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Introduction: Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the differential effect of endocrine therapy (ET) vs chemotherapy followed by endocrine therapy (CET), including the impact of menopausal status, on CRCI is not well understood. Methods: Participants (pts) with hormone receptor positive, HER2 negative breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 enrolled in the RxPONDER trial were randomly assigned to ET alone versus CET. Until the health-related quality of life (HRQoL) accrual goal was reached, English speaking pts in the US were invited to complete HRQoL questionnaires including the 8-item PROMIS Perceived Cognitive Function Concerns (PCF) Short Form questionnaire shortly after randomization (baseline), as well as 6, 12, and 36 months after baseline. Analysis of measures of anxiety and fatigue is presented separately. Standardized T scores (mean 50; SD 10) for PCF were computed with higher scores indicating less cognitive impairment. The primary endpoint of this exploratory analysis was to compare mean PCF T scores by treatment arm and menopausal status. Separately by menopausal status, a generalized estimating equations (GEE) model was fit to the three timepoints adjusting for baseline to estimate the difference between treatment arms and whether there was a time trend over the three follow-up measures. Results: The HRQoL accrual exceeded the goal of 500 patients, with 74% of pts participating voluntarily until the QOL invitation was removed from the protocol (Dec 1, 2012). A total of 139 pre and 429 postmenopausal pts completed the questionnaires at baseline. T scores were similar between ET and CET arms at baseline [Table 1]. In the ET arm, T scores decreased from baseline to 6 and 12 months but recovered to baseline at 36 months. In the CET arm, T scores decreased from baseline to 6 months and 12 months but did not return to baseline at 36 months. The mean score difference between CET and ET over time was -3.02 (p=0.01) and -2.36 (p=0.003) for pre and postmenopausal pts, respectively. Adjusting for baseline, there was no significant time trend over the three follow-up periods for either premenopausal (p=0.12) or postmenopausal (p=0.49) pts. Dropoff occurred over time with 79%, 76%, 60% of pts at baseline participating at 6, 12, and 36 months. Complete endocrine treatment adherence data are not yet available at each timepoint. Conclusion: Chemoendocrine therapy has a greater negative effect on patient-reported CRCI compared to ET alone in both pre- and post-menopausal pts and it is sustained over 36 months. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of patients treated with CET. Table 1. Comparisons of mean Cognitive Function score by treatment arm and menopausal status. Citation Format: Irene Kang, Jamie K. Forschmiedt, Michelle M. Loch, William E. Barlow, Danika L. Lew, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Priya Rastogi, Anne F. Schott, Steven Shak, Priyanka Sharma, Jieling Miao, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky, N. Lynn Henry. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-04.

Background Black women in the USA have a higher incidence and mortality of metastatic breast cancer (mBC) than White women, while Hispanic women have lower rates. Previous studies have focused on first-line (1L) treatment, but little is known about racial differences in treatment beyond 1L and their impact on outcomes. Methods This analysis utilized data from an electronic health record derived de-identified database and included patients with HR+HER2- mBC initiating 2L treatment (including CDK4/6-inhibitor [CDKi]-based, endocrine monotherapy, everolimus combination therapy, and chemotherapy and other systemic therapies) between 2/3/2015 and 7/31/2021. Real-world overall survival (rwOS) was defined as time from 2L initiation to death. Multinomial logistic regression assessed the likelihood of 2L treatment between race/ethnicity groups. Median rwOS was estimated using the Kaplan–Meier method and adjusted hazard ratios were estimated using multivariable Cox proportional hazards models. Results Among all patients who received 2L, non-Hispanic Black (NHB) and Hispanic/Latino patients were less likely to receive 2L CDKi compared to non-Hispanic White (NHW) patients (36%, 39% vs 42%, respectively). Median rwOS was 20.4, 37.6, and 25.3 months, in NHB, Hispanic/Latino and NHW patients, respectively. The rwOS remained poorer among NHB patients after adjustment (HR = 1.16; p = 0.009). In stratified analysis, adjusted rwOS was similar between NHB and NHW patients among those who received 1L CDKi. Conclusions These findings suggest that among patients with HR+HER2- mBC, NHB patients had worse survival beyond front-line setting, mainly among the subset of women who did not receive CDKi at 1L. This inequities in rwOS between race/ethnicity groups was not observed among patients who received 1L CDKi.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visitNCCN.org.

Background Metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (Her2−) breast cancer remains a significant cause of cancer-related mortality. First-line treatment with endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i) has largely become the standard systemic therapy. Following progression, no prospective randomized data exist to help guide second-line treatment. Materials and Methods This study used a nationwide electronic health record (EHR)-derived de-identified database, specifically analyzing 1210 patients with HR+/Her2− metastatic breast cancer (MBC) who were treated in the first-line setting with a CDK4/6i from the years 2015-2020. The aim of this study was to assess what therapies were given after first-line progression on CDK4/6i and to observe treatment patterns over time. Determination of second-line treatment efficacy, specifically assessing real-world progression-free survival (rwPFS) and overall survival (OS) was performed. Results A total of 839 patients received a documented second-line therapy after progression on first-line CDK4/6i treatment. Chemotherapy was chosen for 29.7% of patients, and the use of chemotherapy decreased over time. Three hundred two (36.0%) of patients continued a CDK4/6i. Data were adjusted for age, race, Eastern Cooperative Oncology Group (ECOG) performance status, stage at breast cancer diagnosis, and insurance payer type. Continuation of the CDK4/6i was associated with improved rwPFS (HR 0.48, 95% CI 0.43-0.53, P < .0001) and OS (HR 0.30, 95% CI 0.26-0.35, P < .0001) compared to chemotherapy. A majority of these patients continued the same CDK4/6i in the second-line setting, as was given in the first-line setting. Conclusion While prospective data are needed, analysis of real-world data suggests a survival benefit for continuation of a CDK4/6i beyond frontline progression for patients with HR+/Her2− MBC.

