10-year Risk Of Local Recurrence Research Articles

Abstract PO4-13-02: Molecular Expression Assays Improve the Prediction of Local and Invasive Local Recurrence after Breast Conserving Surgery for DCIS

Abstract Introduction Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast conserving surgery (BCS) in order to reduce the risk of local recurrence (LR) and invasive LR. Nomograms based on clinicopathological features (CPF) and molecular expression assays have been developed in an effort to provide individualized risk estimates and personalize decision-making. However, molecular assays are costly and it remains unclear if they provide more accurate recurrence risk estimates compared to algorithms based on CPF alone. We examined the impact of the 12-Gene DCIS Score (DS) and the 21-Gene Recurrence Score (RS) molecular expression assays, in addition to CPF, on the accuracy of predicting 10-year LR and invasive LR risk compared to predicted estimates based on CPF alone. In addition, we examined if a model including the 21-Gene RS improves the 10-year predicted risks of invasive LR after BCS for DCIS compared to estimates based on the DS+CPF or CPF alone. Methods We used a population-based cohort diagnosed with pure DCIS treated with BCS +/- RT from 1994-2003. All cases had expert pathology review providing contemporary assessment of diagnosis, margin status, margin width, multifocality, presence and extent of comedo necrosis, subtype, nuclear grade, and tumor size. For each case, a representative tissue block or unstained slide was sent to measure the 12-Gene DS and 21-Gene RS. Predictive models were developed using multivariable Cox regression analyses with backward selection and included all CPF, treatment with RT, and interactions. The performance of each model was evaluated based on c-statistic, -2log likelihood estimate (-2LLE), and Akaike information criterion (AIC). Calibration was performed using bootstrap resamples, with replacement. We compared the performance of the best model derived from CPF alone, the 12-Gene DS with CPF, and the 21-Gene RS with CPF on their ability to predict the 10 year risks of LR and invasive LR measured against outcomes observed in the cohort. Results The population-based cohort includes 1226 women, 514 were treated with BCS alone and 712 were treated with BCS + RT. Median age was 56 years. Median follow-up was 10 years. Fifty-two percent of tumors were between 1 and 2.5 cm, 35% were ≤1cm, and 13% were >2.5 cm. Comedo necrosis was present in 68%, and nuclear grade was low, moderate, and high in 7%, 54%, and 39%, respectively. Margins were negative in 90.5% of cases (N=1109). The 12-Gene DS was low, intermediate, and high in 53.5%, 20.9%, and 25.6% and the 21-Gene RS was >25 in 30% of patients. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive LR. Models including either the DS or RS expression assays performed better in predicting the 10-year risk of LR after BCS compared to the model based on CPFs alone, demonstrating higher c-statistics (0.705, 0.699, and 0.662, respectively), lower AIC and lower -2LLE. The two molecular-based predictive models also performed better in predicting the risk of invasive LR compared to CPF model, although with smaller differences in c-statistics (0.684, 0.683, and 0.667, respectively), AIC or -2LLE. The predictive model based on the 21-Gene RS with CPF did not perform better in the prediction of the 10 year risk of invasive LR compared the 12-Gene DS + CPF model. All models were well calibrated. Conclusion The predictive model based on the 12-Gene DS with CPF more accurately predicted the 10-year risk of LR and invasive LR after BCS compared to model based on CPF alone. Inclusion of the 21-Gene RS with CPF did not improve the prediction of the 10-year risk of LR or invasive LR. This suggests that nomograms that include the 12-Gene assay with CPF provide more accurate individualized estimates of recurrence risk after BCS and can help improve personalized decision-making in the management of DCIS. Citation Format: Ezra Hahn, Rinku Sutradhar, Lawrence Paszat, Lena Nguyen, Danielle Rodin, Sharon Nofech-Mozes, Sabina Trebinjac, Cindy Fong, Eileen Rakovitch. Molecular Expression Assays Improve the Prediction of Local and Invasive Local Recurrence after Breast Conserving Surgery for DCIS [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-02.

Overall Survival and Related Factors of Patients Undergoing Breast-Conserving Surgery with Boost Through Interstitial Brachytherapy in a Cancer Center in Medellin, Colombia.

Liza María González-HernándezPatients with breast cancer undergoing conservative surgery require management with radiotherapy to decrease the risk of recurrence. Moreover, the use of tumor bed boost in high-risk patients has shown an absolute reduction in the 10-year local recurrence risk from 23.9 to 13.5%. Therefore, this study aimed to estimate the overall survival of a group of patients undergoing conservative surgery with a boost through interstitial brachytherapy at a cancer center in Medellin, Colombia. A retrospective cohort study was performed, and records from 2014 to 2020 of patients with in situ or infiltrating breast cancer treated with a boost through interstitial brachytherapy were included. Univariate analysis was conducted to characterize the study population; median survival was calculated using the Kaplan-Meier method. Moreover, associations concerning survival were calculated with each of the factors independently. A total of 186 patients were included. Their overall survival was 93.5%, with a median survival of 79 months. The presence of negative hormone receptors, having two or more irradiated fields and having a locally advanced stage were factors associated independently with higher mortality. The overall survival of patients with in situ or infiltrating breast cancer was favorable and correlated with studies regarding intervention with a boost through interstitial brachytherapy and the factors associated with higher mortality, such as having a locally advanced stage.

