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Background: The inability to identify individuals with ductal carcinoma in situ (DCIS) who are at risk of breast cancer (BC) mortality have hampered efforts to reduce the overtreatment of DCIS. The 21-gene recurrence score (RS) predicts distant metastases for individuals with invasive BC, but its prognostic utility in DCIS is unknown., Methods: We performed a population-based analysis of 1362 individuals of DCIS aged 75 years or younger at diagnosis treated with breast-conserving therapy. We examined the association between a high RS (defined a priori as >25) and the risk of BC mortality by using a propensity score-adjusted model accounting for the competing risk of death from other causes, testing for interactions. All statistical tests were 2-sided., Results: With 16 years median follow-up, 36 (2.6%) died of BC, and 200 (14.7%) died of other causes. The median value of the RS was 15 (range = 0-84); 29.6% of individuals had a high RS. A high RS was associated with an 11-fold increased risk of BC mortality (hazard ratio = 11.27, 95% confidence interval [CI] = 3.00 to 42.33; P < .001) in women aged 50 years or younger at diagnosis treated with breast-conserving surgery alone, culminating in a 9.4% (95% CI = 2.3% to 22.5%) 20-year risk of BC death. For women with a high RS, treatment with radiotherapy was associated with a 71% (hazard ratio = 0.29, 95% CI = 0.10 to 0.89; P = .03) relative and a 5% absolute reduction in the 20-year cumulative risk of death from BC., Conclusion: The 21-gene RS predicts BC mortality in DCIS and combined with age (50 years or younger) at diagnosis can identify individuals for whom radiotherapy reduces the risk of death from BC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context.—: The use of neoadjuvant therapy in the management of early-stage invasive breast cancer is increasing. Residual Cancer Burden and other similar tools use pathologic characteristics of post-neoadjuvant therapy breast tumors to determine long-term outcome. However, there are no standardized guidelines for the pathologic evaluation of these specimens in the routine clinical setting., Objective.—: To assess current practices among Canadian pathologists and pathology assistants with regard to the processing and reporting of post-neoadjuvant therapy breast specimens., Design.—: An electronic survey was distributed to pathologists and pathology assistants across Canada., Results.—: Sixty-three responses were obtained. A total of 48% (15 of 31) of surveyed pathologists reported familiarity with the Residual Cancer Burden tool. A total of 40% (25 of 63) of respondents reported a lack of routine use of specimen photography, and 35% (22 of 63) reported a lack of routine use of grossing diagrams. There was significant variation with respect to tumor bed sampling; the most common method was to submit 1 block per centimeter of tumor (20 of 63; 32%). There was also significant variation in the method of measuring residual tumor; the most common method was to measure the largest cross-section of residual tumor (16 of 32; 50%)., Conclusions.—: There is a need for standardization of the evaluation of post-neoadjuvant therapy breast specimens in the routine clinical setting in Canada. We recommend the routine use of specimen mapping, submitting the largest cross section of tumor bed in toto, reporting tumor size as per American Joint Committee on Cancer and Residual Cancer Burden guidelines, and routinely including measurements of residual tumor cellularity and in situ disease in the final pathology report as per Residual Cancer Burden guidelines., (© 2020 College of American Pathologists.)

Purpose: The impact of Ductal Carcinoma in Situ (DCIS) with multiple foci of microinvasion (MI) (≤ 1 mm) on the risks of local recurrence (LR) and invasive LR is unknown, leading to uncertainty if DCIS with multiple foci of MI requires more aggressive treatment. We report a population-based analysis of the impact of multiple foci of MI, confirmed by pathology review, on the 15-year risks of LR and invasive LR treated with breast-conserving surgery (BCS) ± radiotherapy (RT)., Methods: Cohort includes all women diagnosed with DCIS ± MI from 1994 to 2003 treated with BCS ± RT. Cox proportional hazards model was used to evaluate the impact of multiple foci of MI on the risks of LR and invasive LR, adjusting for covariates. The 15-year local and invasive local recurrence-free survival rates were calculated using the Kaplan-Meier method with differences compared by log-rank test., Results: The cohort includes 2988 women treated by BCS; 2721 had pure DCIS (51% received RT), 267 had DCIS with one or more foci of MI (58% had RT). Median follow-up was 13 years. Median age at diagnosis was 58 years. On multivariable analyses, the presence of multiple foci of MI was associated with an increased risk of invasive LR (HR = 1.59, 95% CI 1.01-2.49, p = 0.04) but not DCIS LR (HR = 0.89, 95% CI 0.46, 1.76, p = 0.7). The 15-year invasive LRFS risks for cases with pure DCIS, with 1 focus or multiple foci of MI were 85.7%, 85.6%, 74.7% following treatment by BCS alone, 87.2%, 89.9%, and 77% for those treated with BCS + RT without boost and 89.2%, 91.3%, and 95% for women treated with BCS + RT and boost., Conclusions: The presence of multiple foci of MI in DCIS is associated with higher 15-year risks of invasive LR after breast-conserving therapy compared to women with pure DCIS but treatment with whole breast and boost RT can mitigate this risk.

A subset of patients with ductal carcinoma in situ (DCIS) of the breast develop ipsilateral invasive breast cancer after breast-conserving surgery with or without adjuvant radiotherapy. Risk assessment and prediction of adverse outcomes for individual patients based on traditional clinical and pathological parameters are limited. The Oncotype DCIS Score is a commercially available multigene assay that has been independently validated in a prospective clinical trial and a population-based cohort. The score helps to identify a subset of women >50 years old with unifocal disease that carries <10% risk of any local recurrence after breast-conserving surgery alone. In this population, individual patients and physicians may consider omitting adjuvant radiotherapy. In this article, we review the literature and summarize the evidence regarding the role of the Oncotype DCIS Score in estimating the risk of ipsilateral local recurrence and ipsilateral invasive breast cancer recurrence. The available data on clinical utility and cost-effective analysis for optimizing decisions on adjuvant treatments are discussed., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Although the rate of carcinoma upgrade for atypical ductal hyperplasia (ADH) diagnosed on core needle biopsy (CNB) is variable, current standard treatment consists of surgical excision (SE) for all ADH CNB diagnoses. Our objective was to identify features of ADH on CNB that may stratify carcinoma upgrade risk on SE., Methods: We retrospectively analyzed cases diagnosed as ADH on CNB. An independent slide review and detailed analysis of radiological and clinical data was performed. Statistical analyses were used to identify predictors for upgrade. Using variables predictive of upgrade, a model to stratify the probability of upgrade of ADH diagnosed on CNB was constructed., Results: We identified 124 ADH cases with subsequent SE. Of these, 62 cases (50%) were upgraded to carcinoma. Features predictive of upgrade were as follows: diagnosis of "At least ADH", percentage of cores involved by ADH, radiologic lesion size, presence of ipsilateral carcinoma, and patient age. A 4-tiered predictive model using percentage of cores involved by ADH, histologic extent of ADH, radiologic lesion size, and patient age was constructed. This predictive model has a fair accuracy, with an area under the ROC curve of 0.76., Conclusion: We have identified several predictors of carcinoma upgrade for ADH diagnosed on CNB. Our predictive model may be used to stratify the risk of carcinoma upgrade on SE., (© 2018 Wiley Periodicals, Inc.)

