Ipsilateral Breast Event Research Articles

Abstract GS5-08: A validation of DCIS biological risk profile in a randomised study for radiation therapy with 20 year follow-up (SweDCIS)

Abstract Background: Women diagnosed with ductal carcinoma in situ (DCIS) and their physicians need tools that assess individualized risk and predict treatment benefit. A DCIS biologic signature was previously validated in an observational study at Kaiser Permanente NW. We evaluated the results of the signature for predictive utility in a national randomized clinical trial (SweDCIS) by assessing the 10-year benefit of adjuvant radiotherapy (RT) on ipsilateral breast event (IBE) and invasive breast cancer (IBC) risks. Methods: The signature was validated in a prospective-retrospective study in women from the SweDCIS trial (n=1046) performed by the Swedish Breast Cancer Group. Women were treated with breast conserving surgery (BCS) between 1987-1999 and randomized to RT or no RT. A central pathology review of paraffin embedded tissue blocks (n=873) was performed at Uppsala University (UU). Freshly cut slides were provided to PreludeDx for biomarker testing. Extended follow-up of SweDCIS was published in 2014. A panel of biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assayed and scored in PreludeDx's CLIA lab by board-certified pathologists. Continuous Decision Scores (DS) were calculated with the biologic signature using the biomarker and clinical factors (age, size, margin, and palpability) blinded to patient outcome. The DS results were provided to the Uppsala Regional Cancer Center for analysis. A predefined and co-developed statistical analysis plan was executed. Absolute 10-year RT benefit was assessed using Kaplan-Meier survival analysis. Hazard ratios (HR) were determined using Cox proportional hazards analysis and the interaction of the DS and RT benefit was assessed. Results: Complete biomarker and clinical information was available in 584 women. In women with clear margins (n=506), 78 IBEs, including 31 IBCs, were recorded within 10 years of diagnosis. The multivariate analysis of DS (0-10 unit scale) and the RT interaction was significant for risk of IBC (p=0.048) and IBE (p<0.001) at 10 years. The DS defined an elevated risk group (>3) for which there was pronounced 10-year benefit of RT (p=0.01) with an absolute risk reduction of 9% for IBC (Table 1). The corresponding low risk group (≤3), which included 48% of all patients, demonstrated no significant RT benefit (p=0.70) with an absolute risk reduction of 1%. The continuous DS variable was correlated with IBE risk, HR 1.49/per 5 units 95%CI[1.02,2.18] (p=0.038), in addition to the RT benefit for IBE in low (p=0.04) and elevated (p<0.001) risk groups. Table 1. 10-year RT benefit in women from the SweDCIS trial.DS Risk GroupsIBC eventsIn Situ or IBC eventsnAbsolute RT-benefitHR [95%CI] Absolute RT-benefit HR [95%CI]Low Risk Group (DS≤3)2431%0.83 [0.32, 2.16]9%0.48 [0.24-0.97]Elevated Risk Group (DS>3)2639%0.24 [0.08, 0.73]17%0.31 [0.17-0.59] Discussion: Evaluation of the SweDCIS trial validated prognostic and RT predictive utility of the biologic signature. Women diagnosed with DCIS and treated with BCS±RT were stratified into clinically relevant low and elevated risk groups (≤3 vs >3). Women in the elevated risk group had twice the treatment benefit for IBC from RT compared to prior randomized trials, while the low risk group had no benefit from RT. Citation Format: Wärnberg F, Garmo H, Folkvaljon Y, Holmberg L, Karlsson P, Sandelin K, Linke S, Lyle S, Simin K, Leesman G, Barry T, Savala J, Whitworth P, Bremer T. A validation of DCIS biological risk profile in a randomised study for radiation therapy with 20 year follow-up (SweDCIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-08.

Abstract P4-15-10: Second breast events after DCIS: Where, what and when?

Abstract Background: Detection and diagnosis of ductal carcinoma in situ has substantially increased since the widespread use of mammographic screening with the incidence of DCIS increasing between 1975 from 5.8 per 100,000 to 33.8 per 100,000 women in 2010. While surgical resection of DCIS remains the main treatment, outcomes in terms of in breast re-occurrence or contralateral disease are unpredictable. Recently, three large clinical trials of active surveillance versus standard of care have been initiated. We sought to compare the clinical, imaging, histopathological features and treatment of DCIS for contemporary patients who subsequently developed a second in situ or invasive breast lesion among women treated within a single institution. Methods: A contemporary prospective cohort study comprising 2,509 women treated for DCIS between 2000 and 2014 was examined for diagnostic imaging, surgery, pathology, adjuvant treatment and second breast events. Patients with primary bilateral DCIS or a bilateral second event were excluded as were patients with antecedent invasive breast cancer. Patients were grouped into two populations based on ipsilateral and contralateral second breast event. Results: Amongst 2,509 women treated for DCIS between 2000 and 2014, of whom 146 had a second breast event (5.8%). 77 (52.7% of events, 3.07% overall) developed an ipsilateral second breast event (37 DCIS, 40 invasive breast cancer) and 69 (47.3%, 2.75%) patients developed a contralateral second breast lesion (34 DCIS, 35 invasive breast cancer). Patients who developed a contralateral second event were older than those who developed an ipsilateral second event (58 years vs. 52 years, p=0.003). Patients receiving segmental mastectomies were more likely to develop an ipsilateral second event than a contralateral event (85.7% vs. 60.9%, p=0.001). Patients who developed a second contralateral breast event were significantly older at diagnosis (63 years vs. 58 years, p=0.003). There was no significant difference in the number of (69 vs. 77) or time between contralateral and ipsilateral second breast events (5.2 years and 5.1 years, p=0.8) nor in the number of patients with invasive or in situ second events (75 vs. 71). Patients with ipsilateral second breasts events were more likely to undergo bilateral mastectomy than those with contralateral second events (15 vs. 2, p=0.003). Conclusions: Following standard of care treatment for DCIS, 1 in 20 women develop further DCIS or invasive disease at a median of 5 years with very similar proportions of ipsilateral or contralateral and DCIS or invasive disease. Current trials of active surveillance should consider a median 5 years follow up as a critical time point for reporting results. Key Words: Ductal carcinoma in situ, invasive breast cancer, population-based cohort, surgery, radiotherapy, endocrine therapy. Citation Format: King LM, Yi M, Krishnamurthy S, Hunt KK, Thompson AM. Second breast events after DCIS: Where, what and when? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-10.

