Low Recurrence Score Research Articles

Abstract P5-13-02: Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25)

Abstract Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [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 P5-13-02.

Trend and survival benefit of Oncotype DX use among female hormone receptor-positive breast cancer patients in 17 SEER registries, 2004-2015.

To examine (1) the trend and associated factors of Oncotype DX (ODX) use among hormone receptor-positive (HR+) breast cancer (BC) patients in 2004-2015; (2) the trend of reported chemotherapy by Recurrence Score (RS); and (3) the survival differences associated with ODX use. ODX data from Genomic Health Inc. were linked with 17 SEER registries data. HR + BC cases with lymph node negative (N0) or 1-3 positive LNs (N1) from 2004-2015 were analyzed. The Cochrane-Armitage trend test, logistic regression, Kaplan-Meier survival curve, and stratified Cox model were performed. Survival analysis was restricted to HR+/HER2- patients from 2010 to 2014, matched on propensity score. ODX use increased substantially from 2004 to 2015 (N0: 2.0% to 42.7%; N1: 0.3% to 27.9%). Non-Hispanic black and Medicaid insured patients had lower odds of receiving ODX. N0 patients with moderately differentiated or 2.1-5.0cm tumor and N1 patients with well-differentiated or < 2.0cm tumor had higher odds of using ODX. The reported chemotherapy use decreased significantly with low and intermediate RS, and increased for high RS among N0 patients. ODX use was associated with better breast cancer-specific survival [hazard ratio (95% CI) N0 1.96 (1.60-2.41), N1 1.90 (1.42-2.54)] and overall survival [N0 2.06 (1.83-2.31), N1 1.72 (1.42-2.09)], especially in the first 36months. ODX use has increased significantly since 2004, nonetheless disparities remain, especially for racial/ethnic minorities and Medicaid insured patients. Administering chemotherapy based on ODX results has been improved among N0 patients. Patients receiving ODX had better survival than those not.

Is there an association between body mass index and 21-gene recurrence score?

PurposeThe 21-gene recurrence score (RS) is an established predictor of recurrence for early stage, hormone receptor positive breast cancer. The association between RS and other risk factors such as obesity has not been fully explored. We hypothesized that patients with obesity may present with primary breast cancers with higher recurrence scores. MethodsWe identified 1546 patients who have body mass index (BMI) recorded around the time of RS assay. Obesity was classified as per CDC definitions of overweight (BMI 25–30 kg/m2) and obesity (BMI >30 kg/m2). RS was assessed as a continuous variable and according to pre- and post-TAILORx classifications. Kaplan Meier survival analysis was employed to assess the interaction between RS and BMI on overall survival (OS) and disease-free survival (DFS). ResultsIn univariate analyses, the median RS in patients with overweight was 15, which was significantly lower than the median RS (16) of patients with normal weight (p = 0.03). The overall recurrence rate of patients with obesity was 4.1%, which was significantly worse than the overall recurrence rate of patients with normal and overweight of 2.6% and 1.5%, respectively (p = 0.05). In multivariate analyses using the inverse probability weighted regression adjustment (IPWRA) method to adjust for imbalances between subgroups, patients with overweight or obesity had significantly lower RS than patients with normal weight, correlating to an average decrease in RS value of 2.37 and 1.71, respectively (both p < 0.01). A similar relationship was seen between BMI categories and RS as a categorical variable stratified according to pre- or post-TAILORx categories. This inverse effect was predominantly seen in post-menopausal patients. Despite the generally lower RS in patients with obesity, a high RS in these patients is associated with diminished DFS (p = 0.04). ConclusionTumors in post-menopausal women with higher BMI generally have lower RS. DFS is significantly worse in women with obesity whose RS ≥ 30. The reasons for poor outcomes for postmenopausal patients with obesity despite lower presenting RS merits further study.

Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer

The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

Impact of 21-gene recurrence score testing on adjuvant chemotherapy decision making in older patients with breast cancer

PurposeTo evaluate the role of 21-gene recurrence score (RS) assay in adjuvant chemotherapy decision-making among older patients with early breast cancer. MethodsConsecutive hormonal receptor-positive, aged ≥60 patients with breast cancer were enrolled from Shanghai Ruijin Hospital between January 2014 and December 2017. Treatment decisions were made by multi-disciplinary team (MDT) before and after 21-gene RS testing, and the actual treatment for each patient was also analyzed. ResultsA total of 511 patients were enrolled, with 331 (64.8%) aged between 60 and 69, 140 (27.4%) between 70 and 79, and 40 (7.8%) over 80 years. There were 138 (27.0%), 287 (56.2%), and 86 (16.8%) patients classified as low, intermediate, and high risk RS, respectively. Multivariable analysis demonstrated that age, tumor stage, nodal status, PR expression, Ki-67, and 21-gene RS were independent impact factors for chemotherapy recommendations (P < .05). Patients with high risk RS and intermediate risk RS (both P < .001) were more often recommended to receive chemotherapy than patients with low risk RS. Treatment recommendations changed in 74 (14.5%) patients after 21-gene RS testing: 17 (3.3%) from chemotherapy to no chemotherapy and 57 (11.2%) from no chemotherapy to chemotherapy. Overall compliance rate to MDT recommendation after 21-gene RS testing was 95.7%. ConclusionAn intermediate and/or high risk 21-gene RS assay was independently associated with receiving adjuvant chemotherapy among older patients with breast cancer. However, it showed a limited impact on adjuvant chemotherapy decision-making. After 21-gene RS testing, compliance with MDT recommendation was relatively high in older patients with breast cancer.

Comparison of 21-gene assay and St.Gallen International Expert Consensus in the treatment decision for patients with early invasive breast cancers

ABSTRACTThis study aimed to evaluate the impacts of 21-gene recurrence score (RS) and St. Gallen International Expert Consensus on treatment decision and prognosis of patients with invasive breast cancer. We retrospectively analyzed the therapy protocol and outcome of 134 cases based on age, body mass index (BMI), menopause, pathological types, tumor-node-metastasis (TNM) stages, percentage of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), Ki-67, molecular subtype, and tumor biomarkers. RS was calculated based on 21-gene assay following traditional (old RS cutoff) and updated (new RS cutoff) National Comprehensive Cancer Network (NCCN) guideline. In addition, we also compared treatment protocol of NCCN guidelines with St. Gallen International Expert Consensus. The results showed that BMI, PR, Ki-67, and molecular subtype are critical for the evaluation of risk factors. Based on the new cutoff, low, middle, and high RS were 18%, 66%, and 16%, respectively. In contrast, based on the old cutoff, low, middle, and high RS were 60%, 29%, and 11%, respectively. The agreement rate of NCCN guidelines and St. Gallen International Expert Consensus for adjuvant treatment was 50. However, there is minimal agreement (0.151, 0.071) in kappa coefficient of old and new cutoff. This study revealed that the combination of NCCN guidelines and St. Gallen International Expert Consensus might improve the benefits of adjuvant treatment in patients with early invasive breast cancer.

250P - The concordance of treatment decision guided by oncotype and the PREDICT tool in early stage breast cancer

BackgroundDecision on adjuvant chemotherapy for early breast cancer can be guided by genomic assays. PREDICT is a validated free online tool that estimates the benefit from adjuvant chemotherapy using clinical and pathological data. The concordance of expected clinical decisions guided by Oncotype analysis and the PREDICT in unknown. MethodsA retrospective single center cohort study comprising all women with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative, node negative disease, whose tumors were sent for OncotypeDX analysis. Estimation of 10-year overall survival (OS) benefit from 2nd generation chemotherapy was calculated using the PREDICT 2.1v tool. Omission of chemotherapy was expected to be advised when Oncotype recurrence score (RS) was ≤25 or when the estimated 10-year OS benefit by the PREDICT was <2%. The tests were considered concordant for women with RS≤25 and estimated PREDICT benefit<2% or for women with RS>25 and estimated PREDICT benefit ≥2%. Concordance was presented using percentages and the K coefficient. The impact on concordance of pre-specified histological features was assessed, including tumor size, intensity of ER and progesterone receptor (PR), grade, Ki67 and perineural and lymphovascular invasion. The difference between the subgroups was calculated using Chi-squared test. ResultsA total of 445 women were included. Overall concordance was 75% (K=0.284), with 55 (12.5%) women with low RS but estimated PREDICT benefit ≥2% and 55 (12.5%) with high RS and estimated PREDICT benefit<2%. The concordance was significantly higher for grade 1 disease compared to grade 2-3 (93% vs 72%, p<0.001), tumor ≤1cm compared to>1cm (85% vs 72%, p=0.009), PR positive compared to PR negative (78% vs 58%, p<0.001) and ki67<20% compared to≥20% (82% vs 54%, p<0.001). The intensity of ER and the presence of perineural or lymphovascular invasion had no significant impact on concordance. ConclusionsCompared to PREDICT, using Oncotype in node negative, ER positive disease is expected to change clinical decision in a quarter of patients. The concordance is influenced by pathological features. The use of Oncotype may not be necessary for clinically very low risk patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureH. Goldvaser: Honoraria (self): Roche. R. Yerushalmi: Honoraria (self): Roche; Honoraria (self): Medison; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Teva. M. Sarfaty: Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Medison; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

