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Positive sentinel lymph node (SLN) findings in ductal carcinoma in situ (DCIS) range from 1 to 22 % but have unknown biologic significance. This study sought to identify predictors of positive SLNs and to assess their clinical significance for patients with an initial diagnosis of DCIS. The study identified 1234 patients with an initial diagnosis of DCIS who underwent SLN dissection (SLND) at our institution from 1997 through 2011. Positive SLN findings were categorized as isolated tumor cells (ITCs) (≤0.2 mm), micrometastases (>0.2–2 mm), or macrometastases (>2 mm). Predictors of positive SLNs were analyzed, and survival outcomes were examined. Positive SLN findings were identified in 132 patients (10.7 %): 66 patients with ITCs (5.4 %), 36 patients with micrometastases (2.9 %), and 30 patients with macrometastases (2.4 %). Upstaging to microinvasive (n = 68, 5.5 %) or invasive (n = 259, 21.0 %) cancer occurred for 327 patients (26.5 %). Factors predicting positive SLNs included diagnosis by excisional biopsy (odds ratio [OR] 1.90; P = 0.007), papillary histology (OR 1.77; P = 0.006), DCIS larger than 2 cm (OR 1.55; P = 0.030), more than three interventions before SLND (4 interventions: OR 2.04; P = 0.022; ≥5 interventions: OR 3.87; P

BACKGROUND Guidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%. METHODS The study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%-9% positive staining for ER (ER-positive 1%-9%) and

Background. Guidelines by the American Society of Clinical Oncology and the College of American Pathologists recently recommended that estrogen receptor (ER) status should be considered positive if 1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. Historically, 10% nuclear staining defined ER-positive status and impacted decision-making regarding endocrine therapy. Currently, no optimal threshold exists for ER either by clinically validating patient outcomes in prospective clinical trials or independently validated from systematically collected archived specimens from randomized clinical trials. In this study, we examined patient, tumor and treatment differences among patients by ER status: ER-positive ≥10%, ER-positive 1–10% and ER negative ( Method. Patients with primary breast carcinoma treated at our center who had complete ER status from January 1990 to December 2011 were included in this study. Patients were excluded if they presented with recurrent or metastatic disease. For statistical analyses, patients who underwent surgery for breast cancer were separated into three groups: ER-positive ≥10%, ER-positive 1–10% and ER negative. Analyses comparing various clinical and pathologic characteristics among patients with different ER status were performed. Survival rates were calculated by the Kaplan-Meier method. Result. Patients whose tumors were ER-positive 1–10% (2.7%) were younger (median age 53 Vs. 56 years, P < 0.0001), more likely to have invasive ductal carcinoma histology with more advanced disease (clinical stage II/III 50.4% Vs. 37.3%, p < 0.0001), and were more likely to receive neoadjuvant chemotherapy (40.9% vs. 25.6%, P < 0.0001), adjuvant chemotherapy (45.5% vs. 31.2%, P < 0.0001), and less likely to receive adjuvant endocrine therapy (19.5% vs. 78.6%, P < 0.0001) compared to patients with ER-positive tumors ≥ 10%. They were also more likely to have HER-2-positive (29.1% vs. 13.4%, P < 0.0001) and grade III disease (82.1% vs. 29.6%, P < 0.0001). Compared to patients with ER negative, patients with ER-positive 1–10% had earlier stage disease (clinical stage II/III 50.4% Vs. 59.3%, p = 0.01), were less likely to receive neoadjuvant chemotherapy (40.9% vs. 48.2%, p = 0.02), and more likely to receive adjuvant endocrine therapy (19.5% vs. 12.6%, p = 0.002). At a median follow-up of 5.1 years, patients with ER-positive 1–10% had worse RFS, DFS and OS rates compared to patients with ER-positive tumors ≥ 10%. The RFS, DFS and OS rates between patients with ER-positive 1–10% and ER negative did not differ significantly. Patients with ER-positive 1–10% and negative still had worse RFS, DSS and OS rates compared to patients with ER-positive tumors ≥ 10% after adjusted by clinical stage, adjuvant chemo and endocrine therapy. Conclusion. Patients whose tumors are ER-positive at 1–10% have clinical and pathologic characteristics different from those whose tumors are ER-positive ≥10%. Similar to patients whose tumors are ER negative, those with ER-positive disease at 1–10% do not appear to benefit from endocrine therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-09.

