it’s tempting to hope that better educating women (and their doctors) about the actual risks of DCIS would reduce anxiety, it’s entirely possible that our measures of risk perception and anxiety are simply markers for the same underlying construct — how women feel about being in the gray zone. They are told that they don’t have cancer, but they are not normal; instead, they are at higher risk for developing cancer. Because DCIS is an asymptomatic and nearly always nonpalpable lesion, the majority of women exposed to this sea of uncertainty got there the same way — via screening mammography. Thus, the associated anxiety must be considered to be a harm of mammographic screening. But anxiety is certainly not the only harm. The fundamental paradox of early cancer detection is that, while some may be helped, others get a diagnosis they’d be better off without. The central harm of screening is overdiagnosis — the detection of abnormalities that meet the pathologic defi nition of cancer but will never progress to cause symptoms. Although this concept may seem implausible to clinicians, basic scientists have begun to uncover biologic mechanisms that halt the progression of cancer ( 6 – 8 ). Overdiagnosis has now been associated with early detection

Clonality of lobular carcinoma in situ (LCIS) and metachronous invasive breast cancer

Lobular carcinoma in situ (LCIS) of the breast is generally considered an indicator for a bilaterally increased risk of invasive breast cancer (IBC). However, as recent studies suggested a clonal relationship between a subset of synchronous LCIS and invasive lobular carcinomas (ILC), we aimed to examine a possible precursor role for LCIS and IBC occurring in the same breast at a later time. Out of a consecutive series of 88 LCIS, nine patients developed IBC (5 ILC and 4 invasive ductal carcinomas) between 2 and 10 years after initial biopsy. For each case, mitochondrial DNA heteroplasmy was analyzed in normal mammary gland epithelia, LCIS and IBC by PCR, direct DNA sequencing and phylogenetic tree clustering. Two cases of LCIS and ILC showed identical patterns of heteroplasmy. In one further case, additional mtDNA mutations were present in the ILC following LCIS. The remaining two cases of ILC and all 4 IDC were clonally unrelated to the previously diagnosed LCIS. While the overall risk for the development of invasive breast cancer following LCIS is relatively low and the majority of cases are clonally unrelated, our data clearly show that some LCIS eventually do progress to ILC. Thus, LCIS represents both an indicator lesion for an increased risk of subsequent invasive breast cancer and in some cases a precursor of ILC.

Excellent survival, cancer type, and Nottingham grade after atypical lobular hyperplasia on initial breast biopsy

Atypical lobular hyperplasia (ALH) is associated with a 10% to 20% risk of subsequent invasive carcinoma, primarily in the ipsilateral breast. Nottingham grading, special tumor types, and survival after invasive cancer diagnosis were analyzed consistently for the first time. A longitudinal follow-up study of 252 women who underwent 261 benign surgical biopsies between 1950 and 1985 with a diagnosis of ALH was undertaken. Subsequent invasive breast cancers were graded and subtyped based on histologic features and the cohort assessed for cancer survival. Forty-eight (19%) women developed invasive breast cancer at an average of 15.1 years. Twenty (42%) of the tumors were special subtype tumors with good prognosis. By an average of 13 years after invasive cancer diagnosis, 2 (10%) of 20 women with special type and variant tumors had died of breast cancer, compared with 9 (32%) of 28 women with tumors of no special type (24 tumors) or an unknown type (4 tumors). Only 1 patient with a tumor of low Nottingham grade died of breast cancer. ALH is a nonobligate cancer precursor associated with a moderate risk of breast cancer and predicts that later cancers are associated with overall excellent survival. Nearly half of the subsequent cancers show classic or variant patterns of special types with a good prognosis and the majority are of low or intermediate combined histologic grade. Treatment of women with ALH should be influenced by their modest elevation in breast cancer risk and the good prognosis and low mortality of many of these cancers.

