Mary F. Dillon

A pathologic assessment of adequate margin status in breast-conserving therapy

BackgroundThe definition of a clear margin in breast-conserving therapy is uncertain. The purpose of this study was to correlate the tumor-margin distance of the excision specimen with the presence of residual tumor at reoperation. We also analyzed predictors of compromised margins and of residual disease.MethodsAll patients who underwent breast-conserving therapy for invasive disease from 1999 to 2003 were reviewed. Pathologic characteristics and the precise tumor distance from the radial margin were recorded. A radial margin was compromised if invasive or (ductal) in situ carcinoma was <5 mm from the margin.ResultsOf the 612 patients who underwent breast conservation, 211 (34%) had compromised margins, and 39 had undetermined margins. Of the 161 patients who had a reoperation for compromised margins, 87 (54%) had residual disease. Residual disease after reoperation was present in 58% (56 of 96), 56% (9 of 16), and 45% (22 of 49) of those with tumor-margin distances <1 mm, ≥1 and <2 mm, and ≥2 and <5 mm, respectively. There was a progressive decline in residual disease for each millimeter until a rate of 22% for tumor-margin distances of ≥4 mm and <5 mm was reached. Pathologic size (P = .004), an extensive intraductal component (P = .002), referral from a symptomatic rather than a population-based screening program (P = .02), and the absence of a preoperative diagnosis by core biopsy (P < .0001) were predictive of compromised margins. Only young age (<45 years) was predictive of finding residual disease on reoperation (P = .02).ConclusionsA total of 45% of patients who had tumor 2 to 5 mm from the radial margin had residual disease on reoperation. Our results support a policy of requiring a 5-mm margin in patients undergoing breast-conserving therapy for invasive disease.The definition of a clear margin in breast-conserving therapy is uncertain. The purpose of this study was to correlate the tumor-margin distance of the excision specimen with the presence of residual tumor at reoperation. We also analyzed predictors of compromised margins and of residual disease. All patients who underwent breast-conserving therapy for invasive disease from 1999 to 2003 were reviewed. Pathologic characteristics and the precise tumor distance from the radial margin were recorded. A radial margin was compromised if invasive or (ductal) in situ carcinoma was <5 mm from the margin. Of the 612 patients who underwent breast conservation, 211 (34%) had compromised margins, and 39 had undetermined margins. Of the 161 patients who had a reoperation for compromised margins, 87 (54%) had residual disease. Residual disease after reoperation was present in 58% (56 of 96), 56% (9 of 16), and 45% (22 of 49) of those with tumor-margin distances <1 mm, ≥1 and <2 mm, and ≥2 and <5 mm, respectively. There was a progressive decline in residual disease for each millimeter until a rate of 22% for tumor-margin distances of ≥4 mm and <5 mm was reached. Pathologic size (P = .004), an extensive intraductal component (P = .002), referral from a symptomatic rather than a population-based screening program (P = .02), and the absence of a preoperative diagnosis by core biopsy (P < .0001) were predictive of compromised margins. Only young age (<45 years) was predictive of finding residual disease on reoperation (P = .02). A total of 45% of patients who had tumor 2 to 5 mm from the radial margin had residual disease on reoperation. Our results support a policy of requiring a 5-mm margin in patients undergoing breast-conserving therapy for invasive disease.

The accuracy of ultrasound, stereotactic, and clinical core biopsies in the diagnosis of breast cancer, with an analysis of false-negative cases.