Purpose Prediction of patients at highest risk for ipsilateral breast tumor recurrence (IBTR) after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The aim of our study was to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center to predict for risk of IBTR in patients with DCIS from our institution. Patients and Methods We retrospectively identified 794 patients with a diagnosis of DCIS who had undergone local excision from 1990 through 2007 at the MD Anderson Cancer Center (MDACC). Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients who had complete data. Results There was a marked difference with respect to tumor grade, prevalence of necrosis, initial presentation, final margins, and receipt of endocrine therapy between the two cohorts. The biggest difference was that more patients received radiation in the MDACC cohort (75% at MDACC v 49% at MSKCC; P < .001). Follow-up time in the MDACC cohort was longer than in the MSKCC cohort (median 7.1 years v 5.6 years), and the recurrence rate was lower in the MDACC cohort (7.9% v 11%). The median 5-year probability of recurrence was 5%, and the median 10-year probability of recurrence was 7%. The nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated imperfect calibration and discrimination, with a concordance index of 0.63. Conclusion Predictive models for IBTR in patients with DCIS who were treated with local excision are imperfect. Our current ability to accurately predict recurrence on the basis of clinical parameters alone is limited.

Purpose American Joint Committee on Cancer (AJCC) staging is used to determine breast cancer prognosis, yet patient survival within each stage shows wide variation. We hypothesized that differences in biology influence this variation and that addition of biologic markers to AJCC staging improves determination of prognosis. Patients and Methods We identified a cohort of 3,728 patients who underwent surgery as the first intervention between 1997 and 2006. A Cox proportional hazards model, with backward stepwise exclusion of factors and stratification on pathologic stage (PS), was used to test the significance of adding grade (G), lymphovascular invasion (L), estrogen receptor (ER) status (E), progesterone receptor (PR) status, combined ER and PR status (EP), or combined ER, PR, and human epidermal growth factor receptor 2 status (M). We assigned values of 0 to 2 to these disease-specific survival (DSS) –associated factors and assessed six different staging systems: PS, PS + G, PS + G L, PS + G E, PS + G EP, and PS + G M. We compared 5-year DSS rates, Akaike's information criterion (AIC), and Harrell's concordance index (C-index) between systems. Surveillance, Epidemiology, and End Results data were used as the external validation cohort (n = 26,711). Results Median follow-up was 6.5 years, and 5-year DSS rate was 97.4%. The PS + G E status staging system was most precise, with a low AIC (1,931.9) and the highest C-index (0.80). PS + G E status was confirmed to stratify outcomes in internal bootstrapping samples and the external validation cohort. Conclusion Our results validate an improved breast cancer staging system that incorporates grade and ER status. We recommend that biologic markers be incorporated into revised versions of the AJCC staging system.