Oncotype DX recurrence score implications for disparities in chemotherapy and breast cancer mortality in Georgia

Among women diagnosed with stage I–IIIa, node-negative, hormone receptor (HR)-positive breast cancer (BC), Oncotype DX recurrence scores (ODX RS) inform chemotherapy treatment decisions. Differences in recurrence scores or testing may contribute to racial disparities in BC mortality among women with HR+ tumors. We identified 12,081 non-Hispanic White (NHW) and non-Hispanic Black (NHB) BC patients in Georgia (2010–2014), eligible to receive an ODX RS. Logistic regression was used to estimate the odds of chemotherapy receipt by race and ODX RS. Cox proportional hazard regression was used to calculate the hazard ratios (HRs) comparing BC mortality rates by race and recurrence score. Receipt of Oncotype testing was consistent between NHB and NHW women. Receipt of chemotherapy was generally comparable within strata of ODX RS—although NHB women with low scores were slightly more likely to receive chemotherapy (OR = 1.16, 95% CI 0.77, 1.75), and NHB women with high scores less likely to receive chemotherapy (OR = 0.77, 95% CI 0.48, 1.24), than NHW counterparts. NHB women with a low recurrence score had the largest hazard of BC mortality (HR = 2.47 95% CI 1.22, 4.99) compared to NHW women. Our data suggest that additional tumor heterogeneity, or other downstream treatment factors, not captured by ODX, may be drivers of racial disparities in HR+ BC.

21-Gene Recurrence Score and Adjuvant Chemotherapy Decision for Breast Cancer Patients with Positive Lymph Nodes

The 21-gene recurrence score (RS) assay is prognostic and predictive for hormone receptor (HR)+/HER2-/node- breast cancer (BC) patients. However, its clinical value in node + patients hasn’t been elucidated. HR+/HER2-/pN1 patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital from January 2014 to December 2018, with available RS results were retrospectively included. Clinico-pathological characteristics were compared. Adjuvant chemotherapy recommendations pre-/post- RS assay and actual usage were analyzed. A total of 303 patients were included, with 59, 178, 66 RS < 18, 18–30 and ≥ 31. Age (P < 0.001), comorbidity (P = 0.013), and RS category (P < 0.001) were independently associated with chemotherapy recommendation. Compared with low RS patients, those with intermediate (OR 6.58, 95% CI 2.37–18.31, P < 0.001) or high (OR 54.14, 95% CI 3.77–776.54, P = 0.003) RS were more likely to be recommended with chemotherapy. RS independently influence chemotherapy decision in postmenopausal population as well. Chemotherapy recommendation changed for 9.57% patients after RS assay. Patient adherence rate to chemotherapy recommendation was 94.72% (287/303). The 21-gene RS independently influenced chemotherapy recommendation in pN1 BC patients, which could provide additional information to guide chemotherapy decision with relatively good treatment adherence rate.

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor–Positive Early Breast Cancer

IntroductionA 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor–positive, lymph node–negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries. Patients and MethodsHormone receptor–positive, lymph node–negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period. ResultsThe median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets. ConclusionA nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.

21-Gene recurrence score influences the chemotherapy decision for patients with breast cancer of different luminal subtypes.