Objective:Preoperative core biopsy in breast cancer is becoming the standard of care. The aim of this study was to analyze the various methods of core biopsy with respect to diagnostic accuracy and to examine the management and outcome of those patients with false-negative biopsies. Methods:All patients undergoing core biopsy for breast abnormalities over a 5-year period (1999–2003) were reviewed. The accuracy rates for each method of core biopsy, the histologic agreement between the core pathology and subsequent excision pathology, and the length of follow-up for cases of benign disease were studied. Patients whose biopsies were benign but who were subsequently diagnosed with cancer underwent detailed review. Results:There were 2427 core biopsies performed over the 5-year period, resulting in a final diagnosis of cancer in 1384 patients, benign disease in 954 patients, and atypical disease in 89 patients. Biopsy type consisted of 1279 ultrasound-guided cores, 739 clinically guided cores, and 409 stereotactic-guided cores. The overall false-negative rate was 6.1%, with specific rates for ultrasound-, clinical-, and stereotactic-guided cores of 1.7%, 13%, and 8.9%, respectively. False-negative biopsies occurred in 85 patients, and in 8 of these patients the diagnosis was delayed by greater than 2 months. In all other false-negative cases, “triple assessment” review allowed prompt recognition of discordant biopsy results and further evaluation. Conclusion:Ultrasound guidance should be used to perform core biopsies in evaluating all breast abnormalities visible on ultrasound. Adherence to principles of triple assessment following biopsy allows for early recognition of the majority of false-negative cases.

Coassociation of Estrogen Receptor and p160 Proteins Predicts Resistance to Endocrine Treatment; SRC-1 is an Independent Predictor of Breast Cancer Recurrence

Purpose: This study investigates the role of the p160 coactivators AIB1 and SRC-1 independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments. Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients. Results: Coassociation of the p160s and estrogen receptor α was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrine-sensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor α following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P < 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1 with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1 and SRC-1 with estrogen receptor α in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively). Conclusions: SRC-1 is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor α can predict the response of patients to endocrine treatment.

The role of major duct excision and microdochectomy in the detection of breast carcinoma

BackgroundThe association of nipple discharge with breast carcinoma has resulted in numerous women undergoing exploratory surgery to exclude malignancy. The aim of this study was to determine whether pre-operative factors can identify those patients that are most at risk of carcinoma.MethodsAll patients over a 14-year period (1991–2005) who had a microdochectomy or subareolar exploration for the evaluation of nipple discharge were assessed. Patient characteristics, pre-operative imaging and pathological findings were analysed.ResultsOf the 211 patients included in this study, 116 patients had pathological (unilateral, uniductal serous or bloody) discharge. On excision, 6% (n = 7) of patients with pathological discharge and 2.4% (n = 2) of patients with non-pathological discharge were diagnosed with carcinoma. Overall, major duct excision resulted in the diagnosis of carcinoma in 4.3% (n = 9), ADH/LCIS in 4% (n = 8), papilloma in 39% (n = 83), and duct ectasia or non-specific benign disease in 53% (n = 111) of patients. In the patients determined to have malignancy, 44% (n = 4) were premenopausal. No patient with a non-bloody discharge in the total population analysed (28%; n = 59/211), or in the population with a pathological discharge (21%; n = 24/116) was found to have carcinoma upon excision.ConclusionMicrodochectomy or major duct excision performed for nipple discharge resulted in a low rate of malignancy on excision. Conservative management of non-bloody nipple discharge can be considered in patients with no other clinical or radiological signs of malignancy.

Needle core biopsy characteristics identify patients at risk of compromised margins in breast conservation surgery.

Selection of patients for breast-conserving surgery relies on inexact parameters such as the preoperative estimation of lesion size. This study investigates the value of needle core biopsy findings, in particular, the relative quantity of DCIS, in improving patient selection for breast conservation. Patients undergoing breast-conserving surgery for invasive ductal carcinoma from 1999 to 2004 were identified. Only patients who had a preoperative diagnosis of carcinoma (DCIS and invasive) on core biopsy were included. All core biopsies were reviewed by a breast histopathologist to document the quantity and characteristics of the DCIS component. Of a total of 281 patients, 46% (n=129) had invasive disease on core biopsy (group 1) and 54% (n=152) had either invasive disease with an accompanying DCIS component or DCIS only on core biopsy (group 2). The compromised margin rate for group 1 was 23% compared to 39% for group 2 (P=0.004). The rate of compromised margins increased progressively as the core biopsy DCIS component increased until a rate of 75% (n=18/24) was reached in patients with DCIS only on core biopsy. In patients with a DCIS component on core biopsy, the presence of necrosis (P=0.002), solid type architecture (P=0.008), high grade DCIS (P=0.007), calcification (P=0.003), and the relative proportion of DCIS present (P<0.001) were associated with compromised margins on univariate analysis. On multivariate analysis of this subgroup, the proportion of DCIS in this subgroup (P=0.048) was an independent predictor of compromised margins. The presence and relative proportion of DCIS on core biopsy provides important information as to whether patients are at risk of compromised margins. Documentation of these parameters may assist patient selection for breast-conserving surgery or identify patients who may benefit from wider margins at the time of initial operation.

Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients

Cyclooxygenase-2 (COX-2) is associated with breast tumour progression. Clinical and molecular studies implicate human epidermal growth factor receptor 2 (HER2) in the regulation of COX-2 expression. Recent reports raise the possibility that HER2 could mediate these effects through direct transcriptional mechanisms. The relationship between HER2 and COX-2 was investigated in a cohort of breast cancer patients with or without endocrine treatment. A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for HER2, ERK1/2, polyoma enhancer activator 3 (PEA3) and COX-2 expression. Subcellular localisation of HER2 was assessed by immunofluorescence and confocal microscopy. Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen. COX-2 expression associated with both membranous and nuclear expression of HER2 (P=0.0033 and P<0.00001 respectively). No association was detected between COX-2 and either ERK1/2 or PEA3 (P=0.7 and P=0.3 respectively). None of the markers were found to be independently prognostic. Membrane HER2, nuclear HER2 and COX-2, however, were all found to predict poor disease-free survival in patients on endocrine treatment (P=0.0017, P=0.0003 and P=0.0202 respectively). Moreover, patients who were positive for COX-2 predicted adverse effects of tamoxifen (P=0.0427). These clinical ex vivo data are consistent with molecular observations that HER2 can regulate COX-2 expression through direct transcriptional mechanisms. COX-2 expression correlates with disease progression on endocrine treatment. This study supports a role for COX-2 as a predictor of adverse effects of tamoxifen in breast cancer patients.

Diagnostic accuracy of core biopsy for ductal carcinoma in situ and its implications for surgical practice

Background: Core biopsy is considered to be a highly accurate method of gaining a preoperative histological diagnosis of breast cancer. Ductal carcinoma in situ (DCIS) is often impalpable and is a more subtle form of breast cancer. Aim: To investigate the accuracy of core biopsy in the diagnosis of cancer in patients with DCIS. Methods: All patients who had invasive cancer (n = 959) or DCIS (n = 92) that was confirmed by excision between 1999 and 2004 were identified. The diagnostic methods, histology of the core biopsy specimen and excision histology were reviewed in detail. Results: Core biopsy was attempted in 88% (81/92) of patients with DCIS and in 91% (874/959) of those with invasive disease. Of those patients who underwent core biopsy, a diagnosis of carcinoma on the initial core was made in 65% (53/81) of patients with DCIS compared with 92% (800/874) of patients with invasive disease (p<0.0001). Smaller lesion size (p = 0.005) and lower grade (p = 0.03) were associated with increased risk for a negative or non-diagnostic core in patients with DCIS. The nature of the mammographic lesion or the method of biopsy did not affect the probability of an accurate core biopsy. Patients who had a preoperative diagnosis of DCIS by core biopsy had a reoperation rate of 36% compared with 65% of those that did not have a preoperative diagnosis (p = 0.007). Conclusion: Although core biopsies are highly accurate forms of obtaining a preoperative diagnosis in patients with invasive breast cancer, this is not the case in DCIS. As the number of surgical procedures can be reduced by core biopsy, it is still of considerable value in the management of DCIS.

Surgical intervention in screen-detected patients versus symptomatic patients with breast cancer

