Axillary Node-negative Breast Cancer Research Articles

Adjuvant Chemotherapy for Low-Clinical-Risk Breast Cancer Defined by Modified Version of Adjuvant! Online: A Propensity Score Matched SEER Analysis

Background: The purpose of this research was to investigate whether the modified version of Adjuvant! Online was able to omit chemotherapy (CT) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and axillary node-negative breast cancer, who are defined as low clinical risk. Methods: From 2010 to 2014, HR-positive, HER2-negative, and node-negative breast cancer patients aged 50 years and older were retrieved from the Surveillance, Epidemiology, and End Results (SEER) 18 database. The propensity score matching method was applied between the no-CT and CT groups. Overall survival (OS) was evaluated using Kaplan-Meier analysis and compared across groups using a log-rank test. Results: A total of 48,857 patients were enrolled. After propensity score matching, the numbers of patients in the no-CT and CT groups were both 3,102. The median follow-up period was 37 months. The 5-year OS rates in the no-CT and CT groups were 92 and 91%, respectively (p = 0.066). In the subgroup with a tumor score (tumor size added to tumor grade) of 2–3, OS was significantly higher in the no-CT group than in the CT group (93 vs. 90%, p < 0.001). In the subgroup with a tumor score of 4, OS was not different between these 2 groups (92 vs. 93%, p = 0.47). Conclusion: This retrospective study provides evidence that CT may not be beneficial to patients 50 years of age or older with HR-positive, HER2-negative, axillary node-negative breast cancer and additionally defined as low clinical risk by a modified version of Adjuvant! Online.

Early discontinuation to adjuvant endocrine therapy in the ECOG-ACRIN TAILORx Trial.

7004 Background: The TAILORx study demonstrated women with an intermediate Oncotype DX score receive the same benefit with endocrine therapy (ET) compared to chemoendocrine therapy (CET). However, early discontinuation of adjuvant ET is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the full 5 years of recommended ET treatment. The aim of this study was to identify patient-level risk factors associated with early discontinuation of ET in the TAILORx study. Methods: TAILORx was coordinated by the ECOG-ACRIN Cancer Research Group. Participants were a subgroup of 954 women who completed additional measures on health-related quality of life (HRQoL) including endocrine symptoms (ES) physical well-being (PWB) and social well-being (SWB) prior to initiating ET, which categorized into three groups by tertile for analysis. All participants were diagnosed with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer who started ET within a year of study entry. Early discontinuation of ET, defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence, was assessed by clinician report. Rate of discontinuation was calculated using Kaplan-Meier estimates, and Cox-proportional hazards joint models were used to analyze the association between rates of adherence to ET with patient-level factors. Results: In a joint model, receipt of CET therapy (vs receipt of ET only; HR = .59, 95% CI .38-.94, p = .02) and age above 40 (versus age &lt; = 40; HR = .30, 95% CI .14-.66, p = .003) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared to no history of depression (HR 1.82, 95% CI 1.19-2.77, p = 0.005), worse ES compared to better ES (HR 1.70, 95% CI 1.06-2.74, p = 0.03), worse PWB compared to better PWB (HR 2.12, 95% CI 1.30-3.45,p = 0.003), and worse SWB compared to better SWB (HR 1.94, 95% CI 1.20-3.13, p = 0.007) were individually and significantly associated with a higher probability of early discontinuation of ET, although none reached statistical significance when all were included in a joint model. Conclusions: Younger women are at risk for early discontinuation and modifiable characteristics such as HRQoL and history of depression are potential risk factors for early discontinuation of ET. These results support systematic screening for HRQoL and depressive symptoms to identify women at risk for discontinuation of ET. Clinical trial information: NCT00310180 .

Statistical machine learning model to predict Oncotype DX risk category in women over age 50.

