High Recurrence Score Research Articles

Impact of 21-Gene Recurrence Score on Chemotherapy Decision in Invasive Ductal Carcinoma of Breast with Nodal Micrometastases.

PurposeThe purpose of this study was to investigate the effect of 21-gene recurrence score (RS) on predicting prognosis and chemotherapy decision in node micrometastases (N1mi) breast invasive ductal carcinoma (IDC).MethodsPatients with stage T1-2N1mi and estrogen receptor-positive IDC diagnosed between 2004 and 2015 were included. The associations of 21-gene RS with breast cancer-specific survival (BCSS), chemotherapy decision, and benefit of chemotherapy were analyzed.ResultsWe identified 4,758 patients including 1,403 patients (29.5%) treated with adjuvant chemotherapy. In the traditional RS cutoffs, 2,831 (59.5%), 1,634 (34.3%), and 293 (6.2%) patients were in the low-, intermediate-, and high-risk RS groups, respectively. In 3,853 patients with human epidermal growth factor receptor-2 (HER2) status available, most patients were HER2-negative disease (98.3%). A higher RS was independently related to chemotherapy receipt, and 14.0%, 47.7%, and 77.8% of patients in the low-, intermediate-, and high-risk RS groups received chemotherapy, respectively. The multivariate analysis indicated that a higher RS was related to worse BCSS (p < 0.001). The 5-year BCSS rates were 99.3%, 97.4%, and 91.9% in patients with low-, intermediate-, and high-risk RS groups, respectively (p < 0.001). However, chemotherapy receipt did not correlate with better BCSS in low-, intermediate-, or high-risk RS groups. There were similar trends using Trial Assigning Individualized Options for Treatment RS cutoffs.ConclusionThe 21-gene RS does predict outcome and impact on chemotherapy decision of N1mi breast IDC. Large cohort and long-term outcomes studies are needed to identify the effects of chemotherapy in N1mi patients by different 21-gene RS groups.

Abstract P3-01-06: Correlation of disseminated or circulating tumor cells with the OncotypeDX recurrence score

Abstract Background: New biomarkers continue to emerge to predict the risk of recurrence in women with early stage breast cancer. A high OncotypeDX Recurrence Score (RS)® has been found to be associated with worse disease-free and overall survival in patients with early stage breast cancer. Similarly, circulating tumor cells (CTCs, blood) and disseminated tumor cells (DTCs, bone marrow) have prognostic value in patients with breast cancer. We sought to evaluate the association between high RS and CTCs and DTCs. Methods: We evaluated patients with hormone receptor positive, HER2 negative, node-negative invasive breast cancer from a prospective database from 1/2005 to 1/2017. RS was classified based on the new TAILORx study cutoff points as low (&amp;lt;11), intermediate (11-25), and high (&amp;gt;25). CTCs were assessed using CellSearch. For DTCs cytospin specimens of bone marrow aspirates, enriched for epithelial cells by density gradient separation, were immunostained using a pancytokeratin cocktail of antibodies, including AE1/AE3, CAM5.2, MNF116, cytokeratin 8 (CK8), and CK18. CTCs and DTCs were considered to be positive if one or more CTCs or DTCs were identified, respectively. Chi square analyses were utilized to evaluate for a relationship between OncotypeDX RS and CTCs or DTCs. Statistical analyses were performed in SPSS version 24 with p value &amp;lt;0.05 considered significant. Results: Two hundred and thirty patients meeting the above criteria were identified from a prospective database, of which 106 had OncotypeDX testing results. Of the patients with available OncotypeDX data, 93 patients had CTC results and 60 patients had DTC results. CTCs were detected in the blood of 18/93 (19.4%) patients, while DTCs were detected in the bone marrow of 20/60 (33.3%) patients. Patients with high RS were not more likely to have CTCs as compared with patients who had low or intermediate RS (16.7% vs 19.8%, p=0.801). Similarly, high RS was not associated with the detection of DTCs, with DTCs present in 44.4% of patients with high RS, compared with 31.4% of patients with low or intermediate RS (p=0.443). In the subgroup of patients ≤50 years of age no associations were found between high RS and CTCs (p=0.720) or DTCs (p=0.151). Conclusions: High OncotypeDX RS did not correlate with CTCs in the blood or DTCs in the bone marrow in our study. Citation Format: Tevis SE, Hall C, Meas S, Hwang R, Lucci A. Correlation of disseminated or circulating tumor cells with the OncotypeDX recurrence score [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 P3-01-06.

Abstract P3-12-23: Utilization and survival benefit of radiation therapy among hormone receptor positive breast cancer patients with recurrence score from Oncotype DX testing