Purpose.—: To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline., Methods.—: Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations., Recommendations.—: Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥2.0; average HER2 copy number <4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results.

Mammary fibroepithelial lesions encompass a wide spectrum of tumors ranging from an indolent fibroadenoma to potentially fatal malignant phyllodes tumor. The criteria used for their classification based on morphological assessment are often challenging to apply and there is no consensus as to what constitutes an adequate resection margin. We studied a retrospective cohort of 213 fibroepithelial lesions in 178 patients (80 fibroadenomas with unusual features and 133 phyllodes tumors: 63 benign, 41 borderline, and 29 malignant) in order to describe the spectrum of changes within each group, with special emphasis on margin evaluation. Outcome data were available for 153 fibroepithelial lesions in 139 patients (median 56 months, range 3-249 months). Positive final margin (tumor transected), age < 50 years and a predominantly myxoid stroma were statistically significant predictors of local recurrence, while age > 50, stromal overgrowth, diffuse marked atypia, necrosis and mitotic index of ≥ 10 per 10 HPF were predictive of distant metastases. Tumors with satellite/bulging nodules were at a significantly higher risk to have a final positive resection margin. Our findings highlight important aspects of the interpretation and reporting of fibroepithelial lesions: the amount of myxoid stroma and the presence of satellite nodules are clinically relevant and should be routinely assessed and reported; infiltrative border might not be a prerequisite for the diagnosis of malignant phyllodes tumor, while the presence of tumor necrosis, massive stromal overgrowth or mitotic index of ≥ 25 per 10 HPF is diagnostic of malignant phyllodes tumor. On the other hand, increased mitotic index outside of the range of the World Health Organization guidelines in the absence of other worrisome features should be treated with caution, as it can be found in benign tumors.

Purpose: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone., Methods: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis., Results: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone., Conclusions: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Background: Detection of HER2/neu receptor overexpression and/or amplification is a prerequisite for efficient anti-HER2 treatment of breast and gastric carcinomas. Immunohistochemistry (IHC) of the HER2 protein is the most common screening test, thus precise and reproducible IHC-scoring is of utmost importance. Interobserver variance still is a problem; in particular in gastric carcinomas the reliable differentiation of IHC scores 2+ and 1+ is challenging. Herein we describe the physical basis of what we called the 'magnification rule': Different microscope objectives are employed to reproducibly subdivide the continuous spectrum of IHC staining intensities into distinct categories (1+, 2+, 3+)., Methods: HER2-IHC was performed on 120 breast cancer biopsy specimens (n = 40 per category). Width and color-intensity of membranous DAB chromogen precipitates were measured by whole-slide scanning and digital morphometry. Image-analysis data were related to semi-quantitative manual scoring according to the magnification rule and to the optical properties of the employed microscope objectives., Results: The semi-quantitative manual HER2-IHC scores are correlated to color-intensity measured by image-analysis and to the width of DAB-precipitates. The mean widths ±standard deviations of precipitates were: IHC-score 1+, 0.64 ± 0.1 μm; score 2+, 1.0 ± 0.23 μm; score 3+, 2.14 ± 0.4 μm. The width of precipitates per category matched the optical resolution of the employed microscope objective lenses: Approximately 0.4 μm (40×), 1.0 μm (10×) and 2.0 μm (5×)., Conclusions: Perceived intensity, width of the DAB chromogen precipitate, and absolute color-intensity determined by image-analysis are linked. These interrelations form the physical basis of the 'magnification rule': 2+ precipitates are too narrow to be observed with 5× microscope objectives, 1+ precipitates are too narrow for 10× objectives. Thus, the rule uses the optical resolution windows of standard diagnostic microscope objectives to derive the width of the DAB-precipitates. The width is in turn correlated with color-intensity. Hereby, the more or less subjective estimation of IHC scores based only on the staining-intensity is replaced by a quasi-morphometric measurement. The principle seems universally applicable to immunohistochemical stainings of membrane-bound biomarkers that require an intensity-dependent scoring.

Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for Ductal Carcinoma in Situ (DCIS) halves the risk of local recurrence (LR). The omission of RT is often supported by the paradigm that patients who develop LR can be salvaged with further breast-conserving therapy leading to higher rates of breast preservation and improved quality of life. However, population-based, long-term rates of breast preservation in women treated by upfront BCS ± RT are unknown., Methods and Materials: Women diagnosed with pure DCIS from 1994 to 2003 treated with BCS ± RT in Ontario were identified. Median follow-up is 12 years. The development and treatment of LR and contralateral breast cancers were determined by administrative databases with validation. The 10-year mastectomy-free survival was calculated using the Kaplan-Meier method. The impact of RT on breast preservation was determined by propensity-adjusted cox proportional hazards model., Results: The cohort includes 3303 women with DCIS; 1649 (50%) underwent BCS alone, 1654 (50%) underwent BCS + RT. Women treated by BCS alone were more likely to develop a LR compared to those treated by upfront BCS + RT (20.8% versus 15.5%, p < 0.001). Mastectomy was used to treat LR in 57.4% (197/343) of women who recurred after BCS alone and 67.6% (174/257) of those who recurred after BCS + RT. Women treated with upfront BCS + RT had higher rates of bilateral breast preservation at 10 years compared to those treated by BCS alone (87.3% vs.82.7%, p = 0.0096)., Conclusion: Local Recurrence after BCS alone does not favor breast preservation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk., Methods: Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994-2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score-adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided., Results: The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT., Conclusions: The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 Cp units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.