Background: Black patients with triple negative breast cancer (TNBC) have worse survival outcomes, even after adjusting for stage at diagnosis, income, insurance status and other socioeconomic factors. Little is known regarding anti-tumor immune responses in Black patients and how these differences affect responses to treatment in TNBC. Limited data exists regarding the stromal tumor infiltrating lymphocytes (sTILs, which are strongly prognostic in TNBC) distribution based on race and ethnicity. Here we evaluate the prevalence, distribution, and prognostic impact of sTILs in TNBC by race/ethnicity from 2 prospective clinical trials of adjuvant anthracycline/taxane-based chemotherapy (E2197 and E1199). Methods: Full-face hematoxylin and eosin-stained sections of 481 tumors from ECOG-ACRIN trials E2197 and E1199 were previously evaluated for density of sTILs and shown to be associated with disease-free survival (DFS), distant recurrence-free interval (DRFI), and overall survival (OS) (Adams, et al JCO 2014). Further analyses were undertaken to evaluate the impact of race/ethnicity. Results: The majority of the 481 TNBC were from White patients (82.3%, n=403); with 12.3% (n=59) Black patients, 1.6% (n=14) other (9 Hispanic, 3 Asian, 2 Other), and 0.5% (n=5) unknown race. Age distribution (mean 49.2 for White and 49.2 for Black) and node negative disease (White 68/403 (42%), Black 24/59 (41%)) were similar. However, tumor size ≤2cm was seen more commonly in White patients (34%, 137/403) compared with Black patients (20%, 12/59). Black patients had a higher proportion of high sTILs (≥30%) with 23.7% (14/59) compared to White patients (11.4%, 46/403). The association of continuous stromal TILs with DFS (hazard ratio for a 10-point difference) was 0.84 (95% CI 0.72, 0.98) for White patients and 0.94 (95% CI 0.73, 1.20) for Black patients [159 DFS events for Whites, 26 DFS events for Blacks]. Conclusions: This is the first dataset from prospective clinical trials evaluating sTILs in TNBC in Black patients. Prevalence of high sTILs was greater in Black patients compared to White patients. The association between increasing sTILs and improved invasive disease-free survival across racial/ethnic groups must be investigated in larger datasets. Table 1.Race/EthnicityTotal (n=481)White (n=403)Black (n=59)Other (n=19)Mean age49.049.249.245.6T1 (tumor 2 and Citation Format: Natalie Klar, Robert J Gray, Sylvia Adams, Joseph A Sparano, Lori J Goldstein, Angela M DeMichele, Antonio C Wolff, Nancy E Davidson, George W Sledge, Sunil S Badve. Stromal tumor infiltrating lymphocytes analysis by race and ethnicity in triple negative breast cancers from 2 phase III randomized adjuvant breast cancer trials: ECOG-ACRIN E2197 and E1199 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-35.

PDF file - 20K, Triple negative lower expression.

Purpose: To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy.Experimental Design: RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests.Results: Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8–14.1] in the low and 20.4% (95% CI, 16.5–25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy.Conclusions:GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered. Clin Cancer Res; 17(22); 7194–203. ©2011 AACR.

Purpose: To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy.Experimental Design: RNA was extracted from archived tumor samples derived from 378 patients with stage I to III HR-positive, HER2-normal breast cancer and analyzed by reverse transcription-PCR for a panel of 374 genes, including the 21-gene recurrence score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a nonrecurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence.Results: TOP2A expression exhibited the strongest association with increased recurrence risk (P = 0.01), and was significantly associated with recurrence (P = 0.008) in a multivariate analysis adjusted for clinicopathologic features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence interval, 1.3-5.2; P = 0.008) in risk of recurrence if the RS was P = 0.003) if there was an intermediate RS of 18 to 30.Conclusions: In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines, which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker. (Clin Cancer Res 2009;15(24):7693–700)

Supplementary Data from Relationship between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer

XLS file - 31K, Patient characteristics by GRB7 expression.

PDF file - 72K, Box plots (with center line at the median and box edges at the quartiles) showing the raw distribution of GRB7, ERBB2, KRT19 and PHB expression for the triple negative (TN) subset, hormone receptor negative (HR-), HER2-positive (HER2+) subset and the combined (over HR status) HER2+ subset, as defined by IHC. Differences between TN and the other groups are highly significant (p

Table S1. Pharmacokinetic parameters of reparixin by cohort; Table S2. Pharmacokinetic parameters of paclitaxel; Table S3. Exploratory biomarkers.

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Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m2/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.

PURPOSE Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (Her2-) breast cancers represent the majority of metastatic breast cancers (mBC) among women and are often treated with sequential courses of endocrine therapy (ET) prior to the eventual need for chemotherapy (CT). Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) block cell cycle progression and decrease proliferation of breast cancer cells. Currently, there are three available CDK4/6i: palbociclib, ribociclib and abemaciclib. Each has been shown to improve progression-free survival (PFS) when given with ET in the frontline setting, compared to ET alone. After progression on CDK4/6i, no standard of care exists for the next line of systemic therapy, and there are no prospective data to help guide clinical practice. Analysis of real-world data may provide insight into optimal second-line treatment for women who have progressed on CDK4/6i therapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was utilized for this analysis. We evaluated patient data collected from 2015-2020 for women with HR+/Her2- mBC who received CDK4/6i as frontline therapy and received a documented second-line systemic therapy. The objectives of this study were to describe what therapies were given as second-line treatment and estimate the real-world PFS (rwPFS) of those therapies. rwPFS was defined as time between initiation of second-line therapy until clinician-recorded progression (or death). Patients (pts) who did not progress or die were considered censored at the end of follow-up or end of second-line therapy. Results: A total of 1,210 pts with HR+/Her2- mBC received CDK4/6i with ET in the frontline setting, including 29.1% with de novo metastatic disease. Average age at diagnosis of metastatic disease was 64.4 years (range 28-84). A majority of pts received palbociclib in the frontline setting (88.2%), and 68.8% received an aromatase inhibitor (AI) as the frontline ET partner. 839 pts subsequently received second-line therapy (Table 1). CDK4/6i was continued as part of second-line treatment in 308 (36.7%) pts. 249 (29.7%) pts received CT as second-line treatment. The proportion of pts who continued CDK4/6i increased from years 2015-2020 (p=0.035), and the proportion who received CT decreased over time (p TABLE 1. Second-Line Therapy Used. F, fulvestrant; T, tamoxifenSECOND-LINE THERAPYOverall (N=839)AI23 (2.7%)CDK4/6i4 (0.5%)CDK4/6i + AI97 (11.6%)CDK4/6i + F160 (19.1%)CDK4/6i + F + AI35 (4.2%)CDK4/6i + F + T3 (0.4%)CDK4/6i + T3 (0.4%)CT249 (29.7%)F70 (8.3%)F + AI14 (1.7%)mTOR99 (11.7%)PARP4 (0.5%)PI3K16 (1.9%)T11 (1.3%)Clinical Trial51 (6.1%) Citation Format: James M Martin, Elizabeth A Handorf, Alberto J Montero, Lori J Goldstein. Analysis of systemic therapies following progression on frontline CDK4/6-inhibitor therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-15.