Evolving Concepts in the Management of Lobular Neoplasia

Lobular neoplasia broadly defines the spectrum of changes within the lobule, ranging from atypical lobular hyperplasia (ALH) to lobular carcinoma in situ (LCIS). This continuum of lesions is associated with an increased risk for developing subsequent invasive breast cancer, with the magnitude of that risk corresponding to the degree of proliferative change. The associated risk for developing invasive breast cancer after a diagnosis of lobular neoplasia is multicentric, bilateral, and equal in both breasts. Lobular neoplasia itself may transform into invasive carcinoma, although the frequency of this occurrence is unknown. Thus, lobular neoplasia is a risk factor for invasive breast cancer and may be a precursor lesion in unusual circumstances. The management of ALH and LCIS depends on the setting in which they are encountered. When ALH and LCIS are diagnosed after core needle breast biopsy, wire localization for surgical excision is required for definitive diagnosis because rates of histologic underestimation approach those of atypical ductal hyperplasia (ADH). When diagnosed on surgical biopsy, ALH and LCIS generally do not require further intervention, even when present at a surgical margin. However, bilateral breast cancer risk must be considered, especially when patients have a family history of breast cancer. In selected situations, bilateral prophylactic mastectomy with or without reconstruction may be considered when atypical hyperplasia or LCIS is diagnosed. Although this reduces risk for developing subsequent breast carcinoma by 90%, patients selected for prophylactic mastectomy represent a small subgroup of lobular neoplasia patients and generally have other risk factors, such as strong family history or evidence of genetic predisposition.

Lobular Carcinoma in Situ (LCIS) in Association with Invasive Breast Cancer: Does LCIS Predict for Local Recurrence?

Purpose/Objective: The significance of associated LCIS remains controversial for patients undergoing breast-conserving therapy for invasive breast cancer. Recent data examining LCIS alone indicates it may have substantial premalignant potential and progress to invasive cancer at the site of the index LCIS lesion in addition to functioning as a general risk factor for subsequent invasive breast cancer. In light of this data, we examined the impact of LCIS on clinical outcome in patients with invasive breast carcinoma treated with breast conserving therapy.

Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance, Epidemiology, and End Results Data

Noninvasive lesions involving the lobules of the breast are increasingly diagnosed as incidental microscopic findings at the time of lumpectomy or core-needle biopsy. We investigated the incidence rates of invasive breast cancer (IBC) after a diagnosis of lobular carcinoma-in-situ (LCIS) by using Surveillance, Epidemiology, and End Results (SEER) data. Patients (N = 4,853) having a diagnosis of primary LCIS in the time period of 1973 to 1998 were identified using the SEER Public Use CD-ROM data. The database was then searched for patients with subsequent primary IBC occurrences (n = 350). The clinical and pathologic characteristics of patients with subsequent primary IBCs were compared with the characteristics of patients with primary IBCs attained during the same time period (N = 255,114). The incidence of IBC increased over time from diagnosis of LCIS, with 7.1% +/- 0.5% incidence of IBC at 10 years. IBCs detected after partial mastectomy occurred in either breast (46% ipsilateral and 54% contralateral); however, after mastectomy, most IBCs were contralateral (94.7%). IBCs occurring after LCIS more often represented invasive lobular histology (23.1%) compared with primary IBCs (6.5%). The standardized incidence ratio (the ratio of observed to expected cases) for developing IBC was 2.4 (95% CI, 2.1 to 2.6) adjusted for age and year of diagnosis. LCIS is associated with increased risk of subsequent invasive disease, with equal predisposition in either breast. The minimum risk of developing IBC after LCIS is 7.1% at 10 years.