Abstract Background: Radiation therapy (RT) improves survival of breast cancer (BC) patients receiving the lumpectomy. Oncotype DX, a 21-gene Recurrence Score (RS) assay, has been validated to predict the risk of recurrence and chemotherapy benefit for hormone receptor positive (HR+) BC without metastatic lymph nodes (PN0). With increasing use of Oncotype DX, it is unclear if the utilization and survival benefit of RT vary by RS in clinical practice. This study aimed to 1) examine if the RS from Oncotype DX testing influences RT utilization among HR+ BC patients with PN0 who received lumpectomy; and 2) investigate if RT is associated with better cause-specific survival (CSS) and overall survival (OS) among patients stratified by the low, intermediate, and high RS. Methods: Data from Genomic Health Inc., the sole Oncotype DX testing provider in the U.S., was linked with routinely collected data from 17 SEER registries. Women who were diagnosed with PN0 and HR+ BC in 2004-2015, received the lumpectomy, and had RS from Oncotype DX testing were included. Patients who had multiple tumors, received RT before or within surgery, or had less than 2 months follow-up were excluded. Patients diagnosed in 2004-2014 and followed through the end of 2015 were included in the survival analysis. RS was categorized into low (&amp;lt;18), intermediate (18-30), and high (&amp;gt;30). RT was categorized into yes, no or unknown. Multivariable logistic regression was applied to examine the association between RS and RT utilization. To compare survival differences, patients receiving RT and patients having no or unknown RT were matched on propensity score, which was calculated based on diagnosis year, age, race, marital status, tumor size, grade, number of lymph nodes examined, chemotherapy, and participating state. Stratified Cox proportional hazards models were used to compare CSS and OS between two matched groups. Proportional hazard assumption was evaluated. Results: Out of 48,615 patients, 56.8% had low, 36.1% had intermediate, and 7.1% had high RS; 84.5% received RT (86.6%, 82.8%, and 76.4% in low, intermediate, and high RS patients, respectively; P &amp;lt; 0.0001). After adjusting for covariates, patients with intermediate (odds ratio [OR] 0.75; 95% CI 0.71-0.79; P &amp;lt; 0.0001) and high RS (OR 0.53; 95% CI 0.47-0.59; P &amp;lt; 0.0001) were less likely to receive RT than patients with low RS. Among patients with low or intermediate RS, having no or unknown RT was associated with worse CSS (low RS: hazard ratio [HR] 6.00, 95% CI 1.77-20.37, P = 0.004; intermediate RS: HR 2.12, 95% CI 1.19-3.77, P = 0.01) and OS (low RS: HR 2.29, 95% CI 1.56-3.35, P &amp;lt; 0.0001; intermediate RS: HR 2.22, 95% CI: 1.54-3.21, P &amp;lt; 0.0001). RT utilization was not significantly associated with CSS or OS among patients with high RS. Conclusions: Among HR+, PN0 BC patients receiving the lumpectomy, lower RS was associated with higher RT utilization. RT was associated with better CSS and OS among patients with low or intermediate RS. Among patients with high RS, no association between RT and survival was observed. Citation Format: Zhang L, Hsieh M-C, Petkov VI, Wu X-C, Yu Q. Utilization and survival benefit of radiation therapy among hormone receptor positive breast cancer patients with recurrence score from Oncotype DX testing [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 P3-12-23.

Abstract P1-08-14: Trend of utilization of Oncotype DX testing among female hormone receptor positive breast cancer patients in 17 SEER registries, 2004-2015

Abstract Background: Oncotype DX, a 21-gene Recurrence Score (RS) assay, has been validated as assay that effectively predicts recurrence and chemotherapy (chemo) benefits for hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC). Although guidelines recommend the test to lymph node (LN) negative (PN0) BC patients, it has also been used in patients with 1-3 positive LN (PN1) in clinical practice. The study aimed to 1) examine the trend of utilization of Oncotype DX testing for HR+ and PN0 or PN1 BC patients from 2004 to 2015, as well as the trend in patients with different clinical risk; 2) investigate the trend of having reported chemo in patients with low, intermediate, and high RS; and 3) compare cause-specific survival (CSS) and overall survival (OS) between patients who had test and those who did not. Methods: Data from Genomic Health Inc., the sole Oncotype DX testing provider in the U.S., was linked with routinely collected data from 17 SEER registries. Women who received surgery for stage I-III, HR+ and PN0 or PN1 BC diagnosed in 2004-2015 were included. The Cochrane-Armitage trend test was conducted for trend analysis. Using the overall sample as standard population (frequency of each age-racial group in overall sample as weight), age-race standardized percentage of test use was calculated. Since HER2 data was available only after 2010, survival analysis was restricted to HR+/HER2- patients diagnosed in 2010-2014 whose BC was the only primary tumor. Patients who used and those who did not use the test were matched on propensity score, which was calculated based on age, race, marital status, insurance, grade, tumor size, surgery type, radiation, and chemo within each diagnosis year. Stratified Cox proportional hazards model was used to compare survival between two matched groups. Proportional hazard assumption was met for each model. Results: Out of 346,380 PN0 and 103,317 PN1 patients, the percentage of using Oncotype DX test increased from 2.0% to 38.2%, and from 0.5% to 28.0% from 2004 to 2015, respectively (P-for-trend &amp;lt; 0.0001 for each). Age-race standardized percentage of test use was the highest and increased most rapidly for tumors with intermediate clinical risk (moderately differentiated or tumor size 2.1-5.0cm) among PN0 patients, but for tumors with low clinical risk (well differentiated or tumor size ≤2.0cm) among PN1 patients. From 2004 to 2015, the percentage of having reported chemo decreased in patients with low (PN0: 14.7% to 1.8%; PN1: 27.3% to 16.2%) and intermediate RS (PN0: 36.1% to 28.6%; PN1: 60.0% to 44.7%), but increased among patients with high RS (PN0: 59.0% to 75.4%; PN1: 66.7% to 74.2%). Test use was associated with better CSS (PN0: hazard ratio [HR] 2.15, 95% CI 1.73-2.67; PN1: HR 2.83, 95% CI 2.02-3.95) and OS (PN0: HR 2.05, 95% CI 1.81-2.33; PN1: HR 2.65, 95% CI 2.10-3.35). Conclusions: The use of Oncotype DX test has increased steadily among female HR+ BC patients since 2004. It reduced unnecessary chemo among patients with low or intermediates RS, and increased chemo use in patients with high RS. Among HR+/HER2- patients, those who used test had better CSS and OS than those who did not. Citation Format: Zhang L, Hsieh M-C, Petkov VI, Yu Q, Wu X-C. Trend of utilization of Oncotype DX testing among female hormone receptor positive breast cancer patients in 17 SEER registries, 2004-2015 [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 P1-08-14.