Background: PD-1 blockade has shown promising clinical activity in mTNBC. We designed an investigator-initiated multi-center clinical trial consisting of a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. A detailed characterization of peripheral immune cell changes may help in understanding responses in mTNBC to immune checkpoint inhibition. Correlative studies for the purpose of understanding the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of this clinical trial. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Treatment consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8 for cohort A, and C (AUC2) + G (800mg/m2) for cohort B. Patients are consented for a peripheral blood (PB) collection pre-treatment on day 1 of cycle 1, and post-treatment on day 1 of cycle 3, in order to phenotype immune changes by flow-cytometry. Results: A total of 60 patients have been consented, 42 patients were enrolled (6 on safety run-in, 36 on the randomized part II). Of those on the randomized part II, blood samples from 17 patients have been analyzed from cycle 1 day 1 and cycle 3 day 3. A decreased expression of PD-1 on effector and memory subsets of both CD4+ and CD8+ T cells from C1D1 to C3D1 was observed in blood from both cohorts, especially cohort A. We found an increased % NK, CD4+ T and CD8+ T cell subsets expressing the activation marker, CD69, in cohort A, but not cohort B, reflecting activation by pembrolizumab.​ There was a parallel increased expression of the proliferative marker, Ki67, in CD56bright (immature) NK cells and effector memory CD8+ T cells in blood from C1D1 to C3D1 in cohort A. We also found an increased % CD56bright (immature) NK and effector memory CD4+ T cells expressing the exhaustion marker, CD39, which was consistent with increased expression of the activation marker, CD69. Conclusions: Although comprising a limited number of patients in this early analysis, our correlative studies found evidence for effective immune stimulation upon combining CT with the PD-1 blockade. The randomized nature of this trial, with our planned pre and post treatment blood collection will be helpful in understanding response to immune check point inhibition combined with chemotherapy in mTNBC. Correlation with absolute lymphocyte counts and outcomes data is planned and will be presented. Citation Format: Elias Obeid, Judy Fang, Alex W McFarlane, IV, Irina Shchaveleva, Shauna Souchuck, Kerry S Campbell, Lori J Goldstein. Title:peripheral blood immuneimpactsin arandomizedphase iiclinical trial ofprogrammed death 1 (pd-1) blockadecombined with platinum-based chemotherapy in patients with metastatic triple negative breast cancer (mtnbc) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-19.

Introduction: Anxiety and fatigue have been reported by women undergoing cytotoxic and endocrine treatment (tx) for breast cancer and can have lasting effects on quality of life (QoL). The differential effects of menopausal (meno) status, tx allocation and duration of symptoms are not well established. Methods: Participants (pts) with hormone receptor positive, HER2 negative breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 enrolled in the RxPONDER trial were randomly assigned to endocrine therapy (ET) alone vs chemotherapy followed by ET (CET). A subset of English speaking pts in the US at the start of the trial were invited to complete health-related QoL (HRQoL) questionnaires shortly after randomization (baseline; BL) and 6, 12, and 36 months after BL until accrual goal reached. BL surveys were completed in clinic; cognitive function results presented separately. Standardized T scores (mean 50; SD 10) were computed for anxiety (PROMIS Emotional Distress – Anxiety Short Form 7a) and fatigue (PROMIS Fatigue Short Form 7a). Higher T scores indicate more anxiety or fatigue. The primary endpoint of this exploratory analysis was to compare mean anxiety and fatigue T score by tx arm by meno status. Separately by meno status, a GEE model was fit to the three follow-up timepoints adjusting for BL to estimate the difference between tx arms and whether there was a time trend over the three follow-up measures. Results: The accrual exceeded the goal of 500 pts with 74% of pts participating voluntarily until the QOL invitation was removed from the protocol (12/1/12). A total of 139 pre and 432 postmenopausal pts completed the anxiety questionnaire at BL. There was no difference in anxiety between tx arms [Table 1]. Mean anxiety score difference between CET and ET over time in the premenopausal cohort was -0.63 (p=0.63) and in the postmenopausal cohort was 0.59 (p=0.45). Although anxiety scores decreased over the three follow-up times, the change was not statistically significant. A total of 139 pre and 429 postmenopausal pts completed the fatigue questionnaire at BL. Fatigue mean T scores in both the pre and postmenopausal cohorts were higher over time in the CET vs ET arm [Table 2]. Fatigue scores were 2.85 points higher for CET vs. ET over time in the premenopausal cohort (p=0.02) and 1.82 points higher in the postmenopausal cohort (p=0.007). Fatigue scores decreased over time for premenopausal (p=0.01), but not for postmenopausal (p=0.62) pts. Dropoff occurred over time with 79%, 76%, 60% of pts at BL participating at 6, 12, and 36 months. Endocrine treatment adherence data are not yet available at each timepoint. Conclusions: CET had a clinically significant negative effect on mean fatigue scores compared to ET alone in both pre and postmenopausal pts over time. Scores improved over time but did not return to BL. Pts had lower mean anxiety scores during tx compared to BL, but differences in scores between CET and ET groups out to 3 years did not significantly differ. Future therapeutic studies must continue to include HRQoL assessments to broaden our understanding of the full impact of chemotherapy and for the development of preventative and therapeutic strategies to manage these toxicities. Table 1. Comparisons of mean Anxiety score by treatment arm and menopausal status. Table 2. Comparisons of mean Fatigue score by treatment arm and menopausal status. Citation Format: Michelle M. Loch, Jamie K. Forschmiedt, Irene M. Kang, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Priya Rastogi, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, William E. Barlow, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky, N. Lynn Henry. Patient-reported anxiety and fatigue in women enrolled in the RxPONDER trial (SWOG S1007) by menopausal status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-06.

