Oncotype DX Ductal Carcinoma In Situ Research Articles

Can Molecular Biomarkers Help Reduce the Overtreatment of DCIS?

Ductal carcinoma in situ (DCIS), especially in the era of mammographic screening, is a commonly diagnosed breast tumor. Despite the low breast cancer mortality risk, management with breast conserving surgery (BCS) and radiotherapy (RT) is the prevailing treatment approach in order to reduce the risk of local recurrence (LR), including invasive LR, which carries a subsequent risk of breast cancer mortality. However, reliable and accurate individual risk prediction remains elusive and RT continues to be standardly recommended for most women with DCIS. Three molecular biomarkers have been studied to better estimate LR risk after BCS-Oncotype DX DCIS score, DCISionRT Decision Score and its associated Residual Risk subtypes, and Oncotype 21-gene Recurrence Score. All these molecular biomarkers represent important efforts towards improving predicted risk of LR after BCS. To prove clinical utility, these biomarkers require careful predictive modeling with calibration and external validation, and evidence of benefit to patients; on this front, further research is needed. Most trials do not incorporate molecular biomarkers in evaluating de-escalation of therapy for DCIS; however, one-the Prospective Evaluation of Breast-Conserving Surgery Alone in Low-Risk DCIS (ELISA) trial-incorporates the Oncotype DX DCIS score in defining a low-risk population and is an important next step in this line of research.

Molecular Signatures in Ductal Carcinoma In Situ (DCIS): A Systematic Review and Meta-Analysis

Adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is debated as benefits are inconstant. Molecular signatures for DCIS have been developed to stratify the risk of local recurrence (LR) and therefore guide the decision of RT. To evaluate, in women with DCIS treated by BCS, the impact of adjuvant RT on LR according to the molecular signature risk stratification. We conducted a systematic review and meta-analysis of five articles including women with DCIS treated by BCS and with a molecular assay performed to stratify the risk, comparing the effect of BCS and RT versus BCS alone on LR including ipsilateral invasive (InvBE) and total breast events (TotBE). The meta-analysis included 3478 women and evaluated two molecular signatures: Oncotype Dx DCIS (prognostic of LR), and DCISionRT (prognostic of LR and predictive of RT benefit). For DCISionRT, in the high-risk group, the pooled hazard ratio of BCS + RT versus BCS was 0.39 (95%CI 0.20-0.77) for InvBE and 0.34 (95%CI 0.22-0.52) for TotBE. In the low-risk group, the pooled hazard ratio of BCS + RT versus BCS was significant for TotBE at 0.62 (95%CI 0.39-0.99); however, it was not significant for InvBE (HR = 0.58 (95%CI 0.25-1.32)), Discussion: Molecular signatures are able to discriminate high- and low-risk women, high-risk ones having a significant benefit of RT in the reduction of invasive and in situ local recurrences, while in low-risk ones RT did not have a benefit for preventing invasive breast recurrence. The risk prediction of molecular signatures is independent of other risk stratification tools developed in DCIS, and have a tendency toward RT de-escalation. Further studies are needed to assess the impact on mortality.

Tumour-infiltrating lymphocytes in ductal carcinoma in situ (DCIS)-assessment with three different methodologies and correlation with Oncotype DX DCIS Score.

Tumour-infiltrating lymphocytes (TILs) are prognostic in invasive breast cancer; however, their prognostic significance in ductal carcinoma in situ (DCIS) has not been established. The Oncotype DX (ODX) Breast DCIS Score test is a genomic assay used to predict the local recurrence risk. The aims of this study were to quantify TILs in DCIS by the use of three methodologies, and correlate them with the ODX DCIS Score. We studied 97 DCIS cases, all with an ODX DCIS Score. Cases with a low ODX DCIS Score were considered as one group, and those with an intermediate/high ODX Score were considered together. TILs were quantified on haematoxylin and eosin-stained slides. The methodologies used to quantify TILS included assessment of stromal TILs, assessment of touching TILs, and assessment of circumferential TILS. In cases with >5% stromal TILS, the percentage of stromal TILS was considered to be high. In cases with a mean number of more than five touching TILs per DCIS duct, TILs were considered to be present. The ODX DCIS Score was intermediate/high in 27 (28%) cases and low in 70 (72%) cases. There were >5% stromal TILs in 33 (34%) cases, and more than five touching TILs per DCIS duct in 15 (15%) cases; circumferential TILs were present in nine (9%) cases. In univariate analysis, a low ODX DCIS Score showed significant associations with absent touching TILS (P=0.027), stromal TILs<5% (P=0.031), and absent circumferential TILs (P=0.002). In logistic regression analysis adjusted for necrosis and nuclear grade, touching TILs and circumferential TILs showed significant associations with the ODX DCIS Score, whereas stromal TILs did not. Our results suggest that both the presence of TILs and the spatial arrangement of TILs or close proximity of TILs to DCIS, and TILs touching or encircling DCIS, may be predictive of recurrence.