Luminal subtypes and the 21-gene recurrence score (RS) are important factors in the decision-making process for adjuvant chemotherapy in patients with hormonal receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, their effect on adjuvant chemotherapy decisions in the real world has not been thoroughly investigated, particularly for patients of the luminal A-like subtype with a high RS or the luminal B-like subtype with a low RS. The present study, a total of 772 HR+/HER2- patients who underwent 21-gene testing, were included in a retrospective analysis. The impact of clinicopathological factors and the 21-gene RS on chemotherapy recommendation was analyzed in the whole population and for patients of different luminal subgroups. The results revealed that chemotherapy was highly recommended for patients of younger age, with larger tumor size, node involvement, higher grade, luminal B-like subtype and higher RS. A high RS was identified to be the most important impact factor for chemotherapy recommendation among all patients [odds ratio (OR), 62.54; 95% CI, 25.58-152.92], the luminal A-like group (OR, 435.05; 95% CI, 29.90-6331.06) and the luminal B-like group (OR, 57.20; 95% CI, 22.42-145.96). For patients of the luminal A-like subtype with a high RS or patients of the luminal B-like subtype with low RS, the 21-gene RS was demonstrated to be the most important independent factor for chemotherapy recommendation, with an adjusted OR of 134.52 (95% CI, 10.39-1741.89). In conclusion, luminal subtypes and the 21-gene RS were found to be associated with chemotherapy recommendation for HR+/HER2- patients. For patients with a discordant luminal subtype and 21-gene RS risk, the 21-gene RS score was found to be the most important factor that influences chemotherapy decision, which warrants further clinical evaluation.

21-Gene Recurrence Score Adds Significant Value for Grade 3 Breast Cancers: Results From a National Cohort.

The 21-gene recurrence score (RS) is used to identify patients with hormone receptor-positive early-stage breast cancer who may benefit from the addition of chemotherapy to endocrine therapy. We hypothesized that many women with poor prognostic histopathologic grade 3 disease may be offered chemotherapy irrespective of RS results, of whom a subset may not benefit from adjuvant chemotherapy. A total of 30,864 women in the National Cancer Database were diagnosed with pT1c to pT2, pN0 to pN1, grade 3 estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive breast carcinoma from 2010 to 2015. RS was stratified as low (less than 18), intermediate (18 to 30), and high (31 or more). Overall survival by RS was evaluated by Kaplan-Meier, log-rank, and multivariable proportional hazards, with adjustment for relevant clinical and demographic variables. RS testing in grade 3 cancers increased between 2010 and 2015 (pN0, 53% to 72%; pN1, 16% to 36%). Among the 13,558 women with pN0 and the 2,840 with pN1 disease with RS testing, 27.1% and 30.0%, respectively, had low scores (less than 18). The 5-year overall survival rate for patients with a high RS, but not low RS, was significantly higher with chemotherapy (v no chemotherapy; absolute differences: high RS pN0 = 12.2% and pN1 = 25.5%, both P < .001; low RS pN0 = 2.5%, P = .07; and pN1 = 1.0%, P = .27), findings that were reinforced in multivariable analyses risk adjusted by clinicopathologic characteristics. Increased use of RS may help to better tailor treatment recommendations by stratifying patients with grade 3 disease into those who will and will not derive survival benefit and should be considered in all patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative T1c to T2, N0 to N1 disease.

Evaluating patterns of utilization of gene signature panels and impact on treatment patterns in patients with ductal carcinoma in situ of the breast

BackgroundBroad patterns of use of the gene signature panel Oncotype DX DCIS and its large-scale impact on postoperative administration of radiation therapy in women with ductal carcinoma in situ of the breast remain unclear. This study sought to evaluate the patterns of use of this gene signature panel in women with ductal carcinoma in situ and the impact of these tools on postoperative radiation therapy administration. MethodsThe National Cancer Database was queried for women with ductal carcinoma in situ treated with breast-conserving therapy who had information regarding whether a gene signature panel was performed between 2010 and 2015. Demographic characteristics, the characteristics of their ductal carcinoma in situ, and whether they received postoperative radiation therapy were compared among patients who did have a gene signature panel performed and those who did not. Patterns of radiation therapy administration were also evaluated based on the recurrence risk score by the gene signature panel. ResultsGene signature panel use increased over time, with a sharp increase in utilization occurring in 2015 (8.0% in 2015 vs 4.4% in 2014, P < .001). Patients with estrogen receptor–positive ductal carcinoma in situ were somewhat more likely to have a gene signature panel ordered (3.9% estrogen receptor positive vs 1.7% estrogen receptor negative, P < .001), as were patients with lower-grade ductal carcinoma in situ (4.5% grade I/II vs 3.1% grade III, P < .001). Gene signature panel utilization was associated with a decrease in the administration of postoperative radiation therapy (48.6% gene signature panel vs 83.4% no gene signature panel, P < .001). Among patients in whom a gene signature panel was performed, postoperative radiation therapy was administered in 81.9%, 72.0%, and 35.9% of patients with high-, intermediate-, and low-recurrence scores, respectively. ConclusionGene signature panel use in patients with ductal carcinoma in situ has increased over time and is more commonly used in women with lower-risk, clinicopathologic features to determine the magnitude of benefit afforded by radiation therapy. Gene signature panel use is associated with decreased rates of postoperative radiation therapy administration, particularly among patients with scores suggesting a low rate of recurrence.