Introduction: Racial disparities in breast cancer (BC) outcomes continues to be a major health care challenge. The 21-gene recurrence score (RS) is an important tool to guide treatment (tx) decisions among women with early-stage BC. We report an analysis of clinical characteristics, survival outcomes and race in association with RS in participants (pts) in the RxPONDER trial. Methods: We analyzed clinical outcomes with respect to race and ethnicity. Unreported race excluded 18.7% of the pts, with most due to privacy rules. The primary outcome was invasive disease-free survival (IDFS). Distant relapse-free survival (DRFS) was also evaluated. Analyses adjusted for assigned tx arm, RS, and grade were performed. There were too few events to include Native American/Pacific Islander (NAPI) women in the survival analyses. Results: A total of 4,048 trial women with Hormone Receptor positive, HER2 negative (HR+/HER2-) BC, 1-3 involved axillary lymph nodes (LNs), RS ≤ 25 and known race/ethnicity were included in this analysis including the following: 2,833 non-Hispanic (NH) White pts (70%), 248 NH Black pts (6.1%), 610 Hispanic pts (15.1%), 324 Asian pts (8.0%), and 33 NAPI pts (0.8%). Asian and Hispanic women were younger than NH Whites (by 7.1 and 2.4 years, respectively) but NH Blacks did not differ in age. RS distribution did not differ among all racial subgroups (p=0.49). There were also no significant differences in tumor size (p=0.10) or number of positive LNs (p=0.26) across all racial groups. However, tumor grade was found to be significantly different with grade 3 tumors higher for NH Blacks (18.0%), NH NAPI (21.1%), and Hispanics (14.5%) vs. NH Whites (10.4%) and Asians (6.5%) (p< 0.001). Overall five-year IDFS was lower for NH Blacks (87.0%) compared to that for Asians (93.9%), NH Whites (91.5%), and Hispanics (91.4%) (Table 1). A multivariable Cox model adjusting for RS and tx arm showed worse IDFS for NH Blacks compared to NH Whites (HR=1.38; 95% CI 1.00-1.90; p=0.048), although Asian pts had better IDFS than NH Whites (HR=0.65; 95% CI 0.44-0.97; p=0.034). In a separate analysis by menopausal status the magnitude of the IDFS hazard ratios (HRs) for NH Blacks was similar, although no longer statistically significant (premenopausal HR=1.37; 95% CI 0.69-2.72; postmenopausal HR=1.38; 95% CI 0.96-1.98). While there was no statistically significant interaction between NH Blacks vs. NH Whites and tx arm for either premenopausal (p=0.99) or postmenopausal women (p=0.44), adjusting for RS, the small number of events in the NH Black cohort, particularly in premenopausal women (n = 9 IDFS events), limit power and inference about differences in chemotherapy benefit. Among postmenopausal women, NH Blacks had worse DRFS compared to NH Whites (HR=1.69; 95% CI 1.12-2.53; p=0.01), adjusting for tx and RS. A similar trend was seen among premenopausal women (HR=1.74; 95% CI 0.79-3.82; p=0.17), although not statistically significant. Data on tx adherence over 5 years was not mature, although NH Blacks were more likely to accept tx assignment compared to NH Whites at randomization (93% vs. 86%, p=0.004). Conclusion: Black women with HR+/HER2- BC, 1-3 involved LNs and RS ≤ 25 have worse outcomes compared to White women despite similar RS results. There was no significant interaction between NH Blacks vs. NH Whites and tx arm, although this analysis was limited due to sample size. There remains an important need for novel approaches to improve clinical outcomes particularly for NH Black Women. Table 1. IDFS by Race and Ethnicity. Citation Format: Yara Abdou, William E. Barlow, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Stephen K. Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, Joseph M. Unger, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky. Race and clinical outcomes in the RxPONDER Trial (SWOG S1007) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-01.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Purpose: To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. Patients and Methods: BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician’s choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results: After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n ¼ 141) versus 3.1 months in the PC arm [n ¼ 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P ¼ 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm. Conclusions: Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib’s activity in this patient population., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer Cancer Stem Cells (CSC): In a phase 1b study, the combination of reparixin (R), an investigational oral inhibitor of CXCR1, and weekly paclitaxel (P) was well tolerated with a sizeable ORR and TTP in metastatic HER-2-ve breast cancer, with some long-term responders (Schott AF et al., CCR 2017). fRida (NCT02370238) is a phase 2, randomized, double-blind study evaluating the safety and efficacy of R+P vs placebo +P in untreated metastatic (m) TNBC. Trial Design: Patients with untreated mTNBC were stratified by prior (neo)adjuvant chemotherapy and randomized 1:1 to R 1200 mg or placebo three times per day dd1-21 and weekly P 80 mg/m2 dd 1, 8, 15 q28dd. Response was assessed per RECIST 1.1 (by central review). The primary endpoint was PFS. Secondary endpoints were OS, ORR and safety. This is the final analysis for PFS (data cut off 2/20/2019). Results: A total of 123 patients were randomized (62 to R+P and 61 to placebo + P). Patient characteristics (safety population) are summarized in Table 1. Median follow-up was 14.5 months. 74 PFS events (R+P 40, placebo+P 34), were observed in the ITT population. Median PFS was not significantly different between the 2 groups [median 5.5 and 5.7 months, HR 1.14 (95% C.I. 0.71-1.81), p=.589]. OS is not expected to reach statistical significance based on the results at the data cut off after 71 events (37 in R+P and 34 in placebo+P groups, respectively) [HR 1.03 (95% C.I. .64-1.56), p=.897). Findings were consistent across de novo stage IV and relapsed patients. BOR was similar between the two groups (R+P 28.1% vs placebo+P 25.9%). Median duration of response was longer in R+P than placebo+P group (median 293 vs 172 days, p=0.767). Among exploratory endpoints, a lower proportion of patients in the R+P group vs the placebo+P group had new metastatic lesions at disease progression (17/39 vs 23/34, respectively, p=.172). In patients where metastatic tissue was available at baseline (n=55), ALDH+ and CD24−/CD44+ CSC centrally evaluated by IHC were found in 17 and 29 patients respectively, with 9 patients displaying both CSC populations. G≥3 ADRs, which occurred in 21.3% and 10% of patients in R+P and placebo+P group, respectively, represented 6% of all ADRs in both groups. Conclusions: fRida is the first randomized, double-blind placebo-controlled clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. Sensitivity analyses are ongoing. The safety profile was consistent with that previously reported for this combination. ALDH+ and CD24−/CD44+ appeared to be largely non-overlapping CSC populations in metastatic tissue, similar to primary breast cancer (Goldstein LJ et al., AACR 2016). Table 1.R+Pplacebo+Page, median (range)57 (29, 79)57.5 (36, 77)PS 0/1 (n)37/2441/19de novo stage IV (n)148relapsed after (neo)adjuvant chemotherapy (n)4752prior taxane (n)4045Liver mets (n)1411Lung mets (n)1224≥3 metastatic sites(n)39 Citation Format: Lori J Goldstein, Mauro Mansutti, Christelle Levy, Jenny C Chang, Stephanie Henry, Isaura Fernandez-Perez, Giuseppe Viale, Guiseppe Viale, Beth Butler, Susan McCanna, Pier A Ruffini, Max Wicha, Anne F Schott. A randomized phase II trial of reparixin, a CXCR1 inhibitor, in combination with paclitaxel in the treatment of mTNBC [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 P3-11-07.

