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Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed anti-tumor activity is limited in breast cancer. Pre-clinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway targeting. We postulate that navicixizumab will demonstrate anticancer efficacy against TNBC. Methods: Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan. TNBC is defined as ER and PR < 1%, and HER2-negative (IHC 0, 1+, or 2+ and negative fluorescence in situ hybridization [FISH]). Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap™ ExTra with the Xerna TME Panel™ to classify patient samples into one of four tumor microenvironment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of < 5% and a 20% PFS rate at 4 months, with targets of 15% and 40% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes. Citation Format: Amelia B. Zelnak, Heinz-Josef Lenz, Kerry Culm, Lukas Makris, Valerie Chamberlain Santos, Hagop Youssoufian, Colleen Mockbee, Kathy D. Miller. ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress) [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 OT2-16-01.

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Purpose:Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i.Patients and Methods:This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.Results:Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.Conclusions:Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Supplemental Figure 1. ER, PI3K/mTOR, and CDK4/6 Pathways in HR+ Breast Cancer Supplemental Figure 2. Median Ctrough From Cycle 1 Day 15 in Cohorts A and B. Supplemental Figure 3. Time to Progression or Time on Study Treatment Supplemental Figure 4. Baseline ctDNA Mutations and Time to Disease Progression or Death

Background: Black women have higher incidence rates of TNBC and may experience worse clinical outcomes compared with White women with TNBC, due to disparities, comorbidities, or differences in TNBC biology (Dietze EG, et al. Nat Rev Cancer. 2015;15:248-254). As a result, Black pts with TNBC may benefit from novel therapies to improve outcomes. SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received FDA approval for pts with mTNBC who received ≥2 prior chemotherapies (at least 1 in the metastatic setting). The confirmatory phase 3 ASCENT study (NCT02574455) in pts treated in second line or greater (2L+) mTNBC setting demonstrated a significant survival benefit of SG over single-agent chemotherapy treatment of physician’s choice (TPC; median progression-free survival, [PFS]: 4.8 vs 1.7 mo, HR 0.43, P Citation Format: Lisa A. Carey, Amelia Zelnak, Hope S. Rugo, Florence Dalenc, Rita Nanda, Michael Danso, Mahasti Saghatchian, Kevin Kalinsky, Nelly Firmin, Manuel Ruiz-Borrego, Anne Favret, Jun Sun, Lee Schwartzberg, Christie Hilton, Coral Omene, Robyn Young, Sara A. Hurvitz, Eliza Harting, See Phan, Aditya Bardia. Assessment of sacituzumab govitecan (SG) in Black patients (pts) from the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC) [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 P5-16-07.

ImportanceIt is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs.ObjectiveTo describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up.Design, Setting, and ParticipantsHER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed.InterventionsPatients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle).Main Outcomes and MeasuresEvaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion–free survival in all patients. Only OS was prespecified before the primary database lock.ResultsAt baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]).Conclusions and RelevanceThis subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.Trial RegistrationClinicalTrials.gov Identifier: NCT02614794

Purpose The role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need. Methods We assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay. Results We observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes. Conclusion These data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O'Shaughnessy, Javier Cortés, Michaela Tsai, Linda Vahdat, Véronique Diéras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [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 GS3-06.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Background Increased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC. Patients and Methods Patients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition. Results Fifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET. Conclusion These results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy.

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3–9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. Clinical Trial Registration: NCT02614794