DUCHESS: an evaluation of the ductal carcinoma in situ score for decisions on radiotherapy in patients with low/intermediate-risk DCIS

Identification of women with DCIS who have a very low risk of local recurrence risk (LRR) after breast-conserving surgery (BCS) is needed to de-escalate therapy. We evaluated the impact of 10-year LRR estimates after BCS, calculated by the integration of a 12-gene molecular expression assay (Oncotype Breast DCIS Score®) and clinicopathological features (CPFs), on its ability to change radiation oncologists' recommendations for RT after BCS for DCIS. Prospective cohort study of women with DCIS treated with BCS. Eligibility criteria were as follows: age > 45years, tumor ≤ 2.5cm, and margins ≥ 1mm. Radiation oncologists provided 10-year LRR estimates without RT and recommendation for RT pre- and post-assay. Primary outcome was change in RT recommendation. 217 patients were evaluable, with mean age = 63years, mean tumor size = 1.1cm, and mean DCIS Score = 32; 140 (64%) were in the low-risk (<39), 32 (15%) were in the intermediate-risk (39-54), and 45 (21%) were in the high-risk groups (≥55). The assay led to a change in treatment recommendation in 76 (35.2%) (95%CI 29.1-41.8%) patients. RT recommendations decreased from 79% pre-assay to 50% post-assay (difference = 29%; 95%CI 22-35%) due to a significant increase in the proportion of patients with a predicted low LRR (< 10%) post-assay and recommendations to omit RT for those with a low predicted risk. The assay was associated with improved patient satisfaction and reduced decisional conflict. The DCIS Score assay combined with CPFs identified more women with an estimated low (<10%) 10-yr LR risk after BCS, leading to a significant decrease in recommendations for RT compared to estimates based on CPFs alone.

Abstract PD5-05: Including a 21-gene assay recurrence score in multivariable predictive model generation improves prediction of local recurrence after breast conserving surgery for ductal carcinoma-in-situ

Abstract Introduction Accurate prediction of local recurrence (LR) after breast conserving surgery (BCS) for ductal carcinoma-in-situ (DCIS) is crucial to personalize recommendations for adjuvant radiotherapy (RT). The 21-gene recurrence score (RS) predicts for distant metastases for woman with invasive breast cancer. We hypothesised that the RS could improve prediction of LR after BCS for DCIS. Methods We performed a population-based analysis of 1226 woman aged ≤74 treated with BCS ± RT for pure DCIS. Expert pathology review was obtained for all cases, as was the RS. Treatment and outcomes were obtained by deterministic linkage to administrative databases and chart review. Clinico-pathologic features obtained included: age, tumor size, nuclear grade, presence of comedonecrosis, multifocality, margins, and adjuvant radiation. The outcome assessed was local recurrence by 10 years from diagnosis of DCIS. The LR prediction model was developed using multivariable Cox regression, where a non-parametric approach was implemented to estimate the baseline hazard function. The proportional hazards assumption was assessed and time-interaction terms were included with each covariate in the model. Models were ranked based on c-statistic, log-likelihood estimate, and Akaike information criterion (AIC). Backward selection was used to obtain the final reduced model with time-interaction terms. Calibration for the best model was examined by grouping predicted 10-year risk of LR into deciles and plotting against observed 10-year risk of LR based on mean Kaplan-Meier estimates. Internal validation was performed by bootstrapping. Results Of the 1226 woman included, 514 were treated with BCS alone and 712 received adjuvant RT. Median follow up from time of treatment was 16 years (interquartile range (IQR): 14-18). The median age was 56 years (IQR: 49-64). Margins were negative in 90.5% of cases. Tumor size was ≤1cm in 430 (35.1%), 1-2.5cm in 633 (51.6%), and &amp;gt;2.5cm in 163 (13.3%). The median RS was 15 (IQR: 8-30) and the mean RS was 21.37 (SD 18.93). The best predictive model included the RS and had a c-statistic of 0.68 as well as the lowest AIC. This model included the following variables: RS, age, tumor size, nuclear grade, margin status, comedonecrosis (≤30% vs higher), multifocality, and treatment (BCS vs BCS+RT); it also included the following interaction terms: treatment and time, RS and time, comedonecrosis and time, and treatment and tumor size. Due to the non-linear relationship between certain characteristics and the risk of LR, quadratic terms for RS and age were also included. This model was well calibrated overall, especially in the lower risk range around the 10% risk threshold. It was also well calibrated in this risk range in the subset of woman who were treated with BCS alone. Conclusion The best performing model generated to predict LR after BCS for DCIS includes the RS. Work is ongoing to compare RS and the 12-gene DCIS score in terms of prediction of LR, as well as prediction of invasive LR specifically. This work can help guide future clinical de-escalation trials by better identifying woman with truly low risk of LR after BCS for DCIS. Citation Format: Ezra Hahn, Rinku Sutradhar, Sumei Gu, Lawrence Paszat, Danielle Rodin, Sharon Nofech-Mozes, Cindy Fong, Eileen Rakovitch. Including a 21-gene assay recurrence score in multivariable predictive model generation improves prediction of local recurrence after breast conserving surgery for ductal carcinoma-in-situ [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-05.