PURPOSE Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS Eligible patients were those with operable, node-positive—or node negative with tumor 1 cm or greater—TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.

Background Geriatric assessment (GA) is recommended for evaluating fitness of an older adult with cancer. Our objective was to prospectively evaluate the gaps that exist in the assessment of older adults with metastatic breast cancer (OA-MBC) in community practices (CP). Methods Self-administered GA was compared to provider’s assessment (PA) of patients living with MBC aged ≥65 years treated in CP Providers were blinded to the GA results until PA was completed. McNemar’s test was used to detect differences between PA and GA. Results One hundred patients were enrolled across 9 CP (median age 73.9). Geriatric assessment detected a total of 356 abnormalities in 96 patients; of which, 223 required interventions. African American and widowed/single patients were more likely to have abnormalities identified by GA. On average, across 100 patients, PA did not detect 25.5% of GA-detected abnormalities, mostly in functional status, social support, nutrition, and cognition. These differences were less pronounced among providers with more clinical experience. Patients with abnormal Timed Up and Go tests more likely had additional abnormalities in other domains, and more abnormalities that were not identified by PA. Providers were “surprised” by GA results in 33% of cases, mainly with cognitive or social support findings, and reported plans for management change for 39% of patients based on GA findings. Conclusions Including a GA in the care of OA-MBC in CP is beneficial for the detection of multiple abnormalities not detected by routine PA.

Collagen fiber organization has been found to be implicated in breast cancer prognosis. In this study, we evaluated whether computerized features of Collagen Fiber Orientation Disorder in Tumor-associated Stroma (CFOD-TS) on Hematoxylin & Eosin (H&E) slide images were prognostic of Disease Free Survival (DFS) in early stage Estrogen Receptor Positive (ER+) Invasive Breast Cancers (IBC). A Cox regression model named MCFOD-TS, was constructed using cohort St (N = 78) to predict DFS based on CFOD-TS features. The prognostic performance of MCFOD-TS was validated on cohort Sv (N = 219), a prospective clinical trial dataset (ECOG 2197). MCFOD-TS was prognostic of DFS in both St and Sv, independent of clinicopathological variables. Additionally, the molecular pathways regarding cell cycle regulation were identified as being significantly associated with MCFOD-TS derived risk scores. Our results also found that collagen fiber organization was more ordered in patients with short DFS. Our study provided a H&E image-based pipeline to derive a potential prognostic biomarker for early stage ER+ IBC without the need of special collagen staining or advanced microscopy techniques.