Abstract P4-15-06: Low dose tamoxifen lowers recurrences after mastectomy for in situ neoplasia. Ten-year results of a monoinstitutional study

Abstract There is no agreement upon the need of a preventive treatment after breast mastectomy for in situ neoplasia. Low-dose tamoxifen (5 mg/day) has comparable antiproliferative effect than the standard dose of 20 mg/day in biomarker trials and has been shown to halve ipsilateral recurrence in a large cohort of postmenopausal ER positive DCIS treated with breast conserving surgery (Guerrieri-Gonzaga et al., Int J Cancer 2016). Here we investigated the effect of low dose tamoxifen in patients treated with mastectomy for an in situ neoplasia and followed-up in a single Institution for a median of 10 years. Our cohort consists of 404 consecutive premenopausal (n=281) or postmenopausal (n=123) women who underwent unilateral mastectomy at the European Institute of Oncology (IEO), with or without nipple preservation, between 1996 and 2011. Patients had a diagnosis of pure LCIS (n=12) or ER positive (ER>1%) DCIS (n=363) or both (n=29) and were treated with tamoxifen 5 mg/day (n=162) or no treatment (n=242) upon medical judgment, patient preference and/or clinical trial assignment. The main subject and tumor characteristics are reported in table 1. Patient and tumor characteristics No tam (n=242)Low dose tam (n=162)P-valueMedian age, years (IQR)46 (41, 54)47 (42, 51)0.65Premenopausal status (n, %)160 (66)121 (75)0.07Median BMI (kg/m2, IQR)22 (20, 25)22 (20, 24)0.7Breast cancer family history (%)29320.44Histology (LCIS, DCIS, both; %)4/92/42/86/120.01Grading (G1,G2,G3;%)11/59/2918/61/200.04Median ER (%, IQR)90 (70, 95)90 (80, 95)0.005Median PgR (%, IQR)40 (5, 80)68 (25, 90)0.0002Median Ki67 (%, IQR)15 (10, 23)14 (10, 20)0.03Radiotherapy (n, %)95 (39)76 (47)0.13 After a median follow-up of 10 years (range 4-21 years) and a median low dose tamoxifen treatment of 4.9 years (IQR 2.7, 5.0), a total of 85 events were observed (28 in situ, 40 invasive breast cancers, 3 metastatic diseases, 12 other primary cancers, 2 deaths). A total of 36 ipsilateral breast events (23 versus 13 in the no tam versus tam group, respectively), 32 contralateral breast events (22 versus 10 in the no tam versus tam, respectively) and 17 other events (11 versus 6 in the no tam versus tam, respectively) occurred. Overall, eleven deaths (3%) occurred and no endometrial cancers were observed. A time-dependent competing risk model was applied for tamoxifen use and we have shown that low-dose tamoxifen was associated with a 48% reduction on all breast events (adjusted HR=0.52, 95% CI: 0.31–0.88, p=0.01), adjusting for radiotherapy and age. Although limited by the observational nature of the study, we show for the first time that treatment with low dose tamoxifen is effective and safe in women who underwent mastectomy for non-invasive breast neoplasms and should be taken into consideration as a risk reduction strategy for premenopausal and postmenopausal women with breast intraepithelial neoplasia. Citation Format: Guerrieri-Gonzaga A, Gandini S, Serrano D, Lazzeroni M, Pruneri G, Varricchio C, Cazzaniga M, Leonardi MC, Galimberti V, Viale G, De Censi A, Bonanni B. Low dose tamoxifen lowers recurrences after mastectomy for in situ neoplasia. Ten-year results of a monoinstitutional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-06.

Outcomes for Women with Minimal-Volume Ductal Carcinoma In Situ Completely Excised at Core Biopsy.

Overdiagnosis and overtreatment of ductal carcinoma in situ (DCIS) are concerns, especially for women with low-volume, screen-detected DCIS. This study aimed to evaluate the outcomes for such patients. Women who had minimal-volume DCIS (mDCIS, defined as DCIS diagnosed by core biopsy but with no residual disease on the surgical excision) treated with breast-conserving surgery from 1990 to 2011 were identified. Ipsilateral and contralateral breast events (IBE and CBE) were compared by competing-risk (CR) analysis. Kaplan-Meier (KM) estimates and log-rank tests were used to evaluate covariates. The study identified 290 cases of mDCIS. The median age of the patients was 53years. Radiation therapy (RT) was performed for 27.6% and endocrine therapy for 16.2% of the patients. The median follow-up period was 6.8years. Overall, the IBE rates were 4.3% at 5years and 12.3% at 10years. Among the women not receiving RT, the 5- and 10-year IBE rates (5.4 and 14.5%) were higher than the CBE rates (1.8 and 2.7%). Among those receiving RT, the IBE rates (1.5 and 6.0%) were lower than the CBE rates (4.1 and 15.6%). The women receiving RT trended toward significantly lower IBE rates (p = 0.07). Age, grade, and endocrine therapy were not significantly associated with IBE risk. Among the patients with mDCIS who did not receive RT, the IBE risk was substantially higher than the CBE risk, demonstrating that even DCIS of very low volume is associated with clinically relevant disease. The finding that the IBE risk was greater than the CBE risk supports current strategies that treat DCIS as a precursor rather than a risk marker. Women with mDCIS are not at negligible risk for IBE in the absence of adjuvant therapy.

Effect of radiotherapy after breast-conserving surgery in older patients with early breast cancer and breast ductal carcinoma in situ: a meta-analysis

BackgroundThere are no consistent agreements on whether radiotherapy after breast-conserving surgery (BCS) could provide local control and survival benefit for older patients with early breast cancer or breast ductal carcinoma in situ (DCIS). The present study aimed to evaluate the efficacy of radiotherapy after BCS in older patients with early breast cancer or DCIS.ResultsRadiotherapy could reduce the risk of local relapse in older patients with early breast cancer. The 5-year AR of local relapse was 2.2% and 6.2% for radiotherapy and non-radiotherapy group, respectively, with low 5-year ARD of 4.0% and high NNT of 25. The 10-year AR of local relapse was 5.3% and 10.5% for radiotherapy and non-radiotherapy group, respectively, with the 10-year ARD of 5.2% and NNT of 20. However, radiotherapy could not improve survival benefits, including overall survival, cancer-specific survival, breast-cancer-specific survival, and distant relapse. Moreover, radiotherapy could reduce the risk of ipsilateral breast events in older patients with DCIS.Materials and MethodsPubMed and Embase database were searched for relevant studies. Hazard ratios (HRs), risk ratios (RRs), absolute risk (AR), absolute risk difference (ARD), and number needed to treat (NNT) were used as effect measures to evaluate the efficacy of radiotherapy in older patients.ConclusionsOur study indicates that radiotherapy could slightly reduce the risk of local relapse in older patients with favorable early breast cancer. However, radiotherapy cannot translate into significant survival benefits.