Purpose: Whole-breast radiation therapy (XRT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) may decrease the risk of local recurrence, but the optimal dose regimen remains unclear. Past studies administered 50 Gy in 25 fractions (conventional); however, treatment pattern studies report that hypofractionated (HF) regimens (42.4 Gy in 16 fractions) are frequently used. We report the impact of HF (vs conventional) on the risk of local recurrence after BCS for DCIS., Methods and Materials: All women with DCIS treated with BCS and XRT in Ontario, Canada from 1994 to 2003 were identified. Treatment and outcomes were assessed through administrative databases and validated by chart review. Survival analyses were performed. To account for systematic differences between women treated with alternate regimens, we used a propensity score adjustment approach., Results: We identified 1609 women, of whom 971 (60%) received conventional regimens and 638 (40%) received HF. A total of 489 patients (30%) received a boost dose, of whom 143 (15%) received conventional radiation therapy and 346 (54%) received HF. The median follow-up time was 9.2 years. The median age at diagnosis was 56 years (interquartile range [IQR], 49-65 years). On univariate analyses, the 10-year actuarial local recurrence-free survival was 86% for conventional radiation therapy and 89% for HF (P=.03). On multivariable analyses, age <45 years (hazard ratio [HR] = 2.4; 95% CI: 1.6-3.4; P<.0001), high (HR=2.9; 95% CI: 1.2-7.3; P=.02) or intermediate nuclear grade (HR=2.7; 95% CI: 1.1-6.6; P=.04), and positive resection margins (HR=1.4; 95% CI: 1.0-2.1; P=.05) were associated with an increased risk of local recurrence. HF was not significantly associated with an increased risk of local recurrence compared with conventional radiation therapy on multivariate analysis (HR=0.8; 95% CI: 0.5-1.2; P=.34)., Conclusions: The risk of local recurrence among individuals treated with HF regimens after BCS for DCIS was similar to that among individuals treated with conventional radiation therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer., Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing., Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations., Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer., Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing., Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations., Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the College of American Pathologists and has been published jointly by invitation and consent in both Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine., (Copyright © 2013 American Society of Clinical Oncology and College of American Pathologists.)

Purpose: To report the outcomes of a population of women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and radiation and to evaluate the independent effect of boost radiation on the development of local recurrence., Methods and Materials: All women diagnosed with DCIS and treated with breast-conserving surgery and radiation therapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. The impact of boost radiation on the development of local recurrence was determined using survival analyses., Results: We identified 1895 cases of DCIS that were treated by breast-conserving surgery and radiation therapy; 561 patients received boost radiation. The cumulative 10-year rate of local recurrence was 13% for women who received boost radiation and 12% for those who did not (P=.3). The 10-year local recurrence-free survival (LRFS) rate among women who did and who did not receive boost radiation was 88% and 87%, respectively (P=.27), 94% and 93% for invasive LRFS (P=.58), and was 95% and 93% for DCIS LRFS (P=.31). On multivariable analyses, boost radiation was not associated with a lower risk of local recurrence (hazard ratio = 0.82, 95% confidence interval 0.59-1.15) (P=.25)., Conclusions: Among a population of women treated with breast-conserving surgery and radiation for DCIS, additional (boost) radiation was not associated with a lower risk of local or invasive recurrence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Ductal carcinoma in situ (DCIS), a non-invasive breast cancer, is usually treated by breast-conserving surgery (BCS). Randomized trials prove that the addition of radiotherapy (XRT) leads to lower rates of recurrence. Despite the evidence, half of women do not receive XRT after BCS. It is unknown how well clinicians identify women with low risk DCIS for treatment by BCS alone or to what extent women with DCIS develop recurrent cancer due to the omission of radiotherapy. We report the outcomes of a population of women with DCIS treated with BCS, alone or with radiotherapy, and evaluate the effectiveness of each therapeutic approach. All women diagnosed with DCIS and treated with BCS, alone or with radiotherapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were validated by chart review. Survival analyses were used to study the development of local recurrence (LR) in relation to patient and tumor characteristics and the use of radiotherapy. The cohort included 3,762 women treated with breast-conserving therapy; 1,895 of whom (50 %) also received radiation. At 10 years median follow-up, LR developed in 233 (12 %) women who received radiotherapy and in 363 (19 %) of women who did not (p < 0.0001). The 10-year actuarial LR rate for women who did and did not receive radiotherapy was 12.7 and 20.0 % (p < 0.0001). Differences were significant for both for invasive LR (7.0 vs. 10.0 %, p < 0.0001) and for DCIS recurrence (6.1 vs. 10.8 %, p < 0.0001). We estimate that 22 % of recurrences diagnosed in Ontario women treated for DCIS between 1994 and 2003 would have been prevented if all patients had received radiotherapy. The omission of radiotherapy after BCS for DCIS resulted in substantive recurrences that might have been avoided with treatment. Additional markers are needed to identify a low risk group in whom radiation can be safely omitted.

Hormone receptor testing (oestrogen and progesterone) in breast cancer at the time of primary diagnosis is used to guide treatment decisions. Accurate and standardised testing methods are critical to ensure the proper classification of the patient's hormone receptor status. Recommendations were developed to improve the quality and accuracy of hormone receptor testing based on a systematic review conducted jointly by the American Society of Clinical Oncology/College of American Pathologists and Cancer Care Ontario's Program in Evidence-Based Care. Evidence-based recommendations were formulated to set standards for optimising immunohistochemistry in assessing hormone receptor status, as well as assuring quality and proficiency between and within laboratories. A formal external review was conducted to validate the relevance of these recommendations. It is anticipated that widespread adoption of these guidelines will further improve the accuracy of hormone receptor testing in Canada., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

It has been proposed that a proportion of non-palpable breast cancers that are diagnosed through mammography represents a very low-risk subgroup of cancers that may not affect survival (overdiagnosis). The salient pathologic features of cancers in this theoretical subgroup are not known, and therefore, it is not possible to predict which patients have a cancer of this type. We reviewed the clinical characteristics and survival experiences of 715 patients with an invasive breast cancer of 5.0 cm or less. The tumour from each patient was represented in triplicate on a tissue microarray. Cases were divided into low-risk and moderate-/high-risk categories based on lymph node status and palpability. Low-risk cancers were those that were non-palpable, node-negative and were only detected by mammographic screening. All other cancers were high/moderate risk. The two groups of cancer patients were compared for a number of tumour characteristics, based on immunohistochemistry. There were 79 low-risk cancers and 636 moderate-/high-risk cancers. The low-risk cancers were characterized by ER-positivity, PR-positivity, HER2-negativity, ck5/6-negativity, EGFR-negativity and p53-negativity. About 54 of the 79 low-risk cancers (68 %) were of the luminal A subtype versus 335 of 636 moderate-/high-risk cancers (53 %; p = 0.008). Among 42 women with a non-palpable, mammogram-detected PR+ HER2- cancer of 5.0 cm or less, the 15-year distant recurrence-free survival rate was 100 %. Small breast cancers that are PR+ and HER2- and that are detectable by mammogram alone have a very low risk of recurrence. A proportion of these may represent examples of overdiagnosis.