524 Background: The 21-gene Oncotype DX Breast Recurrence Score multigene assay (RS) identifies women with ER positive, HER negative, axillary node-negative breast cancer (BC) for whom chemotherapy provides no invasive disease-free survival benefit compared to endocrine therapy alone. International adoption of RS testing is limited by cost and resource availability. We created a supervised statistical machine learning model using standard clinicopathologic data to predict RS risk category in women &gt; 50 years old. Methods: From 2012 to 2018, women with ER positive, HER2 negative, pathologically node-negative BC of all ages were retrospectively identified from a prospective institutional database. Standard clinicopathologic data and RS were collected. Per institutional protocol, RS are ordered for all early-stage, ER positive tumors &gt; 5 mm. Data were randomly split into training (n=3755) and validation sets (n=1609). A random forest model with 500 trees was developed on the training set, then evaluated on the validation set. Model predictors included age, tumor size, histologic subtype, hormone receptor status, lymphovascular invasion, and overall grade. The model was used to predict RS category (low risk: RS ≤ 25, high risk: RS &gt; 25) in women &gt; 50 years old. Results: 5364 unique tumors in 5189 women were identified. 3731 (70%) of tumors were identified in women &gt; 50 years; median age was 63 years (IQR 57-69). In women &gt; 50, median tumor size was 12 mm (IQR 9-17). Most tumors were invasive ductal (79%), low or intermediate grade (79%), and LVI was absent in 82% of tumors. Median ER staining by IHC was 95%; 28% of tumors had negative or weakly positive PR staining (1-20%). The model correctly classified 96.8% of patients as low risk (95% CI: 95.7-97.7). Negative predictive value for identifying low risk category was also high (92.3%, 90.7-93.6). Sensitivity for identifying high-risk women was 44.7% (37.4-52.1) and positive predictive value was 67.2% (58.2-75.3). A classification table on the validation set includes tumors with complete data available, including predictors and RS. Conclusions: Our model was highly specific (96.8%) for identifying women &gt; 50 with RS ≤ 25 who do not benefit from adjuvant chemotherapy. This model may be utilized in lieu of RS testing if cost and availability are prohibitive. True RS &gt; 25 was not as well predicted. The model will be refined following pathologic review of discordant cases to reduce false negatives. [Table: see text]

Breast cancer patients’ insurance status correlates with their adherence to endocrine therapy: Analysis of ECOG-ACRIN TAILORx trial.

7041 Background: Cancer patients spend substantial amounts on their healthcare services, and are at high risk for financial toxicity, a patient-reported outcome shown to be associated with care non-adherence. Even with insurance, cancer patients often face unpredictable or unmanageable costs. In women with breast cancer enrolled in TAILORx trial, we investigated the association between study entry insurance status and adherence to endocrine therapy (ET). Methods: Women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer enrolled in TAILORx clinical trial who started ET within a year of study entry were included. Early discontinuation was defined as stopping ET within 4 years of start for reasons other than distant recurrence or death, and the rate was calculated using Kaplan-Meier estimates. Cox proportional hazards model was used to analyze association between the patients’ insurance status at study entry and early discontinuation of ET incorporating patients’ treatment, age, race and Recurrence Score in the model. Results: A total of 9,475 patients were included (mean age: 55.6; 84% white; 9% Hispanic). A total of 58.0% had private insurance, while 11.7% had Medicare; 5.8% had Medicaid; 0.98% had military/VA insurance; 3.8% were self-pay, and 19.1% were patient recruited from international sites. The rates of 4-year early discontinuation were highest among self-pay (18.7%) and Medicaid patients (18%) and lowest among patients with military/VA insurance (8.6%) and international sites (9.8%). In multivariable analysis, compared to private insurance patients with Medicaid (HR 1.6; 95% CI 1.3-2.0) and self-pay (HR 1.6; 95% CI 1.3-2.1) had higher probability of discontinuing ET within 4 years of start and those at international sites had lower probability of early discontinuation (HR 0.8; 95% CI 0.7-0.9) (All p values &lt; 0.05). Conclusions: Patients’ insurance status plays an important role in adherence to ET with uninsured and underinsured having a high rate of treatment non-adherence. Early identification of patients at risk and enrollment in insurance optimization programs may improve adherence to therapy. Clinical trial information: NCT00310180 .

Evaluation of axillary reverse mapping (ARM) in clinically axillary node negative breast cancer patients - Randomised controlled trial.