Cost effectiveness of Gene Expression Profiling in Patients with Early-Stage Breast Cancer in a Middle-Income Country, Turkey: Results of a Prospective Multicenter Study.

Breast cancer is a heterogenous disease, and genetic profiling helps to individualize adjuvant treatment. The Oncotype DX is a validated test to predict benefit of adjuvant systemic treatment. The aims of this study are to determine the costs of chemotherapy in government hospitals in Turkey and evaluate the cost-effectiveness of the Oncotype DX from the national insurance perspective. A Markov model was developed to make long term projections of distant recurrence, survival, quality adjusted life expectancy, and direct costs for patients with ER+, HER2-, node-negative or up to 3 node-positive early stage breast cancer. Turkish decision impact study patient data were captured for model reference. In that study, ten academic centers across Turkey participated in a prospective trial. Of 165 patients with pT1-3, pN0-N1mic, ER-positive, and HER-2 negative tumors, 57% had low recurrence score (RS), 35% had intermediate RS, and 8% had high RS, respectively. The overall rate of change in chemotherapy treatment decisions following Oncotype DX was 33%. The cost of adjuvant chemotherapy in public hospitals was estimated at $3.649, and Oncotype Dx test was $5.141. Based on the cost-effectiveness analysis, Oncotype DX testing was estimated to improve life expectancy (+0.86 years) and quality-adjusted life expectancy (+0.68 QALYs) versus standard care. The incremental cost-effectiveness ratio (ICERs) of Oncotype DX was estimated to be $7207.9 per QALY gained and $5720.6 per LY gained versus current clinical practice. As Oncotype DX was found both cost-effective and life-saving from a national perspective, the test should be introduced to standard care in patients with ER+, HER-2 negative early-stage breast cancer in Turkey.

Abstract 3298: Oncotype DX recurrence score: Implications for disparities in receipt of chemotherapy and breast cancer-specific mortality in Georgia

Abstract Background: Among women diagnosed with stage I-IIIa, node negative or positive (1-3), hormone receptor positive (HR+) and HER2 negative breast cancer (BC), the Oncotype DX recurrence score is used to guide chemotherapy treatment decisions. There is limited evidence on differences in the distribution of recurrence scores among non-Hispanic Black women (NHB), and whether this could contribute to the well-documented racial disparities in BC-specific mortality. The objective of this study was to evaluate the role of Oncotype DX recurrence score on racial disparities in BC-specific mortality between black and white women in Georgia. Methods: In this study, patients were identified from the Georgia Cancer Registry. We included 4562 non-Hispanic White (NHW) and 1353 NHB women with an initial diagnosis of stage I-III HR+ breast cancer in Georgia (2010-2014), with a corresponding Oncotype DX recurrence score from Genomic Health, Inc. Logistic regression was used to estimate the odds of chemotherapy receipt between NHB and NHW women by Oncotype DX recurrence score (low [&amp;lt;18], medium [18-30], and high [≥31]). Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) comparing BC-specific mortality rates by both race and recurrence score. Results: Compared with NHW breast cancer patients, NHB women were more likely to be classified with a high recurrence score (11% vs. 7%), and less likely to be classified with a low risk of recurrence (53% vs. 59%). In the age-adjusted models, NHB women with a high recurrence score were less likely to receive chemotherapy (OR=0.60, 95%CI 0.35, 1.04), however there was no difference in receipt of chemotherapy between NHB and NHW women with low or medium recurrence risk scores. After adjusting for age, we observed that NHB women with a low recurrence score had 3.05 times the hazard of BC-specifc mortality (95%CI 1.29, 7.04) compared to NHW women. Among women with a medium or high recurrence score we did not observe a racial disparity in BC mortality (HRhigh vs. low=1.49, 95%CI 0.51, 4.37). Conclusion: Our results indicate variation in receipt of chemotherapy by race, particularly among NHB women with a high Oncotype DX score. However, we observed the most pronounced racial disparity in BC-specific mortality among women with low Oncotype Dx recurrence scores. These findings should be replicated in larger studies with robust numbers of NHB women. Additional research is needed to understand differences in chemotherapy treatment decisions and validation of the Oncotype DX recurrence score cut points in diverse populations. Citation Format: Lindsay J. Collin, Brittany Crawford, Ming Yan, Renjian Jiang, Kevin Ward, Mylin Torres, Keerthi Gogineni, Preeti Subhedar, Lauren E. McCullough. Oncotype DX recurrence score: Implications for disparities in receipt of chemotherapy and breast cancer-specific mortality in Georgia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3298.

