Attempt to Substitute the Oncotype DX Breast Recurrence Score® Test by Histopathological Factors and MUC1 Protein Expression.

Background/Aim: Oncotype DX Breast Recurrence Score® test (ODx) is a gene profiling assay predicting the benefit of adjuvant chemotherapy for early-stage hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Meanwhile, to avoid unnecessary financial burden on the patient, many studies have attempted to establish alternatives to ODx using conventional clinicopathological factors, but these have not yet been successful. Thus, we retrospectively investigated clinicopathological factors to establish alternatives to ODx. Patients and Methods: Data from 114 Japanese women who underwent ODx were retrospectively examined to investigate the relationship between ODx recurrence score (RS) and clinicopathological features, including MUC1 staining patterns on immunohistochemical assessment. An RS of 0-25 was defined as low, and 26-100 as high. Results: Ninety patients (79%) had low RS and 24 patients (21%) had high RS. Univariate analysis revealed that low tumor grade, high progesterone receptor (PgR) expression, and low Ki67 labeling index (LI) were significantly associated with low RS (p=0.025, p<0.001, and p<0.001, respectively). Tumors with an apical pattern of MUC1 staining also frequently had a low RS (p=0.024). In multivariate analysis, PgR expression and Ki67 LI were independent factors associated with RS (p<0.001, for both). When the ODx results were categorized with a combination of these two factors, only 2% of the PgR-high and Ki67-low group (one in 51 cases) had a high RS. Conclusion: PgR expression and Ki67 LI were independent factors correlated with RS. MUC1 staining pattern also has the potential to be a useful marker. We believe that it is crucial to continue attempts to identify patients who are unlikely to benefit from ODx.

21-Gene Recurrence Score and Survival Outcomes in the Phase III Multicenter TAILORx Clinical Trial.

BACKGROUND: Recurrence score (RS) based on a 21-gene genomic assay is frequently used to estimate risk of distant recurrence for choice of adjuvant chemotherapy in breast cancer. It remains unclear whether RS is an independent prognostic factor for breast cancer-specific survival (BCSS) and overall survival (OS) in the TAILORx trial population. METHODS: We evaluated the association of RS with BCSS and OS plus recurrence-free interval (RFI) and invasive disease-free survival (DFS) using multivariable Cox proportional hazards regression analysis, adjusting for clinicopathologic measures, in 8,916 patients with hormone receptor-positive, HER2-negative, node-negative breast cancer. Likelihood ratio (LR) test was used to assess the relative amount of prognostic information provided by RS to BCSS, OS, RFI, and DFS, comparatively. RESULTS: Event rates for BCSS, OS, RFI, and DFS were 1.7%, 5.2%, 5.6%, and 12.6%, respectively, by up to 11.6 years of follow-up. Compared with low-range RS (0-10), patients with midrange (11-25) and high-range (26-100) RS had inferior BCSS (adjusted hazard ratio [aHR], 5.12 [95% CI, 2.09-16.92] and 8.03 [95% CI, 2.91-28.47], respectively) and RFI (aHR, 1.68 [95% CI, 1.23-2.36] and 3.05 [95% CI, 2.02-4.67], respectively), independent of clinicopathologic factors. High-range score was associated with an increased risk of DFS (aHR, 1.56 [95% CI, 1.20-2.04]) but not significantly associated with OS (aHR, 1.44 [95% CI, 0.95-2.18]). Midrange score was associated with neither DFS (aHR, 1.15 [95% CI, 0.96-1.38]) nor OS (HR 1.14 [95% CI, 0.87-1.52]). LR-χ2 values were 83.0 and 65.1 for RFI and BCSS, respectively, and 17.5 and 33.6 for OS and DFS, respectively (P<.0001). CONCLUSIONS: RS is an independent measure for BCSS and recurrence prognoses relative to OS in early-stage breast cancer. It carries more prognostic information for breast cancer-specific outcomes.

Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence Between Breast Cancer Index (BCI) and the 21-Gene Oncotype DX Recurrence Score (RS).