Axillary lymph node dissection (ALND) is an important procedure for control of axillary nodal metastasis in breast cancer patients. Lymphedema, restriction of shoulder movement and axillary nodal recurrence are the most disabling complications of the procedure. Axillary reverse mapping (ARM) procedure for arm lymph node identification emerged as a step for their preservation during ALND. Here we are testing the effect of ARM on lymphedema development and whether it compromises oncological safety in early breast cancer patients. 98 clinically node free breast cancer female patients undergoing completion ALND after positive sentinel lymph node biopsy were recruited in the study. They were put into group A (49 patients with ARM+ve preservation ALND) and group B (49 patients in the conventional ALND group). ARM procedure was performed in both groups, ARM positive nodes were preserved in group A, marked and taken out with other axillary LN in group B. The outcome was histopathology of ARM+ve LN, development of arm lymphedema, and restriction of shoulder movement on follow-up. ARM was positive in 46 patients (93.8%) in group A and 43 patients (87.8%) in group B, ARM+ve LN revealed positive metastasis only in 1 patient (2.3%) in group B. Lymphedema developed in 3 (6.5% patients in group A and 9 patients (20.9%) in group B. Restriction of shoulder movement showed a non-significant difference between the two groups. Axillary reverse mapping and preservation of arm lymphatics helped to decrease the lymphedema rate without compromising oncological safety in early breast cancer.

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy

A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. The adjuvant chemotherapy regimen was selected by the treating physician. Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. ClinicalTrials.gov identifier: NCT00310180.

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.)

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update—Integration of Results From TAILORx

This focused update addresses the use of Oncotype DX in guiding decisions on the use of adjuvant systemic therapy. ASCO uses a signals approach to facilitate guideline updating. For this focused update, the publication of the Trial Assigning Individualized Options for Treatment (TAILORx) evaluating noninferiority of endocrine therapy alone versus chemoendocrine therapy for invasive disease-free survival in women with Oncotype DX scores provided a signal. An expert panel reviewed the results of TAILORx along with other published literature on the Oncotype DX assay to assess for evidence of clinical utility. For patients with hormone receptor-positive, axillary node-negative breast cancer whose tumors have Oncotype DX recurrence scores of less than 26, there is little to no benefit from chemotherapy, especially for patients older than age 50 years. Clinicians may recommend endocrine therapy alone for women older than age 50 years. For patients 50 years of age or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the panel recommends that oncologists may offer chemoendocrine therapy to these patients with recurrence scores of 26 to 30. Additional information can be found at www.asco.org/breast-cancer-guidelines.

Cost-effectiveness analysis of multigene expression profiling assays to guide adjuvant therapy decisions in women with invasive early-stage breast cancer.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays' utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