Use of the Twelve-Gene Recurrence Score for Ductal Carcinoma in Situ and Its Influence on Receipt of Adjuvant Radiation and Hormonal Therapy.

Tumor genomic prognostic assays estimate 10-year local recurrence risk in ductal carcinoma in situ (DCIS) and can guide treatment decisions. This study aimed to evaluate which DCIS patients treated with breast-conserving surgery (BCS) underwent DCIS score genomic testing and the influence of the results on adjuvant treatment recommendations. The study identified patients from the National Cancer Database (NCDB) who had DCIS treated with BCS from 2010 to 2016. Of 141,047 patients, 4255 (3%) had a DCIS score assessed, 0.3% in 2010 increasing to 5.8% in 2016 (p < 0.001). The patients most likely to undergo DCIS score assessment had more favorable tumor features in the multivariable analysis. The DCIS score result was documented for 91.4% of the tested patients (n = 3888): 70.5% of the low-risk, 14.9% of the intermediate-risk, and 14.6% of the high-risk patients. The patients with low-risk scores were less likely to have radiation than those with intermediate- or high-risk scores among the patients with either ER + (35.0% vs 71.0% or 81.1%) or ER- disease (48.1% vs 77.0% or 85.5%) (each p ≤ 0.001). The patients who had ER + disease with high- and intermediate-risk scores were most commonly treated with both radiation and hormone therapy (HT) (57.1% and 52.2%), whereas the most common treatment for those with a low-risk DCIS score was HT alone without radiation (37.1%). Comparison of genomic testing with clinicopathologic features showed an independent influence of genomic testing on treatment. Use of the DCIS score increased over time, predominantly for favorable DCIS. Patients with a low-risk score were significantly less likely to receive radiation, supporting an impact of the DCIS score on treatment de-escalation.

A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ.

The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell-specific trait widely associated with aggressiveness. This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n = 133) and a validation cohort (VC, n = 119). DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; P < 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; P < 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratification using CAS (P < 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS = 6.2 vs. HR for VNPI = 1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant RT. CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis.

Abstract OT3-09-01: Use of Oncotype DX DCIS for disease management in a prospective DCIS registry

Abstract Background: Ductal carcinoma in situ (DCIS) now represents nearly a quarter of newly diagnosed breast cancers in the United States. Standard-of-care treatment for DCIS is aggressive local therapy consisting of either mastectomy or breast conserving surgery with radiation. However, DCIS mortality is low regardless of initial treatment, suggesting opportunities to explore a spectrum of treatment options. With these treatment options, there is the potential to create risk-adapted treatment plans, but the question of how to assess risk remains. Molecular tests can help to personalize treatment by stratifying disease sub-types and providing prognosis. One such tool is the Oncotype DX® Breast DCIS Score, a risk measure which was validated in a meta-analysis of 773 patients from the E5194 and Ontario DCIS Cohort studies. Along with calculating a Breast DCIS Score™ from the expression levels of 12 genes, the test provides a predicted 10-year risk of local recurrence from the score result, age, and tumor size for patients who receive breast conserving surgery alone. Understanding how such a tool might impact decision-making will inform its implementation. Eligibility &amp; trial design: The ATHENA Breast Health Network is a consortium of the five University of California Medical centers. Through ATHENA, patients with histologically confirmed DCIS and no concurrent invasive cancer are approached to participate in the Athena DCIS Registry. Patients in the registry facing an active management decision are eligible to participate in the Oncotype DX® DCIS prospective study. Specific aims: The primary aim of the study is to determine whether the additional diagnostic information (i.e. the DCIS Score™) impacts patient treatment decisions and physician recommendation. Additional goals are to correlate the DCIS Score™ with mammographic findings, pathological variables, and treatment recommendations, and to estimate risk within each DCIS Score™ group. Participants and their physicians answer survey questions both before and after receiving the score to evaluate the impact of the DCIS Score™ on treatment recommendations and decisions. Statistical methods: The study will assess the percentage of patients who thought the DCIS risk score influenced their treatment decision. The study will also assess whether a significant proportion of physicians changed their recommendations after considering the DCIS Score™ using the chi-square test. Similarly, the patients’ preferred treatment option pre- and post- test surveys will be evaluated. In addition, the concordance between physicians’ and patients’ choices will be assessed by the Kappa statistic before and after the score. The patients’ and physicians’ confidence levels in their treatment recommendation and decision pre- and post- test will be compared using a Wilcoxon signed-rank test, as well as the percentage of patients and physicians who are glad they used the test. In addition, the study will assess whether the DCIS test influences a patient’s perception of their recurrence risk by comparing the self-reported 10-year breast cancer recurrence risk in their pre- and post- test questionnaires using a Wilcoxon signed-rank test. Current and target accrual: The current accrual across all sites in the Oncotype study is 94 patients. The target accrual for the initial pilot phase data is defined as the first 100 patients accrued. If interested in learning more about the study, please contact Rita Mukhtar, MD (Rita.Mukhtar@ucsf.edu). Citation Format: Jane M Wei, Paul Kim, Cheryl Ewing, Jasmine Wong, Laura J Esserman, Michael D Alvarado, Abimbola O Olusanya, Skye Stewart, Ashley Tydon, Parima Daroui, Jeffrey V Kuo, Hannah L Park, Karen T Lane, Eliza Jeong, Kelsey Brown, Ava Hosseini, Barbara A Parker, Sarah L Blair, Athena Breast Health Network Investigators, Frederick Baehner, Olivier Harismendy, Antonia Petruse, Carlie K Thompson, Helena R Chang, Alexander D Borowsky, Christina Yau, Gillian L Hirst, Richard J Bold, Rita A Mukhtar. Use of Oncotype DX DCIS for disease management in a prospective DCIS registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-01.