Abstract P6-10-20: Ductal carcinoma in situ (DCIS) of the breast: miRNA deregulation correlates with the Oncotype DX risk score

Abstract Background: Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor of invasive breast cancer (IBC). It is estimated that 5-14% of women diagnosed with DCIS experience an ipsilateral IBC. Current clinical criteria do not discriminate well between women with DCIS who will and those who will not develop ipsilateral IBC or a DCIS recurrence. The Oncotype DX DCIS assay (12 genes) was derived from a multigene expression array (Oncotype DX, 21 genes), and includes 5 proliferation genes, PGR, GSTM1, and 5 reference genes. This assay has been shown to predict risk of subsequent ipsilateral IBC and DCIS, and is used by clinicians to evaluate both the risk of local recurrence and need for radiation therapy. Since abnormal expression of microRNAs (miRNAs) is thought to contribute to the development of IBC, and that very few studies have evaluated miRNA expression deregulation in DCIS lesions, we sought to determine if specific miRNA expression changes may help identify DCIS lesions with different Oncotype DX DCIS scores. Methods: For this study, we selected archived specimens from 52 women diagnosed with DCIS between 2012 and 2018, whose DCIS lesions were tested with the Oncotype DX DCIS assay (low (n=35), intermediate (n=11), high (n=6) risk scores). Total RNA was extracted by macrodissection of the DCIS lesions. MiRNA expression differences between DCIS lesions were evaluated using small-RNA next-generation sequencing. Quantitative PCR validations were performed using Taqman miRNA assays on the top 15 differentially expressed miRNAs Results: Small-RNA expression data obtained by next-generation sequencing of 43 DCIS RNA specimens identified miRNAs differentially expressed between the risk score groups. Fifteen differentially expressed miRNAs were selected for their association based on Oncotype DX DCIS score differences (miR-142-3p, miR-142-5p, miR-744, miR-155, miR-30c, miR-150, miR-146a, miR-190b, miR-135b, miR-193b) or on age of the patients (miR-19b, miR-19a, miR-135a, miR-132). QPCR validation of these 15 miRNAs, using RNA from 30 DCIS lesions with known Oncotypes DX DCIS scores, of which 21 were samples that had been sequenced (low (n=8), intermediate (n=9), and high (n=4)), and 9 were not sequenced (low (n=7), intermediate (n=1), high (n=1)) and identified 5 miRNAs (miR-135a (p=&amp;lt;0.05), miR-190b (p=0.043), miR-205 (p=&amp;lt;0.001), miR-30c (p=&amp;lt;0.01), miR-744 (p=&amp;lt;0.038)) that emerged for their association with the score groups. These 5 miRNAs provided a good discrimination tool between low and intermediate-high score samples. A composite score including these 5 miRNAs showed a highly significant association with the Oncotype DX DCIS Score (p=&amp;lt;0.001). Conclusions: Our analyses identified a subset of 5 miRNAs that is significantly associated with the Oncotype DX DCIS score of DCIS lesions. Interestingly, three of these miRNAs (miR-205, miR-744 and miR-135b) have been reported to regulate proliferation pathways, while the other two (miR-30c, and miR-190b) have been associated with estrogen expression pathways in breast cancer cells. Importantly, increased expression of miR-30c in IBC has been associated with benefit from endocrine therapy while increased expression of miR-205 has been associated with benefit from tyrosine kinase inhibitors in IBC, as well. Mir-205 has also been reported as a radiosensitizer in breast cancer cells. Altogether, our data suggest that evaluation of miRNA expression levels may add predictive and prognostic value to the diagnosis of DCIS. Citation Format: Olivier Loudig, Iddo Ben-Dov, Christina Liu, Miglena Komforti, Susan Fineberg. Ductal carcinoma in situ (DCIS) of the breast: miRNA deregulation correlates with the Oncotype DX risk score [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 P6-10-20.

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.