Abstract P3-08-09: The 21-gene recurrence score and chemotherapy use in triple negative breast cancer (TNBC) and HER2 positive breast cancer: A National Cancer Database study

Abstract Background The 21-gene (Oncotype DX) Recurrence Score (RS) is a multi-gene expression assay that is both prognostic and predictive of adjuvant chemotherapy (AdjCT) benefit in estrogen receptor (ER) positive/HER2 negative breast cancer (BC). Use of the RS in TNBC and HER2+ BC is not recommended by national guidelines. Using the National Cancer Database (NCDB), we sought to evaluate whether oncologists use the RS in these subtypes. Additionally, we assessed the prognostic effects of the RS in node negative patients (pts) who did or did not receive adjuvant chemotherapy. Methods Pts with TN and HER2+ BC diagnosed from 2010-2015 in the NCDB were analyzed. Pts with neoadjuvant therapy or stage IV were excluded. Cases with RS testing were classified as low (RS 0-17), intermediate (RS 18-30) or high (RS 31+). Analysis was performed using multivariable logistic regression; overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests. Results 142,330 pts were evaluable: 64,830 TNBC and 77,500 HER2+ (21,768 ER-/HER2+ and 55,732 ER+/HER2+). In these subtypes, RS was performed in 5,369 (3.8%) pts as follows: 1,479 (2.3%) TNBC, 185 (0.8%) ER-/HER2+, and 3,705 (6.6%) ER+/HER2+. Given the small ER-/HER2+ cohort, we focused on TNBC and ER+/HER2+. Within these subtypes, factors associated with RS testing included lower grade, smaller pathologic tumor size, pathologic N0 status, white race, age 60-69, and ILC or IMC histology (each p&amp;lt;0.005). Of the TNBC pts tested, the RS distribution was: low 16.3%, intermediate 13.1% and high 70.6%, while for ER+/HER2+ it was low 30.5%, intermediate 30.7% and high 38.8% (p&amp;lt;0.001). AdjCT was less frequently recommended in pts with low RS; however, this varied by tumor subtype with AdjCT recommended for 66.8% of TNBC with low RS and 37.9% of ER+/HER2+ with low RS. For intermediate RS, rates of AdjCT recommendation were 74.3% and 73.7%, and for high RS were 94.0% and 93.2% for TNBC and ER+/HER2+ respectively. In a multivariable analysis among pts with low RS, factors associated with AdjCT recommendation included younger age, larger pathologic tumor size, node positive disease, and higher grade. In AdjCT untreated TNBC, 5 yr OS did not differ for low RS (96.5%) vs intermediate RS (95.2%, p=0.82). In contrast OS was significantly worse for high RS (76.7%) than the other two groups, each p≤0.04. In AdjCT untreated ER+/HER2+, 5 yr OS was significantly better for low RS (96.7%) vs intermediate RS (92.5%, p=0.03) and vs high RS (92.1%, p=0.003), with no difference between intermediate RS vs high RS (p=0.32). Evaluating pts who did receive AdjCT, there was no significant difference in 5 yr OS for either subtype according to RS (p=0.46 and p=0.83). Interestingly, in patients with low RS, 5 yr OS was similar with or without AdjCT in both TNBC (89.5% vs 96.5%, p=0.25) and ER+/HER2+ (97.6% vs 96.7%, p=0.47). Conclusions RS testing is being conducted in a small fraction of pts with TN and HER2+ BC with lower clinical risk features. The observation that RS is prognostic for survival in AdjCT untreated patients is hypothesis generating, and suggests that further evaluation of the RS and other multigene assays in ER negative and HER2+ BC is warranted. Citation Format: Boughey JC, Hoskin TL, Cocco D, Day CN, Leon-Ferre R, Habermann EB, Goetz MP. The 21-gene recurrence score and chemotherapy use in triple negative breast cancer (TNBC) and HER2 positive breast cancer: A National Cancer Database study [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 P3-08-09.

Abstract P2-07-07: Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients

Abstract INTRODUCTION: Oncotype DX® (ODX) Assay is a valuable prognostic and predictive tool in ER+, Her2- invasive breast cancer (IBC). Initially tested and validated in lymph node (LN) negative patients, the indications of this test have been expanded to include patients with limited LN-positive disease. Several prediction systems have been developed to predict the ODX Recurrence Score (RS) with substantial performance in predicting a high vs low RS score but with low performance when predicting the 3 classes that compose the standard ODX. Additionally, many of these prediction systems have not been developed and/or tested for a population of LN+ patients. OBJECTIVES: The primary objective of this study was to evaluate the performance of several previously published ODX RS predictive systems in a population of LN+ patients. Furthermore, we developed a machine-learning based classification system to accurately predict the ODX 3 category RS for this specific population. METHODS: We conducted a retrospective search of Stanford's pathology database for all patients with LN+ IBC diagnosed between January 2013 and December 2017 with an ODX RS available. A total of 119 patients were identified for inclusion in this cohort. Our multivariate pathologic feature-based discriminatory model aimed to classify each case as belonging to the low, intermediate or high ODX RS category. We performed model validation by the 10-fold cross validation (10F-CV) method. The model's performance was assessed by comparing simple accuracy, balanced accuracy, F1 score (harmonic average of the precision and recall) and several concordance classification metrics. RESULTS: Of the evaluated methods, Magee equations performed well in this population of LN+ patients with the modified Magee equation 2 displaying the best accuracy (70.9%) which was surprisingly better than originally reported (55.8%, in Klein et al. Mod Path. 2013). After an initial screen of methods and tuning of the best performing model, our model achieved an overall accuracy of 78.1% on 10F-CV with a 79.1 % balanced accuracy and no two-step discordances. This corresponded to an increase of weighted Cohen's kappa of 30% versus the best performing Magee equation in this cohort and an increase of 103% versus the modified Magee 1 equation (which uses the same features as our model except for tumor grade). DISCUSSION: Classifiers aimed at providing an alternative to Oncotype DX testing are available and perform consistently across datasets. We are currently validating our approach in a population of 1000 LN-negative patients from the MSKCC and the SEER database. Due to the substantial performance of our machine learning-based classifier based on standard reported pathologic features, our model may be considered an alternative to the ODX standard testing or a screening method for ODX testing, especially for cases with where the cost and availability of the ODX test are a concern. Citation Format: Beca F, Yang S-R, Gruber JG, Barry-Holson K, West R, Wen HY, Allison KH. Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients [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 P2-07-07.

