Fine tuning of the Van Nuys prognostic index (VNPI) 2003 by integrating the genomic grade index (GGI): new tools for ductal carcinoma in situ (DCIS)

Ductal carcinoma in situ (DCIS) is considered a heterogeneous premalignant condition of the breast with a certain probability for progressing to malignancy. There is no standard of care. The updated Van Nuys Prognostic Index (VNPI) 2003 is a clinical tool in treatment decision making. This study assessed the prognostic value of the VNPI after integration of proliferative biomarkers (GGI and Ki-67). DCIS samples were divided into three VNPI subgroups (low risk [score 4-6], intermediate risk [score 7-9], high risk [score 10-12]) based on nuclear grade ± necrosis, tumor size, margin width, and age. Nuclear grade was substituted by the genomic grade index (GGI) to generate the VNPI-GGI and combined with the Ki-67 to generate the VNPI-Ki67. Disease-free survival was calculated by Kaplan-Meier survival plots with log-rank significance. Multiple regression analysis was carried out using Cox proportional hazard regression analysis. A total of 88 cases (median age 54 years) with representative tissue were identified out of 168 DCIS patients. Median follow-up was more than 5 years. Ten patients developed an ipsilateral recurrence of whom nine were invasive: six patients were classified in the VNPI subgroup 2 and three patients in the VNPI subgroup 3. One non-invasive recurrence (DCIS) was classified in the VNPI subgroup III. A statistical association was observed between a high VNPI score and a higher risk of recurrence (HR = 7.72 [95% CI 1.01-58.91], p = 0.049). Ki-67 did not improve the prognostic value of VNPI (HR = 6.5, [95% CI 0.80-53.33], p = 0.08). In contrast, the VNPI-GGI could identify more accurately high-risk DCIS patients with early relapses within 5 years (HR = 18.14 [95% CI 1.75-188], p = 0.015). GGI incorporated into the VNPI improved its prognostic value for DCIS, especially for identifying early relapses. This method should be validated and incorporated in future prospective clinical DCIS trials.     

Value of the Van Nuys Prognostic Index in prediction of recurrence of ductal carcinoma in situ after breast-conserving surgery

BACKGROUND: The Van Nuys Prognostic Index (VNPI), an algorithm based on tumour size, tumour grade, presence of necrosis and excision margin width, is claimed to predict local recurrence after breast-conserving surgery for ductal carcinoma in situ (DCIS). The aim of this study was to examine the validity of the VNPI in a UK population. METHODS: Clinicopathological data, including VNPI subgroups, for 237 patients who had breast-conserving operations for DCIS were examined. Multivariate data analysis was performed using a Cox regression model to examine the independence and relative importance of different variables in predicting recurrence, and to compare the data with those used in derivation of the VNPI. RESULTS: The median follow-up was 47 months. There were 37 ipsilateral local recurrences. Excision margin width (P < 0.001) and tumour grade (by Van Nuys grading (P = 0.014) or simple nuclear grading (P = 0.004)) were the only independent risk factors for local recurrence. Excision margin width had three times more power than grade in predicting local recurrence. Subgrouping data by VNPI score predicted recurrence-free survival (P < 0.001), but stratified 78 per cent of patients into a group with a moderate risk of local recurrence. CONCLUSION: Excision margin width is the most important predictor of local recurrence after breast-conserving surgery for DCIS. The VNPI lacked discriminatory power for guiding further patient management.     

Prognostic Significance of Oncogenic Markers in Ductal Carcinoma In Situ of the Breast: A Clinicopathologic Study