Abstract P2-08-24: The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25

Abstract Introduction: The recent TAILORx results suggests that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone–positive, HER2-negative, axillary node–negative breast cancer who had an Oncotype Dx recurrence score (ODXRS) between 11 and 25. These findings, along with updated results that patients with an ODXRS &amp;lt; 11 have a 9-year recurrence rate of only 3%, suggest that certain populations of patients with an ODXRS ≤ 25 may not benefit from additional systemic chemotherapy. Oncotype Dx is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the United States, and internationally. The test can be performed only at a commercial specialized laboratory. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 2013;26(5):658–664) we published an algorithm based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28(7):921-31) that suggested our algorithm offered a less expensive alternative to Oncotype DX testing. We have validated this algorithm in a multi-institutional study on an additional 619 patients with ODXRS's (in preparation for publication). Our validation data, and our data from the original study, also suggests that the average modified Magee equation can reliably predict patients who will have an ODXRS ≤ 25. Methods: 903 cases with an available ODXRS (2006-2018) were identified from the pathology files at the University of Rochester Medical Center (n = 752) and the University of Louisville (n = 151). Information required to calculate the average modified Magee score, which includes estrogen receptor (ER) and progesterone receptor (PR) status, Her-2 status, Nottingham score, tumor size, and Ki-67 were also extracted from the medical record. 78 patients did not have an available Ki-67, leaving 825 patients for inclusion in this study. Results: 478/488 (98%) patients with an average Modified Magee score ≤ 18 had an ODXRS ≤ 25 (only 2% had an ODXRS &amp;gt; 25 - Table 1). 125/337 (37%) patients with an average Modified Magee score &amp;gt;18 had an ODXRS &amp;gt; 25 (Table 1) . Conclusions: The average Modified Magee Score can be helpful in predicting an ODXRS ≤ 25. Patients with an average Modified Magee score ≤ 18 may not need to be sent out for Oncotype Dx testing. The potential cost savings to the health care system would be enormous. Table 1:Average Modified Magee score and risk of an Oncotype Dx recurrence score (ODXRS) &amp;gt; 25Magee scorenAverage ODXRSMinimum ODXRS valueMaximum ODXRS valueCases with ODXRS &amp;gt; 25 [n (%)]≤ 91811.02190 (0)102110.90261 (4.8)113712.10250 (0)126012.00281 (1.7)136412.00230 (0)147012.90271 (1.4)156513.61313 (4.6)165614.12292 (3.6)175214.50272 (3.8)184514.30250 (0)195418.96379 (16.7)204319.30348 (18.6)215921.193715 (25.4)223819.32496 (15.8)232523.383811 (44)242920.83329 (31)252325.0144011 (47.8)&amp;gt; 25-272729.2174620 (74.1)&amp;gt; 27-301634.9225113 (81.3)&amp;gt; 302345.7317823 (100)≤ 1848812.903110 (2)&amp;gt; 1833723.7078125 (37) Citation Format: Turner BM, Sanders MA, Breaux A, Soukiazian A, Soukiazian N, Hicks DG. The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25 [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 P2-08-24.

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.

Many Women With the Most Common Form of Breast Cancer Can Skip Chemotherapy: Study finds that approximately 70% of patients with this form of the disease do not need adjuvant chemotherapy.

Many Women With the Most Common Form of Breast Cancer Can Skip Chemotherapy: Study finds that approximately 70% of patients with this form of the disease do not need adjuvant chemotherapy.

Tumoral BRD4 expression in lymph node-negative breast cancer: association with T-bet+ tumor-infiltrating lymphocytes and disease-free survival

BackgroundWe previously observed that T-bet+ tumor-infiltrating T lymphocytes (T-bet+ TILs) in primary breast tumors were associated with adverse clinicopathological features, yet favorable clinical outcome. We identified BRD4 (Bromodomain-Containing Protein 4), a member of the Bromodomain and Extra Terminal domain (BET) family, as a gene that distinguished T-bet+/high and T-bet−/low tumors. In clinical studies, BET inhibitors have been shown to suppress inflammation in various cancers, suggesting a potential link between BRD4 and immune infiltration in cancer. Hence, we examined the BRD4 expression and clinicopathological features of breast cancer.MethodsThe cohort consisted of a prospectively ascertained consecutive series of women with axillary node-negative breast cancer with long follow-up. Gene expression microarray data were used to detect mRNAs differentially expressed between T-bet+/high (n = 6) and T-bet−/low (n = 41) tumors. Tissue microarrays (TMAs) constructed from tumors of 612 women were used to quantify expression of BRD4 by immunohistochemistry, which was analyzed for its association with T-bet+ TILs, Jagged1, clinicopathological features, and disease-free survival.ResultsMicroarray analysis indicated that BRD4 mRNA expression was up to 44-fold higher in T-bet+/high tumors compared to T-bet−/low tumors (p = 5.38E-05). Immunohistochemical expression of BRD4 in cancer cells was also shown to be associated with T-bet+ TILs (p = 0.0415) as well as with Jagged1 mRNA and protein expression (p = 0.0171, 0.0010 respectively). BRD4 expression correlated with larger tumor size (p = 0.0049), pre-menopausal status (p = 0.0018), and high Ki-67 proliferative index (p = 0.0009). Women with high tumoral BRD4 expression in the absence of T-bet+ TILs exhibited a significantly poorer outcome (log rank test p = 0.0165) relative to other subgroups.ConclusionsThe association of BRD4 expression with T-bet+ TILs, and T-bet+ TIL-dependent disease-free survival suggests a potential link between BRD4-mediated tumor development and tumor immune surveillance, possibly through BRD4’s regulation of Jagged1 signaling pathways. Further understanding BRD4’s role in different immune contexts may help to identify an appropriate subset of breast cancer patients who may benefit from BET inhibitors without the risk of diminishing the anti-tumoral immune activity.