The incidence of subsequent invasive ipsilateral and contralateral breast cancer in patients with lobular carcinoma in situ (LCIS)

860 Background: Recent studies have indicated that patients with LCIS have higher incidence of ipsilateral breast cancer, suggesting that LCIS is a direct of invasive breast cancer. Methods: Patients with LCIS treated with breast conservation in the Surveillance, Epidemiology, and End Results (SEER) database who developed subsequent invasive breast cancer were analyzed according to the laterality of subsequent invasive breast cancer. Results: Of 5529 patients with LCIS, 447 developed subsequent invasive breast cancer (8.1%). 248 patients developed ipsilateral disease (4.5%) and 199 (3.6%) contralateral disease (p=0.01). The proportion of subsequent invasive lobular carcinoma in patients with LCIS was 40% compared to 10.8% incidence of invasive lobular in SEER overall. The patterns of second breast events for LCIS and ductal carcinoma in situ (DCIS) were similar. Conclusions: Similar to DCIS, LCIS should be regarded as a potential precursor lesion as well as a risk indicator. No significant financial relationships to disclose.

Radiation after lumpectomy for DCIS to reduce the risk of invasive breast cancer: A population-based study

516 Background: Although randomized trials have demonstrated the efficacy of radiation (RT) in reducing the risk of breast cancer after lumpectomy for Ductal Carcinoma in Situ (DCIS), the use of RT in the population remains relatively low. This study was designed to determine the effectiveness of RT after lumpectomy for DCIS in a population-based fashion using SEER data. Methods: We identified women with DCIS treated with lumpectomy in SEER registry data from 1987 through 1996. We evaluated the effect of RT on development of subsequent invasive breast cancer: the overall rate, the rate of ipsilateral invasive cancer, and the rate of contralateral invasive cancer. Using a proportional hazards model, we evaluated the effect of RT on development of invasive breast cancer over time adjusting for potential confounders. Results: A total of 10,034 women underwent lumpectomy for DCIS in this time period; 5063 underwent lumpectomy only and 4971 underwent RT after lumpectomy. Invasive breast cancer developed in 854...

Histopathological and cell biological characteristics of ductal carcinoma in situ (DCIS) of the breast—a comparison between the primary DCIS and subsequent ipsilateral and contralateral tumours

The rate of ipsilateral local recurrence after ductal carcinoma in situ (DCIS) varies (between 5% and 30%) and depends on the type of operation (mastectomy vs. breast-conserving operation), and whether postoperative radiotherapy has been used. Ipsilateral local recurrence can either emanate from the primary lesion or be a new primary tumour. Contralateral lesions may also develop after DCIS. We compared histopathological and cell biological characteristics in 37 subsequent ipsilateral tumours (25 DCIS and 12 invasive cancers) and 13 subsequent contralateral invasive breast cancers with their corresponding primary DCIS. The histopathological parameters were re-evaluated and the cell biological factors were analysed using conventional immunohistochemical techniques in paraffin-embedded material. The concordance rate for high grade (nuclear grade 3) vs. non-high grade (nuclear grades 1+2) between the primary DCIS and the subsequent ipsilateral tumour was higher than between the primary DCIS and the subsequent contralateral invasive cancer (68% vs. 31%). Similar patterns in the concordance rates between the primary DCIS and ipsilateral vs. contralateral tumours were also found in the oestrogen receptor status (83% vs. 50%) and the progesterone receptor status (87% vs. 58%). The pattern persisted in the other factors examined (p53, c-erbB2, bcl-2 and Ki67), although it was less pronounced. The overall high rate of concordance in the characteristics between the primary DCIS and the subsequent ipsilateral tumours suggests that, in most cases, they represent true local recurrences. Subsequent contralateral tumours are more likely to be new primary cancers.

Invasive breast cancer following ductal and lobular carcinomain situ of the breast

We considered the risk of subsequent invasive breast cancer in a population-based series of 579 carcinomas in situ (CIS) of the breast (482 ductal, 88 lobular) registered between 1977 and 2002 in the Swiss Canton of Vaud. A total of 55 cases of invasive breast cancer were observed vs. 12.3 expected, corresponding to a standardized incidence ratio (SIR) of 4.5 (95% confidence interval [CI], 3.4-5.8). The SIR was 4.6 after ductal and 4.2 after lobular CIS, was similar with passing time since CIS diagnosis, but was higher (SIR = 5.5) for women aged <55 years. At 20 years following CIS, the cumulative risk of invasive breast cancer was 26%, similar for lobular and for ductal CIS. The incidence of invasive breast cancer following CIS showed no consistent pattern of trends with age, all rates in subsequent age groups ranging between 10 and 18 in 1,000. This is compatible with the occurrence of a single mutational event in a population of susceptible women.