Abstract: Ductal carcinoma in situ (DCIS) is a heterogeneous malignant condition of the breast with an excellent prognosis. Until recently mastectomy was the standard treatment. As the results of the National Surgical Adjuvant Breast and Bowel Project‐17 trial and the introduction of the Van Nuys Prognostic Index (VNPI) less radical therapies are used. Objectives are to identify clinicopathologic and biologic factors that may predict outcome. Cases of DCIS diagnosed in two Belgian University Centers were included. Paraffin‐embedded material and Hematoxylin and Eosin stained slides of DCIS cases were reviewed and tumor size, margin width, nuclear grade, and comedo necrosis were assessed. Molecular markers (estrogen receptor, progesterone receptor, HER1‐4, Ki67, and c‐myc) were assayed immunohistochemically. Applied treatment strategies were correlated with the prospective use of the VNPI score. Kaplan–Meier survival plots were generated with log‐rank significance and multiple regression analysis was carried out using Cox proportional hazards regression analysis; 159 patients were included with a median age of 54 years (range 29–78); 141 had DCIS and 18 DCIS with microinvasion. The median time of follow‐up was 54 months (range 5–253). Twenty‐three patients developed a recurrence (14.5%). The median time to recurrence was 46 months (range 5–253). Before the introduction of the VNPI, 37.5% of the DCIS patients showed a recurrence while thereafter 6.7% recurred (p < 0.005). Two recurrences occurred in the VNPI group I (7.1%); seven in the VNPI group II (8.5%) (median time to recurrence 66.3 months) and 14 in the VNPI group III (28.5%) (median time to recurrence 40.2 months) (disease‐free survival [DFS]: p < 0.05). A Cox proportional hazards regression analysis indicated that tumor size, margin width, pathologic class, and age were independent predictors of recurrence, but none of the studied molecular markers showed this. Overexpression of HER4 in the presence of HER3 was found to be associated with a better DFS (p < 0.05). This study confirms the value of the VNPI score and questions the benefit of an aggressive approach in the low‐risk DCIS lesions. Independent predictors for recurrence included size, margin width, pathologic class, and age, but none of the molecular markers were part of it. Overexpression of HER4 in the presence of HER3 was associated with a better DFS.     

Management of ductal carcinoma in situ according to Van Nuys Prognostic Index in Australia and New Zealand

Introduction: Clinicians often use the Van Nuys Prognostic Index (VNPI) to determine management of ductal carcinoma in situ (DCIS). The VNPI uses age, extent of DCIS, pathological grade and resection margins to stratify patients into three groups pertaining to risk of local recurrence: low-risk (where breast-conserving surgery - BCS - alone appears adequate), intermediate-risk (where BCS plus radiotherapy is recommended) and high-risk (where mastectomy may be the safest option). The purpose of this study was to determine patterns of management of DCIS in Australia and New Zealand according to the VNPI. Methods: Using the National Breast Cancer Audit for the period 2004-2009, 4578 cases of DCIS were identified where complete data were available. Patterns of management according to the VNPI were determined. The chi-squared test was used for statistical analysis. Results: In VNPI group 1, 77% of patients were treated with BCS compared with 63% in group 2 and 32% in group 3. Of patients in group 1 who underwent BCS, 58% also received adjuvant radiotherapy, compared with 80% in group 2. In group 3, 68% were treated with mastectomy, and of those who underwent BCS, 86% received radiotherapy. Overall, 23% of DCIS cases did not conform to best practice according to individual VNPI prognostic groupings. Conclusions: Significant differences in the management of DCIS according to VNPI groups were observed. The results suggest the possibility that some patients in the low-risk group were over-treated, while a proportion of patients in the intermediate- and high-risk groups were under-treated.     

Treatment Selection for Patients with Ductal Carcinoma In Situ (DCIS) of the Breast Using the University of Southern California/Van Nuys (USC/VNPI) Prognostic Index

The University of Southern California/Van Nuys Prognostic Index (USC/VNPI) is an algorithm that quantifies five measurable prognostic factors known to be important in predicting local recurrence in conservatively treated patients with ductal carcinoma in situ (DCIS) (tumor size, margin width, nuclear grade, age, and comedonecrosis). With five times as many patients since originally developed, sufficient numbers now exist for analysis by individual scores rather than groups of scores. To achieve a local recurrence rate of less than 20% at 12 years, these data support excision alone for all patients scoring 4, 5, or 6 and patients who score 7 but have margin widths ≥3 mm. Excision plus RT achieves the less than 20% local recurrence threshold at 12 years for patients who score 7 and have margins <3 mm, patients who score 8 and have margins ≥3 mm, and for patients who score 9 and have margins ≥5 mm. Mastectomy is required for patients who score 8 and have margins <3 mm, who score 9 and have margins <5 mm and for all patients who score 10, 11, or 12 to keep the local recurrence rate less than 20% at 12 years. DCIS is a highly favorable disease. There is no difference in mortality rate regardless of which treatment is chosen. The USC/VNPI is a numeric tool that can be used to aid the treatment decision‐making process.     