INTRODUCTION: Breast Cancer Index (BCI) is a genomic assay that evaluates the benefit of extending endocrine therapy (ET) from 5 to 10 years and predicts recurrence risk (RR). We evaluated the association between BCI and Oncotype DX (ODX). PATIENTS: Women with hormone receptor (HR)-positive early-stage breast cancer (EBC) who had BCI and ODX performed were included. METHODS: We performed a retrospective review of women with HR-positive EBC. BCI was categorized as predictive of extended ET versus not and ODX recurrence score (RS) as low (0-10), intermediate (11-25), and high (26-100). Univariate and multivariable logistic and linear regression models assessed the relationship between BCI and ODX, factors associated with each, and discordance between scores. RESULTS: We identified 153 women, 22% were premenopausal and 18% were lymph node positive. The univariate logistic and linear models revealed an association between BCI predictive score and ODX RS (OR 7.84, CI, 2.63-23.36, P < .001) and log of BCI RR (Beta 0.04, CI, 0.02-0.06, P < .001). Seventy-four percent of BCI predictive scores were concordant with ODX RS and 83% of BCI RR was concordant with ODX RR. In a univariate logistic regression model, BCI predictive of ET benefit was associated with discordance (OR 28.00, CI, 10.58-74.02, P < .001). Higher ODX RR was associated with discordance (OR 1.92, CI, 1.42-2.59, P < .001). CONCLUSION: We found a significant association between ODX and BCI predictive and prognostic scores. BCI predictive of extended ET benefit was associated with discordance with ODX RS. Higher predicted RR on ODX was associated with discordance with BCI predicted RR.

Corrigendum: Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

[This corrects the article DOI: 10.3389/pore.2024.1611735.].

The REMAR (Rhein-Main-Registry) real-world study: prospective evaluation of the 21-gene breast recurrence score® assay in addition to Ki-67 for adjuvant treatment decisions in early-stage breast cancer.

PURPOSE: Ki-67 is recommended by international/national guidelines for risk stratification in early breast cancer (EBC), particularly for defining "intermediate risk," despite inter-laboratory/inter-observer variability and cutoff uncertainty. We investigated Ki-67 (> 10%- < 40%, determined locally) as a prognostic marker for intermediate/high risk in EBC, pN0-1 patients. METHODS: This prospective, non-interventional, real-world study included females ≥ 18 years, with pN0/pN1mi/pN1, HR+ , HER2-negative EBC, and locally determined Ki-67 ranging 10%-40%. The primary outcome was changes in treatment recommendations after disclosing the Oncotype DX Breast Recurrence Score®(RS) assay result. RESULTS: The analysis included 567 patients (median age, 57 [range, 29-83] years; 70%/1%/29%/ with pN0/pN1mi/pN1 disease; 81% and 19% with RS results 0-25 and 26-100, respectively). The correlations between local and central Ki-67, local Ki-67, and the RS, and central Ki-67 and the RS results were weak (r = 0.35, r = 0.3, and r = 0.46, respectively), and discrepancies were noted in both directions (e.g., local Ki-67 was lower or higher than central Ki-67). After disclosing the RS, treatment recommendations changed for 190 patients (34%). Changes were observed in pN0 and pN1mi/pN1 patients and in patients with centrally determined Ki-67 ≤ 10% and > 10%. Treatment changes were aligned with RS results (adding chemotherapy for patients with higher RS results, omitting it for lower RS results), and their net result was 8% reduction in adjuvant chemotherapy use (from 32% pre-RS results to 24% post-RS results). CONCLUSION: The Oncotype DX® assay is a tool for individualizing treatments that adds to classic treatment decision factors. The RS result and Ki-67 are not interchangeable, and Ki-67, as well as nodal status, should not be used as gatekeepers for testing eligibility, to avoid under and overtreatment.

Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.

Clinicopathological characteristics and genomic profiling of pure mucinous breast cancer.