Purpose: The stage IB designation was added to the AJCC 7th edition staging system to denote micrometastasis in patients with T1 tumors. We have previously examined this group and found that receptor status and nuclear grade were better survival discriminates than the presence of micrometastases. The current study was undertaken to validate this finding in a larger cohort from the American College of Surgeons Oncology Group (ACOSOG) Z0010 study. Methods: Clinicopathologic and outcomes data from patients enrolled on ACOSOG Z0010 were recorded. All patients underwent breast conserving surgery, sentinel lymph node biopsy and whole breast radiation for clinical T1-2, N0 breast cancer. Sentinel lymph nodes were evaluated by H&E locally and if negative, by immunohistochemistry (IHC) at a central laboratory. Patients were staged according to the 7th edition AJCC system and recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were determined using the Kaplan-Meier method and compared using the log-rank test. Results: There were 5210 eligible and evaluable patients enrolled on ACOSOG Z0010. AJCC stage distribution was known in 4590 and included: 2849 (62.0%) stage IA, 376 (8.2%) stage IB, 878 (19.1%) stage IIA, 322 (7.0%) stage IIB, and 170 (3.7%) stage III. Median follow-up for the cohort was 9.0 years (range 0–12.6). Five and 10-year RFS, DSS and OS rates for patients with stage IA versus IB disease are shown in table 1. There were no significant differences between groups. When all stage I patients (stage IA and IB) were evaluated by ER status (positive vs negative) or grade (grade 1 vs 2 vs 3), these biologic factors were able to significantly discriminate patients with respect to RFS, DSS and OS (table 2). Conclusion: Differentiating patients with micrometastases (stage IB) from node negative patients (stage IA) does not stratify patients well with respect to survival. Biologic factors including ER status and grade are better discriminants of survival than the presence of small volume nodal metastases in patients with early stage breast cancer. Breast cancer staging should include biologic factors from the primary tumor. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-06.

1028 Background: Recent studies have reported increased mastectomy rates for the treatment of early stage breast cancer during the last decade. The aims of this study were to examine trends in mastectomy rates at a single institution and in a population-based database and to compare differences between the two cohorts. Methods: Patients with stage 0-II breast cancer diagnosed from 2000 to 2008 were identified from our cancer center institutional database (CC cohort, n=8,915) and the Surveillance, Epidemiology and End Results database (SEER cohort, n=359,572). Patients without primary surgery or unknown surgery type were excluded. Mastectomy rates by the year of diagnosis were evaluated and multivariable logistic regression models were built to identify clinicopathologic factors that predicted mastectomy as the treatment choice. Results: The proportion of patients treated with mastectomy decreased from 44.5% to 37.8% between 2000 and 2005 in the CC cohort (P=0.003) and from 42.8% to 36.6% in the SEER cohort (P

92 Background: American Joint Committee on Cancer (AJCC) staging of breast cancer is used to determine prognosis, yet survival of patients within each stage shows wide variation and remains unpredictable. We hypothesized that differences in underlying biology might influence some of this variation and that the addition of biologic markers to current AJCC staging parameters would improve predictions of prognosis. Methods: We identified an initial cohort of 3,728 patients at our center who underwent surgery as the first intervention between 1997 and 2006. We used a Cox proportional hazards model, with backward stepwise exclusion of factors and stratified on pathologic stage (PS), to test the added significance of modified Black’s nuclear grade (G), the presence of lymphovascular invasion (L), estrogen receptor status (E), progesterone receptor status (P), or combined ER and PR status (EP), or combined receptor subtype (ER+PR+HER2 [M]). We assigned values 0-2 to these disease-specific survival (DSS)–associated factors and then used different combinations to assess different staging systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort (n=26,711) to validate the scoring system. Results: Median follow-up time for the initial cohort was 6.5 years, and the 5-year DSS rate was 97.4%. Six different staging systems were used to predict 5-year patient outcomes: PS, PS+G, PS+GL, PS+EG, PS+GEP, and PS+GM. We compared 5-year DSS rates, Akaike’s information criterion (AIC) and Harrell’s concordance index (C-index) for each staging system. We found that the PS+GEP staging system was most precise with lowest AIC (1927.3) and had the highest C-index (0.80). The ability of the PS+GEP system to stratify outcomes was confirmed in the internal bootstrapping samples and the external validation cohort. Conclusions: Our results validate a new staging system that incorporates tumor grade, ER and PR status into current AJCC staging for breast cancer. We recommend that biologic markers be incorporated into revised versions of the AJCC staging system for patients undergoing surgery as their first intervention.