The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast

BACKGROUND: The original Van Nuys prognostic index (VNPI) was introduced in 1996 as an aid to the complex treatment decision-making process for patients with ductal carcinoma in situ (DCIS) of the breast. This update adds patient age to the previous predictors of local recurrence in breast preservation patients. METHODS: A prospective database consisting of 706 conservatively patients with DCIS was examined using multivariate analysis. Four independent predictors of local recurrence (tumor size, margin width, pathologic classification, and age) were used to derive a new formula for the University of Southern California (USC)/VNPI. RESULTS: In all, 706 patients with pure DCIS were treated with breast preservation. There was no statistical difference in the 12-year local recurrence-free survival in patients with USC/VNPI scores of 4, 5, or 6, regardless of whether or not radiation therapy was used (P = not significant). Patients with USC/VNPI scores of 7, 8, or 9 received a statistically significant average 12% to 15% local recurrence-free survival benefit when treated with radiation therapy (P = 0.03). Patients with scores of 10, 11, or 12, although showing the greatest absolute benefit from radiation therapy, experienced local recurrence rates of almost 50% at 5 years. CONCLUSIONS: Ductal carcinoma in situ patients with USC/VNPI scores of 4, 5 or 6 can be considered for treatment with excision only. Patients with intermediate scores (7, 8, or 9) should be considered for treatment with radiation therapy or be reexcised if margin width is less than 10 mm and cosmetically feasible. Patients with USC/VNPI scores of 10, 11, or 12 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy, generally with immediate reconstruction or reexcision if technically possible.     

Analyzing the Risk of Recurrence after Mastectomy for DCIS: A New Use for the USC/Van Nuys Prognostic Index

Background

Patients with ductal carcinoma in situ (DCIS) who are treated with mastectomy seldom recur locally or with metastatic disease. When patients with DCIS recur with invasive cancer, they are upstaged and their lives are threatened. We questioned whether histopathologic data could be used to predict these infrequent events.

Methods

We reviewed a prospective database of 1,472 patients with pure DCIS. All patients were scored from 4 to 12 using the USC Van Nuys Prognostic Index, an algorithm based on DCIS size, nuclear grade, necrosis, margin width, and patient age. Probabilities of recurrence and death were calculated using the Kaplan–Meier method.

Results

A total of 496 patients with pure DCIS were treated with mastectomy. None received any form of postmastectomy adjuvant treatment. Average follow-up was 83 months. Eleven patients developed recurrences, all of whom scored 10–12 using the USC/VNPI. No patient who scored 4–9 recurred. All 11 patients who recurred had multifocal disease and comedo-type necrosis. The probability of disease recurrence after mastectomy for patients scoring 10–12 was 9.6% at 12 years, compared with 0% for those scoring 4–9. There was no difference in overall survival.

Conclusions

There were no recurrences among mastectomy patients who scored 4–9 using the USC/VNPI. Patients scoring 10–12 were significantly more likely to develop recurrence after mastectomy. At risk were young patients with large, high-grade, and multifocal or multicentric tumors. For every 100 patients with USC/VNPI scores of 10–12, 10 patients will recur by 12 years and 2–3 will develop metastatic disease.     

Ductal carcinoma in situ: USC/Van Nuys Prognostic Index and the impact of margin status

As our knowledge of ductal carcinoma in situ (DCIS) continues to evolve, treatment decision-making has become increasingly complex and controversial for both patients and physicians. Treatment options include mastectomy, and breast conservation with or without radiation therapy. Data produced from the randomized clinical trials for DCIS has provided the basis for important treatment recommendations, but are not without limitations. In this article, we review our prospectively collected database consisting of 1036 patients with DCIS treated at the Van Nuys Breast Center and the USC/Norris Comprehensive Cancer Center. We review the use of the USC/Van Nuys Prognostic Index, a clinical algorithm designed to assist physicians in selection of appropriate treatments, and examine the impact of margin status as a sole predictor of local recurrence.     