Abstract P6-09-05: Optical Prediction of Time Interval to Metastasis (OPTIM): A rapid nondestructive optical assay applied to tissue microarray samples identifying high risk of distant recurrence in the lowest risk groups defined by the TAILORx trial

Abstract Recent reporting of the 9 year follow-up for the TAILORx trial suggests that there may be no benefit with adjuvant chemotherapy for ER +, HER2 -, N(0) breast cancer patients with a Oncotype DX® (ODX) recurrence score (RS) &amp;lt;26. Since endocrine therapy for this group of patients who comply with treatment still results in distant recurrence (rMBC) in 3% and 5% of the ODX low and ODX intermediate risk groups at 9 years, respectively, we are motivated to help find early treatments for these patients by identifying their recurrence risk at diagnosis with improved risk stratification. Methods: Optical Prediction of Time Interval to Metastasis (OPTIM), a novel assay, prognostic for rMBC, is based on an intrinsic optical signature from collagen, derived from the average of point by point ratios of forward to backward (F/B) second harmonic generation (SHG) light scatter that is sensitive to form and structure of fibrillar collagen in the extracellular matrix of archival tissue microarray samples. (Burke et al. BMC Cancer 15 (2015): 929). The 125 patients in this cohort were part of a clinical trial, looking for genomic predictors of rMBC in untreated patients, so we were able to calculate a surrogate 21-gene RT-PCR assay (S-ODX) value based on gene expression data available through NCBI GEO database (Gyorffy et al. Breast Cancer Res Treat (2012) 132:1025). We analyzed these patient's rMBC outcomes using logistic regression and Kaplan-Meier (KM) analysis. Results: OPTIM alone stratified at 2.5X relative risk (RR) between quartiles Q1 and Q4, similar to S-ODX low vs high recurrence score (RS) groups (from TAILORx Trial) with 2.8X RR. Using quartiles of OPTIM vs S-ODX together we stratify patients to recurrence risk (rMBC/at Risk), with an improved risk stratification of 5X RR in the RS&amp;lt;26 low risk groups. OPTIM Quartiles vs RS Risk Groups in TAILORx TrialS-ODX →High (RS&amp;gt;25)Intermediate (RS 11-25)Low (RS &amp;lt;11)AllOPTIM↓↓↓↓Q17/97/12*5/1019/31*Q25/95/142/812/31Q38/12***1/81/11***10/31Q46/10**2/17*0/5**8/32*All26/40***15/518/34***49/125Recurrence at 10 years by KM analysis *p&amp;lt;0.05, **p&amp;lt;0.005, ***p&amp;lt;.0005 Combining S-ODX with OPTIM, low (L) or high (H) risk by assay, shows that they are independent and complementary. Notably 68%=85/125 are classified L by S-ODX (RS&amp;lt;26) and OPTIM effectively reclassifies H and L, and when combined with S-ODX H identifies 92%=45/49 of all rMBC at 10 years without treatment. Risk stratification improves to 6.8X RR comparing highest risk HH 66.7%=12/18 to lowest risk LL 9.8%=4/41. Distant Recurrence Identified by High Risk Group of Each AssayS-ODX AssayHHLLOPTIM AssayHLHLrMBC (total=49)1214194At Risk (total n=125)18224441rMBC at 10 yrs. S-ODX RS&amp;gt;25=H, RS&amp;lt;26=L; OPTIM Q1&amp;Q2=H, Q3&amp;Q4=L Conclusion: OPTIM as an independent prognostic optical bio-marker from collagen in intact tissue. Combination of OPTIM with the Oncotype DX® assay may produce a continuous risk estimator with higher dynamic range than either assay alone and will be the focus of future study, especially in a treated population, to determine if OPTIM might also predict response to treatment. Citation Format: Hill RL, Perry SW, Salzman P, Turner BM, Hicks DG, Brown EB. Optical Prediction of Time Interval to Metastasis (OPTIM): A rapid nondestructive optical assay applied to tissue microarray samples identifying high risk of distant recurrence in the lowest risk groups defined by the TAILORx trial [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 P6-09-05.

Abstract P4-14-05: Confirmation of the TAILORx 21-gene expression trial using a real world observational database