PURPOSE: Pure mucinous breast cancer (PMC) is a rare histological type with a favourable prognosis. However, cases with recurrence have been reported and diagnosed in clinical practice. The mechanisms underlying PMC recurrence remain unknown. In this study, we aimed to identify the prognostic factors associated with PMC. MATERIALS AND METHODS: A total of 166 patients diagnosed with PMC were included. We compared the clinicopathological characteristics between patients with and without recurrence. The 21-gene assay was performed in 10 patients with recurrence and 20 TNM stage-matched patients without recurrence. Whole-exon sequencing was performed in 12 PMC primary tumours and four positive lymph nodes (LNs). RESULTS: Tumour size, lymph node status and TNM staging differed significantly between recurrent group and non-recurrent group. And the 21-gene recurrence scores did not differ significantly between recurrent group and its TNM stage-matched non-recurrent group. The most frequently mutated genes in the primary tumours of regional LN-positive PMCs were ADCY10 (3/6) and SHANK3 (3/6), and they more recurrently harboured gains of 15q23, 17q23.2 and 20p11.21, and loss of 21p11.2. And these alterations were not detected in primary tumours of regional LN-negative PMCs. CONCLUSION: TNM stage is an important prognostic factor in PMC. Although we revealed that regional LN-positive PMCs show increased occurrence of duplication variants at 15q23, 17q23.2 and 20p11.21, and deletion variants at 21p11.2. Further investigation, including multi-omics studies, are needed and may provide additional insights into the nature of PMC.

Correlation of Ki-67 proliferative index with oncotype DX recurrence score in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer with low-burden axillary nodal disease - a review of 137 cases.

The use of chemotherapy in breast cancer management has significantly contributed to the decrease in its mortality. Currently, the prognosis is determined by molecular biomarkers, such as oestrogen receptors, and human epidermal growth factor receptor 2. However, the increasing use of advanced molecular technologies, including oncotype DX recurrence score (ODX-RS), has provided the ability to estimate the risk of recurrence. Research has demonstrated that the ODX-RS helps to predict recurrence risk and the potential benefit of chemotherapy in breast cancer. As a result, it can assist clinicians in making decisions regarding using the chemotherapy. The goal of work is to explore the correlation between the ODX-RS and Ki-67 proliferative index (Ki-67-PI). This study included 137 patients with oestrogen positive, human epidermal growth factor receptor 2-negative early breast cancer, and had non- or early axillary disease. Patients with low Ki-67-PI were as follows: low ODX-RS in 17%, intermediate ODX-RS in 80%, and high ODX-RS in 2%. In the high Ki-67-PI group: low ODX-RS in 12%, intermediate ODX-RS in 48%, and high ODX-RS in 40%. In conclusion, the results show no significant correlation between the ODX-RS and Ki-67-PI (r = 0.511, p-value < 0.9).

Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

Introduction: The 21-gene analysis (OncotypeDX) is validated test for pT1-3, pN0-1 with hormone receptor (HR) positive and normal expression of human epidermal growth factor receptor-2 (HER2) breast cancer (BC) to determine the aggressiveness of the disease based on the calculation of Recurrence Score (RS). Methods: In this retrospective study the authors correlated pathological characteristics and Recurrence Score (RS) by traditional statistical methods and Observed Oriented Modeling (OOM) in a realistic cohort of BC patients. Results: OncotypeDX tests were performed in 94 tumour specimens of 90 BC patients. >83% of node-negative (pN0) and >72% of node-positive (pN1) cases could avoid chemotherapy. For pN0 cases, non-parametric correlation and tests demonstrated significant association in eight types of characteristics [progesterone receptor (PR) expression, Ki-67 value, Ki-67 group, PR group, grade, estrogen receptor (ER) expression, Nottingham Prognostic Index (NPI) and Clinical Risk]. For pN1 cases, parametric correlation and tests showed significant association in six characteristic types (number of positive nodes, ER and PR expression, PR group, Ki-67 group and NPI). Based on OOM for pN0 cases, significant associations were established in three characteristics (Ki-67 group, grade and NPI group). For pN1 cases OOM found significant associations in seven characteristics (PR group, PNI, LVI, Ki-67 group, grade, NPI group and number of positive nodes). Conclusion: First in oncology, OOM was applied, which found some other significant characteristics associated with RS than traditional statistical methods. There were few patients, where no clinical associations were found between characteristics and RS contrary to statistically significant differences. Therefore, the results of these statistical analyses can be neither applied for individual cases nor able to provide the bases for screening patients, i.e., whether they need for OncotypeDX testing or not. OncotypeDX still provides a personalised approach in BC.