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

BackgroundThe use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known.MethodsWe performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger.ResultsThe level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%).ConclusionsClinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)

Talking about risk in the context of genomic tests (TARGET): development and evaluation of an educational program for clinicians

PurposeGene expression profiling (GEP) test scores calculate risks of recurrence and likely benefit of adjuvant chemotherapy in ER-positive, HER2-negative, early-stage breast cancer. As health literacy and numeracy skills in the general population are poor, healthcare professionals (HCPs) require a wide repertoire of communication skills to explain clearly risk of recurrence scores (RSs) and uncertainty. We developed and evaluated an educational program for HCPs discussing GEP test results and adjuvant treatment.MethodsEight-hour workshops contained elements aimed at improving knowledge, communication skills and self-awareness; these included the science underpinning GEP tests, an interactive risk psychology lecture, exercises and facilitated group discussions regarding seven filmed scenarios involving discussions about high, intermediate and low RSs. Attendees were recorded explaining RSs with patient simulators pre and post workshop. Researchers, blinded to time point, analysed recordings using a study-specific scoring system. Primary objective outcomes were improvements post workshop in HCPs’ competence and confidence when communicating 17 pre-specified key information areas. We estimated odds ratios (OR) using conditional logistic regression to compare pre- and post-workshop scores.Results65 HCPs attended. Objective analyses revealed significant positive shifts post workshop which included explaining GEP tests (OR 2.98; 95% CI 1.38–6.42; P = .001), recurrence RSs (OR 3.99; 95% CI 1.72–9.25; P < .001), benefits of chemotherapy (OR 3.99; 95% CI 1.82–8.75; P < .001; and harms OR 2.31; 95% CI 1.37–3.92; P < .001) using jargon free language (OR 5.29; 95% CI 2.27–12.35; P < .001). Patient simulator assessments also showed significant improvements as did HCPs’ self-assessments and ratings of their self-confidence when discussing different GEP tests with diverse patient types (P < .001).ConclusionThese short, intensive, interactive TARGET workshops significantly improved HCPs’ communication about GEP results in ways likely to promote more informed decision-making by patients about chemotherapy.

Stratification of oncotype (ODX) Recurrence Score (RS) by Breast Cancer Index (BCI) and its relation to discordance.

e12025 Background: ODX is a gene-expression panel predictive of 10-year risk of distant recurrence and has shown prognostic value in both node-negative (LN-) and node-positive (LN+) breast cancer (BC) patients. BCI predicts 10-year risk of recurrence and also identifies those that may benefit from extended adjuvant endocrine therapy (EET). We stratified ODX RS by BCI to compare its precision in predicting recurrence category and its relation to discordance. Methods: 49 women with HR+, LN- and LN+ BC with available ODX and BCI RS with median follow up of 6 years were included. BCI risk groups were evaluated using predetermined cutoffs. RS were stratified by traditional ODX and TAILORx cutoffs and were considered discordant if there was a 1-step or 2-step difference between ODX risk group (low, intermediate, high) and tumor grade (well, moderately and poorly differentiated). N (%) or median (range) were used to describe patients’ characteristics between BCI groups and compared by chi-square test or Fisher’s exact at the confidence level of 5%. Results: Using traditional RS cutoffs, BCI reclassified 42.3% of patients with low RS as intermediate (IR) or high risk (HR). 69% with intermediate RS were reclassified to low risk (LR) and 12% were upgraded to HR by BCI. 27% of low and intermediate RS had a high benefit from EET. 2-step discordance was 14.3%. Using TAILORx RS cutoffs, BCI reclassified 20% of patients with low RS as IR. None were upgraded to HR. In the intermediate RS group, 58% were reclassified as LR and 14% as HR. 24% of intermediate RS had a high benefit from EET. 2-step discordance was 2%. Conclusions: Patients classified as LR by TAILORx RS cutoffs are less likely to be reclassified as high or intermediate risk by BCI. No significant association was found between discordance among ODX RS and tumor grade and BCI prediction of recurrence or benefit of EET.