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 P5-18-12: Effectiveness of Oncotype DX DCIS scoring in a community setting

Abstract The Oncotype DX DCIS Score was developed to assist in determining a low risk for recurrence subgroup of patients who can avoid radiation therapy following breast conserving surgery. We sought to evaluate our experience using the Oncotype DX DCIS Score and to see if a greater number of patients who did not receive radiation therapy were experiencing a local recurrence than the score predicted. Between February 23, 2011 and November 29, 2017, 145 women were diagnosed with ductal carcinoma in situ (DCIS) without an invasive component. 126 (87%) underwent breast conserving surgery. Thirty-five underwent Oncotype DX DCIS Score, of whom 26 (74%) were low risk, four were intermediate risk (11%), and five were high risk (14%). The scores ranged from 0 (7 patients) to 100 (1 patient). Of the 26 patients with low risk scores, one chose to undergo mastectomy, three received radiation therapy, 20 chose observation without radiation therapy, and two patients were unknown because they had no further treatment or follow-up at our facility. Two of the four intermediate risk patients underwent radiation therapy and two did not. Four of the five high risk patients underwent radiation therapy, but one did not. Twenty-two of the 35 patients who underwent Oncotype DX Score met the criteria for size (based on grade) and margins (at least 3 mm). Ten patients had margins that were less than 3 mm but met the size criteria. Two patients did not meet the size criteria but had at least 3 mm margins. One patient did not meet either the size or margin criteria. None of our 20 patients with low risk Oncotype DX DCIS Score and who met both the size and margin criteria recurred. With the median follow-up of approximately 2-1/2 years, three of the 21 patients (14%) with low or intermediate risk scores who underwent Oncotype DX DCIS Score and did not receive radiation therapy suffered a local recurrence. The predicted average recurrence risk for these patients based on their Oncotype DX DCIS Score was 12%. Two of these patients who recurred had margins less than 3 mm, and one patient met the size and margin criteria, but had an intermediate risk score. By comparison, five of 61 (8%) of patients who underwent breast conserving surgery and adjuvant radiation therapy had a local recurrence. Twenty of the 23 (87%) low risk Oncotype DX DCIS Score patients did not receive radiation therapy and overall 20/35 (57%) of the patients undergoing Oncotype DX DCIS Score did not receive radiation therapy. Although the follow-up is still relatively short, Oncotype DX DCIS Score allows a considerable number of women to avoid adjuvant radiation therapy. Citation Format: Wheeler JA, Vaghefi H, Liu F, Owens V, Morris L, Denham F, Coody L. Effectiveness of Oncotype DX DCIS scoring in a community setting [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 P5-18-12.

Abstract PD7-03: Cost-effectiveness analysis of intraoperative radiotherapy for ductal carcinoma in situ

Abstract Background Whole breast radiation therapy (WBRT) following lumpectomy for ductal carcinoma in situ (DCIS) is standard of care, however, the risk of local recurrence with and without radiation ranges as low as 0.9% vs. 6.7% over 7 years. Intraoperative radiotherapy (IORT) is a potential alternative with advantages of decreased toxicity to adjacent organs, convenience, and improved quality of life. While prospective trials of IORT for DCIS are ongoing, the objective of this study was to estimate the cost-effectiveness of IORT vs. WBRT vs. no radiation for DCIS. Methods We developed a Markov model using TreeAge Pro 2016 to evaluate the cost-effectiveness of WBRT, IORT, and no radiation in patients with DCIS following lumpectomy. Health states included disease free, local recurrence (ipsilateral DCIS or invasive cancer), distant recurrence or death due to breast cancer, and death due to non-breast cancer causes. A 10-year time horizon and societal perspective were used. Model input parameters were derived from the literature. Costs reflected 2016 Medicare rates. The primary endpoint was incremental cost-effectiveness ratio (ICER), defined as the difference in cost, divided by the difference in quality-adjusted life years (QALYs) of two interventions. We performed analyses of subgroups defined according to DCIS risk (histologic grade, Oncotype Dx® DCIS recurrence score, low risk per RTOG 9804 criteria) and endocrine therapy use (none, tamoxifen, aromatase inhibitor). Sensitivity analyses explored uncertainty in the model. Results IORT was the most cost-effective strategy, with an increase of 0.18 QALYs at an incremental cost of $4,728, corresponding to an ICER of $26,943/QALY when compared with no radiation therapy. WBRT resulted in an increase in 0.18 QALYs at an incremental cost of $6859, corresponding to an ICER of $39,085/QALY. For both strategies, the ICERs did not exceed the willingness to pay (WTP) threshold of $100,000. IORT remained the most cost-effective strategy across DCIS risk groups, but was more cost-effective in higher risk patients, as demonstrated by lower ICERs. In low risk DCIS defined by RTOG 9804 criteria, no radiation was most cost-effective. The ICERs for IORT and WBRT, $152,753 and $208,204/QALY, respectively, exceeded the WTP threshold. IORT remained cost-effective in the setting of endocrine therapy use. Incremental Cost-Effectiveness Ratios (ICER) for each radiation strategy for the base case and scenario analyses ICER ($/QALY) No RTIORTWBRTBase Case Analysis 26,94339,085 Scenario Analysis by DCIS Risk GroupHistologic Grade - Low 36,81152,219- High 25,64337,137 Oncotype Dx DCIS Score - Low 92,892126,398- High 32,00345,690 Low Risk DCIS 152,753208,204 Scenario Analysis by Endocrine TherapyNo Tamoxifen 23,38734,373Tamoxifen 47,81166,616 Tamoxifen 31,96146,272Aromatase Inhibitor 41,31658,674 Conclusion IORT was the most cost-effective radiation strategy for DCIS compared to WBRT and no radiation. This applied to all subgroups with the exception of low-risk DCIS defined by RTOG 9804 criteria for whom no radiation was the most cost-effective strategy. These findings provide support for ongoing studies examining the role of IORT for DCIS with high-risk features, as well as alternative treatment strategies for low-risk DCIS. Citation Format: Onishi M, Connolly EP, Wright JD, Vasan S, Gross T, Tsai W-Y, Chen L, Neugut AI, Accordino MK, Kalinsky K, Crew KD, Hershman DL. Cost-effectiveness analysis of intraoperative radiotherapy for ductal carcinoma in situ [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 PD7-03.