Abstract P6-16-01: Refined local recurrence risk estimates based on a multigene expression assay combined with clinicopathological features significantly impacts radiotherapy recommendation in patients with low/intermediate risk DCIS treated with breast-conserving surgery

Abstract Background: Guidelines recommend that breast radiation (RT) can be omitted for patients with a low risk of local recurrence (LR) after breast-conserving surgery (BCS) for DCIS. The inability to identify women at low risk of LR (&amp;lt;10%) at 10 years after BCS has hampered efforts to de-escalate therapy for DCIS. The Oncotype DX Breast DCIS Score® (DS), a 12-gene expression assay, predicts LR risk after BCS. The revised DS report adds information from the DS with clinicopathological features (CPF) (age, tumor size, year) (BCRT 2018;169;358-690) to provide refined estimates of LR risk and can better identify patients with low 10-year LR risk (&amp;lt;10%) after BCS. We evaluated the impact of refined LR risk estimates on its ability to change radiation oncologists’ recommendations for RT in women with low/moderate risk DCIS treated with BCS. Methods: Prospective cohort study of women with low/moderate risk pure DCIS treated with BCS. Cases with age &amp;lt;45 yrs, margins &amp;lt;1mm, tumor &amp;gt;2.5cm, multifocality, or prior breast cancer were excluded. Baseline CPFs, the DS and risk of LR were collected. Pre-assay, the radiation oncologist provided an estimate of 10-year LR risk without RT and a preliminary recommendation for RT. Post-assay, final recommendations were recorded. The primary outcome was change in treatment recommendation by the radiation oncologist. Target sample size was 220 to provide data on 200 evaluable patients with adequate precision. Results: 217 patients were evaluable: mean age, 63 years and mean tumor size, 1.1 cm. Nuclear grade was low in 26 (12%), intermediate in 116 (53%), and high in 75 (35%) of patients. Mean DS = 32; 140 (64%) low (&amp;lt;39), 32 (15%) intermediate (39-54), 45 (21%) high risk DS (≥5). The assay lead to a change in treatment recommendation in 35.2% (76/216) (95% CI: 29.1-41.8) of cases. The proportion of cases recommended to receive RT decreased from 79% (N=171) pre-assay to 50% post-assay (p&amp;lt;.001). This was due to a significant increase in the proportion of cases (46%) with a predicted low risk of LR (&amp;lt;10%) post-assay and recommendations to omit RT for those with low LR risk. Pre-assay, physician estimates of 10-yr LR risks after BCS based on CPFs alone were &amp;lt;10% in 13 (6%) cases, 10-15% in 76 (35%) cases and &amp;gt;15% in 128 (59%) cases. Post-assay, estimated 10-yr LR risk after BCS was &amp;lt;10% in 101 (46%) patients (83% recommended no RT), 10-15% in 67 (31%) (RT recommended in 66%) and &amp;gt;15% in 49 (22%) (RT recommended in 98%). Conclusion: The use of the DCIS Score combined with CPFs identifies more women with an estimated low (&amp;lt;10%) 10-yr LR risk after BCS leading to a significant change in treatment recommendations with a decrease in recommendations for RT following BCS compared to CPFs alone. Table 1.Post-assay 10-yr LR risk&amp;lt;10%10-15%&amp;gt;15%(N=101)(N= 67)(N=49)Pre-assay estimated 10-yr LR risk• &amp;lt;10% (N=13)922• 10-15% (N=76)50188• &amp;gt;15% (N=128)424739RT recommended• Yes17 (17%)44 (66%)48 (98%)• No83 (83%)23 (34%)1 (2%) Citation Format: Eileen Rakovitch, Anne Koch, Laval Grimard, Hany Soliman, Christiaan Stevens, Francisco Perera, Iwa Kong, Senti Senthelal, Margaret Anthes, Ericka Wiebe, Jeffrey Cao, Mira Goldberg, Sally Smith, Luciana Spadafora, Sameer Parpia, Timothy Whelan. Refined local recurrence risk estimates based on a multigene expression assay combined with clinicopathological features significantly impacts radiotherapy recommendation in patients with low/intermediate risk DCIS treated with breast-conserving surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-01.