Risk of subsequent invasive breast carcinoma after in situ breast carcinoma in a population covered by national mammographic screening

Sweden was the first country to establish a nationwide breast cancer screening service. We used the Swedish Family-Cancer Database to evaluate the risk of invasive carcinoma after in situ carcinoma of the breast. Risk estimates for contralateral and ipsilateral invasive malignancies following age and histology specific in situ breast carcinomas were calculated using Poisson's regression analysis. The agreement between concordant and discordant morphologies of invasive and in situ breast cancer was measured using the kappa statistic. Women with in situ breast cancer showed a relative risk of 2.03 for contralateral and 3.94 for ipsilateral invasive breast cancer. The risk was higher for in situ carcinomas diagnosed before the age of 50 years and after lobular in situ breast cancers. A comparison of the risks during the past decades suggested that the risk of ipsilateral breast cancer has increased in Sweden but that of contralateral breast cancer has remained unchanged. In situ and the subsequent invasive breast cancers did not seem to share their morphologies.

Mammographic findings and occupational exposure to pesticides currently in use on Crete

This is a preliminary report of an outreach mammographic-screening programme on Crete. The screening is part of a study to test if occupational exposure to pesticides in greenhouses (mainly organophosphates and organocarbamates), may increase the risk of malignant or premalignant findings in mammographic examination. A total of 1062 women (aged 40–75 years) were recruited between 1988 and 1993 and followed-up until 1998: 522 worked for at least 10 years in greenhouses for more than 4 h daily (exposed), and 540 never worked in agriculture (non-exposed). Statistics include detection rates and relative risks of mammographic findings. ‘Exposed’ women had a significantly ( P<0.05) higher risk than ‘non-exposed’ for fibroadenoma, ductal hyperplasia, sclerotic adenosis, fibrohyperplastic disease, cystic disease and inflammatory mastitis. There were no significant differences in the detection rates of fibrocystic changes, lipoma and malignant changes or malignant tumours. Compared with older women (aged 50–75 years), younger women (aged 40–49 years), particularly in the ‘exposed’ group, had a higher detection rate of malignant tumours. These preliminary results indicate that ‘exposed’ women may have higher risks of incidence for a number of lesions, which are risk markers for subsequent invasive breast cancers. They confirm also that early screening for breast cancer is effective and provides an opportunity for a reduction in breast cancer mortality.

DMBA-Induced Mammary Pathologies are Angiogenic In Vivo and In Vitro

We have previously shown that human pre-invasive diseases of the breast are angiogenic. In addition, normal epithelium from women with coincident or subsequent invasive breast cancer is more vascular than normal epithelium from women with no breast cancer. To develop a model in which to study the regulation of angiogenesis in pre-invasive mammary pathologies, we examined 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tissues for the presence of neovascularization in pre-invasive histopathologies. These studies included morphometric analysis of tissue vascularity in pre-invasive lesions. In addition, we isolated fresh tumors and histologically normal epithelium (organoids) from DMBA or vehicle-treated control rats to test their ability to induce endothelial cell tubule formation in vitro. Finally, we examined tumors for their ability to produce vascular endothelial cell growth factor. The morphometric studies documented that with epithelial progression, the ability of individual cells to elicit angiogenesis increases. The in vitro studies showed that isolated tumors from these animals stimulate angiogenesis. Furthermore, normal epithelium from DMBA-treated rats is more angiogenic than epithelium from control animals. Finally, DMBA-induced tumors produce vascular endothelial growth factor (VEGF) mRNA, therefore, DMBA-induced mammary tumorigenesis is one model in which to test the dependency of progression on angiogenesis.

Risk of subsequent invasive breast cancer after breast carcinoma in situ

The standardised incidence rates for invasive breast cancer were estimated in a cohort of 3455 women with a primary lobular or ductal carcinoma in situ of the breast.