Càncer de mama; Marcadors predictius; Pronòstic Cáncer de mama; Marcadores predictivos; Pronóstico Breast cancer; Predictive markers; Prognosis Prior pooled analysis of eribulin studies (301 and 305) indicated eribulin prolonged overall survival (OS) in patients with locally advanced/metastatic breast cancer (MBC) regardless of visceral or nonvisceral disease. This hypothesis-generating post hoc analysis examined the efficacy of eribulin according to the location of metastatic sites at baseline in 1864 pretreated patients with locally advanced/MBC from studies 301 and 305. Analyses included OS, progression-free survival (PFS), and objective response rate; OS and PFS were also analyzed according to estrogen-receptor status. Eribulin appeared efficacious in patients with locally advanced/MBC, irrespective of the location of metastases at baseline. A nominally significant difference in OS in favor of patients randomized to eribulin compared with control in patients with bone, lymph node, and chest wall/breast/skin metastases at baseline was observed. Additionally, a difference in OS was also seen in patients with liver metastases randomized to eribulin versus control (median: 13.4 versus 11.3 months, respectively; hazard ratio, 0.84 [95% CI: 0.72, 0.97]). Results of this exploratory analysis suggest that eribulin may be efficacious for the treatment of locally advanced/MBC for patients with bone, liver, lung, lymph node, and chest wall/breast/skin metastases. This study was funded by Eisai Inc., Woodcliff Lake, NJ. Medical writing support was provided by Jeffrey Bratz, PhD, Oxford PharmaGenesis, Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff Lake, NJ, USA.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Background Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. Methods In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24−/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. Results Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24−/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. Conclusions Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. Clinical trial registration Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Purpose: To define the prevalence of HER2 positive breast cancer (HER2+ BC) in women with gBRCA1/2-BC and to determine whether there are significant differences in the prevalence of HER2 positivity in BRCA1 mutation carriers compared to BRCA2 mutation carriers. Background: It is estimated that 5-10% of patients with breast cancer have a BRCA1 or BRCA2 mutation. Two poly ADP ribose polymerase inhibitors (PARPi) have been approved for metastatic HER2-negative gBRCA1/2-BC, as trials excluded those with HER2+ BC and gBRCA1/2 mutations. Most often, breast tumors in BRCA1 carriers lack the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 receptor or gene amplification (HER2). BRCA2 tumors have similar rates of ER positivity as sporadic controls, but are less likely to be HER2+. The prevalence of HER2 positivity among BRCA1 and BRCA2 mutation carriers has been variably reported in the literature. The prevalence of HER2 positivity has generally been reported as lower among BRCA1 carriers than BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers and BRCA2 carriers has ranged from 0-10% and 0-13% respectively. The true prevalence of HER2+ breast cancer in gBRCA1/2-BC remains poorly defined. Methods: In this study, we assessed the prevalence of HER2 positivity among a cohort of 137 BRCA1 and BRCA2 mutation carriers who consented for participation in a single institution risk assessment program registry between 2009 and 2019. To be eligible for this study, participants had to have a documented diagnosis of invasive breast cancer and be a confirmed BRCA1 or BRCA2 mutation carrier. Participants with all stages of invasive breast cancer were included. Fisher’s exact tests and univariate logistic regression were used to analyze differences between BRCA1 and BRCA2 mutation carriers. Results: 69 BRCA1 mutation carriers and 68 BRCA2 carriers were included in the study. Only 38 BRCA1 mutation carriers and 41 BRCA2 mutation carriers had complete HER2 data and were included in this analysis for prevalence. 12.6 % (10/79) of the study participants had HER2+ invasive breast cancer; 3 of these participants were BRCA1 carriers and 7 were BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers was 7.9%. The prevalence of HER2 positivity among BRCA2 carriers was 17.0% (7/41). In this small sample, the prevalence of HER2 positivity in BRCA 2 mutation carriers was numerically higher than that in BRCA1 mutation carriers, although this difference was not statistically significant (p= 0.3145). Conclusion: In this analysis, the rates of HER2 positivity among BRCA1 mutation carriers are consistent with the range of rates previously reported (0-10%). However, the rates of HER2 positivity in BRCA2 mutation carriers (17.0%) are higher than those previously reported (0-13%). This study included participants who received breast cancer treatment at our institution where their HER2 status was verified with a pathology report, but also participants who received their breast cancer treatment at outside institutions. In the latter, HER2 status most often was obtained by verbal self-reporting. It is possible that this led to over-reporting of positive HER2 status in either BRCA1 or BRCA2 mutation carriers. Thus, estimates of HER2 positivity might be slightly overestimated. Despite some variation in HER2 positivity rates among BRCA1 and BRCA2 mutation carriers, this study demonstrates that HER2 positive breast cancers may not be as rare in gBRCA1/2-BC as previously reported in initial studies (0-3% in either BRCA1 or BRCA2 carriers). Given that BRCA1/2 mutation carriers could potentially derive therapeutic benefit from drugs, such as PARPi, it is important that future studies include gBRCA1/2-BC with HER2 positive breast cancer. Citation Format: Kristen Whitaker, Elias Obeid, Lori Goldstein, Mary Daly. Prevalence of HER2 positivity in germline BRCA 1/2-associated breast cancers (gBRCA1/2-BC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-21.

e12510 Background: Standard adjuvant chemotherapy for early stage BC includes taxane therapy with paclitaxel or docetaxel. Taxanes are associated with peripheral neuropathy in some patients, which can impact appropriate dosing and quality of life. In this study, we investigated whether there is an association between the levels of heavy metals in serum or urine and the development of high-grade peripheral neuropathy, defined as grade ≥2 (utilizing CTCAE v.4.0) in a cohort of BC patients undergoing neo/adjuvant taxane chemotherapy. Methods: BC patients undergoing treatment with taxanes were identified in the clinic. Patient eligibility included: histologically confirmed invasive mammary carcinoma, Stage I-III BC, undergoing neo/adjuvant treatment with taxane chemotherapy. Patients previously treated with chemotherapy or who had pre-existing neuropathy were not eligible. Patients were consented and prior to study enrollment, study participants provided blood and urine samples to assess for heavy metals. Neurotoxicity was measured using the NCI CTCAE v.4 criteria throughout patient’s taxane treatment. Serum and urine samples collected at baseline were analyzed for heavy metals by inductively coupled plasma mass spectrometry (ICP-MS). Results: 115 female patients were enrolled. 111 patients were included in the analysis; 4 patients were excluded due to withdrawal from study prior to receiving any taxane treatment. Participants were 78% White (6% of Hispanic origin), 19% Black and 3% Asian with an average age of 51 years (range 26-72). ICP-MS was used for the analysis of Aluminum (Al), Manganese (Mn), Cobalt (Cu), Zinc (Zn), Arsenic (As), Cadmium (Cd), Mercury (Hg), Thallium (Tl), and Lead (Pb) levels in patients’ serum and urine. Patients with neurotoxicity grade >=2 had significantly lower serum Arsenic levels (mean=0.37 [SD=1.08], n=89] than subjects with toxicity grades 0-1 [mean=1.21 (SD=2.33), n=22] (p=0.037; Wilcoxon test). Other than Arsenic no relationship of the other heavy metals and neurotoxicity was found in the serum. We did not observe significant associations between heavy metal levels in urine and neurotoxicity grade. Conclusions: Taxane treatment is an effective BC therapy but its utility is limited by its associated toxicity of peripheral neuropathy. The source of the higher arsenic levels is unclear. We conclude that there is no evidence that high levels of heavy metals were associated with taxane induced neurotoxicity in our study.

