ER-negative Ductal Carcinoma In Situ Research Articles

Impact of Surgical Delay on Tumor Upstaging and Outcomes in Estrogen Receptor–Negative Ductal Carcinoma in Situ Patients

The delay of elective surgeries by the coronavirus 2019 (COVID-19) pandemic prompted concern among surgeons to delay estrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) for fear of missing an ER-negative invasive cancer and compromising survival of patients. Female patients ≥40 years old diagnosed with ER-negative DCIS from 2004 to 2017 were examined from the National Cancer Database. Multivariable logistic regression, adjusting for patient and tumor factors, was used to determine factors associated with tumor upstage. Multivariable Cox proportional hazards modeling was used to determine if surgical delay impacted overall survival of ER-negative DCIS patients that were upstaged to invasive disease. There were 219,731 patients with DCIS of which 24,338 (11.1%) had tumor upstage. Of these patients, 5,675 (16.2%) of ER-negative and 18,663 (10.1%) of ER-positive DCIS patients were upstaged (p ≤ 0.001). From 2004 to 2017, ER-negative DCIS upstage rates increased from 12.9% to 18.9%. Independent factors associated with tumor upstage were younger age (odds ratio [OR] 0.75 [95% CI 0.69 to 0.81]) and Black race (OR 1.34 [95% CI 1.22 to 1.46]). Compared with patients with ≤30 days between biopsy and surgery, patients with a 31- to 60-day interval (OR 1.13 [95% CI 1.05 to 1.20]) and a >60-day interval (OR 1.12 [95% CI 1.02 to 1.23]) had an increased rate of tumor upstage. Among ER-negative DCIS patients whose tumors were upstaged to invasive disease, Cox proportional hazard regression modeling showed no association between the number of days between biopsy and surgery and overall survival. Delays in surgery were associated with higher tumor upstage rates but not with worse overall survival.

The Utility of SOX10 Immunohistochemical Staining in Breast Pathology.

SOX10 expression helps identify melanocytic lesions. Over time, novel uses have been identified, such as expression in triple-negative breast cancer (TNBC). We evaluated the usefulness of SOX10 in breast pathology-specifically, identification and subtyping of TNBC and distinction from gynecologic carcinomas, use as a myoepithelial marker, and in the distinction of usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH). Several breast and gynecologic carcinoma tissue microarrays containing a total of 492 cases were stained with SOX10. Whole sections of 34 ADH, 50 UDH, and 29 ductal carcinoma in situ (DCIS) samples were also stained with SOX10. SOX10 expression was identified in 67% of consecutive TNBC cases. Expression was mostly seen in nonapocrine, androgen receptor (AR)-negative TNBCs. All gynecologic carcinomas (n = 157) were negative. All UDH cases showed mosaic SOX10 expression, while all ADH cases lacked expression. All estrogen receptor (ER)-positive DCIS (n = 19) specimens were negative for SOX10, while 2 of 10 ER-negative DCIS specimens were positive for SOX10. The latter 2 cases showed SOX10-positive invasive carcinomas. SOX10 identifies nonluminal AR-type TNBC and is useful in distinguishing TNBC from gynecologic carcinomas. SOX10 can distinguish UDH from ADH. SOX10 is not useful in distinguishing ADH from DCIS.

Subtype-Specific Tumour Immune Microenvironment in Risk of Recurrence of Ductal Carcinoma In Situ: Prognostic Value of HER2.

Increasing evidence suggests that the significance of the tumour immune microenvironment (TIME) for disease prognostication in invasive breast carcinoma is subtype-specific but equivalent studies in ductal carcinoma in situ (DCIS) are limited. The purpose of this paper is to review the existing data on immune cell composition in DCIS in relation to the clinicopathological features and molecular subtype of the lesion. We discuss the value of infiltration by various types of immune cells and the PD-1/PD-L1 axis as potential markers of the risk of recurrence. Analysis of the literature available in PubMed and Medline databases overwhelmingly supports an association between densities of infiltrating immune cells, traits of immune exhaustion, the foci of microinvasion, and overexpression of HER2. Moreover, in several studies, the density of immune infiltration was found to be predictive of local recurrence as either in situ or invasive cancer in HER2-positive or ER-negative DCIS. In light of the recently reported first randomized DCIS trial, relating recurrence risk with overexpression of HER2, we also include a closing paragraph compiling the latest mechanistic data on a functional link between HER2 and the density/composition of TIME in relation to its potential value in the prognostication of the risk of recurrence.

Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial.

The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS. Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method-analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed. ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66-9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84-3.53; P = 0.14), P heterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53-4.61). PgR status did not add to the prognostic information provided by ER. ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Androgen Receptors in Resected Ductal Carcinoma In Situ of Breast: Novel Insights With Possible Implications for Testing and Targeted Endocrine Chemoprevention Trials.

Mammary ductal carcinoma in situ (DCIS) is classically treated by combinations of excision, radiation, and endocrine therapy, based upon the specific needs of individual patients. Estrogen receptor (ER) status is generally assessed by immunohistochemistry (IHC) in newly diagnosed cases of DCIS, and endocrine therapy in this setting is thought to be chemopreventive. The potential impact of androgens on mammary carcinogenesis has been studied in recent years, and several authors have proposed androgen receptor (AR) IHC testing and targeted antiandrogenic therapy in patients with locally advanced or metastatic triple-negative invasive breast cancer (ie, negative for ER and progesterone receptor and HER-2). Very little has been published on AR in DCIS. We report results of AR IHC on archival tissue blocks from 221 adult female patients, each of whom underwent definitive breast resection of DCIS. Of the 221 cases, 72 (33%) were shown to express AR in their DCIS at or above the 10% threshold often used for invasive carcinoma. AR expression was seen in all grades of DCIS. Of the 72 positive AR cases, 21 (29%) were ER negative, corresponding to 10% (21/221) of all patients. The majority of the AR-positive cases were high grade, and the most common histologic subtype in this subset was a solid growth pattern with apocrine features. Early data from clinical trials evaluating AR antagonists in invasive/metastatic triple-negative breast cancer suggest that some patients may benefit from androgen blockade. IHC testing and potential clinical trials of AR antagonists for chemoprevention in patients with AR-positive and ER-negative DCIS could be considered.

Endocrine Therapy Initiation among Older Women with Ductal Carcinoma In Situ.

Background Although treatment of ductal carcinoma in situ (DCIS) is controversial, national guidelines recommend considering endocrine therapy for women with estrogen receptor- (ER-) positive DCIS or those undergoing breast conserving surgery (BCS) without radiation. We evaluated uptake and predictors of endocrine therapy use among older women with DCIS. Methods In the SEER-Medicare database, we identified women aged 65+ years diagnosed with DCIS during 2007–2011. We evaluated demographic, tumor, and treatment characteristics associated with endocrine therapy initiation. Results Among 2,945 women with DCIS, 41% initiated endocrine therapy (66% tamoxifen, 34% aromatase inhibitors). Initiation was more common among women with ER-positive than ER-negative DCIS (48% versus 16%; HR = 3.75, 95% CI: 2.91–4.83); 28% of women with unknown ER status initiated endocrine therapy. Initiation was less common after BCS alone compared to BCS with radiation (32% versus 50%; HR = 0.69, 95% CI: 0.59–0.80). Conclusions Less than half of older women with DCIS initiate endocrine therapy to prevent second breast cancers. Our findings suggest use was more common, but not exclusive, among women with ER-positive DCIS, but not among women who underwent BCS alone. Endocrine therapy should be targeted toward patients most likely to benefit from its use.

CD10-positive myoepithelial cells are usually prominent around in situ lobular neoplasia of the breast and much less prominent or absent in DCIS

AimsTo study the relationship between the neoplastic cells of in situ lobular neoplasia (ILN) and ductal carcinoma in situ (DCIS) and the surrounding CD10-positive myoepithelial cells.Materials and methodsTwenty consecutive cases...

Abstract P6-13-04: Metformin for the treatment of ductal carcinoma in situ (DCIS)