Abstract P1-11-02: A comparison of models (physician, the Van Nuys prognostic index, the Memorial-Sloan-Kettering Cancer Center DCIS nomogram)to predict ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) of the breast after breast-conserving surgery failed to replicate results of the oncotype DCIS recurrence score

Abstract Purpose: To compare ipsilateral breast event (IBE) risks in patients with DCIS of the breast post-lumpectomy, as estimated by breast radiation oncologists, the Van Nuys Prognostic Index (VNPI) studies, the Memorial Sloan Kettering Cancer Center (MSK) DCIS nomogram, and the 12-gene DCIS Recurrence Score assay. Materials/Methods: 12-gene DCIS Recurrence Score of 91 DCIS lumpectomy cases were identified from our practice. Clinicopathologic factors (excluding DCIS score) were summarized for blinded review. 3 radiation oncologists independently estimated the 10-year IBE risk and rated the impact of age/menopausal status, tumor morphology, tumor span, and margin width. Corresponding VNPI and MSK nomogram estimates were generated. Differences and correlations between the IBE estimates and clinicopathologic factors were evaluated with univariate and multivariate analysis. Results: Median age was 60, 25% margins < 3 mm, 48% DCIS span > 10 mm, 48% would have been ineligible for E5194. All comparisons were initially examined for similarity (non-significant differences) and susequently tested for a significant correlation. In three possible physician comparisons only 1 (AA-CL) had similar IBE estimates and strong correlation (r=0.792). Comparison of physicians to either VNPI nomogram or MSK DCIS calculator had similar estimates with strong correlation in only 2 of 6 possible comparisons in the all cases and the E5194 eligible patient cohorts respectively; and in 1 of 6 comparisons in the E5194 ineligible cohort. The DCIS Recurrence Score showed no strong correlation in regard to similar IBE estimates for any comparisons including either physicians, VNPI nomogram or MSK DCIS calculator. Tumor size was highly correlated with all physician IBE estimates (r = 0.547 to 0.799), while margin size showed moderate to high inverse correlations (r = -0.324 to -0.619). All 3 physicians rated margin width as having the most impact on their IBE risk estimates, then tumor morphology and tumor span. Source of EstimateAll Cases (n = 91)E5194 Eligible (n = 47)E5194 Ineligible (n = 44)DCIS Score15.1%, 5.3 (14.0-16.2)14.2%, 4.8 (12.8-15.6)16.1%, 5.7 (14.3-17.8)MSK DCIS Nomogram (Rudloff et al., 2010)18.8%, 7.7 (17.2-20.4)23.4%, 18.6 (19.6-27.3)16.1%, 4.1 (14.9-17.3)21.7%, 9.4 (18.8-24.6)VNPI studies23.4%, 18.6 (19.6-27.3)15.6%, 15.5 (11.0-20.1)31.9%, 18.1 (26.4-37.4)AA18.9%, 14.1 (16.0-21.9)11.7%, 8.8 (9.1-14.3)26.6%, 14.7 (22.2-31.1)CL19.9%, 11.8 (17.5-22.4)14.5%, 6.6 (12.5-16.4)25.8%, 13.3 (21.7-29.8)DC26.8%, 13.9 (23.9-29.7)19.8%, 5.9 (18.1-21.6)34.2%, 16.1 (29.3-39.1) Conclusion: IBE risk estimates for this cohort of DCIS cases vary significantly among commonly available clinical predictive tools and individual physician estimates. Surgical margins and tumor size continue to factor prominently in physician decision algorithms. In our observations, neither the VNPI nomogram, MSK DCIS calculator nor physician IBE risk estimates have similar values with strong enough correlation to reliably replicate the DCIS Recurrence Score. Citation Format: Leonard C, Lei R, Antell A, Nowels M, Fryman S, Howell K, Dennis C. A comparison of models (physician, the Van Nuys prognostic index, the Memorial-Sloan-Kettering Cancer Center DCIS nomogram)to predict ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) of the breast after breast-conserving surgery failed to replicate results of the oncotype DCIS recurrence score [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-02.

Abstract P1-09-06: Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: The prognostic abilities of most gene expression signatures in breast cancer are often due to detection of proliferative activity measured from expression of genes regulated as a function of cell cycle progression. Cell Cycle Progression (CCP) score is an important prognostic factor in prostate cancer, and has shown promising results for renal and lung cancer; its role in ductal carcinoma in situ (DCIS) has not been explored. We investigated the prognostic and predictive relevance of CCP Score in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy (RT) or both as adjuvant treatment in DCIS. mRNA expression of 25 S- and M-phase CCP genes was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. CCP score is an un-weighted average of the expression values of CCP genes after normalisation with 14 housekeeping genes. CCP score was analysed as a continuous variable and also as an ordinal variable using tertile-based cut-offs. Exploratory analyses with subgroups defined by HER2 status by immunohistochemistry were performed. Results: CCP scores were evaluable in 521 (134 recurrence events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Increase in CCP score (median 1.15; IQR 0.71-1.74) was associated with increased risk of ipsilateral breast event (IBE) [Hazard ratio (HR) = 1.28; 95% Confidence Interval (95%CI) 1.08-1.51; p = 0.0049]. CCP score however was not an independent predictor in multivariate analyses [HR = 1.16; 95%CI 0.95-1.42; p = 0.14]. CCP scores were categorised as CCP low (<0.87), CCP intermediate (>/= 0.87 to < 1.52) and CCP high (>/= 1.52) by tertiles. The benefit of RT in reducing IBE was significant when CCP score was low [HR = 0.35; 95%CI 0.14-0.87; p = 0.024] or intermediate [HR = 0.23; 95%CI 0.09-0.59; p = 0.0023], however, those with high CCP score did not derive significant RT benefit [HR = 0.59; 95%CI 0.31-1.13; p = 0.11]. In exploratory subgroup analyses, HER2 negative DCIS with high CCP score (20.9% of all DCIS cases) did not derive RT benefit and the largest RT benefit was seen for DCIS that expressed HER2 and did not have a high CCP score (23.2% of all DCIS cases). Benefit of RT and 10-year IBE rates by CCP score (categorised) and HER2 status subgroups.SubgroupneventsHR (95%CI)p10-year IBE rates (%) - No RT10-year IBE rates (%) - RTCCP-high & HER2 neg106220.83 (0.35-1.97)0.6722.5 (14.0-35.0)20.0 (10.5-36.0)CCP-high & HER2 pos67210.43 (0.16-1.17)0.09840.6 (27.1-57.6)20.4 (8.9-42.9)CCP-non-High & HER2 neg217300.43 (0.18-0.99)0.04816.2 (10.7-24.0)8.1 (4.0-16.3)CCP- non-High & HER2 pos118330.14 (0.04-0.46)0.001239.5 (29.3-51.6)7.1 (2.3-20.4)CCP-non-High = low or intermediate CCP score Conclusions: CCP score is not independently associated with the risk of IBE but appears to be a predictor of RT benefit. Exploratory analyses suggest that combined with HER2 status, it may help in identifying a large DCIS subgroup where RT is highly indicated and another large subgroup where mastectomy may be merited. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-06.