Association between perceived benefits and receipt of radiotherapy among older breast cancer patients.

While radiotherapy can be safely omitted in many older women with early-stage breast cancer after lumpectomy, approximately two-thirds of eligible women still undergo this treatment. We surveyed 63 older women with stage I (T1N0M0), estrogen-receptor-positive breast cancer who underwent lumpectomy, and were considering/receiving radiotherapy. Participants perceived that radiotherapy would reduce their 10-year risk of local recurrence by an average of 18.7%, which is significantly higher than the 8% risk reduction reported in literature. Multivariate analyses demonstrated that participants who reported a large perceived benefit were significantly more likely to undergo radiotherapy treatment (odds ratio 10.34; 95% confidence interval: 1.66-66.35).

Comparison of Local Recurrence Risk Estimates After Breast-Conserving Surgery for DCIS: DCIS Nomogram Versus Refined Oncotype DX Breast DCIS Score.

A ductal carcinoma in situ (DCIS) Nomogram integrating 10 clinicopathologic/treatment factors and a Refined DCIS Score (RDS) that incorporates a genomic assay and three clinicopathologic factors (Oncotype DX DCIS Score) are available to estimate DCIS 10-year local recurrence risk (LRR). This study compared these estimates. Patients 50years of age or older with DCIS size 2.5cm or smaller and a genomic assay available were identified. An RDS within 1-2% of the range of Nomogram LRR estimates obtained by assuming use and non-use of endocrine therapy (Nomogram ± ET) was defined as concordant. Assuming a 10-year risk threshold of 10% for recommending radiation, Nomogram ± ET and RDS estimates were compared, and threshold concordance was determined. For 54 (92%) of 59 patients, the RDS and Nomogram ± ET LRR estimates were concordant. For the remaining 5 (8%) of the 59 patients, the RDS LRR estimates were lower than the Nomogram+ET estimates, with an absolute difference of 3-8%, and thus were discordant. For these five patients, the RDS estimates of 10-year LRR were lower than 10% (range 5-8%) and the Nomogram + ET estimates were 10% or higher (range 11-14%). These five patients with both discordant and threshold-discordant estimates all had close margins (≤ 2mm). Among 92% of women 50years of age or older with DCIS size 2.5cm or smaller, free-of-charge online Nomogram 10-year LRR estimates were concordant with those obtained using the commercially available RDS (> $4600). Among the 8% with discordant risk estimates, the RDS appeared to underestimate the LRR and may lead to inappropriate omission of radiotherapy. Unless other data show a clinically significant advantage of the RDS (Oncotype DX DCIS Score), the study data suggest that for women 50years of age or older with DCIS size 2.5cm or smaller, its use is not warranted.

Oncotype DX DCIS use and clinical utility: A SEER population-based study.

e12046 Background: OncotypeDX DCIS is a 12-gene assay designed to predict the 10-year risk of local recurrence and to guide treatment decisions, specifically the benefit of radiation therapy in breast ductal carcinoma in situ (DCIS). The test became available in December 2011 and is not currently recommended by guidelines. The Surveillance, Epidemiology and End Results (SEER) program captures cancer data at the population-level and has been conducting annual linkages with Genomic Health Clinical Laboratory, the only lab performing the test, to identify patients receiving the test. Methods: SEER cases diagnosed with in situ breast cancer (DCIS or papillary in situ) between 2011-2015 were included in the analysis. SEER data on patient demographics, tumor characteristics, and treatments were combined with linkage variables for OncotypeDX DCIS tests reported by Genomic Health. Logistic regression was used to identify which patient related factors were associated with having received the test and to evaluate the relationship between test generated risk categories and treatments. Results: Of the 68,826 in situ breast cancer cases, 2,155 were linked to DCIS test data. Test utilization increased from &lt; 1% to 5.3% for patients diagnosed in 2011 vs. 2015. Patients were less likely to receive the test if they had larger and higher-grade tumors, were divorced, had Medicaid insurance, and were in the lowest socioeconomic status tertile. The majority of patients (68%) were at low risk, 17% intermediate, and 15% in the high risk group. Patients at intermediate or high risk were more likely to receive radiation (OR = 2.4, 95% CI: 1.8-3.2 and OR = 3, 95% CI: 2.3,4.1, respectively) than the low risk group. High risk patients were more likely than low risk patients to receive chemotherapy (OR = 4.3, 95% CI: 1.2, 14.4) and to undergo mastectomy than lumpectomy (OR = 1.47, 95% CI: 1.12-1.93). Conclusions: Clinical adoption of the OncotypeDX DCIS test has been slow. The association between multiple demographic factors and receiving the test indicated disparities in the US population. Clinical factors also influenced whether patients received the test. OncotypeDX DCIS results appeared to guide clinical decisions.