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2–negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease–free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)–positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2–negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

Background: EarlyR is a prognostic gene signature score in ER+ breast cancer (BC) computed from the expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR using a nonlinear mathematical formula. EarlyR has been validated in multiple cohorts profiled on Affymetrix and Illumina microarrays and by RNA-seq. This study sought to assess the prognostic features of EarlyR in a cohort of E2197. Patients and Methods: Illumina DASL assay was used to measure gene expression in FFPE tissue of primary BC from a case-cohort sampling subset of women in E2197 treated with doxorubicin plus docetaxel (AT) or doxorubicin plus cyclophosphamide (AC). ER+ patients received hormone therapy at physician's discretion. After 79.5 months median follow-up, disease-free survival was 85% in both treatment arms. Among patients centrally reviewed with sufficient RNA material for the DASL assay, 319 with ER+ status and assessed for EarlyR are included in the analytic cohort. EarlyR scores and pre-specified risk strata (≤25=low, 26-75=intermediate, >75=high) were computed, while blinded to clinical data. The analysis endpoint was disease-free survival (DFS), defined as the time from randomization to date of invasive BC recurrence or death from any cause within 8 years. Weighted Cox proportional hazards models were used to associate EarlyR score or risk strata with DFS. Variances of the estimated coefficients were adjusted to account for the case-cohort design. Results: The distribution of the EarlyR risk groups was 59% low, 11% intermediate and 30% high risk in this ER+ cohort. The continuous EarlyR score was significantly prognostic of DFS up to 8 years after randomization (p = 0.02). Patients with low EarlyR score (≤ 25) had significantly lower risk of BC recurrence within 8 years (p = 0.031, univariate HR=0.562, 95%CI: 0.334-0.948) compared to those with high EarlyR score (> 75). Analysis within the AC arm showed that patients with low EarlyR score had significantly lower risk of 8-year BC recurrence (p = 0.023, univariate HR=0.392, 95%CI: 0.175-0.878) compared to those with high EarlyR score. Within the AT arm there was no significant difference in 8-year DFS prognosis between any of the EarlyR risk groups. Conclusions: This study confirmed the prognostic significance of EarlyR using FFPE tissue in a cohort of patients treated with AC chemotherapy from E2197. Patients with high EarlyR score who were treated with AC had significantly higher risk of recurrence than low EarlyR score patients treated with AC. On the other hand, prognosis of high EarlyR score AT-treated patients was not significantly lower than the prognosis of low EarlyR score AT-treated patients. Further study in a larger cohort is needed to assess the relative benefits of AC versus AT within the EarlyR high risk group and the EarlyR low risk group. Citation Format: Badve S, Wang V, Willis S, Leyland-Jones B, Gokmen-Polar Y, Shulman L, Martino S, Sparano J, Davidson N, Goldstein L, Buechler S. Independent validation of EarlyR gene signature in E2197: A randomized clinical trial comparing doxorubicin plus docetaxel to doxorubicin plus cyclophosphamide as adjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-08.

Adjuvant endocrine therapy (AET) has substantially improved the mortality rate among breast cancer survivors. Despite the proven efficacy, the non-adherence rate to therapy is still high. This study is aimed to examine women’s challenges related to AET adherence and management. Semi-structured interviews were conducted with six Caucasian and six African American breast cancer survivors who were prescribed for AET. The transcripts of audio-taped interviews were qualitatively analyzed. Key themes were: 1) positive beliefs in AET, 2) uncertainty about long-term adherence, 3) experiences with side effects, 4) forgetting and remembering, 5) other concerns and information needs, 6) potential intervention format, and 7) culturally-coping among African American women. The findings provided insight into women’s experiences and beliefs and how these behaviors might influence AET adherence. Although most women in this study took AET as prescribed, many experienced a range of side effects and emotional distress, often without seeking support or help. New models of programs to promote adherence, support symptom management, and ultimately improve survival are critically needed. Developing culturally sensitive interventions for African American women is desirable.

Purpose Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. Methods Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. Results A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)–positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer–free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 ( P = 3.8E-14) outperformed MKI67 ( P = 1.06E-8) and AURKA ( P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 ( P = 3.88E-5) outperformed MKI67 ( P = .477) and AURKA ( P = .820). Conclusion FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker.

Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. In Phase I, the SAHA dose was modified in cohorts of 3–6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. The recommended dose was determined to be 200 mg twice a day on days 1–14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

6541 Background: In the US, African American (AA) women have similar incidence of breast cancer (BC) as White women, but have 40% higher BC mortality. This disparity results from differences in biological and social determinants of cancer treatment. Previous studies have focused primarily on first-line(1L) treatment, but little is known about racial differences in treatment beyond 1L and the impact these differences may have on outcomes. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with mBC initiating 2L treatment between 2/3/2015-2/29/2020. 2L treatment was caterogized broadly as CDK 4/6 inhibitors (CDKi), endocrine monotherapy, everolimus combination therapy, and chemotherapy and other systemic therapies. Real-world overall survival (rwOS) was defined as time from 2L initiation to death (censored at last EHR activity). Multinomial logistic regression was used to assess the likelihood of 2L treatment between AA and White (reference) pts, adjusted for demographics and clinical factors, including ECOG performance score, 1L treatment and 1L progression. Median rwOS was estimated using the Kaplan-Meier method and adjusted hazard ratios (aHR) were estimated using multivariable Cox proportional hazards models additionally adjusted for 2L treatment. Stratified analysis was conducted by 1L and 2L treatment. Results: A total of 389 AA and 2776 White pts were included. Compared to White pts, AA pts were younger (median age: 61 vs 65) and more likely to be under-insured (8% vs 3%), and present with de novo metastatic disease (30% vs 26%). AA pts were also less likely to receive CDKi in 2L (29% vs 35% in White), but this difference was not statistically significant after adjustment (OR = 0.83; 95% CI: 0.62-1.11). Compared to White pts who had a median rwOS of 25.6 months (95% CI: 24.5-27.4), AA pts had a median rwOS of 20.4 months (95% CI: 17.3-24.0). Poorer rwOS among AA pts was observed across all 2L treatment groups. After adjusting for covariates and 2L treatment, the observed rwOS difference was no longer statistically significant. However, in stratified analysis among pts who did not receive 1L CDKi, AA pts had 48% higher hazard of death if they received 2L CDKi (aHR = 1.48; 95% CI: 1.08-2.00), and 49% higher hazard of death if received 2L endocrine monotherapy (aHR = 1.49; 95% CI: 1.15-1.94). In contrast, adjusted rwOS was similar between AA and White pts among those who received 1L CDKi. Conclusions: These exploratory findings suggest that AA pts were less likely, partially associated with other factors, to receive CDKi at 2L. In addition, AA pts had worse rwOS than White pts even after receiving 2L CDKi among those who did not receive 1L CDKi. This disparity was not observed among patients who received 1L CDKi.