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

BackgroundThe recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.MethodsWe performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death).ResultsEndocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.ConclusionsAdjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180.)

MicroRNA-10b expression in node-negative breast cancer-correlation with metastasis and angiogenesis.

Metastasis accounts for the majority of cases of mortality in patients with axillary lymph node-negative (ANN) breast cancer. Angiogenesis is an essential component of the metastatic pathway. Studies regarding microRNA (miR)-10b expression in patients with ANN breast cancer and the function of angiogenesis in breast cancer remain scarce. The present study was performed in order to determine the biological significance of miR-10b, and investigate the association between miR-10b and microvessel density (MVD) measured in ANN breast cancer. miR-10b expression and immunohistochemical analysis for MVD were assessed in 195 patients with ANN of invasive ductal carcinoma, including 65 cases with distant metastasis ‘poor group’, and 130 cases without any recurrence ‘good group’. miR-10b expression was higher in the ‘poor group’ (73.8%) compared with that in the ‘good group’ (51.5%; P=0.003). Multivariate logistic regression demonstrated that miR-10b retained independent prognostic significance for distant metastasis along with MVD and vascular invasion. Among 195 patients, miR-10b expression was significantly associated with tumor grade, tumor size and molecular subtypes (P<0.05). In addition, miR-10b expression was positively associated with the MVD count (r=0.370; P<0.001), tumor grade (r=0.168; P=0.019) and tumor size (r=0.175; P=0.014). The results of the current study suggest that miR-10b is a useful marker for predicting metastasis and angiogenesis in ANN breast cancer.

Apparent diffusion coefficient in estrogen receptor-positive and lymph node-negative invasive breast cancers at 3.0T DW-MRI: A potential predictor for an oncotype Dx test recurrence score.

To measure the apparent diffusion coefficient (ADC) values in estrogen receptor-positive (ER+) and axillary lymph node-negative (LN-) invasive breast cancer and investigate the correlation of ADC with Oncotype Dx test recurrence scores (ODxRS). This was a Health Insurance Portability and Accountability Act (HIPAA)-compliant single-site retrospective study. Patients underwent preoperative 3.0T MRI scans with additional diffusion-weighted imaging sequential scans (b = 0, 600 and b = 0, 1000 s/mm2 ) from January 2011 to 2013. The study population included 31 ER+/LN- invasive breast cancers, which underwent ODxRS genomic testing. ADC600 and ADC1000 parametric maps were generated, and ADC values were calculated from a user-drawn region of interest. ODxRS predicts 10-year recurrence risk in individual patients: low (RS <18), intermediate (RS: 18-30), or high (RS >30). All breast lesions, including subgroups of invasive ductal carcinoma (IDC) lesions and mass-only lesions were dichotomized by RS scores, low-risk versus intermediate/high-risk, and statistical analysis was performed using Mann-Whitney's test (statistical significance at P < 0.05) and receiver operating characteristic (ROC) curves. Multivariate analysis was also performed. Invasive breast cancers, when scored as low-risk by ODxRS, had significantly higher ADC values compared with intermediate/high-risk lesions for both ADC600 (P = 0.007) and ADC1000 (P = 0.008) mean values. This was true both when analyzing only mass-lesions (P = 0.03 and 0.01) or only IDCs (P = 0.001 and 0.009). Preliminary findings suggest that lesion ADC values correlate with recurrence risk likelihood stratified using ODxRS. Hence, ADC is a potential surrogate biomarker for tumor aggressiveness. 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:401-409.