Abstract P4-09-01: The DCIS score predicts risk of local recurrence risk after breast-conserving surgery more accurately than ER plus HER2

Abstract Introduction: Improved individual prediction of 10 yr local recurrence (LR) risk following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is needed to identify women at low risk, for whom radiotherapy (RT) may be omitted. We hypothesized that LR prediction that includes the Oncotype DCIS score (DS) would be more accurate, and would identify more women with very low LR risks compared to models that include estrogen receptor (ER) plus HER2 without the DS. Methods: Three predictive models of LR (clinicopathological factors (CPFs) alone; CPFs+ER+HER2; CPFs+DS) were developed and compared in 1,102 cases of DCIS for whom complete covariate and outcome data were available. CPFs included age at diagnosis, lesion size, nuclear grade, comedonecrosis, multifocality, and resection margin width. Categorizations of discrete variables and transformations of continuous variables were examined in Cox models; two-way interactions and interactions with time were assessed. Internal validation was performed by bootstrapping. Individual predicted 10-yr LR risks after treatment with BCS alone were computed from covariate values, estimated regression parameters and the estimated baseline survival function. Model performance was assessed by c-statistics and calibration plots. Results: 863/1,102 (78.3%) women were age &amp;gt;= 50 years at diagnosis. Lesion size was &amp;lt;= 10 mm in 555/1,102 (50.4%). Nuclear grade was low or moderate in 62.4%. Comedonecrosis was present in 22.1%. Multifocality was observed in 25.2%. Post-BCS RT was received by 54.4%. Mean DS = 37.49 (sd 23.29). DS risk category = low in 611/1,102 (55.4%). ER = positive in 1,025 /1,102 (93.0%) cases. HER2 overexpression = positive in 212/1,102 (19.2%), equivocal in 95 / 1,102 (8.6%) and negative in 795 / 1,102 (72.1%) cases. Adjusting for all CPFs, the hazard ratios (HR) for LR per 50-unit increase in DS = 2.00 (95% CI 1.42, 2.83), for ER positive = 0.58 (95% CI 0.36, 0.95) and for HER2 positive = 0.73 (95% CI 0.41, 1.30). The strongest prediction model incorporated CPFs+DS. C-statistics for CPFs+DS, CPFs+ER+HER2, or CPFs alone models were 0.7025, 0.6879, and 0.6825. The CPFs+DS model was better calibrated at predicting low (&amp;lt;=10%) individual 10-yr LR risks after BCS alone than models incorporating CPF+ER+HER2 or CPFs alone, evidenced by c-statistics and plots of observed by predicted risks. Specifically, among women age &amp;gt;= 50 with no adverse CPFs, the CPFs+DS model identified the greatest proportion of women (62.3%) with predicted 10-year LR risk &amp;lt;= 10% without RT, compared to the CPFs+ER+HER2 (50.9%) or CPFs alone (46.5%) models. When applying the prediction equations to similar women as those in the cohort who were treated with RT, the CPFs+DS model again identified the greatest proportion of women (44.4%) with a low predicted 10-yr LR risk without RT (for whom RT could have been omitted) compared to the CPFs+ER+HER2 model (39.4%) and the CPFs alone model (32.3%). Conclusion: Individual prediction of LR risk that incorporates the DCIS score plus clinicopathological factors is more accurate than prediction models based on ER plus HER2, and identifies a higher proportion of women with a low predicted risk of LR after BCS alone, for whom radiotherapy may be omitted. Citation Format: Rakovitch E, Sutradhar R, Zhou L, Nofech-Mozes S, Hanna W, Paszat L. The DCIS score predicts risk of local recurrence risk after breast-conserving surgery more accurately than ER plus HER2 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-01.

Abstract P5-18-09: Performance of Oncotype DX DCIS score across diverse ethnic populations

Abstract There is a paucity of data on Oncotype DX DCIS Score and ethnic variation. It has been postulated that there are different molecular features /drivers among different ethnic populations. The Oncotype DX DCIS Score is a genomic test designed to analyze the expression of a group of 12 genes which can quantify 10-year local recurrence risk after surgery. The purpose of this study is to evaluate diverse ethnic patients with DCIS relative to traditional clinical pathologic factors and Oncotype DX DCIS Score We analyzed consecutive cases of DCIS from 2011-2017 who underwent Oncotype DX DCIS Score testing at a single institution. Eighty-four female patients were divided into 5 groups based on self-reported ethnicity: White (36%), African American (AA) (48%), Asian (8%), Hispanic (4%) and Other (4%). Clinical and traditional pathologic factors were collected including age, nuclear grade (NG), ER/PR status and Oncotype DX DCIS Score. The distribution of NG and Oncotype DX DCIS Score was analyzed across ethnic groups. The mean age at diagnosis was 63. Overall 99 % of cases were hormone positive. Comparison of White and AA patients revealed a correlation between ethnic group and DCIS Score, with a p value of 0.0087 (Table 1). Similarly, we looked at all five ethnic groups and Oncotype DX DCIS Score and found a p value of 0.022. We evaluated ethnicity with White and AA patients versus NG and obtained a p value of 0.084 (Table 2). In addition, we assessed all five ethnic groups and NG. We obtained a p value of 0.068. No AA patients with DCIS had a high DCIS Score. No patients with low NG DCIS had a high DCIS Score. Analysis of the three factors (NG, ethnicity and DCIS Score) concurrently showed that they are not independent. In summary, our study provides valuable data on Oncotype DX DCIS Score and NG across a diverse patient population. These data highlight the importance of incorporating both traditional clinical pathologic factors and DCIS Score molecular testing for making treatment decision across different ethnic patient populations. Table 1.Comparison of DCIS Score and Ethnic GroupEthnic GroupLow DCIS ScoreIntermediate DCIS ScoreHigh DCIS ScoreAA3730White2704p=0.0087 Table 2.Comparison of Nuclear Grade and Ethnic GroupEthnic GroupNuclear Grade 1Nuclear Grade 2Nuclear Grade 3AA17194White1399p=0.084 Citation Format: Mittar P, Casella S, Bombonati A, Emiloju O, Jablon L, Schultz D, Leighton JC, Solin LJ. Performance of Oncotype DX DCIS score across diverse ethnic populations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-09.