Abstract Background: The TAILORx study (NCT00310180)(TRx) has demonstrated the efficacy of endocrine therapy alone in early stage, lymph node negative, hormone receptor positive, her2neu oncogene negative breast cancer harboring an intermediate recurrence score (RS) on a 21-gene profile (OncotypeDx), obviating the need for adjuvant chemotherapy in a large subset of women. The study randomized and followed 6711 patients (pts) and required 9 years to reach its conclusion endpoints. The availability of the electronic health record (EHR) permits automated reviews, facilitating more rapid “real world” hypothesis testing (but not a replacement for randomized clinical trials), especially when there are clear variations in common practice patterns. However physician bias in treatment selection needs to be considered. Methods: A retrospective review of the Cota Observational Cancer database, drawn from EHRs, of female pts with breast cancer who were 18 to 75 years of age; had hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer harboring an OncotypeDx RS 11-25 receiving adjuvant therapy following surgical resection of a 11-50 mm primary tumor (similar to TRx eligibility). Results: 1009 pts from 23 cancer centers (107 oncologists) were identified, 850 (84.2%) received adjuvant endocrine therapy alone (E) and 159 (15.8%) received adjuvant chemoendocrine therapy (CE) as part of standard care (no randomization). 285 pts were age &amp;lt;50 yrs (E:218, CE:67) and 601 pts has RS 16-25 (E:453, CE:148). Treatment selection was imbalanced with oncologists more likely to utilize CE in younger pts (median age E: 59 yrs, CE: 53 yrs; p&amp;lt;0.01), larger tumors (median tumor size E: 16mm, CE: 20mm; p&amp;lt;0.001) and higher RS (median RS E: 16, CE: 21; p&amp;lt;0.001). With a median follow-up for survival since diagnosis of 3.7 years, the Kaplan-Meier estimated 5 yr overall survival rates were 98.9% with E and 97.8% with CE (p=0.23); the corresponding 5-yr OS in TRx were E: 98% and C: 98.1%. With a median 1.7 years follow-up for recurrence, 19 pts have suffered a disease distant or local recurrence (E: 13, CE: 6) yielding a 5-year recurrence-free survival of E: 95.2% and CE: 91% (p=0.05); the corresponding TRx result was E: 96.9% and CE: 97%. The 5-yr invasive disease-free survival (IDFS = death, local/distant, second primary) with 32 events was E: 92.7% and CE: 81.9% (p= 0.05); corresponding TRx E: 92.8 % and CE: 93.1%. Given the imbalance in treatment allocations, a multivariate analysis was performed, with older age (&amp;lt;0.001), CE choice (&amp;lt;0.006) and larger tumor size (p&amp;lt;0.05) remaining significant, but not increased RS (p=0.16) for 5-year IDFS. Among women age &amp;lt;50 with RS 16-25 (E: 118; CE: 60) the 5-yr IDFS was E: 95% and CE: 94%; the corresponding RS 16-20 TRx E: 92% and CE: 94.7% and RS 21-25 E: 86.3% and CE: 92.1%. Conclusions: Using a real world data source, endocrine therapy alone appears to yield excellent 5-yr survival rates among pts with 21-gene RS 11-25 similar to the TAILORx trial. Treatment selection bias (with perceived higher risk pts allocated to CE) and shorter median follow-up limits full confirmation by this dataset. Citation Format: Waintraub SE, Isaacs C, Norden AD, Graham DA, McNamara DM, O'Neill SC, Lakshmanan A, Wu T, Maresca A, Pecora AL, Goy AH, Goldberg SL. Confirmation of the TAILORx 21-gene expression trial using a real world observational database [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 P4-14-05.

Abstract P2-07-11: Prediction of the Oncotype Dx recurrence score (RS) from clinicopathologic factors

Abstract Background: The Oncotype Dx assay is currently used as an aid to therapeutic decisions for the adjuvant treatment of women with ER-positive, Her2-negative, lymph node-negative or -micrometastatic breast cancer. The recently reported TAILORx study showed that no or minimal benefit is derived from adjuvant chemotherapy in patients with an Oncotype Dx Recurrence Score (RS) of 25 or less. Methods: Charts of breast cancer patients that had the Oncotype Dx test in our cancer center in a nine-year period were reviewed. Data on demographic, and cancer-specific characteristics of the included patients were extracted. Predicted disease recurrence from the Oncotype Dx test was recorded and correlated with select clinicopathologic characteristics. Results: Two hundred and thirty patients with ER-positive, Her2-negative, lymph node-negative or micrometastatic breast cancer were included. Mean age was 65 years-old (SD 9.9). Two hundred and three patients (88.3%) were post-menopausal and one hundred and thirty-three patients (57.8%) were 65 years-old or older. Two hundred and nine patients (90.9%) had lymph node-negative disease. Oncotype Dx recurrence score was low (&amp;lt;11) in sixty-four patients (27.8%), intermediate (11-25) in one hundred and forty patients (60.9%) and high (&amp;gt;25) in twenty-six patients (11.3%). High tumor grade and low progesterone receptor (PR) staining by IHC were the two clinicopathologic factors most associated with a high Oncotype Dx RS (x2 test p &amp;lt;0.00001 and Fisher's exact test p &amp;lt;0.0001). A predictive index (PI) was constructed, assigning one point each for grade 3 and PR staining in 20% or less of tumor cells. A PI of 0 was observed in one hundred and thirty-eight patients (60%), a PI of 1 was observed in seventy-one patients (30.9%), and a PI of 2 was observed in twenty-one patients (9.1%). One hundred and thirty-four patients (97.1%) with a PI of 0 had a RS of 25 or less. Patients with a PI of 1 and 2 had a RS of &amp;gt;25 in 12.7% and 61.9% of cases, respectively. Conclusion: The PI based on tumor grade and PR we propose is a simple predictor of Oncotype Dx RS. 97.1% of patients with a grade 1 or 2 tumor and PR positivity in &amp;gt;20% of tumor cells had a RS of 25 or less. The Oncotype Dx test and its associated cost can therefore be avoided in these patients, especially in low-resource settings. Citation Format: Voutsadakis IA, Thibodeau S, Reed M. Prediction of the Oncotype Dx recurrence score (RS) from clinicopathologic factors [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 P2-07-11.