BRCA1/2 mutation carriers vs the general breast cancer population (N = 799,986): 21-gene assay-based molecular characterization.

PURPOSE: We compared 21-gene recurrence score (RS) distribution and expression of the single-gene/gene groups within this assay between BC patients with pathogenic variants (PV) in BRCA1/2 vs the general 21-gene-tested BC population. METHODS: This retrospective study included consecutive 21-gene-tested female ER + HER2-negative BC patients with germline PVs in BRCA1/2. RS/gene expression data were compared to a previously described commercial use database (CDB, N = 799,986). Chi-square and 1-sample t test were used to compare RS distribution and single-gene/gene group scores between the study group and the CDB. RESULTS: Study group patients (N = 81) were younger and their RS results were higher compared to the CDB (age: median [IQR], 56 [47-61.5] vs 60 [51-67] years; p < 0.001; proportion of patients with RS ≥ 26: 49.4% vs 16.4%, p < 0.001). Expression of 12/16 cancer genes in the assay and the ER, proliferation, and invasion gene group scores differed significantly between the study group and the CDB, all in a direction contributing to higher RS. The differences between the study group and the CDB were mostly retained, upon stratifying the patients by menopausal status. CONCLUSION: BC patients with PVs in BRCA1/2 have higher RS results that stem from distinct gene expression profiles in the majority of genes in the 21-gene assay.

Neuroendocrine Breast Tumors: Could Multigene Assays Help in Guiding Treatment Decisions? Case Presentation.

BACKGROUND/AIM: Breast cancer remains the most prevalent type of cancer among women worldwide, and it remains the primary cause of cancer-related deaths in this demographic. Neuroendocrine breast cancer (NBC), an uncommon subtype comprising less than 1% of cases, typically occurs in older women and displays as a slow-growing, low-grade condition. NBC exhibits distinct histological patterns and immunohistochemical markers. Given the limited data on NBC, assays are required that will provide information on molecular profiling and assist in clinical decision making. The aim of the study was to investigate whether a modern Multigene Assay (MGA) could assist on treatment planning of NBC patients. CASE REPORT: A cohort of four patients was analyzed using a MGA. The presented cases featured young, pre-menopausal women with clear NBC, lacking family history. All were lymph node-negative, with robust expression of neuroendocrine markers. Despite high hormone receptor expression, all tumors were poorly differentiated with elevated Ki67 levels. Oncotype DX analysis indicated a need for chemotherapy in three cases and not in one. This underscores the heterogeneity within NBC, emphasizing the importance of personalized treatment decisions. CONCLUSION: While NBC is rare and lacks extensive studies, the use of multigene assays like Oncotype DX may play a pivotal role in treatment planning, especially in cases with varying histological parameters.

Enhancing clinical decision support with genomic tools in breast cancer: A Scottish perspective.

INTRODUCTION: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. MATERIALS & METHODS: Pan-Scotland study between August 2018-August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. RESULTS: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. CONCLUSIONS: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland. It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate.

Correlation between postoperative treatment selection and prognosis determined using the Oncotype DX® test data: a retrospective multicenter study in Japan.