Abstract P4-15-09: Refined estimates of local recurrence risk in a clinical utility study: Integrating the DCIS score, patient age and DCIS tumor size

Abstract Background:Better tools are needed to estimate the risk of local recurrence (LR; DCIS or invasive) after breast-conserving surgery (BCS) for pts with DCIS in order to inform treatment decisions. Traditional clinico-pathologic (CP) factors, e.g., age and tumor size, provide an average LR risk derived from clinical trials and population studies. The Oncotype DX 12-gene DCIS Score assay has been validated to provide individual 10 yr LR risk estimates (Solin JNCI 2013; Rakovitch BCRT 2015). Previously we reported the impact of the DCIS Score result on radiotherapy (RT) recommendations including the pre-assay LR risk and RT recommendation and the change in RT recommendation from pre- to post-assay (Manders Ann Surg Oncol 2016).Recently a patient specific meta-analysis (MA) combined data from E5194 and Ontario DCIS Cohort (ODC) adjusting for pertinent clinico-pathologic factors to provide refined prediction estimates of LR risk after BCS alone (Rakovitch ASCO 2017). Herein we applied these risk estimates integrating DS, tumor size and patient age with adjustment for diagnosis in the year 2000 or later to refine estimates of LR in DCIS patients from the Manders et al study. Methods: 13 U.S. sites enrolled pts with DCIS treated with BCS alone from 3/2014 to 5/2015. Pts with LCIS but no DCIS, invasive BC, or planned mastectomy were excluded. Data were prospectively collected on CP factors, physician estimates of LR risk, and DCIS Score. Refined estimates of 10-yr risk of LR are presented by DCIS Score result category (0-38; 39-54; 55-100), age group (≥50 vs &amp;lt;50 yr) and tumor size (≤1; &amp;gt;1-2.5; &amp;gt;2.5 cm). Results: Of the 127 pts enrolled, median age was 60 yr,79.5% were postmenopausal. Median size was 8mm &amp; 39% were ≤5mm. Median margin width was 3.0mm. ER and PR by IHC were positive in 89% and 78% of pts, respectively. For patients ≥50 yr with tumors ≤1 cm and low risk DS, the 10-yr LR risk ranges from 5.3-10.0%. A high DS result is associated with a higher 10-yr median predicted risk of LR in all subsets (table 1). The DCIS Score integrated with tumor size and patient age and the adjustment for diagnosis in 2000 or later provided risk estimates that are often lower than those provided by the DCIS Score alone without adjustment for diagnostic year. Using DS alone the percentage of patients with risk of LR &amp;lt;8% was 0%; however, incorporating patient age and tumor size with the DS and adjusting for diagnosis in 2000 or later, it increased to 30.9% of patients. Conclusions: Integration of the DCIS Score assay, that provides individual risk estimates of LR, with patient age and DCIS tumor size and adjusting for diagnosis in 2000 or later, provides refined estimates of 10-yr LR risk after BCS alone for DCIS. This integration enhances prognostic LR risk estimates and frequently provides lower risk estimates with which to guide individualized treatment decisions. Distribution of 10-year risk of local recurrence using DCIS Score (DS), tumor size, and age, adjusting for diagnosis in 2000 or later. Low DS (&amp;lt;39)Inter DS (39-54)High DS (≥55)Tumor Size(cm)Age(Yr)NMedian (Min-Max)%NMedian (Min-Max)%NMedian (Min-Max)%≤1≥50457.0 (5.3-10)810.8 (10.2-11.8)1015.1 (12.9-18.6) &amp;lt;50810.3 (7.4-12.1)414.9 (14.1-15.4)0 &amp;gt;1-2.5≥50249.5 (7.3-12.6)914.2 (12.9-15.6)519.6 (16.5-20.4) &amp;lt; 50216.4 (16.1-16.7)220.4 (19.8-21.1)122.2 (22.2-22.2)&amp;gt;2.5≥50515.7 (14.9-23.7)0 138.4 (38.4-38.4) &amp;lt;500 141.2 (41.2-41.2)149.3 (49.3-49.3) Citation Format: Manders JB, Solin LJ, Leonard CE, Mamounas EP, Lu R, Turner M, Baehner FL, White J. Refined estimates of local recurrence risk in a clinical utility study: Integrating the DCIS score, patient age and DCIS tumor size [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 P4-15-09.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies

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

Comparison of predictive models for local recurrence of DCIS after breast conserving surgery.