Abstract P4-08-27: The 21-gene Recurrence® (RS) Score assay in estrogen receptor positive node negative breast cancer: Real-world chemotherapy usage and patient characteristics within the intermediate and high-risk RS category

Abstract Background: The Oncotype Dx, a 21-gene recurrence score (RS) assay, has been validated as a prognostic tool in early-stage, hormone receptor-positive, HER2-negative breast cancer. A RS of ≥ 31 is predictive for chemotherapy benefit. However, it has not been clearly established whether more intensive chemotherapy regimens for these patients provide further benefit and whether higher RS stratifications (≥41) influence treatment decisions. Methods: From the prospective British Columbia (BC) Breast Cancer Outcomes Unit database, we identified patients with N0 disease who received Oncotype Dx testing from May 2010 to December 2016. Patients with previous or synchronous breast cancer, and patients treated with neoadjuvant chemotherapy were excluded. Groups were defined that had an Oncotype Dx RS of 31-40 and ≥ 41. Demographic characteristics and type of chemotherapy received were collected. Additional subgroups were defined for patients who had a RS of 21-25 and who were ≤ 50 years old and &amp;gt; 50 years old. Results: We identified 1,202 patients who received Oncotype Dx testing over the time period studied, with 14.8% (n=178) having a RS of ≥ 31. Among these high-risk patients, the median age was 58 (range 34-79), 90% received hormonal therapy and 85% received chemotherapy. In this cohort, 46% received docetaxel and cyclophosphamide for 4 cycles and 28% received 3rd generation chemotherapy. The use of 3rd generation chemotherapy in patients with a RS of ≥ 41 was significantly higher than in patients with RS between 31-40 (39% vs 22%, p = 0.006). Among patients who had a RS of 21-25 and who were ≤ 50 years old (n = 49), 53% received chemotherapy. Of patients who had a RS of 21-25 and who were &amp;gt; 50 years old (n = 127), 16% received chemotherapy. Conclusions: Among patients with a RS ≥ 31, decisions regarding chemotherapy usage were heterogeneous with docetaxel and cyclophosphamide for 4 cycles being the most commonly used regimen. However, in those with a RS ≥ 41, 3rd generation chemotherapy was preferred. Patients with a RS between 21-25 and who were ≤ 50 years old received more chemotherapy than patients who were &amp;gt; 50 years old. RS 31-40 (n=116)RS ≥ 41 (n=62)RS ≥ 31 (n=178)Median age58.0 (range, 36-79)57.5 (range 34-78)58.0 (range 34-79)Pre-menopausal28.4%29.0%28.7%Hormonal therapy93.1%83.9%89.9%Chemotherapy86.2%82.3%84.8%DCx4 (1)54.3% (n=63/116) Median age 59.0 (range, 36 – 78)30.6% (n=19/62) Median age 64.0 (range, 42 – 78)46.1% (n=82/178) Median age 59.5 (range, 36 – 78)3rd generation chemo (2)21.6% (n=25/116) Median age 56.0 (range, 39 – 79)38.7% (n=24/62) Median age 52.0 (range, 34 – 76)27.5% (n=49/178) Median age 54.0 (range, 34 – 79)Other chemo10.3% (n=12/116) Median age 57.5 (range, 52 – 78)12.9% (n=8/62) Median age 64.0 (range, 42 – 72)11.2% (n=20/178) Median age 58.5 (range, 42 – 78)(1) Docetaxel and cyclophosphamide, 4 cycles (2) Anthracycline and Taxane containing regimens, 6 cycles or 8 cycles Citation Format: Le D, Chia S, Simmons C, Speers C, Gondara L, Nichol A, Lohrisch C, Gelmon KA. The 21-gene Recurrence® (RS) Score assay in estrogen receptor positive node negative breast cancer: Real-world chemotherapy usage and patient characteristics within the intermediate and high-risk RS category [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 P4-08-27.

Factors Determining Anthracycline Use in Hormone Receptor Positive, Early-Stage Breast Cancer

BackgroundAnthracyclines are associated with significant toxicities whereas nonanthracyclines have proven to be better tolerated. A 21-gene assay allows clinicians to predict who will not benefit from adjuvant chemotherapy and avoid systemic toxicities. Physicians are using the recurrence score to guide chemotherapy selection, despite the lack of evidence. In this study we examined factors associated with prescribing patterns for an anthracycline-based chemotherapy in hormone receptor-positive stage I to III breast cancer. Materials and MethodsThis was a retrospective study using the Michigan Breast Oncology Quality Initiative data set (February 1, 2006 to December 31, 2015). Women with histologically confirmed stage I to III invasive breast cancer with estrogen receptor and/or progesterone receptor-positive, HER2/neu-negative receptor status were included. We used χ2 analysis to determine associations of these characteristics with the 21-gene assay score and anthracycline use. ResultsA total of 17,788 patients were evaluated. Most tumors were stage I (60%). Most procedures were lumpectomy with radiation (66%). Anthracyclines were used more often in stage III patients (69%), younger patients (40% for patients younger than 65 years), and those with higher 21-gene recurrence scores. Patients with low recurrence scores were more likely to receive anthracyclines if lymph node-positive (10%) than if lymph node-negative (1%; P < .001). Patients with high recurrence scores and lymph node-positive status were just as likely to receive an anthracycline-based as a nonanthracycline-based regimen (47.5% vs. 49.2%; P = .89). ConclusionThese data indicate that medical oncologists might be anticipating the results of Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer study (TAILORx) and the Clinical Outcomes in ER+HER2-node-positive Breast Cancer Patients Who Were Treated According to the Recurrence Score Results: Evidence From a Large Prospectively Designed Registry (RxPonder) trials and are avoiding the potential serious complications associated with anthracycline treatment in patients least likely to receive benefit.

21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer.