PURPOSE: Oncotype DX® is a frequently used multigene assay for hormone receptor-positive breast cancers. However, limited evidence is available regarding its application in Japan owing to the lack of insurance coverage. Therefore, we conducted this large-scale, retrospective study by collecting data from nine Japanese institutes and assessed postoperative treatment choice and prognosis by using Oncotype DX®. METHODS: Six hundred thirty-two patients who underwent breast surgery and whose recurrence score (RS) data were available were included. They were divided into RS 0-25 and RS ≥ 26 groups. The groups were compared in terms of clinicopathological factors, treatment options, and prognosis. RESULTS: After the median follow-up period of 10.1 years, the disease-free survival (DFS) rates were significantly better in the RS 0-25 group (p = 0.02). Per the recurrent event type, there was no significant intergroup difference in locoregional recurrence (p = 0.139). However, a trend toward better distant DFS was observed in the RS 0-25 group (p = 0.08). Overall survival was also significantly better in this group (p = 0.027). Considering chemotherapy use, DFS worsened among chemotherapy-treated patients with an RS of 0-25 and those with an RS ≥ 26 who did not receive chemotherapy (p < 0.001). Seven (1.35%) chemotherapy-treated patients with an RS of 0-25 showed disease recurrence. CONCLUSIONS: This study presents the largest database-derived prognostic data in Japanese patients, utilizing the Oncotype DX® treatment selection. Further studies are needed to determine the impact on treatment choice, considering the clinical risk, and the need for additional postoperative treatment.

Axillary nodal disease burden is not associated with an elevated 21-gene recurrence score in post-menopausal women presenting with a clinically negative axilla.

BACKGROUND: The predictive and prognostic value of the recurrence score (RS) has emphasized the importance of tumor biology and has reduced the prognostic implications of limited nodal burden in post-menopausal women with HR+/HER2-invasive breast cancer (IBC). It is unclear whether routine axillary staging has a continued role in the management of small, clinically node negative (cN0) HR+/HER2- IBC. We sought to estimate the association of RS with pN stage. METHODS: Patients >50yo diagnosed with cN0, HR+/HER2- IBC (2015-2019) with an available RS were identified from the National Cancer Database. The clinicopathologic characteristics and rates of pN-stage (pN0, pN1, pN2/3) were compared for RS of ≤25 vs. >25. RESULTS: The median patient age was 64.1 (IQR 58-69) and the majority (75%) of tumors displayed ductal histology. Most (81.6%) were cT1 on presentation and pT1 (74.7%) on final pathology. There were 130,568 (86.2%) with a RS â€‹≤ â€‹25 and 20,879 (13.8%) with a RS â€‹> â€‹25. On final pathology, 128,995 (85.2%) were pN0 and 21,991 (14.5%) pN1. Of the pN1, 2699 (12.3%) yielded a RS â€‹> â€‹25. There were 461 (0.3%) patients with pN2-pN3 disease. Of those, 57 (12.4%) had RS â€‹> â€‹25. CONCLUSION: In our analysis, pN0 and pN1 tumors are biologically similar by gene expression assay in postmenopausal patients with similar proportions of high RS. These data support the notion that tumor biology examined via RS may have more prognostic and predictive value than metastatic dissemination to limited lymph nodes. These findings support the ongoing evaluation of routine axillary staging in postmenopausal patients with HR+/HER2- IBC.

21-gene recurrence score in predicting the outcome of postoperative radiotherapy in T1-2N1 luminal breast cancer after breast-conserving surgery.

BACKGROUND: In those with one to three positive lymph nodes (N1) breast cancer (BC), the 21-gene recurrence score (RS) classification can be referred for decision-making on adjuvant chemotherapy. This study aimed to investigate the effect of RS in predicting the survival benefit of postoperative radiotherapy (PORT) in T1-2N1 BC with estrogen receptor-positive and human epidermal growth factor receptor 2-negative disease after breast-conserving surgery (BCS). METHODS: We included patients with BC and available RS data from the Surveillance, Epidemiology, and End Results Oncotype DX database. The chi-square test, Kaplan-Meier method, propensity score matching (PSM) as well as multivariable Cox proportional hazard analyses were used for statistical analyses. RESULTS: We included 6509 patients in the analysis. Of these patients, 5302 (85.5%) were treated with BCS + PORT, and 207 (15.5%) had BCS alone. There were 1419 (21.8%), 4319 (66.4%), and 771 (11.8%) patients being low-, intermediate-, and high-risk RS, respectively. After PSM, PORT was significantly associated with a 5-year overall survival (OS) advantage (95.1% vs. 90.5%, P < 0.001) compared to those without PORT, which similar breast cancer-specific survival (BCSS) was found between the treatment arms (P = 0.126). The sensitivity analyses showed that PORT was not associated with a better BCSS (P = 0.472) and OS (P = 0.650) than those without PORT in the low-risk RS cohort. However, PORT was associated with a better BCSS (P = 0.031) and OS (P < 0.001) compared to those without PORT in the intermediate/high-risk RS cohorts. CONCLUSIONS: Our study highlights the possible role of the RS in predicting the outcome of PORT in T1-2N1 luminal BC patients undergoing BCS.