Abstract P1-12-02: Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group

Abstract Purpose: To compare the sequential versus the concurrent administration of epirubicin and docetaxel as adjuvant therapy in high risk axillary node negative women with early breast cancer. Patients and treatment: Women 18-75 years old with invasive breast adenocarcinoma surgically resected with no infiltrated axillary lymph nodes and absence of metastatic disease were randomized to receive 4 cycles of epirubicin 90mg/m2 followed by 4 cycles of docetaxel 75mg/m2 (sequential regimen) or 6 cycles of epirubicin 75mg/m2 followed by docetaxel 75mg/m2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with prophylactic G-CSF support for days 3-10 only for the concurrent regimen. Stratification was based on menopausal status, tumor size and hormone receptor expression. By protocol amendment in 2008 women with HER2 positive tumors were excluded. The primary endpoint of the study was to compare the disease-free survival (DFS) at 5 years and 329 patients were scheduled to enroll on each arm. Results: Between 2001-2013, 658 women were randomized and received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 and 52 years, premenopausal status 43.8% versus 44.1%, tumor size &amp;lt;2cm in 44.1% versus 44.4%, histological grade 3 tumor in 52% versus 53.5% and hormone receptor negative disease in 33.1% versus 37.4% of patients in the sequential and concurrent regimens, respectively. After a median follow up of 70.5 and 70 months, there were 29 (8.8%) versus 42 (12.8%) disease relapses (p=0.102) and 11 (3.3%) versus 19 (5.8%) deaths (p=0.135), in the sequential and concurrent arms, respectively. The median DFS has not yet been reached in either arm (p=0.053) and the 5-year DFS rates were 92.6% versus 88.2% for sequential and concurrent arms, respectively. Dose reduction was required in 1.2% versus 3% (p=0.001) of the treatment cycles in the sequential and concurrent arms, respectively. Toxicity included grade 2-4 neutropenia in 54% versus 41% (p=0.001), febrile neutropenia 2.7% versus 6.1% (p=0.06), anemia 12% versus 17% (p=0.07), nausea/vomiting 18.5% versus 12.4% (p=0.03) of patients in the sequential and concurrent arms, respectively. There were no toxic deaths. Conclusion: In this interim analysis both the efficacy and the toxicity profile seem to favor the sequential over the concurrent regimen. Citation Format: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Timotheadou E, Rigas G, Varthalitis I-I, Kalbakis K, Agelaki S, Georgoulias V. Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-02.

Abstract P2-08-01: Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry

Abstract Background: The Trial Assigning Individualized Options for Treatment (TAILORx) is a prospective trial evaluating the role of endocrine therapy or chemoendocrine therapy in patients 18-75 years of age with estrogen receptor (ER)-positive, HER2-negative breast cancer, a primary tumor between 0.6-5.0 cm, and negative axillary nodes, a population for whom chemotherapy is typically recommended or least considered based on National Comprehensive Cancer Center Network (NCCN) guidelines. Methods: The trial was designed to demonstrate non-inferiority of endocrine therapy compared with chemoendocrine therapy in the randomized group with an Oncotype DX Recurrence Score (RS) of 11-25. Patients with a low RS &amp;lt; 11 were assigned to endocrine therapy alone and with a high RS &amp;gt; 25 assigned to chemoendocrine therapy, and both groups were followed in a prospective registry. The definition of an intermediate RS differed in this trial (RS 11-25) from the original reports (RS 18-30) in order to reduce the risk of chemotherapy undertreatment in patients with a mid-range or low RS (Sparano &amp; Paik. J Clin Oncol 2008; 26:721-728). Results: The trial enrolled 10,273 patients between April 2006 and October 2010, of whom 6907 patients (67.2%) had a mid-range RS of 11-25, 1737 (16.9%) had a high RS &amp;gt; 25, and 1639 (15.9%) had a low RS of &amp;lt; 11. At the fourth planned interim analysis, the ECOG-ACRIN data monitoring committee recommended that the study continue as planned for the randomized group with a RS 11-25, and that the results be released to the investigators for the low risk group with a RS &amp;lt;11. The characteristics of the low risk registry population are as follows: age 50 or less (27%), 51-60 (35%), &amp;gt; 60 (39%); tumor size &amp;lt; 1 cm (8%), 1-2 cm (61%), &amp;gt; 2 cm (31%); histologic grade low (34%), intermediate (59%), high (7%); breast conservation (68%) or mastectomy (32%). Initial endocrine therapy included tamoxifen in 35%, aromatase inhibitors in 59%, ovarian function suppression in 3%, and unspecified therapy in 3%; 5 patients received adjuvant chemotherapy (1 of whom relapsed). Five-year rates (and 95% confidence intervals [CI]) for low RS group were 99.2% (98.5, 99.6%) for distant relapse free interval, 98.5% (97.7, 99.1%) for relapse-free interval, 93.7% (92.2, 94.9%) for invasive disease free survival, and 98.2% (97.3, 98.7%) for overall survival. Information regarding ER, PR, and HER2 RNA expression will be presented. Conclusions: Despite meeting guidelines for recommending or at least considering adjuvant chemotherapy based on classical clinicopathologic features, the risk of recurrence was very low at 5 years in patients with ER-positive, HER2-negative, axillary node-negative breast cancer and a low RS of &amp;lt; 11 treated with endocrine therapy alone without chemotherapy. Citation Format: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer Jr CE, Dees EC, Perez EA, Olson Jr JA, Zujweski J, Keane MM, Gomez Moreno HL, Reddi RP, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Atkins JN, Berenberg JL, Sledge Jr GW. Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-01.