Background: The use of molecular tools for prognosis and prediction of CT benefit in EBC has increased the complexity of decision making. The 21-gene RS (Oncotype DX) is included in the ASCO (2007) and NCCN guidelines (2006) for prognosis (risk of distant recurrence [DR]) and prediction of CT benefit in N0, ER+ EBC. In 2015, the NCCN added that the RS assay could be considered for select patients with 1-3 N+, ER+ EBC. Recently the ASCO BC biomarker/guideline group (J Clin Oncol 2016) advised that the “clinician should not use the 21-gene RS to guide decisions” and called the evidence quality “intermediate” and the recommendation “moderate” based on review of 2 N+ studies. It also advised no change in N+ clinical practice until the prospective SWOG S1007 study (RxPONDER) matures in several years. These discordant recommendations have led to major confusion among physicians, pts and payers. To address this controversy we herein report a comprehensive analysis of the body of evidence regarding the clinical utility of the RS in N+, ER+ EBC. Methods: All published studies involving N+, ER+ EBC with RS data were analyzed by type of study design and category of trial (validation, supportive, decision impact, cost-effectiveness, and prospective outcomes). Results: 30 studies provided clinical evidence supporting the value and utility of the RS in N+, ER+ pts. 7 studies employed a prospective-retrospective design or were prospective outcomes with clinical utility in >8000 N+ pts (Table). 23 additional studies assessed the impact of RS on CT decisions or cost-effectiveness. Study in N+/ER+Type of studyNEndpoints/resultsSWOG S8814 (Lancet Oncol 2010)Pro-retro36710-year DFS and BCSS: RS predicts risk of DFS event, BC death, and CT benefit (none to slightly worse if very low risk RS and 1-3 N+)TransATAC (JCO 2010)Pro-retro3069-year DR: RS predicts risk of DR in pts treated with ET without CTECOG E2197 (JCO 2008)Pro-retro2325-year DR: RS predicts DR risk in CT+ET treated ptsNSABP B-28 (ASCO-BCS 2012)Pro-retro106510-year DRFI: RS predicts DR risk in CT+ET treated ptsPACS-01 (ASCO 2014)Pro-retro5305-year DRFI/DFS: RS predicts DR risk in CT+ET treated ptsSEER (npj BC 2016)Prospective outcomes46915-year BCSM: RS predicts BCSM; pts with RS Conclusions: The 21-gene RS has now been studied in >10,000 N+, ER+ EBC pts across 30 studies worldwide, including 2 prospective outcomes studies in >5000 pts, confirming that the RS consistently identifies low risk 1-3 N+ pts in whom CT can effectively and safely be avoided. This evidence suggests that ER+ pts with few N+ and low RS should have a discussion of the pros and cons of adjuvant CT until the results of RxPONDER provide a definitive answer in several years. Citation Format: Mamounas E, Goldstein L, Penault-Llorca F, Roche H, Gluz O, Harbeck N, Nitz U, O'Shaughnessy J, Albain K. Chemotherapy (CT) decision in patients (pts) with node-positive (N+), ER+, early breast cancer (EBC) in the wake of new ASCO guideline – A different take on the evidence for the 21-gene recurrence score (RS) assay [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-02.

Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180863; and in part by Susan G. Komen for the Cure® Research Program, The Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health, Inc. Acknowledgement: The authors wish to thank Dr. Ana M. Gonzalez-Angulo, MD, for her invaluable contributions to the design and implementation of this study. Background: The clinical utility of the RS to determine CT benefit is well established in pts with HR+, HER2-, axillary lymph node (LN)-negative BC. Retrospective analyses from SWOG S8814 support the potential prognostic and predictive role of RS for CT benefit in postmenopausal pts with LN+ BC. SWOG S1007 is a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with 1-3 +LN and a RS < 25 (NCT01272037). Methods: Eligibility criteria included women > 18 years of age with HR+, HER2- BC and 1-3 +LN and no contraindications to taxane and/or anthracycline based CT. Women with a RS < 25 were randomized to receive ET or CET in 1:1 randomization using 3 stratification factors: (1) RS (0-13 vs.14-25); (2) menopausal status; and (3) axillary nodal dissection vs. sentinel node biopsy. The primary objective was to determine the effect of CT on invasive disease-free survival (IDFS) and whether the effect depended on the RS. The primary analysis was to test for a significant interaction of the treatment arm and continuous RS using a Cox regression model for IDFS, adjusting for treatment, RS, and menopausal status. A total of 832 IDFS events were expected for the final analysis. Secondary objectives included overall survival (OS). The protocol specified that interaction between treatment and the stratification variables was to be tested and, if significant, separate analyses performed by stratum. Annual interim analyses were planned starting at 24% of events. At the third interim analysis with 410 IDFS events, the Data and Safety Monitoring Committee recommended reporting results, with a decision by the NCI’s Cancer Therapy Evaluation Program, the study sponsor. Results: Of the 9,383 women screened from 2/28/11-9/29/17, 5,083 pts (54.2%) were randomized. With a median follow-up of 5.1 years, 447 IDFS events have been observed. For the primary analysis, the interaction test for CT benefit and continuous RS was not statistically significant, p=0.30. In a model with CT, RS, and menopausal status (no interaction term), higher continuous RS was associated with worse IDFS [HR 1.06, 2-sided p Citation Format: Kevin Kalinsky, William E Barlow, Funda Meric-Bernstam, Julie R Gralow, Kathy S Albain, Daniel Hayes, Nancy Lin, Edith A Perez, Lori J Goldstein, Stephen Chia, Subkhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martín, Miguel Gil Gil, Claudia Arce-Salinas, Etienne Brain, In Hae Park, Jean-Yves Pierga, Ana Hernandez Lluch, Manuel Ramos Vasquez, Manuel Ruiz Borrego, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steve Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debu Tripathy, Gabriel Hortobagyi, Lajos Pusztai. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-00.