Aims: Accelerated partial breast irradiation (APBI) is an alternative to whole breast irradiation that is delivered over a shorter period of time with less toxicity. Appropriate patient selection is critical to its success and the American Society for Radiation Oncology (ASTRO) has published detailed selection criteria for 'suitable' patients. This study evaluated the effect of those selection criteria on APBI eligibility based on pathology reports., Materials and Methods: From March 2004 to March 2007 all patients referred to a single cancer centre for breast radiotherapy were screened for participation in a phase I/II trial of permanent breast seed implant brachytherapy. Eligible patients underwent a computed tomography simulation and those referred from an outside institution had a secondary expert breast pathology assessment. Initial and expert pathology reports were compared regarding completeness and accuracy., Results: In total, 143 patients were eligible for the trial; 79 patients had surgery carried out outside our institution. In the initial pathology report, the most frequently missing critical information was the resection margin width (29.1%) and the presence of extensive in situ carcinoma (11.4%). Comparing initial and reviewed pathology, the agreement was higher than 90% for most features. The main source of disagreement was the width of the negative resection margin, with 34.4% disagreement (P=0.016), although it changed eligibility in only 3.6%. There was major disagreement in the evaluation of lymphovascular invasion. Overall, pathology review changed the eligibility for a patient from 'suitable' for APBI to 'cautionary' in 18.6% of the cases., Conclusion: Using stringent eligibility criteria has a direct effect on patient screening for APBI. The use of synoptic pathology reporting and a quality assurance programme with secondary expert assessments are recommended., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Determination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS., Materials and Methods: We reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu-), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER-, PR-, HER2neu+), triple negative (ER-, PR-, HER2neu-)]. We evaluated the association between the molecular subtype and the development of local recurrence., Results: In total, 180 cases of DCIS were included in the study (luminal A, n=113; luminal B, n=25; HER2neu type, n=29; triple negative, n=13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio=1.98; 95% confidence interval: 1.11, 3.53, P=0.02)., Conclusion: HER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that may progress to invasive cancer. Identification of factors that predict recurrence and distinguish DCIS from invasive recurrence would facilitate treatment recommendations. We examined the prognostic value of nine molecular markers on the risks of local recurrence (DCIS and invasive) among women treated with breast-conserving therapy., Methods: A total of 213 women who were treated with breast-conserving therapy between 1982 and 2000 were included; 141 received breast-conserving surgery alone and 72 cases received radiotherapy. We performed immunohistochemical staining on the DCIS specimen for nine markers: oestrogen receptor, progesterone receptor, Ki-67, p53, p21, cyclinD1, HER2/neu, calgranulin and psoriasin. We performed univariable and multivariable survival analyses to identify markers associated with the recurrence., Results: The rate of recurrence at 10 years was 36% for patients treated with breast-conserving surgery alone and 18% for women who received breast-conserving surgery and radiotherapy. HER2/neu+/Ki-67+ expression was associated with an increased risk of DCIS recurrence, independent of grade and age (HR=3.22; 95% CI: 1.47-7.03; P=0.003). None of the nine markers were predictive of invasive recurrence., Conclusion: Women with a HER2/neu/neu+/Ki67+ DCIS have a higher risk of developing DCIS local recurrence after breast-conserving surgery.

Several adjuvant endocrine strategies exist for postmenopausal women with breast cancer. This study compared the effect of two sequences of aromatase inhibitor use [steroidal (exemestane) and non-steroidal (anastrozole)] on serological and pathological biomarkers when given in the neoadjuvant setting to postmenopausal women with breast cancer. Thirty women were assigned to receive exemestane 25 mg or anastrozole 1 mg each given for 8 weeks in a randomized sequence. The effect of this treatment on serum estrone sulfate and estradiol levels, as well as tumor changes in the proliferation biomarker Ki67 were evaluated at baseline, 8 weeks and 16 weeks. WHO clinical response criteria, patient preference, and quality of life were also assessed. Assessable data was available from 28 patients. There were no differences in concentration changes of serum estradiol or Ki67 between patients in the two arms. Overall clinical response rate was 68% (19/28 assessable patients) and clinical benefit was 93% (26/28 assessable patients). There was no significant difference in toxicity or quality of life scores. The majority of patients expressed a personal preference for anastrozole over exemestane. Results suggest that the order of steroidal and non-steroidal aromatase inhibitors has little effect on outcome. The majority of patients express clear preferences for drug treatments.

Background: Women with invasive breast cancer who are treated with breast-conserving surgery and radiotherapy face a cumulative risk of local disease recurrence of approximately 10% at 10 years. To the authors' knowledge, the role of mammographic density as a risk factor for the development of local recurrence has not been thoroughly evaluated to date., Methods: Medical records were reviewed for 335 patients who underwent breast-conserving surgery for invasive breast cancer and for whom a pretreatment mammogram was available. Information was recorded concerning mammographic density as well as tumor features, patient characteristics, and adjuvant treatments received. Patients were categorized for mammographic density based on the Wolfe classification as either low (<25% density), intermediate (25-50% density), or high (>50% density). A multivariate survival analysis was conducted using the Cox proportional hazards model with local disease recurrence as the primary endpoint., Results: Patients in the high mammographic density group experienced a much greater risk of local disease recurrence compared with women with the least dense breasts (10-year actuarial risks: 21% vs 5%; hazards ratio [HR], 5.7 [95% confidence interval, 1.6-20; P=.006]). The difference in the rates of disease recurrence at 10 years was pronounced for women who did not receive radiotherapy (40% vs 0% for patients with >50% density and <25% density, respectively; P<.0001)., Conclusions: Mammographic breast density is an important risk factor for local breast cancer recurrence among women not receiving breast irradiation. Mammographic density should be taken into consideration when stratifying patients for clinical trials of partial breast radiotherapy. If confirmed, mammographic density might be used to help determine which patients might benefit from radiotherapy., (Copyright (c) 2009 American Cancer Society.)