Ductal carcinoma in situ of the breast and heparanase-1 expression: a molecular explanation for more aggressive subtypes

BACKGROUND: Ductal carcinoma in situ of the breast (DCIS) forms a heterogeneous group of lesions with varying invasive potential. This study tested whether heparanase-1 (HPR1), an endoglycosidase that specifically degrades the heparan sulfate (HS) proteoglycans in the breast extracellular matrix, was associated with the most aggressive DCIS subtypes. STUDY DESIGN: Fifty-seven DCIS specimens and 10 normal breast specimens were examined for HPR1 expression using immunohistochemical staining. Twenty-seven arbitrarily selected specimens were also examined for HS deposition by immunofluorescence staining, confirming HPR1 activity. Patient medical records were obtained to explore a possible association between biologic potential using Van Nuys Prognostic Index (VNPI) and HPR1 expression. RESULTS: Twenty-one (75%) of 28 comedo and microinvasive DCIS specimens stained HPR1 positive; 4 (14%) of 29 other subtypes (papillary, cribriform, and solid subtypes) stained HPR1 positive on immunohistochemistry (p = 0.003). Among 27 DCIS stained for HS, we found that 8 (67%) of 12 HPR1-negative DCIS had intact HS deposition in the extracellular basement membrane; none of the 15 HPR1-positive DCIS stained HS positive. Six (86%) of seven DCIS with VNPI scores 8 to 9 and 14 (50%) of 28 DCIS with VNPI scores 5 to 7 were HPR1 positive; only 3 (17%) of 18 DCIS with VNPI scores 3 to 4 were HPR1 positive. Median VNPI score in patients with HPR1-positive DCIS was 7 (range 3 to 9), compared with 4.5 (range 3 to 7) in patients with HPR1-negative DCIS (p < 0.001). CONCLUSIONS: HPR1 was expressed at a significantly higher frequency in the invasive comedo and DCIS with microinvasion subtypes than in the noninvasive subtypes. HPR1 expression was inversely associated with HS deposition in the extracellular basement membrane of the DCIS. HPR1 expression was associated with a higher VNPI score. These observations suggest that HPR1 expression in DCIS can play an important role in development of DCIS into an invasive breast cancer.     

Preliminary results and evaluation of MammoSite balloon brachytherapy for partial breast irradiation for pure ductal carcinoma in situ: a phase II clinical study