Abstract S5-01: DCIS biological risk profile predicts risk of recurrence after breast conserving surgery in a Kaiser Permanente NW population

Abstract Background: Patients with DCIS and their physicians need tools that provide better information about the individual patient's biological risk profile to help make treatment decisions. Prelude and the Kaiser Permanente Northwest Center for Health Research (KPCHR) validated a biological risk signature based test to assess ipsilateral breast event (IBE) risk after breast conserving surgery (BCS) with radiation (+RT) or without radiation therapy (-RT). Methods: The Prelude DCIS test was independently validated in a retrospective cohort from the Kaiser Permanente Northwest (KPNW) integrated healthcare system in patients diagnosed with DCIS from 1990- 2007 and treated with BCS±RT(n=608). KPCHR performed central pathology review to identify patients meeting study eligibility criteria with formalin fixed paraffin embedded (FFPE) tissue samples (n=475); KPCHR also reviewed medical records to collect patient, treatment, and outcome data. FFPE patient samples were provided to Prelude for testing. REMARK guidelines were followed. A panel of biomarkers (HER2, PR, Ki-67, COX2, p16/INK4A, FOXA1 and SIAH2) were assayed by the Prelude CLIA lab and scored by board-certified pathologists (n=455). Prelude's DCIS test was executed independently using biomarker and clinicopathologic data while blinded to patient outcome data. The risk results were provided to KPCHR under a Data Transfer Authority. KPCHR biostatisticians executed a predefined and co-developed statistical analysis plan. IBE rates were assessed using Kaplan-Meier survival analysis. Hazard ratios (HR) were determined using Cox proportional hazards analysis, with RT as a covariate. Results: The Prelude DCIS test score was statistically associated with total IBE as a continuous linear variable (0-10 unit scale) on a per unit basis, HR of 1.12, 95% CI [1.03,1.23], p=0.01. The DCIS test score (0-10) corresponded to recurrence risks ranging from 10% to 42% (≤2, >7) for patients treated with BCS-RT and ranging from 4% to 11% (≤2, >7) for patients treated with BCS+RT. Patients treated with BCS ±RT with an elevated test score (≤3 vs >3) had a higher recurrence risk, n=455, HR=1.87 [1.03 - 3.38], p=0.04. In patients treated with BCS-RT in this sample, patients with a higher DCIS signature had an elevated recurrence risk, n=78, HR=2.37, 95% CI [0.82, 6.85], p=0.11. The 10-year contralateral breast event rate was 4%, 95% CI [2%, 6%]. Median follow-up time was 10.4 years. Discussion: Patients diagnosed with DCIS and treated with BCS ±RT, were stratified into clinically relevant low and elevated risk groups (≤3 vs >3) in an independent validation of the Prelude DCIS test. Patients in the elevated risk group had substantially higher likelihood of 10-year total IBE. The number of patients treated with BCS -RT was limited and while the stratification by risk group for BCS -RT was in the expected direction, it did not reach statistical significance. Two additional validation studies are scheduled to be completed in 2016. 10-YEAR IBE RISKBCS –RTBCS +RTRisk, [95% CI]PrevalenceNRisk, [95% CI]PrevalenceNBaseline Total Risk20%, [12%, 32%]100%788%, [5%, 11%]100%377Low Risk Group (≤3)10% [3%, 29%]53%415%, [2%, 10%]40%149Elevated Risk Group (>3)30%, [17%, 51%]47%3710%, [6%, 15%]60%228 Citation Format: Bremer T, Whitworth P, Leo M, Barry T, Goldstein N, Ganders C, Francisco M, Leesman G, Linke S, Patel R, Pellicane J, Weinmann S. DCIS biological risk profile predicts risk of recurrence after breast conserving surgery in a Kaiser Permanente NW population [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-01.

The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast

Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained. We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive. Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767). TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients.

Cost Effectiveness of the Oncotype DX DCIS Score for Guiding Treatment of Patients With Ductal Carcinoma In Situ

Purpose The Oncotype DX DCIS Score short form (DCIS Score) estimates the risk of an ipsilateral breast event (IBE) in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery without adjuvant radiation therapy (RT). We determined the cost effectiveness of strategies using this test. Materials and Methods We developed a Markov model simulating 10-year outcomes for 60-year-old women eligible for the Eastern Cooperative Oncology Group E5194 study (cohort 1: low/intermediate-grade DCIS, ≤ 2.5 cm; cohort 2: high-grade DCIS, ≤ 1 cm) with each of five strategies: (1) no testing, no RT; (2) no testing, RT only for cohort 2; (3) no RT for low-grade DCIS, test for intermediate- and high-grade DCIS, RT for intermediate- or high-risk scores; (4) test all, RT for intermediate- or high-risk scores; and (5) no testing, RT for all. We used utilities and costs extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios and examined the number of women needed to irradiate per IBE prevented. Results No strategy using the DCIS Score was cost effective. The most cost-effective strategy (RT for none or RT for all) was sensitive to small differences between the utilities of receiving or not receiving RT and remaining without recurrence. The numbers needed to irradiate per IBE prevented were 10.5, 9.1, 7.5, and 13.1 for strategies 2 to 5, respectively, relative to strategy 1. Conclusion Strategies using the DCIS Score lowered the proportion of women undergoing RT per IBE prevented. However, no strategy incorporating the DCIS Score was cost effective. The cost effectiveness of RT was exquisitely utility sensitive, highlighting the importance of engaging patient preferences in this decision. Physicians should discuss trade-offs associated with omitting or adding adjuvant RT with each patient to maximize quality-of-life outcomes.

A multi-marker prognostic to assess risk of invasive recurrence in DCIS patients.

1019Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease associated with a spectrum of risk for ipsilateral breast events (IBE). Reducing overtreatment is an important unmet need for DCIS patients. Methods: Patients were from Uppsala University Hospital diagnosed 1986 - 2004, and University of Massachusetts diagnosed 1999 -2008, treated with breast conserving surgery (BCS) with (56%) or without (44%) radiation therapy (RT). Biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2 via IHC/ISH) were assessed in FFPE tissue by board-certified pathologists. Pathological and clinical data were collected from medical records. A multi-marker based prognostic was developed on the combined patient sets (n = 600, 8.1 year median follow-up) using multiple cross-validation (patients divided into independent training and testing subsets). Patients with DCIS detected by mammography screening (n = 379) were then stratified into risk categories defined by the multi-marker based prognostic or clinico...

Ductal Carcinoma In Situ: How Much Treatment Is Enough, How Much Is Too Much?