Prospective Validation of a 21-Gene Expression Assay in Breast Cancer

BackgroundPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.MethodsWe performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).ResultsOf the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).ConclusionsAmong patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)

Abstract A2-61: Functional enrichment and pathway analysis of the transcriptome related to lymphovascular invasion and recurrence in axillary-node negative breast cancer

Abstract We previously reported that the presence of Lymphovascular invasion (LVI) is an independent predictor of recurrence in axillary node-negative breast cancer (ANNBC). We produced a unique set of gene expression microarrays specifically designed to identify genes with altered expression in LVI+ tumors (n= 37) compared to LVI- tumors (n = 68). We further examined expression differences in a second analysis designed to discover, within LVI+ tumors alone, clinically relevant genes involved in early recurrence (n = 4, smaller than 4 years) vs. no recurrence for at least 10 years (n = 41). To identify genes and pathways involved in LVI and recurrence in ANNBC, we performed a functional analysis of the expression data. We used the publicly available database tool via WebGestalt to perform a web-based enrichment analysis including Gene ontology, KEGG and the Cytogenetic band. In parallel, using Ingenuity pathway® (IPA), we identified networks, upstream regulators and canonical pathways. IPA provides the probability that the association between the genes in the dataset and the canonical pathways could be explained by chance alone through a right-tailed Fisher's exact test p-value. IPA use a z-score algorithm for predicting activation which reduces the chance that random data will generate significant predictions. In LVI+ vs LVI- analysis, the top IPA activated biofunctions are related to proliferation and migration. In LVI+REC+ vs LVI+REC- analysis, they are related to cell survival and migration as well as lipid synthesis and metabolism. The subset of genes identified in both comparisons include those involved in polarization of cells, oxidation of lipids, cellular homeostasis and growth of the lymphatic system component, with decreased cell death and apoptosis biofunctions. Our bioinformatics analyses are consistent with a migratory phenotype for cancer cells associated with LVI. In addition, we observed that inflammation related pathways are enriched in the LVI+ subgroup that undergoes early recurrence. In the upstream regulator IPA analysis, TGFb NFKb and PI3K are involved in the LVI+ in respect to LVI tumors as well as in LVI+REC+ tumors in respect to LVI+REC- tumors. The results suggest important pathways as well as upstream regulators associated with LVI and recurrence that are involved in invasion and cell fate biofunctions. The findings are currently being evaluated through mRNA and protein validation as well as functional studies. Citation Format: Mathieu Blais, Shelley B. Bull, Dushanthi Pinnaduwage, Irene L. Andrulis. Functional enrichment and pathway analysis of the transcriptome related to lymphovascular invasion and recurrence in axillary-node negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-61.