Abstract BACKGROUND: Each year about 60,000 new cases of breast ductal carcinoma in situ (DCIS) are diagnosed in the United States. DCIS significantly increases the risk of invasive breast cancer. To reduce this risk, tamoxifen is offered to patients with ER-positive DCIS in the adjuvant setting. In contrast, no adjuvant therapy exists for ER-negative DCIS. Metformin is a frontline therapy for type 2 diabetes and its safety and side effect profiles are well documented. Preclinical, epidemiologic, and retrospective data all support an antitumor effect of metformin in breast cancer. Metformin may act via activation of AMP kinase (AMPK), a sensor of cellular energy, which in turn inhibits mTOR activity and shuts down global protein synthesis. Previous data from our group showed that metformin treatment is associated with a higher rate of pathologic complete response in diabetic breast cancer patients receiving preoperative chemotherapy. In the current study, using preclinical models, we explored the effects of metformin in DCIS and its progression to invasive breast cancer. EXPERIMENTAL DESIGN AND METHODS: We tested the anti-tumor activity of metformin in terms of proliferation and invasion using both DCIS cell lines and a mouse intraductal (MIND) transplantation model previously developed by us. The latter involves intraductal injection of human DCIS cells into mouse mammary glands, and importantly recapitulates the progression of DCIS to invasive cancer seen in human breast cancer. Western blot and immunofluorescent staining for AMP kinase, mTOR, and other relevant targets, as well as flow cytometry, were used to investigate mechanism. RESULTS: Metformin significantly inhibited cell proliferation, migration, and invasion in all DCIS cell lines tested. In the mouse model, using metformin at a dose that is readily achievable in human patients, metformin significantly reduced the tumor burden in terms of median number of ducts filled, from 11 to 2 using DCIS.com cells (p &amp;lt; 0.001) and from 10 to 3 using SUM.225 cells (p = 0.004). In addition, importantly, metformin inhibited the progression of DCIS lesions to invasive breast cancer significantly, with a reduction in invasive lesions from 74 to 17% (p = 0.003). In mechanistic studies, metformin showed activation of AMPK and subsequent inactivation of mTOR and other downstream targets. Treatment with metformin did not lead to significant cell cycle arrest but rather to increased cell death. We found that cell death by apoptosis increased only modestly with metformin treatment, while cell death by necrosis increased significantly. CONCLUSION: Metformin inhibits the growth of DCIS and its progression to invasive breast cancer. To our knowledge, this is the first reported evidence of metformin’s anti-tumor activity in DCIS. Our data support the exciting prospect of developing metformin clinically for the treatment of DCIS. Citation Format: Atreyi Dasgupta, David G Edwards, Frances S Kittrell, Susan G Hilsenbeck, Daniel Medina, Sao Jiralerspong. Metformin for the treatment of ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-04.

Clinicopathologic, mammographic, and sonographic features in 1,187 patients with pure ductal carcinoma in situ of the breast by estrogen receptor status

The clinicopathologic, mammographic, and sonographic findings in patients with pure ductal carcinoma in situ (DCIS) were assessed by estrogen receptor (ER) expression. After institutional review board approval, patients with pure DCIS evaluated from January 1996 to July 2009 with known ER status and available imaging were identified. Images were reviewed as per the ACR BI-RADS(®) lexicon (4th edition). Clinical, pathologic, and imaging characteristics were analyzed by ER status using t test, Chi square test, and Fisher's exact test. Of 1,219 patients with pure DCIS and known ER status identified, 1,187 with complete data were included. Mammography was performed in all 1,187 patients and sonography in 519 (44 %). There were 972 (82 %) patients with ER-positive and 215 (18 %) with ER-negative disease. ER-negative DCIS was more likely to be high grade (93 vs 44 %, p < 0.0001), associated with comedonecrosis (64 vs 29 %, p < 0.0001), and multifocal (23 vs 15 %, p = 0.009). On sonography, ER-negative DCIS was more likely to be visible (61 vs 46 %, p = 0.004), larger (mean size, 2.3 vs 1.6 cm, p = 0.006), and show posterior shadowing (53 vs 28 %, p = 0.006). Mastectomy was more frequently performed for ER-negative DCIS (47 vs 37 %, p = 0.008). Palpable DCIS was visible on sonography in 55 % of cases and mammography in 81 %. Compared with ER-positive palpable DCIS, ER-negative palpable DCIS was larger and more likely to be visible on sonography. Compared with ER-positive noncalcified DCIS, ER-negative noncalcified DCIS was less likely to be visible on mammography. ER-positive and ER-negative pure DCIS have different clinicopathologic and imaging characteristics. ER-negative DCIS is associated with worse prognostic factors than ER-positive DCIS. On sonography, ER-negative DCIS is more frequently visible than ER-positive DCIS, tends to be larger, and more frequently demonstrates posterior shadowing.

Breast cancer risk reduction among patients with DCIS.