In the accompanying article, Wood concisely reviews currentmanagement of ductal carcinoma in situ (DCIS), with a focus on the use of radiotherapy (RT) after breastconserving surgery (BCS). The crux of his argument is that because RT does not prolong survival, its usemust be considered optional and the risks and benefits of RT considered in the context of patient values. Henotes that“nearly twice asmanywomen will have an inferior cosmetic outcome result as will benefit from avoiding a recurrent breast lesion,” and that the use of RT for initial treatment necessitates mastectomy for any subsequent recurrence. The importance of considering patient preference in decision making when there is equipoise in survival outcomes is inarguable.Wesurveyedpatients aboutpriorities and treatment choices in a population-based study of 1,629 patientswithDCIS and stage I and II breast cancer. Concern about disease recurrence was the most important factor in treatment choice, greatly influencing 37%, whereas concerns about radiation or body image greatly influenced only 15% and5%of patients, respectively. Prevention of local recurrence in DCIS is particularly relevant to patient concerns, because 50% of these recurrences are invasive carcinoma, and randomized trials have demonstrated a significant increase in mortality in patients experiencing invasive recurrence after DCIS treatment. Thus, it is not particularly surprising that risk-averse patients opt for RTor, increasingly, forbilateralmastectomy. Endocrine Therapy Wood also notes that endocrine therapy is an alternative to RT for risk reduction in women with DCIS. Endocrine therapy has the advantage of reducing the incidence of both ipsilateral and contralateral breast events, but the absolute benefit of 5 years of treatment is modest. In a meta-analysis of the National Surgical Adjuvant Breast and Bowel Project B24 trial and the United Kingdom, Australia, New Zealand trials of adjuvant tamoxifen in DCIS, no significant difference in all-cause mortality was seen with tamoxifen treatment compared with placebo, but tamoxifen treatment did statistically significantly reduce ipsilateral and contralateral DCIS events and contralateral invasive cancers, with a trend toward reduction of ipsilateral invasive cancer. The number needed to treat for a protective effect against all breast events was 15. However, ameta-analysis of 10-year event rates in9,404patientswithDCIS found that the local recurrence rate after BCS and RTwas 14.4%, compared with 24.7% with BCS and tamoxifen, suggesting that if the goal is to minimize recurrence, RT is the more effective strategy. A decision to use tamoxifen (or an aromatase inhibitor) also subjects the patient to 5 years of the welldocumented side effects of endocrine therapy. Most importantly, the acceptance of tamoxifen among patients with DCIS is limited. In a Canadian population-based cohort of women with DCIS treated in

Abstract P3-07-02: Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: As compared to invasive breast cancer (IBC), HER2 is much more frequently overexpressed in ductal carcinoma in situ (DCIS). Unlike IBC, the prognostic significance of HER2 overexpression remains to be established in DCIS and large studies to investigate its predictive role are lacking. We investigated the prognostic and predictive relevance of HER2 protein and ERBB2 mRNA expression in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. ERBB2 mRNA expression was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. ERBB2 mRNA expression was analysed as a continuous variable and also as a binary variable using a cut-off to reproduce HER2 expression distribution similar to that observed with immunohistochemistry (IHC). HER2 protein expression was evaluated by IHC using HercepTest™ and scored as per ASCO-CAP 2013 recommendations; HER2 equivocal (IHC2+) were grouped with HER2 negative (IHC 0 or 1+) for main analyses. Additional analyses using binary ERBB2 mRNA expression as a reflex test for HER2 IHC2+ were also performed. Results: HER2 protein expression was evaluable in 713 (181 events) of 755 available samples (DCIS absent or lost during assay in 42). ERBB2 mRNA expression was evaluable in 521 (134 events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Both results were available in 508 cases (130 events). Increase in ERBB2 mRNA expression (median 0.62; range 0.07-36.76) was associated with increased risk of in situ ipsilateral breast event (DCIS-IBE) [Hazard ratio (HR) = 1.07; 95% Confidence Interval (95%CI) 1.04-1.10; p &amp;lt; 0.0001] but not with increased risk of invasive ipsilateral breast event (I-IBE) [HR = 1.03; 95%CI 0.97-1.10; p = 0.3209]. HER2 positivity by IHC was similarly associated with increased risk of DCIS-IBE [HR = 2.90; 95%CI 1.91-4.40; p &amp;lt; 0.0001] but not with increased risk of I-IBE [HR = 1.40; 95%CI 0. 0.81-2.42; p = 0.2313]. Reclassification of HER2 IHC2+ cases using binary ERBB2 mRNA expression (46 as negative, 16 as positive; 18 expression data unavailable) further improved prognostic discrimination of HER2 IHC [ΔX2 (1d.f.) 5.51; p = 0.0189] for any recurrence. The effect of radiotherapy (RT) for reducing I-IBE was greater in HER2 positive (by ERBB2 mRNA expression) cases [HR = 0.24; 95%CI 0.07-0.83; p = 0.0237] as compared with HER2 negative cases [HR = 0.60; 95%CI 0.23-1.55; p = 0.2925]. Kaplan-Meier estimates of 10-year I-IBE rates with and without RT were 4.5% (2.5%-1.4%) and 15.8% (9.6%-25.3%) in HER2 positive DCIS; rates in HER negative DCIS were 5.2% (2.1%-2.4%) and 7.3% (4.3%-12.2%) respectively. The differential benefit of RT by HER2 status was also seen for reduction in DCIS-IBE. Conclusions: HER2 overexpression is associated with increased risk of DCIS-IBE but not of I-IBE. HER2 status is predictive of radiotherapy response with larger reductions in both I-IBE and DCIS-IBE seen in HER2 positive DCIS. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-02.