Budget Impact of the Oncotype DX Breast Recurrence Score® Test in Patients with Early Primary Hormone-Receptor-Positive, HER2-Negative, Node-Positive Breast Cancer in Germany.

Background: Gene expression tests can inform decisions on whether to recommend or omit chemotherapy for patients with early HR+, HER2- breast cancer. The benefit of these tests is well established and fully reimbursed by sickness funds for lymph node-negative (pN0) patients in Germany. A budget impact model was built to evaluate the effect of using the Oncotype DX Breast Recurrence Score® test also for node-positive (pN1: 1-3 positive lymph nodes) patients. Methods: The prospective randomized clinical trial, RxPONDER, defined conditions (Recurrence Score result 0-25 for postmenopausal patients with 1-3 positive lymph nodes) under which omitting chemotherapy does not significantly impact invasive disease-free survival with results currently reported for 5-year follow-up. The present budget impact model calculates average total cost per node-positive patient versus no testing from a sickness funds perspective, taking into account not only the budgetary impact of avoiding chemotherapy and associated side effects, but also the costs of treating those patients who develop distant metastasis. The stability of the results was investigated by probabilistic multivariate sensitivity analysis. Results: After deducting testing cost, applying the Oncotype DX Breast Recurrence Score test yielded an average savings per node-positive patient of EUR 4,272. Without the test costs, the greatest savings resulted from reductions in direct treatment costs and costs arising from the treatment of chemotherapy-related side effects, which together averaged EUR 6,677. The targeted use of chemotherapy after testing also resulted in slightly lower costs for treatment of distant metastasis, if it did occur. The multivariate sensitivity analysis also almost exclusively resulted in cost savings. Conclusion: Analogous to the pN0 situation, this budget impact model demonstrates that the Oncotype DX Breast Recurrence Score test can also reduce healthcare costs in Germany in treatment of node-positive (pN1: 1-3 positive lymph nodes) patients by minimizing both unnecessary chemotherapy and undertreatment. Additional benefits to patients would include reduced morbidity and improved quality of life for those patients who can safely avoid chemotherapy or undertreatment.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Nomogram Update to Predict the High Genomic Risk Breast Cancer by Different Races.

PURPOSE: To develop a nomogram to predict the high-risk recurrence score (RS) and to customize the nomogram for different races in early-stage hormone receptor (HoR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. METHODS: Patients diagnosed between 2010 and 2015 were included from the surveillance, epidemiology, and end results oncotype DX database. The nomogram was assessed with a receiver operating characteristic curve to measure the area under the curve (AUC) with a 95% confidence interval (95% CI). The nomogram was developed and internally validated for discrimination and calibration, and then validated in different races. RESULTS: A total of 48,464 patients were included and randomly assigned to the training cohort (n = 36370, 75.0%) and validation cohort (n = 12,094, 25.0%). Patients in the training cohort were identified to develop the nomogram, including 32,683 (89.9%) White women, 3135 (8.6%) Black women, and 552 (1.5%) Chinese women. Five independent predictive factors for high-risk RS were included to develop the nomogram, including tumor grade, progesterone receptor status, histological subtype, race, and tumor stage. The AUC was 0.696 (95% CI, 0.682-0.710) in the training cohort and 0.700 (95% CI, 0.676-0.724) in the validation cohort. There was no significant difference between the training cohort and the validation cohort. When validating the nomogram classified by race, the AUC was 0.694 (95% CI, 0.682-0.706) for the White cohort, 0.708 (95% CI, 0.673-0.743) for the Black cohort, and 0.653 (95% CI, 0.565-0.741) for the Chinese cohort. CONCLUSION: The developed nomogram for predicting high-risk RS is available for different races in patients with HoR+/HER2- breast cancer, which could be used as qualified surrogates before ordering the 21-gene RS testing.