Breast cancer-specific survival outcomes among patients based on 21-gene recurrence score.

537 Background: The 21-gene recurrence assay predicts cancer recurrence rates and benefit from adjuvant chemotherapy among patients with hormone-receptor-positive breast cancer. The National Cancer Institute and Genomic Health collaborated to provide Recurrence Score (RS) results to complement data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Program. Methods: Using the SEER database with linked RS results, a cohort of female breast cancer patients, age greater than 20 years, was identified by RS (low: &lt; 18, intermediate: 18-30, high: &gt; 30) diagnosed between the years 2004 and 2007. A retrospective analysis was conducted to determine eight-year breast cancer-specific survival rates based on RS and other variables. Results: 10,318 patients were identified in the cohort. 5,194 had a low risk RS; 4,282 had an intermediate risk RS; 872 had a high risk RS. Histologic subtypes were: 7,459 infiltrating ductal carcinoma, 941 mixed infiltrating and lobular carcinoma, 933 lobular carcinoma, 327 mixed infiltrating ductal and other histology, 244 mucinous adenocarcinoma, 101 tubular adenocarcinoma, 45 mixed lobular and other histology, 268 other histologies. 644 low risk RS patients received chemotherapy (12.4%); 1,608 intermediate risk RS patients received chemotherapy (37.8%); 593 high risk patients received chemotherapy (68.0%). The eight-year breast cancer-specific survival rates (with 95% confidence intervals) among low risk RS patients without known chemotherapy administration was 98.9% (98.5, 99.2), and 98.4% (97.0, 99.1) with chemotherapy; intermediate risk RS patients without known chemotherapy was 97.0% (96.2, 97.6), and 96.9% (95.9, 97.7) with chemotherapy; high risk RS patients without known chemotherapy was 89.7% (85.4, 92.8), and 92.9% (90.4, 94.7) with chemotherapy. Conclusions: Among a large cohort of patients identified in a population-based cancer registry between 2004 and 2007, there was no statistically significant difference in eight-year breast cancer-specific survival rates among those who received chemotherapy and those who did not, regardless of RS risk group.

Oncotype recurrence score (RS) and discordance in patients with secondary invasive breast events (SIBE).

e12016 Background: Oncotype RS is a 21-gene assay used to predict the likelihood of distant recurrence and benefit of chemotherapy in patients with node-negative, tamoxifen treated breast cancer (BC). We developed a database to determine rates of SIBE and identify cases of discordance between Oncotype RS and tumor grade (TG). Our goal was to recognize patients with discordant tumors who had SIBE, with implications for patient management. Methods: We identified 618 patients (645 samples) with early-stage, hormone positive BC treated between 2006-2018, with tumor characteristics available for analysis. Among these patients, there were 24 SIBE (n = 24) from 23 patients (3.7%). When stratified by RS using traditional cutoffs (Paik, 2004), rates of SIBE were 2.8%, 5.0% and 4.5% in low, intermediate and high-risk groups respectively. Discordance was defined as 1 or 2-step difference between RS (low, intermediate, high risk) and TG (well (WD), moderately (MD) and poorly (PD) differentiated). Prior studies demonstrated 7-19% “2-step discordance” between TG and RS (i.e. PD tumors with low-risk RS or WD tumors with high-risk RS). N(%) or median were used to describe patients’ characteristics between groups and compared by Mann-Whitney U test at the confidence level of 5%. Results: Of the 24 SIBE, 42% had low RS ( &lt; 18), 46% had intermediate RS (18-30) 12% had high RS ( &gt; 31). Median RS was 22 and median age at secondary event was 61 (67% post-menopausal). At time of SIBE, 54% were metastatic, 25% locally recurrent and 21% contralateral. Within this dataset, 63% were 1-step and 4% were 2-step discordant. Significantly fewer patients were treated with systemic chemotherapy in the discordant group (p &lt; 0.01), though 94% displayed MD or PD TG. Discordant tumors tended to have lower RS (median 14 vs. 24) and be larger. There were no significant differences in menopausal status or Oncotype ER/PR score. Conclusions: Although the sample size of patients with SIBE is small, our data suggests that patients with discordant tumors of low-risk RS but higher TG may be receiving inadequate treatment (i.e. no chemotherapy). In addition to RS, other factors such as discordance, TG and size should perhaps be considered when determining treatment plans.