Patient Experiences and Clinician Views on the Role of Radiation Therapy for Ductal Carcinoma In Situ

To evaluate patient experiences with decisions regarding radiation therapy (RT) for ductal carcinoma in situ (DCIS), and to assess clinician views on the role of RT for DCIS with favorable features in the present era. A sample of women with newly diagnosed breast cancer from the population-based Georgia and Los Angeles County Surveillance, Epidemiology, and End Results (SEER) registries were sent surveys approximately 2months after undergoing breast-conserving surgery (BCS), with a 70% response rate. The analytic sample was limited to 538 respondents with unilateral DCIS. We also surveyed 761 surgeons and radiation oncologists treating breast cancer in those regions, of whom, 539 responded (71%). After BCS, 23% of patients omitted RT, with twice the rate of omission in Los Angeles County relative to Georgia (31% vs 16%; P<.001). The most common reasons for omitting RT were advice from a clinician that it was not needed (62%) and concern about side effects (24%). Cost and transportation were not reported as influential considerations. After covariate adjustment, low- and intermediate-grade disease (odds ratio [OR] 5.5, 95% confidence interval [CI] 2.5-12; and OR 3.2, 95% CI 1.7-6.1, respectively) and Los Angeles County SEER site (OR 4.3, 95% CI 2.3-8.2) were significantly associated with greater RT omission. Of the responding clinicians, 62% would discuss RT omission for a patient with DCIS with favorable features. Clinicians in Los Angeles County were more likely to discuss RT omission than were those in Georgia (67% vs 56%; P=.01). Approximately one third of clinicians would obtain the Oncotype DX DCIS score. The heterogeneity in RT omission after BCS for DCIS continues to be substantial, with systematic differences in provider opinions across the 2 regions we studied. Enhanced precision of recurrence estimates, guidance from professional organizations, and better communication are needed to improve the consistency of treatment in this controversial area.

Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions.

Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging.

Multigene Expression Assay and Benefit of Radiotherapy After Breast Conservation in Ductal Carcinoma in Situ.

Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994-2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score-adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

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.

Concordance of Van-Nuys Prognostic Index, Memorial Sloan Kettering Breast Cancer nomogram and Oncotype Dx DCIS scores in prediction of ductal carcinoma in situ(DCIS) recurrence risk.