Abstract P3-07-01: Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: Majority of studies investigating prognostic role of ER and PgR expression in ductal carcinoma in situ (DCIS) have failed to show a significant relationship with recurrence. Branched evolutionary tumour growth and resulting intratumour heterogeneity is now increasingly acknowledged in a variety of cancers. DCIS offers the opportunity to investigate relevance of clonal populations in different ducts that may have evolved differently and may impact outcome differently. We investigated prognostic role of ER and PgR expression in DCIS and impact of clonal variation in ER/PgR expression using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. A nested case-control design was used; cases (patients with recurrence) were matched by treatment arm and age to 2 controls each (no recurrence). ER and PgR expression was evaluated on whole sections by immunohistochemistry using 1D5, PGR636 antibodies and EnVisionTM FLEX + detection system (Dako). Assays were scored by Allred method (positive if expression &amp;gt;1%) and clonal method. Clonal method documented presence of ducts with complete lack of ER or PgR expression in otherwise ER or PgR positive (Allred method) DCIS. Analyses categorising such multi-clonal DCIS as ER or PgR positive as per current practice (standard) and categorising these as ER or PgR negative DCIS (clonal method) were performed. Results: Of 540 samples (180 cases, 360 controls), ER and PgR status was evaluable in 504 and 498 patients respectively. ER expression was absent (ER-) in 148 (29.4%), 356 (70.6%) were ER positive (ER+) with 39 (7.7%) of these displaying multi-clonal expression (ERmulti-clonal). PgR expression was absent in 163 (32.7%), 335 (67.3%) were PgR positive with 84 (16.9%) of these displaying multi-clonal expression. ER- DCIS showed increased risk (Table) of in situ ipsilateral breast event (DCIS-IBE) and invasive ipsilateral breast event (I-IBE) (borderline significance). Prognostic discrimination was higher when ER status was determined by clonal method (ΔX2 1.57 for I-IBE and 9.05 for DCIS-IBE). Increases in the risk of I-IBE and DCIS-IBE were similar for ER- and ERmulti-clonal DCIS. TableEndpointComparisonScoring MethodHazard Ratio (95%CI)pI-IBEER- vs. ER+Standard1.75 (0.99-3.09)0.0544 ER- vs. ER+Clonal1.90 (1.10-3.30)0.0224 ER- vs. ER+*Clonal1.89 (1.05-3.41)0.0337 ERmulti-clonal vs. ER+*Clonal1.93 (0.74-5.03)0.1759DCIS-IBEER- vs. ER+Standard2.58 (1.68-3.94)&amp;lt;0.0001 ER- vs. ER+Clonal3.13 (2.02-4.85)&amp;lt;0.0001 ER- vs. ER+*Clonal3.11 (1.97-4.93)&amp;lt;0.0001 ERmulti-clonal vs. ER+*Clonal3.20 (1.62-6.34)0.0008* ER+ DCIS not exhibiting multi-clonal expression Lack of PgR expression was only associated with increased risk of DCIS-IBE and PgR status did not add to the prognostic information provided by ER status. Conclusions: ER expression is prognostic for recurrence in DCIS. ER+ DCIS with distinct ER- clones has a recurrence risk similar to ER- DCIS. ER scoring should take clonality of expression into account. Citation Format: Thorat MA, Jones LJ, Levey PM, Elia G, Evagora CA, Bundred NJ, Fentiman IS, Forbes JF, Cuzick J. Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-01.

Comparison of Risk of Ipsilateral Breast Event After Lumpectomy for Ductal Carcinoma In Situ, As Estimated by Breast Radiation Oncologists, Van Nuys Prognostic Index, Memorial Sloan Kettering Cancer Center DCIS Nomogram, and the 12-gene DCIS Score

Quality Consortium (MROQC), a statewide assessment of breast cancer patients undergoing radiation therapy and crude rates were used for comparisons. Results: For left sided cancers, mean heart dose was 3.09 Gy. The use of a breast cup resulted in mean V20 for lung of 5.6% and V5 of 11%. Mean dose to the contralateral breast was 3.29 Gy. Twenty patients (42.5%) experienced grade 2 skin toxicity; one patient (2.1%) experienced a grade 3 skin toxicity. Moist desquamation rates: 44.7% compared to 45.5% MROQC. Moist desquamation for patients with a BMI >35 was 52.2% vs 42.8% MROQC. For a breast volume >1550cc, moist desquamation was seen in 48.6% vs 45.5% MROQC. Conclusion: Our results indicate that use of the breast cup can allow for improved dose homogeneity with similar acute toxicities as compared with patients treated without the cup while minimizing the dose to the heart and lungs. Our clinical experience shows that breast cups can be used with ease, and allow for good setup reproducibility. It appears that the slight increase in moist desquamation was associated with increased BMI. In conclusion, we recommend that use of a breast cup be considered in appropriately selected patients with large or pendulous breasts. Author Disclosure: P.R. Sevak: None. K. Aldridge: None. C. Fraser: None. C.K. Glide-Hurst: None. E.M. Walker: ACR appropriateness criteria expert panel member; ACR. RTOG Foundation advisory board member; RTOG. Breast working group; NRG. health disparities working group member; NRG. Institutional PI for NRG; NRG.

No Surgery for Low-Grade Ductal Carcinoma In Situ?

Since the more widespread use of routine screening mammography, the incidenceofductal carcinoma in situ (DCIS)has increased dramatically and accounts for about 20% to 30%of all newly diagnosed breast cancers.1 Deaths from breast cancer among women with DCISmayoccur fromunidentified invasive disease at the time of diagnosis, progression of inadequately excised DCIS, or the development of an independent recurrent invasive breast cancer.2 Our current inability to accurately predict which women with DCIS are at the greatest risk for developing invasive disease generally necessitates thatallpatientsdiagnosedashavingDCISundergo treatment. Despite the relatively benign course of DCIS, most women undergo aggressive surgical and radiation treatment. The risk of overtreatment has been recognized.2 Sagaraetal3usedapropensityscoreanalysis toevaluate the survivaloutcomesofpatientswithDCIS intheSurveillance,Epidemiology, andEndResultsdatabaseandconcluded that there wasnosurvival benefit for surgical excisionof low-gradeDCIS. Therewasasurvivalbenefit forsurgicalexcisioninpatientswith intermediate-orhigh-gradeDCIS.Therefore,Sagaraetal3questiontheneedandbenefit forsurgicalexcisionof low-gradeDCIS. We urge physicians to exercise cautionwhen generalizing this population-basedcohort analysis to currentpractice.Thereare inherent limitationstopopulation-basedcancerdatawithregard to specificpatient and tumorcharacteristics. For example, 14% of the nonoperative group received radiation therapywithout undergoingsurgicalexcision.This isnotastandardapproachfor DCISandthedetailssurroundingthesediscrepanciesarenotclear withintheSurveillance,Epidemiology,andEndResultsdatabase. Inaddition, it is impossible todeterminehowmanywomenmay havehadan initial diagnosis ofDCISbasedon their coreneedle biopsy but who then had an upgrade to invasion on final excision.Thosepatientswouldhavebeenexcludedfromthisanalysis. Most importantly, we argue that DCIS grade is not an appropriate surrogate for genomic profile and biologic outcomes. Molecular markers that provide prognostic and predictive informationhold themostpromise for tailoring therapy on an individual level. The 21-gene recurrence score for estrogen receptor–positive invasive breast cancer was used as a benchmark for the development of a 12-gene subset that has been used to develop and validate a DCIS score that divides patients into low risk, intermediate risk, and high risk for 10year local in-breast recurrence.4 Multivariable models of risk for ipsilateral breast events both excluding and including the DCIS scorehavebeenperformed.Tumor size,menopausal status, andDCIS scorewere the only factors significantly associatedwith risk for an ipsilateral breast event. Tumor grade and thepresenceof comedonecrosiswerenot associatedwith risk for ipsilateral breast events.4 The ability to profile entire tumor genomes relatively quickly and affordablywill aid our understanding of the relationship between DCIS and invasive disease so that targeted approaches can be taken. We advocate for less treatment in those patients who have a low risk for invasive recurrence and/or progression. That knowledge is unlikely to come from our standard clinicopathologic characteristics. For now, surgeons should hold onto their scalpels.