BACKGROUND: This report presents the preliminary results and evaluation of the MammoSite balloon catheter (MammoSite Radiation Therapy System; Cytyc Corporation, Marlboro, MA) as the sole method of delivering partial breast irradiation to the lumpectomy bed with breast-conserving surgery in patients with pure ductal carcinoma in situ (DCIS). METHODS: Twelve institutions are participating in this phase II clinical study. A total of 133 patients have been enrolled and 100 patients have successfully completed the prescribed radiation therapy. A dose of 34 Gy was delivered in 10 fractions over 5 days prescribed to 1 cm from the applicator surface using iridium-192 high-dose rate brachytherapy. Patients who met the following criteria were selected for enrollment into the study: age 45 years or older, unicentric pure DCIS, mammographic lesion of 3 cm or less, negative margins as defined by 1 mm or more, postoperative final gross pathologic size of tumor of 5 cm or less, clinically node negative, and a postlumpectomy mammogram showing the absence of any residual suspicious microcalcifications. The placement of the MammoSite catheter was performed either at the time of the lumpectomy or postlumpectomy. The minimum distance from the balloon surface to the surface of the skin is greater than 5 mm. Data collection points are at time of enrollment, time of implant, 3 months, 6 months, and then yearly at 1- to 5-year follow-up visits. Data collected are local control rates, cosmetic outcome using the Harvard Scale, toxicities, serious adverse events, disease-free survival, cause-specific survival, and contralateral breast failure. The Van Nuys Prognostic Index scores were calculated for each patient. Local recurrence is defined as either invasive or noninvasive recurrence within the target volume. Ipsilateral elsewhere recurrence is defined as either an invasive or noninvasive recurrence occurring outside of the target volume in the previously treated breast. This recurrence is classified as a new primary tumor. RESULTS: The mean follow-up period was 9.5 months (range, 1-24 mo). The MammoSite catheter was explanted for the following reasons: inadequate skin distance (5.1%; 6 of 117), poor cavity conformance (5.1%; 6 of 117), positive margins (2.6%; 3 of 117), final histology (.85%; 1 of 117), and physician decision (.85%; 1 of 117). Of the patients in whom the MammoSite was explanted because of skin spacing or cavity conformance, 50% were at sites of new users (institutions that have placed fewer than 10 Mammosite catheters). Cosmetic results were rated as excellent in 63%, good in 35%, and fair in 2% in the 86 patients with a follow-up visit. Two patients were diagnosed with an ipsilateral local recurrence, 1 outside of the target volume and 1 true recurrence/marginal miss. One patient was diagnosed at 8 months and the other was diagnosed at 11 months. Both of these ipsilateral failures were DCIS. The Van Nuys Prognostic Index of these 2 patients was 9 and 8, respectively. Data collected showed the mean age at placement was 60.8 y, mean tumor size was 10.6 mm, mean actual closest surgical margin was 6.8 mm (range, .1-40 mm), a re-excision rate of 35%, postlumpectomy placement was 71%, and the mean skin-to-balloon surface distance was 13 mm with 89% > or =7 mm. No serious adverse events were reported. The infection rate was 4.0%. CONCLUSIONS: Accelerated partial breast irradiation delivered with the MammoSite balloon was clinically successful in patients entered into a phase II clinical study with pure DCIS, with results comparable with other studies reported in the literature that have evaluated use of the MammoSite balloon brachytherapy for delivery of radiation therapy in early breast cancers. Inadequate skin distance and poor cavity conformance were the main factors limiting the use of the MammoSite device. Cosmetic results were good to excellent in 98%. There have been 2 ipsilateral breast recurrences.     

Prognostic Factors and Local Recurrence in Patients with Ductal Carcinoma In Situ of the Breast

Abstract: Local recurrence is an important event when it occurs in a patient previously treated for ductal carcinoma in situ. Therefore, the ability to predict the probability of local recurrence after breast preservation therapy would be extremely valuable in the treatment decision-making process. In an attempt to predict the likelihood of local recurrence, 30 prognostic factors were evaluated in 622 patients with ductal carcinoma in situ treated at the Van Nuys Breast Center from 1979 through June 1996. Four factors emerged as significant independent predictors of local recurrence. These included treatment, tumor size, margin width, and pathologic classification.     

The consequence of undertreatment of patients treated with breast conserving therapy for ductal carcinoma in-situ

Background

The use of clinical features to allocate adjuvant therapy in the treatment of ductal carcinoma in situ with breast-conserving therapy remains controversial.

Methods

A review of patients with ductal carcinoma in situ treated with breast-conserving therapy was performed. The recurrence rate was examined in relation to patient age, tumor characteristics, Van Nuys Prognostic Index, and the receipt of prescribed adjuvant therapies.

Results

Six percent of patients (17 of 294) had developed local recurrences after a median follow-up period of 63 months. Fifty-nine percent of patients (91 of 154) with estrogen receptor–positive tumors did not receive prescribed tamoxifen. Thirty-one percent of patients (45 of 147) with Van Nuys Prognostic Index scores ≥7 did not receive recommended radiation therapy. Receipt of prescribed adjuvant therapy did not result in a decrease in the rate of local recurrence. Patient age was the only factor associated with local recurrence on univariate but not on multivariate analysis (P = .374).

Conclusions

A low rate of local recurrence was achieved despite a large number of patients' not receiving prescribed adjuvant therapies.     