PURPOSE: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i which has recently demonstrated significant OS benefit in 2 phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. METHODS: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− BC. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. RESULTS: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% CI, 31.1%−51.6%), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. CONCLUSION: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Background: Combination cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) is a standard-of-care treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, disease progression inevitably occurs during CDK4/6i + ET treatment, highlighting the need for effective subsequent regimens. TRINITI-1 (NCT02732119) assessed triplet therapy with CDK4/6i ribociclib (RIB), mTORi everolimus (EVE), and ET exemestane (EXE) in patients (pts) with HR+/HER2− ABC who experienced disease progression on CDK4/6i treatment. We previously reported pooled Phase I/II results from TRINITI-1 demonstrating promising efficacy (per investigator assessment) and tolerability with RIB + EVE + EXE triplet therapy (Bardia, et al. Clin Cancer Res. 2021). Here we present the final efficacy (central review and OS) and safety data from the phase 2 study, and the final biomarker data. Methods: TRINITI-1 was a phase 1/2, multicenter, open-label study that enrolled postmenopausal women with ET-refractory HR+/HER2− ABC with most recent disease progression after ≥ 4 months of CDK4/6i treatment. Pts received once-daily, oral EXE 25 mg with either RIB 300 mg + EVE 2.5 mg (group 1) or RIB 200 mg + EVE 5 mg (group 2); all pts were given a prophylactic steroid mouthwash. Group 1 was enrolled first, followed by group 2; both began enrollment in phase 1 and were expanded in phase 2. Endpoints included clinical benefit rate (CBR) by 24 weeks (primary endpoint), progression-free survival (PFS), overall survival (OS), tumor response, and safety/tolerability. Results: A total of 79 pts (n = 46, group 1; n = 33, group 2) were enrolled and treated. Median age was 58.0 years (range, 32.0-83.0 years) and median prior CDK4/6i duration was 12.1 months (range, 3.5-34.0 months). As of the cutoff date (June 15, 2020), 73 pts (92.4%) had discontinued study treatment; the primary reasons included progressive disease (67.1%) and physician decision (16.5%). The CBR by week 24 (central review) was 65.2% and 59.4% for groups 1 and 2, respectively; the objective response rate was 6.5% and 9.4%, respectively (Table). Median PFS by central review was 8.0 months in group 1 and 4.7 months in group 2. For pts with ≥ 12 months of prior CDK4/6i, median PFS was 12.8 months in group 1 and 5.5 months in group 2; for those with < 12 months of prior CDK4/6i, median PFS was 5.3 months in group 1 and 3.6 months in group 2. Biomarker analysis showed numerically shorter median PFS when tumors expressed ESR1 or PIK3CA alterations. Median OS was 27.4 months in group 1 and not reached (NR) in group 2 at study end. For pts with ≥ 12 months of prior CDK4/6i, median OS was NR in both groups, and was 20.3 months (group 1) and 18.8 months (group 2) for pts with < 12 months of prior CDK4/6i. The most common all-grade adverse events were stomatitis (54.3%), infections (50.0%), neutropenia (43.5%), and fatigue (43.5%) in group 1, and infections (48.5%), nausea (42.4%), stomatitis (36.4%), and thrombocytopenia (36.4%) in group 2. There was no grade > 2 QTc prolongation. Conclusions: Results from TRINITI-1 demonstrate that triplet therapy with RIB + EVE + EXE is a relatively well tolerated and clinically active regimen directly following treatment with a CDK4/6i. There was a trend toward better outcomes in pts with longer durations of prior CDK4/6i treatment, wild-type ESR1, and wild-type PIK3CA. Tumor response by central reviewGroup 1: RIB 300 mg,. EVE 2.5 mg, EXE 25 mg (n = 46)Group 2: RIB 200 mg,. EVE 5 mg, EXE 25 mg (n = 32)aCBR, n (%) by week 24b30 (65.2)c19 (59.4)dORR, n (%)e3 (6.5)3 (9.4)SurvivalMedian PFS by central review, months8.04.7HR (95% CI) = 0.740 (0.424-1.291)Median OS, months27.4NESurvival by duration of prior CDK4/6iGroup 1: RIB 300 mg,. EVE 2.5 mg, EXE 25 mg (n = 46)Group 2: RIB 200 mg,. EVE 5 mg, EXE 25 mg (n = 32)a< 12 months. (n = 27)≥ 12 months. (n = 19)< 12 months (n = 11)≥ 12 months (n = 21)Median PFS, months5.312.83.65.5Median OS, months20.3NR18.8NRMedian PFS by tumor mutation status, monthsWTAlteredHR (95% CI)ESR19.1 (n = 59)2.8 (n = 30)1.678 (0.995-2.828)PIK3CA 9.1 (n = 59)5.7 (n = 30)1.275 (0.756-2.150)BOR, best overall response; CBR, clinical benefit rate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; CR, complete response; ESR1, estrogen receptor 1; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PFS, progression-free survival; PR, partial response; pt, patient; RIB, ribociclib; SD, stable disease; WT, wild type. aOne pt did not progress on prior CDK4/6i and thus was not evaluable for efficacy. bBOR of CR, PR, SD, or non-CR/non-PD. cn = 10 required to show a clinical benefit. dn = 8 required to show a clinical benefit. eBOR of CR or PR. Citation Format: Sara A. Hurvitz, Amy S. Clark, Hope S. Rugo, Aditya Bardia, Amelia Zelnak, Denise A. Yardley, Meghan Karuturi, Tara Sanft, Sibel Blau, Lowell Hart, Cynthia Ma, Das Purkayastha, Colleen Eppig, Angela DeMichele. Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1 [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 PD13-03.