Abstract P6-13-01: Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study

Abstract Background: The ECOG E5194 study was a prospective trial designed to evaluate surgical excision (lumpectomy) without radiation for selected women with ductal carcinoma in situ (DCIS) of the breast with low risk clinical and pathologic features. Methods: Eligible patients were enrolled on two study cohorts (not randomized): (1) low or intermediate grade DCIS, tumor size &amp;lt; 2.5 cm; or (2) high grade DCIS, tumor size &amp;lt; 1.0 cm. Cohort assignment was based on pathology assessment from the treating institution. Protocol specifications included surgical excision of the DCIS tumor with a minimum negative margin width of at least 3 mm or no tumor on re-excision. Radiation treatment was not allowed. From April 1997 to October 2002, 665 evaluable patients were enrolled through ECOG or NCCTG (561 in Cohort 1; 104 in Cohort 2). Tamoxifen was optional (not randomized) beginning in May 2000, and was given to 30% of the patients. The primary study endpoint was the rate of developing an ipsilateral breast event (IBE), defined as local recurrence of DCIS or invasive carcinoma in the treated breast. The median follow-up was 12.3 years. We have previously reported 7-year results (L. Hughes, J Clin Oncol 27:5319, 2009; median follow-up 6.3 years; 66 IBE’s), and we herein provide 12-year results. Results: Median patient age was 60 years and 58 years for Cohort 1 and Cohort 2, respectively. Tumor size was &amp;lt; 10 mm for 79% and 80% of patients, respectively. The minimum negative margin width was &amp;gt; 5 mm for 64% and 69% of patients, respectively. There were 99 IBE’s, of which 51 (52%) were an invasive IBE. The IBE and invasive IBE rates increased over time in both cohorts (see Table). The 12-year rates of an IBE were 14.4% for Cohort 1 and 24.6% for Cohort 2 (p = 0.003), and for an invasive IBE, 7.5% and 13.4%, respectively (p = 0.08). No difference was seen for the 12-year rates of overall survival (84.0% vs 82.8%; p = .96) or contralateral breast events (6.7% vs 12.0%; p = 0.16). On multivariate analysis, study cohort (hazard ratio = 1.81; p = 0.01) and tumor size (p = 0.01) were statistically significant for an IBE, and study cohort was borderline statistically significant for an invasive IBE (p = 0.08). On central pathology review (75% of cases), neither grade nor comedo necrosis was associated with the risk of an IBE or invasive IBE (all p &amp;gt; 0.15). Salvage treatment at the time of an IBE included mastectomy for 42% (31/74) and 64% (16/25) of the patients, respectively. Conclusions: For these selected patients with favorable DCIS based on clinical and pathologic characteristics treated with surgical excision without radiation, the rates of an IBE and an invasive IBE continued to increase through at least 12 years of follow-up. IBE Rates According To Study Cohort. Cohort 1 (Low or Intermediate Grade)Cohort 2 (High Grade)TimeIBEInvasive IBEIBEInvasive IBEAt 5 years6.0% (4.0%, 8.1%)2.7% (1.3%, 4.1%)15.0% (7.7%, 21.7%)5.3% (0.8%, 9.7%)At 7 years9.5% (7.0%, 12.0%)4.8% (2.9%, 6.6%)18.2% (10.6%, 25.8%)7.6% (2.2%, 13.0%)At 10 years12.5% (9.5%, 15.4%)6.4% (4.2%, 8.6%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%)At 12 years14.4% (11.2%, 17.6%)7.5% (5.1%, 10.0%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%) Citation Format: Lawrence J Solin, Robert Gray, Lorie L Hughes, William C Wood, Mary Ann Lowen, Sunil Badve, Frederick L Baehner, James N Ingle, Edith A Perez, Abram Recht, Joseph Sparano, Kathy Miller, Nancy E Davidson. Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-01.

Abstract P6-13-06: Tamoxifen acceptance by DCIS patients and effect on subsequent ipsilateral and contralateral breast events

Abstract Introduction: Existing data demonstrate that the use of endocrine therapy decreases the risk of in-breast recurrence and contralateral new primary cancers. However, the acceptance of tamoxifen is relatively low in women with DCIS, with reported acceptance rates ranging from 32% to 67%. We reported 67% tamoxifen acceptance in 2005 (Nakhlis F, JACS, p688); we now re-examine this question to assess the impact of patient and tumor characteristics, and the use of tamoxifen, on new breast events in women with DCIS undergoing breast conserving therapy (BCT) or mastectomy. Methods: We conducted a retrospective review using a prospective database; 695 patients with DCIS were identified between 1998 and 2009. Patient and tumor characteristics included age, tumor grade, tumor size, margin status, re-excision status, use of BCT, adjuvant radiation therapy (RT) and tamoxifen therapy. Women undergoing bilateral mastectomy were excluded for analysis of in-breast events. The demographic data were examined for differences in continuous variables using the Wilcoxon rank sum test, and differences in categorical variables between groups were assessed using Fisher’s exact test. Multivariate odds ratios were obtained using logistic regression. Results: The mean age of the patient population was 61.5 ± 11.4 (median and range: 61 (30-99). 44.9% of patients were over the age of 50. The median follow up time was 60 months. Among the BCT group, 58.5% of 348 women with ER+ DCIS accepted tamoxifen therapy, compared to 50.7% of 71 mastectomy patients with ER+ DCIS. 188 women (27.1%) underwent mastectomy (122 unilateral and 66 bilateral); 507 (72.9%) received BCT. Among all women with complete radiation and tamoxifen data, the number of new events was 88 (16.9%). Of these, 8 (1.5%) were in the mastectomy group, and 80 (17.9%) in the BCT group (p=0.0007). Ipsilateral events occurred in 1/99 (1%) woman undergoing mastectomy. In the BCT group complete radiation and tamoxifen data were available on 448 women, of whom 54 (12%) experienced ipsilateral events (p&amp;lt;0.0001). The multivariate odds ratio (OR) for ipsilateral breast events in the BCT group receiving RT+ surgery, was 0.66 (95%CI 0.25-1.71); among those receiving tamoxifen + surgery it was 0.65 (95% CI 0.20-2.1) and for the combination of RT, tamoxifen, and surgery it was 0.23 (95% CI 0.08-0.65, p=0.006). In a model that included these treatment parameters, patient age, DCIS size and grade were non-significant whereas the presence of free margins was highly significant (OR 0.27, 95%CI 0.10-0.71, p=0.008). Overall, 29% of new breast events were invasive. Contralateral events occurred in 14/467 women (3%) of BCT and mastectomy patients with hormone receptor positive DCIS, but eight of these were non-compliant. Conclusions: The use of optimal DCIS therapy (complete excision, RT, tamoxifen) decreased the odds of ipsilateral breast events by 73%, whereas RT alone or tamoxifen alone in addition to surgery were less effective. Despite relatively high acceptance of tamoxifen, lack of compliance remains an issue and will be further examined. Citation Format: Anna M Higham, Irene B Helenowski, Shruti R Zaveri, Daniel H Schneider, Nora M Hansen, Kevin P Bethke, Seema A Khan. Tamoxifen acceptance by DCIS patients and effect on subsequent ipsilateral and contralateral breast events [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-06.