Local control in ductal carcinoma in situ treated by excision alone: incremental benefit of larger margins

BACKGROUND: Margin width has been shown previously to be the most important predictor of local treatment failure after breast conservation for ductal carcinoma in situ (DCIS). METHODS: Five variables thought to be associated with local recurrence were evaluated by univariate and multivariate analysis in 455 nonrandomized patients with DCIS treated with excision alone. RESULTS: Multivariate analysis showed that margin width, age, nuclear grade, and tumor size all were independent predictors of local recurrence, with margin width as the single most important predictor. After adjusting for all other predictors the likelihood of local recurrence for patients with margins less than 10 mm was 5.39 times as much as that for patients with margins of 10 mm or more (95% confidence interval, 2.68-10.64). CONCLUSIONS: Margin width, the distance between DCIS and the closest inked margin, was the single most important predictor of local recurrence. As margin width increases, the risk for local recurrence decreases.     

Defining negative margins in DCIS patients treated with breast conservation therapy: The University of Chicago experience

Management of ductal carcinoma in situ (DCIS) has been evolving and the majority of women are now being treated with breast-conserving surgery and radiation therapy (i.e. breast conservation therapy [BCT]). Controversies still exist regarding the histologic features and margin status that are associated with local recurrence. The goal of this study was to review our institution's experience in patients diagnosed with DCIS and treated with BCT to determine pathologic features that can predict local recurrence, with particular emphasis on the final surgical margin status. We analyzed 103 consecutive patients with DCIS who were treated with BCT between 1986 and 2000. The slides were reviewed to determine the final margin status, type of DCIS, size of DCIS, nuclear grade, presence of necrosis and calcification, and volume of excised specimen. Margins were considered positive when DCIS touched or was transected at an inked margin. Negative margins were further categorized as close (less than 1 mm), 1--5 mm, and more than 5 mm. The size of the DCIS was determined based on either the maximal dimension on a slide or from the number of consecutive slides containing DCIS. Morphology and immunohistochemical profiles of the recurrent DCIS cases were compared with original DCIS. All patients were treated uniformly with external beam radiation therapy to the entire breast (median dose 46 Gy) with a boost to the tumor bed (median dose 14 Gy). The median follow-up was 63 months (range 7--191 months). The actuarial 5-year local control rate was 89%. The median time to local recurrence was 55 months. There were 13 local recurrences, of which 9 recurred as pure DCIS and 4 as invasive ductal carcinomas. Univariate analysis showed a significant association with local recurrence for positive margin (p=0.008), high nuclear grade (p=0.02), and young age at diagnosis (p=0.03). If margins were negative, the 5-year local control was 93%, as compared to 69% if margins were positive. A multivariate analysis showed that early age at diagnosis, positive margin status, and high nuclear grade were independently associated with local recurrence. The morphology and immunohistochemical stains of all nine recurrent DCIS were similar to those of the original DCIS. Breast conservation can be achieved with excellent local control by obtaining microscopically negative margins as strictly defined by DCIS not touching the inked surgical margins, and postoperative radiation that includes boost therapy to the tumor bed.     

Duct carcinoma in situ: A personal perspective

In the recent past, DCIS was a rare diagnosis established by biopsy of palpable breast masses or nipple changes. Mammography increased the frequency of a DCIS diagnosis by 20 × resulting in a tsunami of small circa 10 mm lesions detected only by mammography. The impact of pathologic technique in examining and characterizing such lesions is reviewed, and the development of algorithms incorporating prognostic factors and histology based on serial sequential processing techniques are described and contrasted with those which relied on tissue sampling. The development of the initial clinical trails of irradiation all demonstrated the significant benefit of irradiation but none could identify subsets with a more favorable outcome. The latter was precluded by their common practice of tissue sampling: Size could not be calculated and margin width and microinvasion could not be reliable demonstrated. Multigene signature assays are increasingly being utilized, most prominently Oncotype DCIS. However, these assays must be interpreted in conjunction with the limitations set forth in the validating studies—in the case of Oncotype DCIS—the size, margin width, and grade which defined the baseline study (E5194). Tamoxifen and other anti‐hormonal agents (aromatase inhibitor therapy) have been shown to have a limited impact on ipsilateral recurrence which makes their use given their morbidities problematic. Such interventions do impact the frequency of contralateral occult in situ and invasive lesions. In the one study which permitted a comparison of local recurrence in irradiated vs nonirradiated breast, there was no added benefit of Tamoxifen in irradiated breasts. Some are attempting to identify a low‐risk subset of DCIS which can be treated without surgical re‐excision for margins or adjuvant irradiation. These studies are in progress but surrogates identified within the Van Nuys prospective series defined by grade and inadequate margins (≤ 1 mm) would suggest a significant recurrence and progression rate. DCIS remains a work in progress both in terms of classification and treatment. However, limited our progress in these areas we have certainly advanced from the oft‐proclaimed mantra: “Radiation and Tamoxifen are standard of care.”     