Objectives: The impact of population-based screening for breast cancer on the rate of breast-conserving surgery has not been established. We sought to evaluate whether surgical intervention in patients with screen-detected breast cancer differed from those with clinically detected tumours. Settings: St Vincents University Hospital and the BreastCheck Merrion Unit, part of the Irish National Breast Screening Programme, were the setting for the study. Methods: A total of 902 patients referred for surgery to St Vincents University Hospital over a four-year period (2000–2003) were studied. Patients with breast cancers detected during the prevalent round of screening (n=325) were compared with patients presenting with symptomatic disease (n=577). The operative procedure, nature of axillary surgery and histopathological findings were recorded in each case. Results: There was an increase in breast-conserving therapy in the screened population compared with symptomatic cases (68% screened versus 53% symptomatic; p<0.0001), with a corresponding reduction in axillary clearance rates (65% screened versus 81% symptomatic; p<0.0001). Nodal positivity was similar following correction for size in all tumours >1 cm, regardless of method of detection. Sentinel node biopsy was successfully undertaken in 39% of tumours <2 cm (T1 tumours) in the screening population. Conclusions: The screened population was statistically more likely to have breast-conserving therapy than the symptomatic group. Sentinel node biopsy has evolved into an acceptable alternative to axillary clearance in T1 cancers, particularly in screen-detected cases.

Coassociation of ERα and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3032 The p160 coactivators AIB1 and SRC-1 are known to play a critical role in modulating transcription in breast cancer cells in conjunction with ligand-bound estrogen receptor. The interactions of the p160 proteins with this nuclear receptor are also important in the development of resistance to endocrine treatments. Using quantitative coassociation immunofluorescent microscopy, the colocalisation of the p160s and ERα was increased in the LY2 endocrine resistant cell line following treatment with the anti-estrogen tamoxifen in comparison to the endocrine sensitive MCF-7 cell line. In cell cultures derived from patient tumours at the time of primary surgery prior to treatment, there was an increase in association of the coactivators with ERα following treatment with estrogen but dissociation was evident in the presence of tamoxifen. Immunohistochemical staining of a tissue microarray, constructed from 560 breast cancer patients, revealed that SRC-1 was a strong predictor of reduced disease-free survival, both in patients receiving adjuvant tamoxifen treatment and untreated patients (p<0.0001 and p=0.0111 respectively). AIB1 was not a significant independent predictor of disease recurrence. SRC-1 was assigned a hazard ratio of 2.12 when survival analysis using a Cox proportional hazards model was applied. Quantitative coassociation analysis of the p160 coactivators with ERα in the patient TMA revealed significantly stronger colocalisation of SRC-1 and ERα in patients who are known to have relapsed than those patients who did not recur (p=0.00001). This data suggests SRC-1 is pivotal in tumour aggressiveness and is a powerful predictor of progression of disease in breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3032.

The value of level III clearance in patients with axillary and sentinel node positive breast cancer.

Background:The value of level III axillary clearance is contentious, with great variance worldwide in the extent and levels of clearance performed. Objective:To determine rates of level III positivity in patients undergoing level I–III axillary clearance, and identify which patients are at highest risk of involved level III nodes. Methods:From a database of 2850 patients derived from symptomatic and population-based screening service, 1179 patients who underwent level I–III clearance between the years 1999–2007 were identified. The pathology, surgical details, and prior sentinel nodes biopsies of patients were recorded. Results:Eleven hundred seventy nine patients had level I–III axillary clearance. Of the patients, 63% (n = 747) were node positive. Of patients with node positive disease, 23% (n = 168) were level II positive and 19% (n = 141) were level III positive. Two hundred fifty patients had positive sentinel node biopsies prior to axillary clearance. Of these, 12% (n = 30) and 9% (n = 22) were level II and level III positive, respectively. On multivariate analysis, factors predictive of level III involvement in patients with node positive disease were tumor size (P < 0.001, OR = 1.36; 95% CI: 1.2–1.5), invasive lobular disease (P < 0.001, OR = 3.6; 95% CI: 1.9–6.95), extranodal extension (P < 0.001, OR = 0.27; 95% CI: 0.18–0.4), and lymphovascular invasion (P = 0.04, OR = 0.58; 95% CI: 0.35–1). Lobular invasive disease (P = 0.049, OR = 4.1; 95% CI: 1–16.8), extranodal spread (P = 0.003, OR = 0.18; 95% CI: 0.06–0.57), and having more than one positive sentinel node (P = 0.009, OR = 4.9; 95% CI: 1.5–16.1) were predictive of level III involvement in patients with sentinel node positive disease. Conclusion:Level III clearance has a selective but definite role to play in patients who have node positive breast carcinoma. Pathological characteristics of the primary tumor are of particular use in identifying those who are at various risk of level III nodal involvement.