21 Background: Efforts have been made to identify women for whom radiotherapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in-situ (DCIS) can be omitted. These include development of the Memorial Sloan-Kettering (MSK) nomogram, the Van Nuys Prognostic Index (VNPI), and the DCIS Score. We assessed correlation of the predictive qualities of these 3 approaches to determine risk of local recurrence (LR) and need for RT. Methods: We calculated VNPI score and used the MSK nomogram to determine LR risks for 48 women on whom DCIS Scores were available since January 2012. Given that the DCIS Score does not account for HT, MSK risks were calculated with and without its use. 10-year LR risks from DCIS Score reports were compared with MSK nomogram estimates using the Pearson correlation coefficient. These comparisons were done for MSK LR risks with and without HT. VNPI scores yield low, intermediate and high risk categories. To compare the 3 predictive models, each patient was assigned an RT recommendation per instrument. Two 10-year LR risk “thresholds” to recommend RT were used - 10 and 15% - to account for M.D. preference. Results: For LR risk, the MSK nomogram (excluding HT) and the DCIS Score showed weak positive correlation (R = 0.346, p &lt; 0.02), weaker when including HT (R = 0.179, p: 0.224). VNPI Score could not be calculated on 5 patients and they were excluded in comparisons involving VNPI. DCIS Score, using 15% LR risk as the RT recommendation threshold, and VNPI RT recommendations correlated in 72.1% of cases. Lowering the threshold to10% reduced the correlation to 32.6%. Comparison of the 3 approaches’ RT recommendations with a 15% threshold showed agreement in 65.1% (28/43) of cases, and a 10% threshold reduced the agreement to 18.6% (8/43). Conclusions: Our analysis shows some correlation between the MSK nomogram and the DCIS Score, more when HT is excluded. Lowering the threshold 10-year LR risk to recommend RT from 15 to 10% reduced agreement among the 3 instruments.

Is a higher boost dose of radiation necessary after breast-conserving therapy for patients with breast cancer with final close or positive margins?

To determine rates of loco-regional recurrence (LRR), distant failure and overall survival for patients with breast cancer treated with breast-conserving therapy (BCT) with a close or positive surgical margin (C/PM) treated with standard dose boost radiation compared with a higher boost of radiation. We retrospectively studied 1476 patients with T1-T3 invasive breast cancer treated with BCT between 1992 and 2009. Median age was 57years. Patients were divided into three groups: Group I included 1197 patients (81%) with negative margins who received a standard boost (median 60Gy) total dose to the lumpectomy cavity; Group II included 116 patients (8%) with C/PM who received a standard boost (median 60Gy); and Group III included 163 patients (11%) with C/PM who received a higher boost (median 68Gy). Biological subtypes (e.g., ER, PR, HER2/neu) were available for 858 patients (58%) and were also assessed for any relationship to LRR rate. The Kaplan-Meier, Cox-regression, and log-rank tests were used to estimate rates of LRR and the significance of risk factors. Median follow-up was 8.6years. The overall 5- and 10-year cumulative incidences of LRR were 2.1% (95% CI 0.8-2.1%) and 4.5% (95%CI 3.4-6.0%), respectively. The 5- and 10-year cumulative incidences of LRR for Group I (negative margins+standard boost) were 1.9 and 4.4%; for Group II (C/PM+standard boost) were 3.9 and 7.0%; and for Group III (C/PM+higher boost) were 2.9 and 3.8%, respectively. No statistically significant differences in LRR rates were found among the three groups (p=0.4). Similar results were obtained for distant failure (p=0.3) and overall survival (p=0.4). On multivariate analysis, tumor grade (p=0.03), systemic-therapy (p=0.005), node positivity (p=0.05), young age (p=0.001), and biological subtype (p=0.04) were statistically significantly associated with higher LRR. Higher boost dose and margin positivity were not significant. Our data suggest that the 10-year risk of local recurrence for patients with close or positive margins receiving a standard boost was 7% compared to 3.8% for those receiving a higher boost; however, this difference was not significant. A higher boost dose did not significantly improve local control, nor did margins impact LRR risk in our cohort of patients.

Ductal Carcinoma In Situ: A Rose by Any Other Name

Ductal Carcinoma In Situ: A Rose by Any Other Name

Selecting Individualized Treatment for Patients With Ductal Carcinoma in Situ of the Breast: The Search Continues

Selecting Individualized Treatment for Patients With Ductal Carcinoma in Situ of the Breast: The Search Continues

Breast Conservation Treatment With Radiation: An Ongoing Success Story

Breast Conservation Treatment With Radiation: An Ongoing Success Story