Age and associated fibrocystic changes are prognostically significant in patients with small node-negative (T1a,bN0) invasive breast cancer

Some patients with small (≤1.0 cm) node-negative (T1a,bN0) invasive breast cancer (IBC) who undergo only local therapy experience recurrences. There is limited information on prognostic factors in these patients. We sought to identify prognostic factors associated with disease-free survival (DFS) and overall survival (OS) in patients with T1a,bN0 IBC. Histologic sections from 273 T1a,bN0 IBC patients treated at M. D. Anderson Cancer Center (MDACC) between 1980 and 1999 were reviewed. Microscopic tumor size; multifocality; histologic type, grade of tumor; presence, type, grade of associated ductal carcinoma in situ (DCIS); presence of fibrocystic changes (FCC) with/without atypia; and lymphovascular invasion were identified. The Kaplan-Meier method was used to evaluate DFS and OS. Median patient age was 58 years, median follow-up period was 10.8 years, and median tumor size was 0.8 cm. Multifocal disease was identified in 26% of cases. At 10 years, the DFS and OS rates were 91% and 88%, respectively. Twenty-one percent of patients had extensive (>50%), and 30% had grade 3 DCIS. Nonproliferative FCC and proliferative FCC with/without atypia were present in 80%, 36%, and 38% of patients, respectively. In univariate analysis, age at diagnosis (p < 0.0001), grade (p = 0.015), and percent (p = 0.046) of DCIS were significantly associated with DFS; presence of FCC was associated with longer DFS and OS. In multivariable models, age and presence of FCC remained significantly associated with survival. Age at diagnosis and associated FCC are significant factors in predicting recurrence in patients with T1a,bN0 IBC. Adjuvant systemic therapy should be discussed with and considered for young patients with T1a,bN0 IBC.     

Pathological and Biological Differences Between Screen-Detected and Interval Ductal Carcinoma in situ of the Breast

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has risen dramatically with the introduction of screening mammography. The aim was to evaluate differences in pathological and biological characteristics between patients with screen-detected and interval DCIS. METHODS: From January 1992 to December 2001, 128 consecutive patients had been treated for pure DCIS at our institute. From these, 102 had been attending the Dutch breast cancer screening program. Sufficient paraffin-embedded tissue was available in 74 out of the 102 cases to evaluate biological marker expression (Her2/neu, ER, PR, p53 and cyclin D1) on tissue microarrays (TMA group). Differences in clinicopathological characteristics and marker expression between screen-detected and interval patients were evaluated. Screen-detected DCIS was classified as DCIS detected by screening mammography, when the two-year earlier examination failed to reveal an abnormality. Interval patients were classified as patients with DCIS detected within the two-year interval between two subsequent screening rounds. RESULTS: Screen-detected DCIS was related with linear branching and coarse granular microcalcifications on mammography (p < .001) and with high-grade DCIS according to the Van Nuys classification (p = .025). In univariate analysis, screen-detected DCIS was related with Her2/neu overexpression (odds ratio [OR] = 6.5; 95%CI 1.3-31.0; p = .020), and interval DCIS was associated with low-grade (Van Nuys, OR = 7.3; 95% CI 1.6-33.3; p = .010) and PR positivity (OR = 0.3; 95%CI 0.1-1.0; p = .042). The multivariate analysis displayed an independent relation of Her2/neu overexpression with screen-detected DCIS (OR = 12.8; 95%CI 1.6-104.0; p = .018). CONCLUSIONS: These findings suggest that screen-detected DCIS is biologically more aggressive than interval DCIS and should not be regarded as overdiagnosis.     