In this article, the probability of finding malignancy on surgical excision after applying well-defined morphological criteria combined with immunohistochemical evaluation of cytokeratin 5/6 for the diagnosis of atypical ductal hyperplasia on core biopsies is examined. On the basis of morphology alone, the reviewers reclassified the diagnoses of 140 core biopsies as follows: atypical ductal hyperplasia (n = 64), ductal hyperplasia of usual type (n = 44), flat epithelial atypia (n = 11), and miscellaneous benign (n = 21). Cytokeratin 5/6 immunostain was negative in 85.7% of atypical ductal hyperplasia cases and positive in 77.8% of ductal hyperplasia of usual type cases. The probability of predicting malignancy in a surgical specimen following a core biopsy increased from 43.6% to 67.8% (P = .002) by adhering to defined criteria and using cytokeratin 5/6 immunostain. Expertise and adherence to defined criteria are required to establish an accurate diagnosis of atypical ductal hyperplasia. Cytokeratin 5/6 can be a useful adjunct in cases with ductal hyperplasia but not in columnar cell lesions, where it is universally negative.

Purpose: There is concern that women with multifocal ductal carcinoma in situ (DCIS; confined to one quadrant) who are treated with breast-conserving surgery face a high risk of local recurrence; therefore, many are treated with mastectomy. The objective of this study is to evaluate the significance of multifocality and the outcomes of women with multifocal DCIS treated with breast-conserving therapy., Methods: The records of patients treated with breast-conserving surgery for DCIS between 1982 and 2000 were reviewed. Multivariate analyses were performed to evaluate the effects of multifocality and other prognostic factors on the rate of local recurrence., Results: Of 615 cases of DCIS reviewed, 310 (41%) received breast-conserving surgery and 305 (40%) received breast-conserving surgery plus radiation (n = 260 with multifocality, n = 314 without multifocality, and n = 31 focality unreported). On multivariate analysis, multifocality (hazard ratio [HR] = 1.80; 95% CI, 1.15 to 2.80; P = .01), radiation treatment (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.74; 95% CI, 1.03 to 2.92; P = .04), and high nuclear grade (HR = 1.65; 95% CI, 1.02 to 2.65; P = .04) were associated with risk of local recurrence. The detrimental effect of multifocality was limited to women who did not receive radiotherapy; the local recurrence-free survival rate at 10 years was 59% for women with multifocal disease and 80% for women without multifocality (P = .02). Among women treated with breast-conserving surgery plus radiation, there was no difference in 10-year local recurrence-free survival (80% v 87%; P = .35). There was no association between multifocality and the development of invasive recurrence., Conclusion: Multifocality is a significant predictor of local recurrence in women who receive breast-conserving surgery for DCIS without radiotherapy; however, low recurrence rates can be achieved if adjuvant radiation is administered.

Background: A recent SEER study identified significant variations in the care of women with DCIS, yet several potential confounding variables were not included. We report a patterns of care study of women with DCIS to better understand the gap between evidence-based knowledge and the management of DCIS., Methods: We studied all cases of DCIS diagnosed through the Ontario Breast Screening Program from 1991 to 2000. Data was obtained by database linkage and chart abstraction. A logistic regression model using generalized estimating equations to adjust for clustering was used., Results: About 320,236 women were screened and 727 individuals were diagnosed with DCIS. The rate of mastectomy was 30% and was associated with multifocality (OR: 3.5 [1.7, 7.1], P = 0.0005), tumor size (OR: >2 cm vs. 1 cm (OR: 2.4 [1.3, 4.4], P = 0.006). Half of cases with margins <1 cm did not receive XRT., Conclusions: Our study corroborates previous reports on the persistent rates of mastectomy and axillary nodal dissection and the limited use of XRT in the treatment of DCIS.

HER2/neu is overexpressed in about 20% of invasive breast carcinomas. Numerous studies have shown that there is high level of concordance between the HER2/neu status of the primary breast cancer and the metastases of a given patient. Recently, changes in HER2/neu status with tumor progression have been reported, suggesting the possibility of an emerging different tumor clone. Little is known about intratumoral heterogeneity with regard to HER2/neu oncoprotein overexpression. We identified nine cases of invasive ductal carcinoma that showed intratumoral variation in HER2/neu oncoprotein expression by immunohistochemistry. This was confirmed by the intratumoral variation in the amplification status of the HER2/neu gene by fluorescence in situ hybridization and by chromogenic in situ hybridization. The results of this study suggest that some cases of primary breast carcinoma are heterogeneous in regard to HER2/neu gene amplification or protein overexpression. Heterogeneity of HER2/neu status in a tumor may be a rare event or underestimated. This phenomenon should be examined as it may contribute to a better understanding of the variation in therapeutic responses and the conflicting data in studies about the prognostic and predictive role of HER2/neu status in subsets of breast cancer patients.

The kinase inhibitor p27Kip1 regulates the G1 cell cycle phase. Here, we present data indicating that the oncogenic kinase Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Src inhibitors increase cellular p27 stability, and Src overexpression accelerates p27 proteolysis. Src-phosphorylated p27 is shown to inhibit cyclin E-Cdk2 poorly in vitro, and Src transfection reduces p27-cyclin E-Cdk2 complexes. Our data indicate that phosphorylation by Src impairs the Cdk2 inhibitory action of p27 and reduces its steady-state binding to cyclin E-Cdk2 to facilitate cyclin E-Cdk2-dependent p27 proteolysis. Furthermore, we find that Src-activated breast cancer lines show reduced p27 and observe a correlation between Src activation and reduced nuclear p27 in 482 primary human breast cancers. Importantly, we report that in tamoxifen-resistant breast cancer cell lines, Src inhibition can increase p27 levels and restore tamoxifen sensitivity. These data provide a new rationale for Src inhibitors in cancer therapy.

Introduction: Before any new methodology can be introduced into the routine diagnostic setting it must be technically validated against the established standards. To this end, a ring study involving five international pathology laboratories was initiated to validate chromogenic in situ hybridisation (CISH) against fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) as a test for assessing human epidermal growth factor receptor 2 (HER2) status in breast cancer., Methods: Each laboratory performed CISH, FISH and IHC on its own samples. Unstained sections from each case were also sent to another participating laboratory for blinded retesting by CISH ('outside CISH')., Results: A total of 211 invasive breast carcinoma cases were tested. In 76 cases with high amplification (HER2/CEP17 ratio >4.0) by FISH, 73 cases (96%) scored positive (scores >or= 6) by 'outside CISH'. For FISH-negative cases (HER2/CEP17 ratio <2.0), 94 of 100 cases (94%) had CISH scores indicating no amplification (score or= 6. CISH intra-laboratory concordance with IHC was 92% for IHC-negative cases (IHC 0/1+) and 91% for IHC 3+ cases. Among IHC 2+ cases, CISH was 100% concordant with samples showing high amplification by FISH, and 94% concordant with FISH-negative samples., Conclusion: These results show that CISH inter- and intra-laboratory concordance to FISH and IHC is very high, even in equivocal IHC 2+ cases. Therefore, we conclude that CISH is a methodology that is a viable alternative to FISH in the HER2 testing algorithm.

Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation). Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence. In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS. This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis. However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.

A comprehensive differential gene expression screen on a panel of 54 breast tumors and >200 normal tissue samples using DNA microarrays revealed 15 genes specifically overexpressed in breast cancer. One of the most prevalent genes found was trichorhinophalangeal syndrome type 1 (TRPS-1), a gene previously shown to be associated with three rare autosomal dominant genetic disorders known as the trichorhinophalangeal syndromes. A number of corroborating methodologies, including in situ hybridization, e-Northern analysis using ORF EST (ORESTES) and Unigene EST abundance analysis, immunoblot and immunofluorescence analysis of breast tumor cell lines, and immunohistochemistry, confirmed the microarray findings. Immunohistochemistry analysis found TRPS-1 protein expressed in >90% of early- and late-stage breast cancer, including ductal carcinoma in situ and invasive ductal, lobular, and papillary carcinomas. The TRPS-1 gene is also immunogenic with processed and presented peptides activating T cells found after vaccination of HLA-A2.1 transgenic mouse. Human T cell lines from HLA-A*0201+ female donors exhibiting TRPS-1-specific cytotoxic T lymphocyte activity could also be generated.

Background: Current guidelines include a recommendation that a pathologist with expertise in breast disease review all ductal carcinoma in situ (DCIS) specimens due to the presence of significant variability in pathologic reporting of DCIS. The objective of this study was to evaluate the completeness and accuracy of pathologic reporting of DCIS over the past decade and to determine the current impact of expert breast pathology assessment on the management of DCIS., Methods: All patients with a diagnosis of DCIS referred to a single regional cancer centre between 1982 and 2000 have been reviewed. Inter-observer variability between initial and secondary reports has been evaluated using kappa statistics. For each case, the Van Nuys Prognostic Index (VNPI) using pathologic data obtained from the initial and reviewed pathology reports were compared. The impact of expert breast pathology on risk assessment and treatment was determined., Results: 481 individuals with DCIS were referred and pathology review was performed on 350 patients (73%). Inter-observer agreement was high for the main pathologic features of DCIS. From 1996 to 2000, secondary pathology assessments lead to a change in the assessment of local recurrence risk in 100 cases (29%) and contributed to a change in treatment recommendation in 93 (43%) cases., Conclusion: Expert breast pathology assessments continue to be necessary in the management of DCIS.

The histogenesis as well as the biological and molecular differences in mammary Paget's disease (MPD) and extramammary Paget's disease (EPD) are not well understood. HER-2/neu oncogene overexpression is associated with poor prognosis in breast cancer patients. It is also believed that the spread of Paget's cells through the epidermis is induced by a motility factor that acts via the HER-2/neu receptor. However, previous studies on HER-2/neu expression in MPD and EPD have given conflicting results. Recent studies have suggested that vimentin expression in breast cancer confers a more aggressive phenotype with a possible role in tumor invasion and metastasis. We examined 58 cases of MPD and EPD for HER-2/neu overexpression and vimentin status to study the role of these markers in the production of the Paget's phenotype. Thirty-five of the 38 cases (92.1%) of MPD were associated with an underlying carcinoma, while none of the cases of EPD were associated with an underlying malignancy. Thirty-six of the 38 cases of MPD (94.7%) overexpressed the HER-2/neu oncoprotein and 17 cases (44.7%) showed vimentin expression. In contrast, only 1 of the 20 cases of EPD (5%) showed positivity for HER-2/neu oncoprotein and all were negative for vimentin. Our results indicate that the cell motility enhancing effect of HER-2/neu oncoprotein and possibly vimentin plays a significant role in the pathogenesis of MPD which appears to be a pagetoid spread of an underlying ductal malignancy (secondary), while EPD is an in situ malignant transformation of a totipotential epidermal cell or glandular epithelium.

Background: A positive correlation between breast tumor size and the number of axillary lymph nodes containing tumor is well established. It has been reported that patients with BRCA1-related breast carcinoma are more likely than patients with nonhereditary breast carcinoma to have negative lymph node status. Therefore, the authors questioned whether the known positive correlation between tumor size and lymph node status also was present in women with BRCA1-related breast carcinomas., Methods: The relation between the greatest dimension of the resected breast tumor (size) and the presence of positive axillary lymph nodes (expressed as a percentage of all lymph nodes examined) was evaluated in 1555 women with invasive breast carcinoma who were ascertained at 10 centers in North America between 1975 and 1997. There were 276 BRCA1 mutation carriers, 136 BRCA2 carriers, and 1143 women without a known mutation (208 BRCA1/BRCA2 noncarriers and 935 untested women). Patients were stratified according to tumor size, and odds ratios were estimated for the presence of positive lymph nodes with increasing tumor size., Results: A highly significant positive correlation between tumor size and the frequency of positive axillary lymph nodes was seen for BRCA1/BRCA2 noncarriers, for BRCA2 carriers, and for untested women (overall P < 0.0001 for each). In contrast, there was no clear correlation between tumor size and positive lymph node status in BRCA1 carriers (overall P = 0.20)., Conclusions: The relation between tumor size and lymph node status in patients with breast carcinoma appears to be different in BRCA1 carriers compared with BRCA2 carriers and noncarriers. These findings have important implications for estimating the route of metastatic spread and for evaluating the effectiveness of early diagnosis in patients with BRCA1-related breast carcinoma., (Copyright 2003 American Cancer Society.)

The stroma of fibroadenoma and phyllodes tumor usually consists of fibroblastic proliferation. Rarely the stroma contains bundles of smooth muscle. Pseudoangiomatous hyperplasia of the mammary stroma has been described in fibroadenomas. However, true benign vascular stroma has not been reported. We report a case of a 34-year-old Chinese woman who presented with a large mass occupying the entire left breast. Left mastectomy was performed and showed a large, well-circumscribed, lobulated, rubbery-firm tumor measuring 13 x 10 x 6 cm. Microscopic examination revealed a fibroepithelial tumor formed by an organoid pattern of ductal structures with a very striking stromal appearance composed of extensive vascular proliferation and that demonstrated strong immunoreactivity for CD31, CD34, and Factor VIII. Ultrastructural examination revealed intercellular junctions, basal lamina, pinocytotic vesicles, and Weibel-Palade bodies in the cells lining the vascular spaces, confirming their endothelial nature. These findings rule out the diagnosis of pseudoangiomatous hyperplasia. The patient developed local recurrence a year later, and the resection showed malignant phyllodes tumor with ductal carcinoma in situ. The extensive vascular stroma noted in the primary tumor may have played a role in the malignant transformation of the epithelial and stromal components in this tumor.