56 Background: Ductal Carcinoma in situ (DCIS) has a wide spectrum of bioagressiveness. Three models used to assess recurrence risk (RR) of DCIS include: the Van-Nuys Prognostic Index (VN), Memorial Sloan Kettering Breast Cancer Nomogram (MN) and Oncotype Dx DCIS Score (OD; Genomic Health, Redwood City, CA). The aim of our study was to evaluate the concordance between these RR models. Methods: An IRB-approved retrospective chart review was performed on 37 consecutive patients at our institution with DCIS from 12/2011-4/2015 who underwent breast conservation surgery and in whom an OD was obtained. The OD and ‘any recurrent event at 10-years’ scores were used to stratify patients into low risk (LR; OD DCIS score &lt;39/&lt;17%), intermediate risk (IR; 39-54/17-24%) and high risk (HR; &gt;54/&gt;24%), as outlined in the original OD study. The ‘10-year RR’ scores from MN were stratified using the same percentile breakdown as OD. The VN were stratified into LR (4-6), IR (7-9) and HR (&gt;9) groups based on the updated VN study’s guideline. Pathologic slides were re-reviewed by one pathologist blinded to OD score to determine size and margin width based on the protocol outlined in the original VN paper. The three scores for each patient were compared. Results: Eleven patients (29.7%) had concordance between all three scores and all were LR. In 10.8% of patients, there was no concordance between the three scores. The concordance between the OD and VN, OD and MN, and VN and MN was 64.9%, 48.6% and 35.1%, respectively. Conclusions: In evaluating RR, determining LR may have the greatest implication since this group may be the least likely to benefit from adjuvant radiotherapy. Concordance between all three models was seen only in LR patients. All patients who were LR by VN were also LR by OD and MN. Determining a VN initially may help guide additional testing. The added value of OD may be primarily in patients who are not LR by VN. The MN seems to be of limited value in this study. Larger studies assessing these relationships and their outcomes in predicting potential RR in DCIS are warranted.

A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone

Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX® DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 Cp units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3464-6) contains supplementary material, which is available to authorized users.

Is Wide Excision Alone an Appropriate Therapy for DCIS?

With the widespread use of screening mammography, the number of ductal carcinoma in situ (DCIS) cases has increased dramatically. Current treatment includes wide local excision (WLE) and adjuvant radiation therapy (RT). The benefit of RT in decreasing local recurrence was established based on the results of four randomized trials and a subsequent meta-analysis. However, RT has a number of side effects and no demonstrated survival benefit in women with in situ breast cancer. This review explores the current literature on the management of DCIS with WLE alone. Although there is insufficient evidence to identify truly low-risk DCIS based on histopathological and immunohistochemical factors, emerging data appear promising in understanding the biological behavior of DCIS. In particular, the Oncotype DX DCIS Score, a multigene assay, predicts local recurrence in women treated with WLE. Risk stratification of DCIS to guide treatment decisions remains elusive, but one of great importance in tailoring therapies to the biology of this heterogeneous disease.

E08. Highlights in benign and pre-invasive breast disease

E08. Highlights in benign and pre-invasive breast disease

Risk of recurrence of ductal carcinoma in situ by oncotype Dx technology: Some concerns

Predicting which patients with ductal carcinoma in situ (DCIS) will develop local disease recurrence: we have been trying to do that for 30 years. But now we can. The Holy Grail has been recovered in the form of Oncotype Dx, or so we have been told.1 A single genetic test capable of identifying the risk of local disease recurrence after breast conservation in patients with mammographically detected DCIS would obviate the need to factor in DCIS grade, size, and margin width, and patient age. The Oncotype Dx DCIS gene signature assay was validated in a registration trial2 that strictly defined a permissible size of ≤25 mm for low-to-intermediate grade tumors and ≤10 mm for high-grade tumors and those with margin widths of ≥3 mm. Unfortunately, most medical oncologists ordering the Oncotype Dx DCIS assay do not appreciate the limitations of the validated results. They order the $4000 test for patients with DCIS of all sizes and all margin widths. The test, if valid, is only valid if the strict protocol required of the Eastern Cooperative Oncology Group (ECOG) E5194 trial is adhered to. A transected DCIS is likely to recur in spite of a low score on the Oncotype Dx assay. A recent example of a 46-year-old woman with a low-risk Oncotype Dx score had 42 mm of disease and 3-mm margins. Her DCIS grade was intermediate with focal necrosis. A Van Nuys Prognostic Index calculation3 results in a total score of 9 (grade score of 2, size score of 3, margin score of 2, and age score of 2). Oncotype Dx provided a 10-year risk of disease recurrence of 15%, whereas the University of Southern California/Van Nuys Prognostic Index projects a local recurrence risk of 40% to 50% without irradiation. The Oncotype Dx assay is in essence a grading system based on gene expression, and is comparable to histologic grading of DCIS. Because it does not factor in a variety of important predictive factors such as age, margin width, extent of DCIS, nuclear grade, and necrosis, it is not likely to be accurate for the majority of patients. No single test, especially one in which other prognostic factors are ignored, can validly estimate the risk of local recurrence among patients with DCIS. The authors made no disclosures. Michael D. Lagios, MD1 Melvin J. Silverstein, MD2 1The Breast Cancer Consultation Service, Tiburon, California 2Department of Breast Surgery, Hoag Memorial Hospital Presbyterian, Newport Beach, California

Ductal Carcinoma In Situ: A Rose by Any Other Name

Ductal Carcinoma In Situ: A Rose by Any Other Name