Background: Tucatinib is an oral tyrosine kinase inhibitor highly specific for HER2 that is approved for use in combination with trastuzumab and capecitabine in adults with advanced or metastatic HER2+ breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. In the HER2CLIMB trial, the tucatinib regimen significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ metastatic breast cancer (Murthy, NEJM 2020), including in patients with untreated, treated stable, and treated progressing brain metastases (Lin, J Clin Oncol, 2020). With an additional 15.6 months of follow-up, addition of tucatinib continued to show clinically meaningful prolongation of PFS and OS in the total study population (Curigliano, ASCO Meeting, 2021). We report updated results of exploratory efficacy analyses in patients with brain metastases. Methods: All patients in HER2CLIMB had a baseline brain MRI. Patients with brain metastases were eligible and classified as untreated, treated stable, or treated progressing. Patients were randomized 2:1 to receive tucatinib 300 mg twice daily or placebo, in combination with trastuzumab and capecitabine. Following the primary analysis, the protocol was amended to unblind sites to treatment assignment and allowed crossover from the placebo regimen to the tucatinib regimen. Efficacy analyses in patients with brain metastases at baseline were performed at approximately 2 years from the last patient randomized by applying RECIST 1.1 to the brain based on investigator evaluation. OS and CNS-PFS (progression in the brain or death) were evaluated in all patients with brain metastases. Patients without CNS-PFS events were censored at the last brain MRI. Confirmed intracranial (IC) objective response rate (ORR-IC) was evaluated in patients with measurable IC disease. Results: At a median follow-up of 29.6 months, median OS was 21.6 months vs 12.5 months in all patients with brain metastases (HR: 0.60; 95% CI: 0.44, 0.81), 21.4 months vs 11.8 months in patients with untreated/treated progressing brain metastases (HR: 0.52; 95% CI: 0.36, 0.77), and 21.6 months vs 16.4 months in patients with treated stable brain metastases (HR: 0.70; 95% CI: 0.42, 1.16). Median CNS-PFS was 9.9 months vs 4.2 months in all patients with brain metastases (HR: 0.39; 95% CI: 0.27, 0.56), 9.6 months vs 4.0 months in patients with untreated/treated progressing brain metastases (HR: 0.34; 95% CI: 0.22, 0.54), and 13.9 months vs 5.6 months in patients with treated stable brain metastases (HR: 0.41; 95% CI: 0.19, 0.85). ORR-IC was higher in the tucatinib arm (47.3%; 95% CI: 33.7, 61.2) vs the placebo arm (20.0%; 95% CI: 5.7, 43.7) for patients with brain metastases, and median duration of response (DOR) was 8.6 months (95% CI: 5.5, 10.3) vs 3.0 months (95% CI: 3.0, 10.3). Conclusions: With 15.6 months of additional follow-up, the tucatinib-trastuzumab-capecitabine regimen resulted in a robust and durable prolongation of OS for all patients with HER2+ metastatic breast cancer and brain metastases. Additionally, this benefit was maintained in patients with untreated/treated progressing and treated stable brain metastases. Treatment with tucatinib continued to show clinically meaningful benefit in CNS-PFS consistent with the primary analysis. Citation Format: Nancy U Lin, Rashmi K Murthy, Vandana Abramson, Carey Anders, Thomas Bachelot, Philippe Bedard, Virginia Borges, David Cameron, David Cameron, Lisa Carey, A Jo Chien, Giuseppe Curigliano, Michael DiGiovanna, Karen Gelmon, Gabriel Hortobagyi, Sara Hurvitz, Ian Krop, Sherene Loi, Sibylle Loibl, Volkmar Mueller, Mafalda Oliveira, Elisavet Paplomata, Mark Pegram, Dennis Slamon, Amelia Zelnak, Jorge Ramos, Wentao Feng, Eric Winer. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2-positive metastatic breast cancer with brain metastases (HER2CLIMB) [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 PD4-04.

This abstract was not presented at the symposium.

Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [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 GS3-08.

Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer. Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death. Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction. Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340. Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [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 P6-16-03.

Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.

The successful development of therapies targeting the human epidermal growth factor receptor 2 (HER2) has altered the natural progression of disease among patients with HER2-positive metastatic breast cancer. The monoclonal antibody trastuzumab was the first HER2-directed agent and it was associated with significantly improved outcomes for patients. Subsequently, other HER2-directed agents such as the monoclonal antibody pertuzumab, the tyrosine kinase receptor inhibitor lapatinib, and the immunoconjugate trastuzumab emtansine were developed to overcome resistance to trastuzumab and provide additional treatment options for patients. Recent data have demonstrated that the use of these HER2-directed agents improves outcomes. However, with the emergence of new HER2-targeted agents, the optimal sequencing of treatment remains unclear. Ongoing research is investigating new HER2 combinations, the role of sequencing, novel HER2-directed agents, and combinations with other targeted agents to overcome resistance.

Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

Background: Trastuzumab targets the human epidermal growth factor receptor-2 (HER2). Cardiotoxicity is a potential adverse effect, manifesting as either an asymptomatic decline in left-ventricular ejection fraction or infrequently as largely reversible symptomatic heart failure (HF). Monitoring recommendations differ between product labeling and 2012 guidelines, and the clinical utility of serial cardiac monitoring in patients with metastatic breast cancer remains controversial. Objective: The objectives of this study were to describe the frequency of monitoring, incidence of symptomatic or asymptomatic HF, overall effect on treatment, and cost of monitoring for cardiotoxicity. Methods: We preformed an institutional review board–approved retrospective chart review of breast cancer patients receiving trastuzumab from January 1, 2009, through January 1, 2014, at an academic medical center. Results: Out of 154 treatments, 72% were adjuvant, and 28% were metastatic. In the adjuvant setting, a mean of 4.5 (interquartile range [IQR] = 4-5) echocardiograms (echos) over a mean of 11.5 (IQR = 11-12) months were performed. In the metastatic setting, a mean of 3.1 (IQR = 1-5) echos over a mean of 20.2 (IQR = 9-31) months were performed. Symptomatic HF events occurred in 4 adjuvant (3.6%) and 2 metastatic patients (6.5%); 10 patients (6.5%) had a treatment interruption, with 9 (90%) tolerating restart of trastuzumab. Two patients (1.3%) changed treatment as a result of cardiotoxicity. Using population incidence of HER2-positive breast cancer, $13 million could be saved if monitoring were reduced by 1 echo per patient. Conclusions: Given the low incidence of clinically significant HF and cost of monitoring, less frequent monitoring may be justified.

BACKGROUND: African American (AA) women experience higher breast cancer mortality than white (W) women. These differences persist even among estrogen receptor (ER)-positive breast cancers. The 21-gene recurrence score (RS) predicts recurrence in patients with ER-positive/lymph node-negative breast cancer according to RS score—low risk (RS, 0-18), intermediate risk (RS, 19-31), and high risk (RS, >31). The high-risk group is most likely to benefit from chemotherapy, to achieve minimal benefit from hormonal therapy, and to exhibit lower ER levels (intrinsically luminal B cancers). In the current study, the authors investigated racial differences in RS testing, scores, treatment, and outcome. METHODS: Tumor registry data from 3 Atlanta hospitals identified women who were diagnosed with breast cancers during 2005 through 2009. Medical record abstraction provided information on RS and other tumor/treatment factors. Statistical analyses used chi-square/exact tests and logistic regression. RESULTS: Of 2186 patients, including 1192 AA women and 992 W women, 853 women had stage I or II, ER-positive/lymph node-negative disease and, thus, were eligible for RS testing (AA = 372 [31.2%]; W = 481 [48.5%]; P < .0001); and 272 women (31.8%) received testing (AA = 76 [20.4%]; W = 196 [40.7%]; P < .0001). Tumors were distributed into the following groups according to risk: low risk (n = 133), medium risk (n = 113), and high risk (n = 26). The mean RS did not differ by race, but risk groups did (low-risk group: 46.1% vs 50% for AA women and W women, respectively; high-risk group: 15.8% vs 7.1%, respectively; P = .043). In multivariate analyses, AA race (odds ratio, 3.6) was associated independently with high risk scores. CONCLUSIONS: AA women were half as likely as W women to receive 21-gene RS testing but were 2-fold more likely to be categorized as high risk. The current data suggested that testing guidelines are not applied equivalently, testing bias may attenuate racial differences in RS, and disparate outcomes may be explained in part by differences in RS, although compliance and pharmacogenomics also may play a role. Cancer 2012;. © 2011 American Cancer Society.

This contribution deals with new design of digital calliper for transferring of width dimension scale from the ring interface to tyre of railway wheel. Based on the problem definition were solved variants of design with possibility of improvement current measurement technique. For selected variant of production was developed calibration procedures for ensure of required accuracy. At the end solution that was significantly influenced by economic recession was realized variant for single production. Manufacturer and exclusive supplier of this digital calliper is UNIMETRA Company, Ltd.