Impact of reactive changes on multigene testing: histopathologic analysis of low-grade breast cancers with high-risk 21-gene recurrence scores.

PURPOSE: The 21-gene recurrence score (RS) assay predicts the recurrence risk and magnitude of chemotherapy benefit in patients with invasive breast cancer (BC). This study examined low-grade tumors yielding a high-risk RS and their outcomes.Kindly check the edit made in the article titleOk  METHODS: We compared patients with grade 1 BC and a high-risk RS to those with low-risk RS. Histologic sections were reviewed and features reported to elevate the RS were noted, mainly biopsy cavity and reactive stromal changes (BXC). RESULTS: A total of 54 patients had high-risk RS (median RS of 28, range 26-36). On review, BXC were seen in all cases. Thirty BCs in this group also had low to negative PR. Treatment regimens included: chemoendocrine therapy (63%), endocrine therapy alone (31%) and no adjuvant therapy (6%). There were no additional breast cancer events over a median follow-up of 54.0 months (range 6.2 to 145.3). A total of 108 patients had low-risk RS (median RS of 7, range 0-9). BXC were seen in 47% of cases and none were PR negative. One patient had a recurrence at 64.8 months while the rest had no additional events over a median of 68.1 months (2.4 to 100). CONCLUSION: We provide further evidence that reactive stromal changes and/or low-PR scores enhance the elevation of the RS. A high-RS result in low grade, PR-positive BC may not reflect actual risk and any suspected discrepancies should be discussed with the management teams. Multigene testing results should be interpreted after correlation with pathologic findings to optimize patient care.

Discordance of Oncotype DX scores in synchronous bilateral and unilateral multifocal breast cancers.

PURPOSE: Oncotype DX, a 21-gene expression profiling test, has become standard of care in the management of estrogen receptor (ER)-positive breast cancer. In multifocal tumors, it is unclear whether testing of the different foci is necessary. We evaluated the concordance of Oncotype DX recurrence scores (RS) between 2 tumor foci in synchronous bilateral or unilateral multifocal tumors and characterized pathological predictors of discordance. METHODS: We reviewed 713 ER+, HER2- primary invasive breast cancer patients with Oncotype RS and identified 17 bilateral synchronous patients (34 tumors) and 13 unilateral multifocal patients (26 tumors) with available Oncotype RS on all foci. Discordance in Oncotype RS between synchronous tumors was recorded and associations with clinicopathologic features including tumor size, histology, Nottingham histologic grade, progesterone receptor staining, and Ki67 index were analyzed. RESULTS: Bilateral synchronous tumors were present in older patients (median age 59 years) and had larger tumor (median size 17 mm) and more discordant histology (10/17, 59%) as compared to unilateral multifocal tumors (median age 49 years, p < 0.01; median tumor size 12 mm, p = 0.01; discordant histology 2/13, 15%, p = 0.03). Oncotype RS were discordant in 47% (8/17) of bilateral and 54% (7/13) of unilateral multifocal tumors. Concordant Oncotype RS was associated with similar histologic grade and Ki67 index in 78% (7/9) of bilateral and 100% (6/6) of multifocal tumors. In contrast, only 25% (2/8) of bilateral (p = 0.06) and 14% (1/7) of unilateral multifocal (p < 0.01) cases with discordant Oncotype RS had concordant histology grades and Ki67 levels. In synchronous tumors with discordant Oncotype RS and Ki67 index, all (4/4) foci with higher RS had higher Ki67 index. CONCLUSION: Discordance of Oncotype RS is common in both bilateral and unilateral multifocal breast cancer and is likely associated with discordant histologic grade or Ki67.