Lobular Carcinoma In Situ of the Breast.

LCIS was first described in 1941 as a distinct pathologic entity by Foote and Stewart who called it a "rare form of mammary carcinoma." It is thought to represent a transitional intra-epithelial, or in situ, stage in the evolution of breast cancer from hyperplastic breast epithelium. With the wide application of mammography, its detection has increased in recent years, being found in approximately 1% of all breast biopsy specimens and 5% of all breast malignancies. Its true incidence is unknown, because the absence of any clinical or radiographic manifestations makes its detection completely arbitrary and random. LCIS has distinct pathologic features characterized by proliferation of bland, homogeneous malignant cells within the terminal duct-lobular apparatus. The lobular architecture and investing basement membrane remain intact with no evidence of invasion into the surrounding stoma. It is assumed to be widely disseminated throughout all breast tissue whenever it is found, having close to 100% incidence of multicentricity and bilaterality. The cells are typically of low histologic and nuclear grade, highly estrogen receptor positive, and have tumor marker characteristics of indolent growth and good prognosis. This is very different from its noninvasive ductal counterpart, DCIS, which is typified by more aggressive cytologic and biologic characteristics. Although LCIS imparts as much as a 12-fold increased risk of subsequent invasive breast carcinoma, its natural history suggests it is more of a marker of risk rather than a true premalignant lesion. Most subsequent malignancies occur more than 15 years after diagnosis, and are ductal rather than lobular. This risk is also equally applied to both breasts, regardless of which breast contains the diagnosed focus. Subsequent invasive breast cancers are typically early with very low mortality, most likely due to the strict mammographic surveillance provided to these women. Although originally treated by mastectomy, most now manage LCIS by careful non-operative observation, in the same way that other risk factors such as family history or atypical hyperplasia are managed. In fact, it has been questioned whether there should be any real distinction between lobular hyperplasia and LCIS. There is no role for excision of biopsy sites of LCIS to obtain clear margins, nor for cytotoxic chemotherapy. However, the NSABP P-1 Prevention Trial strongly suggests that subsequent risk can be significantly reduced by tamoxifen. The only rational surgical treatment, if ablation is judged necessary, would be bilateral mastectomy, which appears far too aggressive in view of its low overall risks. Further investigation should clarify the optimal management of LCIS.

Invasive breast cancer risk in women with sclerosing adenosis.

To assess sclerosing adenosis (SA) as an independent risk factor for subsequent invasive breast cancer (IBC), the authors reviewed 10,366 benign breast biopsy specimens (BB) obtained between 1950 and 1968 and identified 547 cases of SA meeting strict histologic criteria of expanded lobular units with whorled compressed acini. Of those women targeted for follow-up (3303, of whom 349 had SA), 84% were successfully followed for an average of 17 years. The relative risk for IBC among patients with SA regardless of the presence of atypical hyperplasia (AH) was 2.1. This risk decreased to 1.7 when patients with AH were excluded, and rose to 6.7 when only those patients with SA and AH were analyzed. The coexistence of a family history of IBC in a first-degree relative did not further elevate risk above that of SA alone when women with AH were excluded. Sclerosing adenosis was found to be positively associated with atypical lobular hyperplasia (ALH) as ALH was present in biopsy specimens with SA 2.7 times more frequently than in other biopsy specimens. Perimenopausal age, histologic calcification, and family history of IBC (FH) were also positively associated with SA. Sclerosing adenosis was most frequent in the perimenopausal period and had a weak association with family history of IBC. No association with atypical ductal hyperplasia (ADH) was identified. The authors conclude sclerosing adenosis represents an independent risk factor for subsequent invasive breast cancer apart from its association with ALH, and the risk (excluding patients with coexistent atypical hyperplasia) is in the range of 1.7, times thereby justifying inclusion of sclerosing adenosis as a component of a group of histopathologically defined lesions termed "proliferative breast disease without atypia" which implies a relative cancer risk of 1.5 to 2.0.