Small size ductal carcinoma in situ of the breast: predictors of positive margins after local excision

One of the most important predictors of local recurrence after local excision of ductal carcinoma in situ (DCIS) is margin status. The aim was to study the association between margin status and clinical, radiological, and pathological characteristics and to determine predictors of positive margins after local excision of small size (< or = 4 cm) DCIS. Data were tested for differences regarding margin status, and logistic regression was used to determine predictors of margin status. The population consisted of 105 cases. Overall, 51 cases (49%) had free margins and 54 cases (51%) had positive margins. Positive margins were more often associated with a mean mammographic tumor size of 2.1 cm (P = 0.044) and absence of fine granular calcifications (P = 0.004). Also, high-grade (P = 0.013) and a mean pathological size of 3.2 cm (P < 0.001) were associated with positive margins. The only independent predictor of margin status was pathological grade (P = 0.010).     

Local recurrence of ductal carcinoma in situ after skin-sparing mastectomy

BACKGROUND: The incidence of local recurrence (LR) after conventional total mastectomy for ductal carcinoma in situ (DCIS) ranges from 1% to 3%. Skin-sparing mastectomy (SSM) preserves the native skin envelope to facilitate immediate breast reconstruction. Because DCIS is generally not clinically apparent, there is a potential for inadequate excision when SSM is performed. Risk factors for local recurrence after SSM for DCIS are examined. STUDY DESIGN: A retrospective review of 223 consecutive patients with DCIS treated by SSM and immediate reconstruction was performed. Age younger than 50 years, tumor size > 40 mm, high tumor grade, tumor necrosis, surgical margins < 1 mm, type of biopsy (excisional versus core), and SSM type were examined as risk factors for recurrence. RESULTS: Mean followup was 82.3 months (range 4.9 to 123.2 months). Recurrences developed in 11 patients (5.1%), including: local (n = 7; 3.3%), regional (n = 2; 0.9%), and distant (n = 2; 0.9%). All seven local recurrences were detected by physical examination. No patients received adjuvant radiation therapy. Two of 19 patients with surgical margins < 1 mm developed LR (10.5%). Univariate analysis showed high tumor grade (p = .019) to influence LR. CONCLUSIONS: The incidence of local recurrence of DCIS after SSM is similar to conventional total mastectomy. Reexcision of close margins should be performed if possible and adjuvant radiation therapy should be considered.     

Predicting the likelihood of residual disease in women treated for ductal carcinoma in situ

Background: To identify women at risk for residual disease after excision of ductal carcinoma in situ (DCIS), we assessed the relationship between characteristics of the initial biopsy and the presence of residual DCIS at a subsequent operation.Study Design: We identified 134 consecutive “paired” operations from 112 women who had undergone 2 or more operations for DCIS between February 1995 and December 1996. Cancer status of the margins, patient age and leading presentation, tumor subtype and grade, and the presence of multifocal-extensive disease were assessed as potential predictors.Results: Residual DCIS was found in 60 patients (45%): in 2 of 12 patients (17%) with negative margins, in 11 of 36 (31%) with close margins (< 2 mm), in 30 of 52 (58%) with positive margins, and in 17 of 34 patients (50%) with margins of unknown status. Patients with positive or unknown margins were 7.7 and 8.3 times, respectively, more likely to have residual disease than patients with negative margins (95% CI 1.1–59.1; 1.1–66.4). Patients with clinical presentations were 8.0 times more likely to have residual disease than patients who presented with abnormal mammograms (95% CI 2.3–27.6). Multifocal-extensive DCIS was associated with residual disease (adjusted odds ratio [OR] = 7.7, 95% CI 2.9–20.5), as was comedo subtype (OR = 2.7, 95% CI 1.1–6.7).Conclusions: Positive or unknown biopsy margins, a clinical presentation, multifocal-extensive cancer, and the comedo subtype are associated with higher risk of residual DCIS.