1562 Background: The incidence of ductal carcinoma in situ (DCIS) has dramatically increased with widespread mammographic screening. Although risk of recurrence of DCIS is low, it is associated with a higher risk for subsequent contralateral breast cancer (CBC), for which preventive measures are available. We evaluated the uptake of surgical and pharmacologic interventions to reduce CBC risk at our institution and investigated factors that may influence treatment choices for DCIS. Methods: City of Hope (COH) DCIS patients were identified using two sources, the Circulating Breast Tumor Marker (BrTM) Registry and the National Comprehensive Cancer Network (NCCN) database. Datasets were linked together, and treatment variables were cross-tabulated with patient and tumor characteristics. Results: Of 782 patients with breast malignancy diagnosed since 1997, 370 were excluded due to concurrent or prior invasive disease, 8 due to suspected misclassification based on therapies received, and 4 due to treatment on protocol. Of the remaining pure DCIS patients, treatment choices were recorded for 289. Of those, 40 (14%) chose bilateral risk reduction mastectomy (BRRM), 82 (28%) unilateral mastectomy, 165 (57%) lumpectomy, and 2 had no surgery. Hormonal therapy (HT) was recorded for 215 individuals who did not pursue BRRM: 124 (57%) took tamoxifen, 3 of whom switched to raloxifene, 5 (2%) started with raloxifene, and 7 (3%) took an unspecified hormonal agent, for a total HT uptake of 55%. This included 8 of 29 women with ER-negative DCIS who chose HT for CBC risk reduction. Younger age at diagnosis was associated with BRRM (24% of women diagnosed before age 50, 10% of those diagnosed 50-64, and 5% of women 65+ had BRRM, p&lt;0.001) and HT (59% of women &lt;65 chose HT compared to 40% of women 65+, p=0.009). Within ethnic minorities, more Asian women chose BRRM (22% vs 7% of other minorities, p=0.08). Interestingly, fewer high grade DCIS women opted for HT (39% vs 55% for low to intermediate grade, p=0.06). Conclusions: Young women tend to pursue surgical prophylaxis. Among women who keep their breasts, HT uptake was high across all age and ethnic groups, except for those older than 65 at diagnosis. It is unclear if this is due to patient choice or reflects age bias in physician recommendation.

Adjuvant Tamoxifen Reduces Subsequent Breast Cancer in Women With Estrogen Receptor–Positive Ductal Carcinoma in Situ: A Study Based on NSABP Protocol B-24

The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-24 study demonstrated significant benefit with adjuvant tamoxifen in patients with ductal carcinoma in situ (DCIS) after lumpectomy and radiation. Patients were enrolled without knowledge of hormone receptor status. The current study retrospectively evaluated the relationship between receptors and response to tamoxifen. Estrogen (ER) and progesterone receptors (PgR) were evaluated in 732 patients with DCIS (41% of original study population). An experienced central laboratory determined receptor status in all patient cases with available paraffin blocks (n = 449) by immunohistochemistry (IHC) using comprehensively validated assays. Results for additional patients (n = 283) determined by various methods (primarily IHC) were available from enrolling institutions. Combined results were evaluated for benefit of tamoxifen by receptor status at 10 years and overall follow-up (median, 14.5 years). ER was positive in 76% of patients. Patients with ER-positive DCIS treated with tamoxifen (v placebo) showed significant decreases in subsequent breast cancer at 10 years (hazard ratio [HR], 0.49; P < .001) and overall follow-up (HR, 0.60; P = .003), which remained significant in multivariable analysis (overall HR, 0.64; P = .003). Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit was observed in ER-negative DCIS. PgR and either receptor were positive in 66% and 79% of patients, respectively, and in general, neither was more predictive than ER alone. Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer. The use of adjuvant tamoxifen should be considered for patients with DCIS.

Protocol for the Examination of Specimens From Patients With Ductal Carcinoma In Situ of the Breast

Authors Susan C. Lester, MD, PhD, FCAP* Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts Shikha Bose, MD, FCAP Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California Yunn-Yi Chen, MD, PhD, FCAP Department of Pathology, UCSF Medical Center, San Francisco, California James L. Connolly, MD, FCAP Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Monica de Baca, MD, FCAP Physicians Laboratory, Sioux Falls, South Dakota Patrick L. Fitzgibbons, MD, FCAP Department of Pathology, St. Jude Medical Center, Fullerton, California Daniel F. Hayes, MD, Department of Medical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan Celina Kleer, MD, FCAP Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan Frances P. O’Malley, MD, FCAP Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, University of Toronto, Ontario, Canada David L. Page, MD, FCAP Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee Barbara L. Smith, MD, PhD Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts Donald L. Weaver, MD, FCAP Department of Pathology, College of Medicine and Vermont Cancer Center, University of Vermont, Burlington, Vermont Eric Winer, MD Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts Jean F. Simpson, MD, FCAP† Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee For the Members of the Cancer Committee, College of American Pathologists