To determine the effect of the 21-gene recurrence score (RS) on outcome and chemotherapy decision in breast invasive lobular carcinoma (ILC). We included 6467 patients with early stage and estrogen receptor-positive ILC from the Surveillance, epidemiology, and end results database. A total of 9.1, 31.4, and 70.1% of patients with low-, intermediate-, and high-risk RS groups received chemotherapy, respectively. A higher RS was independently associated with poor breast cancer-specific survival, and receipt of chemotherapy was not related to better breast cancer-specific survival in low-, intermediate-, or high-risk RS groups. The 21-gene RS could impact chemotherapy decision making in early-stage ILC. However, adjuvant chemotherapy does not appear to improve outcome in high-risk RS cohort.

The Distribution and Outcomes of the 21-Gene Recurrence Score in T1-T2N0 Estrogen Receptor-Positive Breast Cancer With Different Histologic Subtypes.

Background: The clinical value of 21-gene recurrence score (RS) in various breast cancer histologic subtypes is not well established.Aims: To assess the distribution and outcomes of the 21-gene RS among various T1-T2N0 estrogen receptor-positive breast cancer histologic subtypes.Methods: Using the Surveillance, Epidemiology and End Results database, we investigated the distribution and outcomes of the 21-gene RS among various breast cancer histologic subtypes between 2004 and 2015. The histologic subtypes with 200 or more cases were further analyzed.Results: We identified 83,665 patients including eight histologic subtypes. The most common subtype was invasive ductal carcinoma not otherwise specified (IDC NOS) (77.9%), followed by lobular carcinoma NOS, mixed infiltrating duct and lobular carcinoma (IDC-L), mucinous adenocarcinoma, tubular adenocarcinoma, micropapillary ductal carcinoma, cribriform carcinoma NOS, and intraductal papillary adenocarcinoma with invasion with 10.8, 7.7, 2.1, 0.6, 0.3, 0.2, and 0.2%, respectively. The 5-years breast cancer specific survival (BCSS) was 98.8, 98.8, 98.9, 99.6, 100, 100, 100, and 100%, respectively (P = 0.011). Patients with IDC NOS (8.9%), micropapillary ductal carcinoma (8.8%), and intraductal papillary adenocarcinoma with invasion (8.2%) had significantly higher percentage of high-risk RS compared to other histologic subtypes (1.0–3.8%) (P < 0.001). The mean RS was higher in IDC NOS, lobular carcinoma NOS, and IDC-L compared to other subtypes. In multivariate analysis, 21-gene RS was the independent prognostic factor in patients with IDC NOS (P < 0.001), lobular carcinoma NOS (P < 0.001), and IDC-L (P < 0.001), patients with a higher RS was associated with poor BCSS.Conclusion: Our results demonstrate that there is a significant difference in distribution of 21-gene RS in T1-T2N0 estrogen receptor-positive breast cancer with different histologic subtypes. Long-term studies with larger series are needed to confirm the role of the 21-gene RS array in prognosis assessment and chemotherapy decision-making in special histologic subtypes with favorable prognosis.

OncotypeDX Recurrence Score Does Not Predict Nodal Burden in Clinically Node Negative Breast Cancer Patients.

OncotypeDX recurrence score (RS)® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden. Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant. A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015). OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Oncotype DX® Recurrence Score as a Predictor of Response to Neoadjuvant Chemotherapy.

The Oncotype DX® assay has been validated in predicting response to adjuvant chemotherapy in breast cancer. Its role in neoadjuvant chemotherapy (NCT) has not been established. The National Cancer Database was used to identify all patients with T1-T3, ER-positive, HER2-negative primary invasive breast cancer diagnosed from 2010 to 2015 who had Oncotype DX recurrence scores (RS) and received NCT. RS were classified as low, intermediate, or high. Unadjusted and adjusted regression analyses were performed to determine the association between pathologic complete response (pCR) and RS. A total of 989 patients (mean age, 54.6years) with available RS who underwent NCT were identified. RS were low in 227 (23.0%) patients, intermediate in 450 (45.5%) patients, and high in 312 (31.5%) patients. Most patients had a T1 (431 [43.6%]) or T2 tumor (451 [45.6%]). Most had N0 disease (757 [76.5%]). Tumor grades were 1 (123 [12.4%]), 2 (517 [52.3%]), or 3 (349 [35.3%]). pCR was achieved by 42 (4.3%) patients. Adjusted multivariable analysis showed a significant association between pCR and high RS (odds ratio 4.87; 95% confidence interval 2.01-11.82). High Oncotype DX RS was associated with pCR after NCT in this national cohort of ER-positive, HER2-negative patients. Oncotype DX testing could help to identify patients most suited for NCT and should be considered for incorporation into the multidisciplinary decision-making process.

21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer

The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18–30, ≥31, and the TAILORx cutoffs: <11, 11–25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan–Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18–30 groups, 1.7 and 6.7% were HER2 positive. In the RS ≥ 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rank P = 0.06), but substantial benefit from chemotherapy remained in the RS ≥ 31 cohort (HR = 0.18; 95% CI: 0.07–0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12–0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx.

Evaluation of the role of pharmacy technicians in reviewing the eligibility for Oncotype DX genomic test and the impact of the test on treatment plans in breast cancer patients.