Knowledge of HER2 status is a prerequisite when considering a patient's eligibility for Herceptin (trastuzumab) therapy. Accurate assessment of HER2 status is essential to ensure that all patients who may benefit from Herceptin are correctly identified. There are several assays available to determine HER2 status: the most common in routine clinical practice are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Various factors can affect the results achieved with these assays, including the assay antibody/probe, the methodology and the experience of personnel. Many countries have implemented national testing guidelines in an attempt to standardize testing procedures and make results more accurate. These guidelines vary in the level of detail and the number of recommendations. This review looks at areas of consensus between the different national testing guidelines and highlights where errors may arise during the testing procedure. The key point underlined by this review is that whatever method is used to test for HER2 status, the technology must be validated first, and there must be regular internal and external quality control and quality assurance procedures.

There has been a recent increase in the diagnosis of in situ duct carcinoma of the breast (DCIS) as a result of mammographic screening. DCIS is heterogeneous in appearance and likely in prognosis. There is no generally accepted model to predict progression to invasive carcinoma. We investigated the prognostic effect of clinical presentation and pathologic factors for women diagnosed with primary DCIS. A cohort of 124 patients was accrued between 1979 and 1994 and was followed to 1997; 78 had DCIS detected mammographically, and 88 underwent lumpectomy alone. In this article, we provide details about characteristics affecting the choice of primary therapeutic modality, and we examine the effects of factors on progression for the two patient subgroups. Presentation with bloody nipple discharge was associated with a significant increase in DCIS recurrence (p=0.07). The pattern of duct distribution was important: DCIS in which the involved ducts were more widely separated had a significantly greater recurrence of DCIS than when the involved ducts were more concentrated (p=0.08 for mammographically detected DCIS, p=0.07 for patients who underwent lumpectomy alone). For mammographically detected DCIS, younger patients had more DCIS recurrence (p=0.07). We found considerable heterogeneity in nuclear grade; 50% of patients exhibited more than one grade. Nuclear grade, necrosis, and architecture were not significantly associated with either recurrence of DCIS or development of invasive carcinoma. Longer follow-up will allow further evaluation of the prognostic relevance of the factors assessed.

In breast cancer amplification of the HER-2/neu oncogene and over-expression of the protein product is associated with poor prognosis, predicts response to some chemotherapeutic regimens and is the target for Herceptin treatment. To date there are several methods to assess the amplification/over-expression of HER-2/neu with each having advantages and disadvantages. We have studied amplification and over-expression of HER-2/neu in 250 consecutive cases of breast cancer (220 invasive and 30 in situ carcinomas) presenting to the Department of Pathology at Women's College Campus of Sunnybrook and Women's College Health Sciences Center. Thirty percent of the invasive carcinomas were node positive. HER-2/neu protein over-expression was assessed by immunohistochemistry (IH) using antibody CB11 and amplification of the gene by differential PCR. The percentage of tumor cells showing CB11 staining was determined and the most significant cut off point for positivity was > or =10% moderate or strong complete membranous staining. The gene was considered amplified if the density score of the product was > or =2. There was 94% concordance between the two methods (P value.0001). Both methods were positive in 16% of cases and negative in 78% of cases. Discrepant cases were examined by FISH which confirmed the IH results in 9/11 invasive carcinomas. These results show that there is excellent concordance between IH and PCR. However, immunohistochemistry is easier to perform and cheaper than PCR and could be used in routine assessment of HER-2/neu in breast cancer patients.

Objective: We evaluated the association between organochlorines and breast cancer subtype defined by the tumor characteristics: estrogen receptor status, progesterone receptor status, tumor size, and grade., Methods: A case-control study was conducted from 1995 to 1997 in Kingston and Toronto, Canada. Breast adipose tissue, taken from 217 cases and 213 biopsy controls frequency-matched on age, was analysed for 14 polychlorinated biphenyl (PCB) congeners and 10 pesticides., Results: Adjusting for age, geometric means of several organochlorines differed by estrogen receptor status and tumor grade (p < 0.05). Odds ratios (ORs) for each organochlorine relative to the common control group for breast cancers of differing subtype were compared using polytomous logistic regression. Although the ORs did not differ significantly by subtype, the ORs of PCBs and p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were higher with risk of estrogen receptor-negative breast cancer than estrogen receptor-positive breast cancer. One of the most extreme differences was with DDE, where the OR for the association with risk of estrogen receptor-negative breast cancer was 2.4 (95% confidence interval (CI) 1.0-5.4) in the uppermost tertile relative to the lowest, whereas the corresponding OR for risk of estrogen receptor-positive breast cancer was 1.1 (95% CI 0.6-1.9). PCBs also tended to be more strongly positively associated with risk of larger and higher-grade tumors., Conclusions: The association between organochlorines and breast cancer risk did not significantly differ by subtype, but many PCBs were more strongly associated with tumors of poor prognosis.

Extensive radiologically dense breast tissue is associated with a marked increase in breast cancer risk. To explore the biological basis for this association, we have examined the association of growth factors and stromal matrix proteins in breast tissue with mammographic densities. Ninety-two formalin-fixed paraffin blocks of breast tissues surrounding benign lesions were obtained, half from breasts with little or no density and half from breasts with extensive density, matched for age at biopsy. Sections were stained for cell nuclei, total collagen, the stromal matrix regulatory protein tissue metalloproteinase-3 (TIMP-3), and the growth factors, transforming growth factor-alpha and insulin-like growth factor (IGF-I). The area of immunoreactive staining was measured using quantitative microscopy. Breast tissue from subjects with extensive densities had a greater nuclear area (P = 0.007), as well as larger stained areas of total collagen (P = 0.003), TIMP-3 (P = 0.08), and IGF-I (P = 0.02) when compared with subjects with little breast density. Differences were greater for subjects less than 50 years of age. These data indicate that increased tissue cellularity, greater amounts of collagen, and increased IGF-I and TIMP-3 expression are found in tissue from mammographically dense breasts and suggest mechanisms that may mediate the associated increased risk of breast cancer.