Abstract A34: Curcumin downregulates IL-8 in ER negative DCIS breast cancer model: Correlation between HER-2-induced inflammation and tumorigenecity

Abstract A34 Introduction Overexpression of HER-2 oncogene is reported in more than 60% of ductal carcinoma in situ (DCIS) breast cancer, including 30% estrogen receptor negative chemotherapy resistant high-grade tumors with metastatic phenotype. Recent studies show high correlation between MRI characteristics and lower ER score, higher grade, much higher CD68 count (inflammatory marker) and extensive comedo necrosis of DCIS. The inflammatory cytokine IL-8 is found to be overexpressed in most ER- breast cancers and is recently suggested as a marker of tumor invasion and metastasis. Curcumin (CUR) the active component of the spice turmeric, known for its immunomodulatory, antimutagenic and antitumorigenic properties and was found to inhibit cell proliferation and mitogenic signal transduction pathways in ER negative, HER-2 positive DCIS breast cancer model. Material and Methods Normal 184-B5 breast epithelial cells and transformed 184-B5/HER cells in log phase were exposed to 0, 5, 10 and 20 μM CUR for 24 and 48 hours and analyzed for dose response, cell viability, cell cycle distribution, gene expression and HER-2 signal transduction protein markers. Results 184-B5/HER cells exhibit hyper-proliferation, shorter population doubling time, higher saturation density, reduced rate of apoptosis, higher anchorage independent growth and tumorigenecity compared to the non-tumorigenic ER-, PR-, HER2-, EGFR+ and p53+ parental immortalized 184-B5 cells. Cell cycle analysis of 184-B5/HER cells exposed to 20μM CUR showed cytostatic arrest of growth, 85% inhibition of colony formation, decreased G0/G1: S+G2/M ratio and increased apoptosis. Microarray data showed 557 probes to be modulated in 20μM CUR (24 hrs) treated 185-B5/HER cells (117 upregulated, 380 downregulated). These include reduced expression of cell cycle regulatory genes such as cyclin A (-2.79), cyclin B2 (-3.89), cyclin D1 (-1.50), cdk2 (-1.69) and Cdc25c (-3.80). Decreased levels of Cyclin B2, cdk2 and Cdc25c cell cycle proteins in 184-B5/HER cells, reflect CUR induced cell cycle arrest in S and G2/M phases. Treatment with CUR decreased NFkB (-1.86) in 184-B5/HER cells suggesting modulation of downstream signaling pathways including the inflammatory cascade. We observed a 10 fold higher levels of interleukin-8 (IL-8) gene expression in 184-B5/HER cells compared to 184-B5 cells, while treatment with CUR dramatically reduced the IL-8 gene expression as revealed by both microarray and real-time PCR. Conclusion Treatment of breast epithelial 184-B5/HER cells with CUR show preventive efficacy in this ER negative DCIS model via cytostatic arrest in S and G2/M phases of the cell cycle, by downregulation of ERK pathway and induction of apoptosis, verified at both the gene and protein levels. Moreover, CUR down-regulates key regulatory proteins such as NFkB and IL-8 expression thus preventing the inflammatory cascade and possible progression of DCIS into invasive ductal carcinoma. Reduced expression of metastatic molecular marker IL-8 by CUR in 184-B5/HER cells suggests its preventive/therapeutic potential [Support: NIH-NCI CA122394]. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A34.

Molecular markers and therapeutic targets in ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) of the breast is a premalignant condition which accounts for approximately 20% of all new breast cancers and up to 40% of neoplastic lesions detected by mammographic screening. Since recurrence is common after DCIS treated with breast conservation surgery, there is a need to determine molecular factors that predict recurrence. In parallel with this and with the finding that oestrogen receptor (ER) positive breast cancer can be prevented with anti-oestrogens, there have been recent advances in the understanding of the molecular biology of DCIS. Receptor coexpression in DCIS has been determined largely by immunohistochemistry. Animal models have provided evidence for the signalling pathways involved in the regulation and dysregulation of proliferation and apoptosis in both normal breast and in situ cancer. ER-negative DCIS has been shown to be hormone-independent. Blockade of the pathways involved in cell proliferation in ER-negative DCIS is possible and will be necessary to prevent ER-negative breast cancers if the goal of breast cancer chemoprevention is to be realistically achieved.

Studies of epidermal growth factor receptor inhibition in breast cancer.

Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.