The Oncotype DX genomic test is a treatment decision-making tool. Test results are presented as recurrence scores which are used to help decide between adjuvant hormonal therapy (low recurrence score) or chemotherapy (high recurrence score). Since 2014, the Oncotype DX test has been funded at the cancer treatment centres in our province for patients with early breast cancer. Eligibility criteria for funding include patient and tumour characteristics. Pharmacy technicians were assigned to review and approve requests based on the eligibility criteria and with access to consultation to an oncology pharmacist and a medical oncologist. We assessed the clinical role of pharmacy technicians in this review process and the impact of recurrence score on treatment decisions. This was a retrospective, multi-centre study to evaluate the Oncotype DX test eligibility review process from June 2014 to May 2015. The main objectives were to assess (1) the discrepancy rate of approval by the pharmacy technicians in this review process and (2) the concordance rate between the recurrence score from the Oncotype DX test and the adjuvant treatment given. Four hundred and forty requests for Oncotype DX test were received during the study period. A total of 90.8% of requests were approved and 9.2% were denied. The discrepancy rate of approval by pharmacy technicians was 1.1%. The average review time was 13.8 min, with the reviewing pharmacist and oncologist consulted in 5.5 and 15.2% of the requests, respectively. The concordance rate between the recurrence score and given treatment was 96%. The discrepancy rate of our pharmacy technicians appears to be similar to that reported with other expanded technician roles in literature, suggesting that the current task and other similar clinical tasks can be reliably delegated to technicians. The concordance rate of the recurrence score and given treatment in our study was higher than what has been reported in literature, suggesting that most of our patients were treated in accordance to recurrence score-based recommendations. Pharmacy technicians were able to expand their clinical role by accurately reviewing the Oncotype DX test requests with a low discrepancy rate. The Oncotype DX test results appeared to successfully guide the adjuvant treatment given to patients in accordance to recurrence score-based recommendations.

A predictive model for high/low risk group according to oncotype DX recurrence score using machine learning

BackgroundOncotype DX(ODX) is a 21-gene breast cancer recurrence score(RS) assay that aids in decision-making for chemotherapy in early-stage hormone receptor-positive(HR+)breast cancer. We developed a prediction tool using machine learning for high- or low-risk ODX criteria (i.e., RS < 11 for low-risk; RS > 25 for high-risk). MethodsWe performed a retrospective review of 301 breast cancer patients who underwent surgery between April 2011 and July 2017 and then an ODX test at Samsung Medical Center in Seoul, Korea.Among them, 208 cases were defined as the modeling group and 76 cases were defined as the validation group. We built a supervised machine learning classification model using the Azure ML platform. ResultsFor the high RS group, accuracy was 0.903 through Two-class Decision Jungle method in test set. For the low RS group, the accuracy was 0.726 when the Two-class Neural Network method was applied. The AUC of the ROC curve was 0.917 in the high RS group and 0.744 in the low RS group in test set. In addition, we conducted an internal validation using 76 patients who underwent ODX testing between January 2017 and July 2017. The accuracy of validation was 0.880 in the high RS group and 0.790 in the low RS group. ConclusionWe developed a predictive model using machine learning that could represent a useful and easy-to-access tool for the selection of high ODX RS patients. After additional evaluation with large data and external validation, worldwide use of our model could be expected.

Predictors for Survival and Distribution of 21-Gene Recurrence Score in Patients With Pure Mucinous Breast Cancer: A SEER Population-Based Retrospective Analysis

BackgroundPure mucinous breast cancer (PMBC) is a rare pathologic type of breast cancer, the prognostic factors of which have not been clearly defined. This study aimed to analyze the prognostic markers and distribution of 21-gene recurrence score (RS) in patients with PMBC. Patients and MethodsUtilizing the Surveillance, Epidemiology, and End Results (SEER) database, a retrospective analysis of PMBC cases was conducted. Multivariate analyses were used to evaluate the indicators for prognosis and the correlations between RS and traditional clinicopathologic characteristics. Disease was subdivided into 4 molecular phenotypes using estrogen receptor (ER) status and tumor grade. ResultsOf the 8048 patients, most had ER-positive and node-negative tumors. Multivariate analysis revealed that molecular phenotype as well as age, race, tumor size, and lymph node status was an independent prognostic factor for patients with PMBC (P < .05). The 5-year breast cancer–specific survival of patients among different phenotypes was significantly different (97.9% for ER-positive and grade I tumor, 96.9% for ER-positive and grade II-III tumor, 96% for ER-negative and grade I tumor, 90.1% for ER-negative and grade II-III tumors, P < .001). The proportions of patients categorized into low, intermediate, and high RS risk group were 64.9%, 31.9%, and 3.2%, respectively. Grade, progesterone receptor status, and age were identified as independent variables associated with RS. ConclusionPMBC had favorable biological features and relatively good prognosis. Molecular phenotype as well as age, race, tumor size, and lymph node status were independent prognostic markers. Furthermore, age, progesterone receptor status, and grade could independently predict RS.

Multifocal/Multicentric Ipsilateral Invasive Breast Carcinomas with Similar Histology: Is Multigene Testing of All Individual Foci Necessary?

Multiple synchronous ipsilateral invasive breast carcinomas (BCs) with similar histology usually have concordant receptor status. It is unknown whether individual foci with similar histology also share molecular and biological similarities or are heterogenous. This study examined the concordance of the 21-gene recurrence score (RS) in multiple synchronous morphologically similar ipsilateral BCs. We identified patients with multiple ipsilateral BCs and available RS treated at our institution from 1/2014 to 6/2018. BCs were divided into three groups based on RS: (1) RS in same risk category, (2) RS in different risk categories but within 2-unit difference (e.g., RS 17 and RS 19), and (3) RS in different risk categories and a change of > 2 units. BCs in groups 1 and 2 were considered as concordant (no significant clinical impact) and BCs in group 3 as discordant (variation affects management). A total of 53 patients met the study criteria. RS was concordant in 46 (87%) cases. Seven (13%) cases were discordant (group 3). Of these, three (43%, 3/7) had biopsy cavity changes (BXC) adjacent to the BC with highest RS. In two cases the focus with higher RS had a lower percentage of progesterone receptor-positive tumor cells. In two cases, extensive ductal carcinoma in situ was associated with the BC focus with lower RS. Morphologically similar multifocal ipsilateral BCs have concordant RS in 87% (46/53) of cases. Our results suggest that, in cases of morphologically similar multifocal BCs, testing of a single focus provides accurate prognostic and predictive information.