Incorporation of a new biological marker such as HER2 into routine clinical practice requires proof that it provides reproducible information independent of, and better than, conventional pathologic criteria, and that it influences treatment decisions. In breast cancer, HER2 amplification/overexpression predicts for a poor clinical outcome and an enhanced survival benefit from the HER2-targeted therapy, Herceptin, and may predict for resistance to some conventional therapies. Thus, HER2 is considered to be a clinically important molecule and testing for HER2 abnormalities is already part of routine patient assessment in many parts of the world. There is currently no gold standard for HER2 testing. The main challenge is to standardize and technically validate HER2 testing methodologies. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the most common HER2 tests used, and show a high level of concordance. HER2 testing approaches based on the polymerase chain reaction (PCR) are under extensive investigation and appear promising. A Canadian HER2 testing algorithm designed to increase the validity and reproducibility of HER2 testing has been compiled. HER2-positive cases are defined as those with >10% of tumor cells with moderate/strong, complete membrane staining in the invasive component, by IHC. Confirmatory HER2 testing using either FISH or quantitative PCR is recommended for indeterminate cases. Additional studies are required to calibrate HER2 testing results to clinical outcome., (Copyright 2001 S. Karger AG, Basel)

Background: We have been following a cohort of patients who underwent a lumpectomy without receiving adjuvant radiotherapy or adjuvant systemic therapy. We now report the experience of a postmenopausal subgroup., Methods: The postmenopausal subgroup included 244 patients accrued between 1977 and 1986 and followed up. The end point was ipsilateral local breast cancer recurrence. The factors studied were the patient's age in years; tumor size (in mm); nodal status (N-, Nx, N+); estrogen and progesterone receptor status (< 10, - 10 fmol/mg protein); presence or absence of lymphovascular/perineural invasion; presence or absence, and type, of DCIS (none, non-comedo, comedo); percentage of DCIS; histological grade (1,2,3); and nuclear grade (1,2,3). Univariate analyses consisted of Kaplan-Meier plots and the Wilcoxon (Peto-Prentice) test statistic; the multivariate analyses were step-wise Cox and log-normal regressions., Results: The median follow-up of those patients still alive was 9.1 years, and the overall relapse rate was 24% (59/244). The univariate results indicated that the characteristics of smaller tumor size, negative nodes, positive ER status, and no lymphovascular or perineural invasion were associated with significantly (P <.05) lower relapse. From the multivariate analyses, the factors lymphovascular or perineural invasion, age, and amount of DCIS were all significantly associated with local relapse with both Cox and log-normal regressions. Additionally, there was weak evidence of an association between ER (P = .08 in the Cox regression and in the log-normal) and nodal status (P = .09 in the log-normal regression) with local relapse. We also are able to define a low-risk subgroup (N-, age -65, no comedo, ER positive, no emboli) with a crude 10-year local recurrence rate of 9%., Conclusion: With longer follow-up, and for postmenopausal patients, there continues to be support for the theory that local relapse is affected by the factors lymphovascular or perineural invasion, age, amount of DCIS, ER, and nodal status. A low risk subgroup has been identified.

Background: Invasive breast cancer is a frequently diagnosed disease that now comes with an ever expanding array of therapeutic management options. We assessed the effects of 20 prognostic factors in a multivariate context., Methods: We accrued clinical data for 156 consecutive patients with stage 1-3 primary invasive breast cancer who were diagnosed in 1989-1990 at the Henrietta Banting Breast Center, and followed to 1995. There is complete follow-up for 91% of patients (median follow-up of 4.9 years). The event of interest was distant recurrence (for distant disease-free survival, DFS). We used Cox and log-normal step-wise regression to assess the multivariate effects of the following factors on DFS: age, tumor size, nodal status, histology, tumor and nuclear grade, lymphovascular and perineural invasion (LVPI), ductal carcinoma-in-situ (DCIS) type, DCIS extent, DCIS at edge of tumor, ER and PgR, ERICA, adjuvant systemic therapy, ki67, S-phase, DNA index, neu oncogene, and pRb., Results: There was strong evidence against the Cox assumption of proportional hazards for nodal status, and nodal status was not in the Cox step-wise model. With step-wise log-normal regression, a large tumor size (P < .001), positive nodes (P = .002), high nuclear grade (P = .01), presence of LVPI (P = .03), and infiltrating duct carcinoma not otherwise specified (P = .05) were associated with a reduction in DFS., Conclusions: For nodal status, there was strong evidence against the Cox assumption of proportional hazards, and it was not included in the Cox model although it was in the log-normal model. Only traditional factors were included in the step-wise models. Thus, this statistical management of prognostic markers in breast cancer appears to be very important.

We optimized the assay for detection of cytokeratin 19 (CK19) mRNA by the reverse transcriptase-polymerase chain reaction (RT-PCR) in blood as an index of circulating tumor cells in breast cancer patients. The limit of detection of < 1 MCF7 tumor cells per 10(6) peripheral blood leukocytes (PBL) was achieved in mixing experiments. We did not detect CK19 mRNA in control bloods (0/30) or in the blood of patients with benign breast disease (0/15). In blood samples from 109 patients with invasive breast cancer, CK19 mRNA was detected in 7/23 patients with node-negative disease, in 21/58 with node-positive disease, and in 20/28 with distant metastases. There was a significant association (P < 0.01) of CK19 positivity with distant metastatic versus both node-negative and node-positive disease, but not with any other histopathological parameter examined. In a small number of patients with distant metastases, increased intensity of the CK19 RT-PCR signal was associated with a reduced survival.

Numerous studies have examined the relationship between organochlorines and breast cancer, but the results are not consistent. In most studies, organochlorines were measured in serum, but levels in breast adipose tissue are higher and represent cumulative internal exposure at the target site for breast cancer. Therefore, a hospital-based case-control study was conducted in Ontario, Canada to evaluate the association between breast cancer risk and breast adipose tissue concentrations of several organochlorines. Women scheduled for excision biopsy of the breast were enrolled and completed a questionnaire. The biopsy tissue of 217 cases and 213 benign controls frequency matched by study site and age in 5-year groups was analyzed for 14 polychlorinated biphenyl (PCB) congeners, total PCBs, and 10 other organochlorines, including p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene. Multiple logistic regression was used to assess the magnitude of risk. While adjusting for age, menopausal status, and other factors, odds ratios (ORs) were above 1.0 for almost all organochlorines except five pesticide residues. The ORs were above two in the highest concentration categories of PCB congeners 105 and 118, and the ORs for these PCBs increased linearly across categories (Ps for trend < or =0.01). Differences by menopausal status are noted especially for PCBs 105 and 118, with risks higher among premenopausal women, and for PCBs 170 and 180, with risks higher among postmenopausal women. Clear associations with breast cancer risk were demonstrated in this study for some PCBs measured in breast adipose tissue.