Abstract P1-01-05: Effects of preoperative MRI on rate of ipsilateral and contralateral recurrence of breast cancer

Abstract Introduction: Preoperative MRI of the breast is the most sensitive imaging modality in the detection of multifocal or multicentric breast cancer, as well as simultaneous contralateral breast cancer. The aim of this retrospective review was to evaluate the effect of preoperative MRI on local control for patients with breast cancer. Methods: The Enterprise Data Warehouse of Northwestern Medicine was searched for women who underwent breast conserving surgery for ductal carcinoma in situ (DCIS) or primary invasive breast cancer in the interval of 2004-2010. The use of preoperative MRI, and the clinical and therapeutic details of the patients thus identified were extracted by direct review of the electronic medical record. A breast event was defined as a local recurrence in the treated breast more than six months after completion of treatment (ipsilateral) or a new breast cancer in the untreated breast (contralateral). Differences in the frequency of all events (local and distant), for ipsilateral breast events, and for contralateral breast events was evaluated with Cox proportional hazards model, adjusting for patient age, tumor size, nodal status, the presence of triple negative disease, and the use of radiotherapy and systemic therapy. Results: In our cohort of 1097 patients, 526 had preoperative MRI and 571 had no MRI. The patients who had preoperative MRI were younger (59 vs. 66 years, p&amp;lt;0.0001), were more commonly premenopausal (37.8% vs. 27.3%, p=0.0004), were more likely to present with palpable tumors (34.8% vs. 26.6%, p=0.004), were more likely to have invasive lobular disease (16% vs. 11.6%), and less likely to have DCIS (16.5% vs. 29%, p=0.001 for differences in histologic pattern). Mean tumor size was equivalent in the two groups (17.5 and 17.3 mm), but nodes were more frequently positive in the MRI group (23.9% vs. 19.1%, p=0.045). Triple negative tumors were more frequent in the MRI group (14.1% vs. 7.5%, p=0.0003). Mean follow up was 51.5 months in the MRI group and 59.4 months in the no MRI (p&amp;lt;0.0001). The number of events was 49 in the MRI group and 68 in the no MRI group. The Cox hazard ratio (HR) for all events (adjusted for follow-up duration and factors described in the Methods) was equivalent between the two groups (HR 0.90, 95% CI 0.59-1.36, p=0.61). The HR for ipsilateral (HR 0.93, 95% CI 0.57-1.51, p=0.76) and contralateral events (HR 1.22, 95% CI 0.57-2.62, p=0.61) was equivalent between the two groups. Conclusions: In analyses adjusted for important prognostic features, the use of preoperative breast MRI was not associated with a reduced hazard of any breast cancer event, or of in-breast events (ipsilateral or contralateral). However, the MRI group had a more adverse tumor and patient profiles; a propensity score analysis will be performed, to further adjust for these differences. These findings add weight to the position that routine use of preoperative MRI for all breast cancer patients is not beneficial. Citation Format: Amanda L Amin, Irene B Helenowski, Thomas E Kmiecik, Shruti R Zaveri, Nora M Hansen, Kevin P Bethke, Seema A Khan. Effects of preoperative MRI on rate of ipsilateral and contralateral recurrence of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-01-05.

Are the Randomized Trials of Radiation Therapy for Ductal Carcinoma in Situ Still Relevant?

The article by Warnberg et al that accompanies this editorial completes a recent series of updates of four randomized trials begun between 1985 and 1990 comparing outcome with or without radiation therapy (RT) after breast-conserving surgery for patients with ductal carcinoma in situ (DCIS; Table 1). Rates of local failure (sometimes referred to as ipsilateral breast events [IBE]) at median follow-up intervals of approximately 13 to 17 years were 25% to 35% in the unirradiated arms compared with 10% to 20% in the irradiated arms. But are these findings still relevant today? So many aspects of patient evaluation and selection for breast-conserving therapy were different then than they are now. There was much less use of magnification mammography resulting in underestimation of lesion extent. Pathologic evaluation was not standardized, and only limited sampling was performed even with large specimens. For example, in the National Surgical Adjuvant Breast and Bowel B-17 trial, a median of nine slides were sent for central pathology review with a range of one to 70 slides. Interestingly, that review also reclassified 18% of patients as having involved or inevaluable margins. The trials had broad selection criteria with regard to patient age at diagnosis, the means of presentation (mammographically detected or symptomatic), lesion size, and histologic features. Finally, they required only negative resection margins, which was defined as the absence of tumor at the inked specimen edges. The Swedish trial also accepted patients with positive or unknown margins, who constituted approximately 20% of the study population. Clues appeared in the late 1980s, and after that, the minimum tumor-free margin width was a critical variable for the risk of IBE for unirradiated patients. Other studies found that larger size and the presence of high nuclear grade and comedo-type necrosis increased local recurrence rates. An influential study assigned points for histology, tumor size, and margin width and combined them into a single number, which predicted the risk of relapse after lumpectomy with or without RT. This index was later revised to include patient age. With a median follow-up of 75 months, unirradiated patients with a University of Southern California-Van Nuys Prognostic Index score of 4 to 6 had a 10-year IBE rate of 6%—only slightly higher than those who were irradiated. A study from the S. Orsola Malpighi Hospital in Bologna, Italy, found a 10-year disease-free survival rate of 5% among 144 such low-score patients with mean follow-up of 130 months. Other groups have also proposed prognostic indices, although these have not always been reliable. The first prospective trial in the United States testing whether a group could be chosen that would do well with excision alone was conducted from 1995 to 2002 in Boston. Patients were eligible if they had DCIS of predominant nuclear grade 1 or 2 that was 25 mm or smaller, a minimum tumor-free margin width of 10 mm or no tumor on reexcision, and no calcifications on postoperative mammography.