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Introduction Triple negative breast cancer (TNBC) is a heterogeneous breast cancer subtype which continues to portend a particularly poor prognosis compared to other breast cancer subtypes. Immune checkpoint inhibitor (ICI) therapies have emerged as promising options for locally advanced and metastatic TNBC. However, clinical trials have demonstrated mixed results with respect to ICI response. Given varied outcomes and the potential for immune-related adverse events associated with ICIs, there is critical need for identification of accurate biomarkers of response and improved strategies to counteract ICI resistance and/or toxicity. Methods Advanced immunoprofiling of peripheral blood mononuclear cells (PBMCs) and plasma from 7 metastatic TNBC patients with variable responses to anti-PD1 or anti-PDL1 therapy was performed. Samples were analyzed from blood draws obtained: (i) prior to first administration, (ii) while receiving ICI treatment, and (iii) at the time of conformed clinical progression or response to therapy. Response was determined by standard radiological assessment. Immunoprofiling included high parameter flow cytometry, single cell transcriptomics (10x genomics) and secretome analysis (Isoplexis). Single cell RNA profiles from 63,984 cells were analyzed. Results High parameter flow cytometry identified higher circulating levels of a subpopulation of activated CD4+ T cells with a phenotype of CXCR3low CD62Llow CD45RAhigh and CD57high expression in responders versus non-responders. Higher effector function of CD4+ T cells was corroborated by significantly elevated plasma concentrations of IL-2 (p=0.02) and IL-5 (p< 0.0001) among responders. Single cell transcriptomic analysis revealed clusters of B and T cells with distinct activation patterns that were associated with radiographic response. Strikingly, genes involved in B cell activation and T cell-B cell conjugation such as CD81 were found to be highly upregulated among CD4+ T cells from responders. Conclusions Our results are consistent with previous reports describing an association of increased B cell activity in TNBC with improved overall survival. We identified a subpopulation of CD4+ T cells with effector functions consistent with type 2 helper T cells that may not only target cancer cells by direct cytotoxic function, but also promote increased B cell anti-tumor activity. Our study provides insight into specific mechanisms of immune cell interplay that may drive response to ICI therapy. These cell populations and their associated pathways may represent potential biomarkers of response and/or targets for resistance reversal. Citation Format: Avia D. Wilkerson, Patricia A. Rayman, Paul G. Pavicic Jr, Hana Husic, Vladimir Makarov, Ivan Juric, Timothy Chan, Alberto J. Montero, Marcela Diaz-Montero. A multiomic approach to the identification of immune signatures of anti-PD1/PDL1 therapy responders in metastatic triple negative breast cancer: new implications in the role of helper T-cell and B-cell interplay [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 P1-04-04.

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.

Figure S1. Correlative Angiogenesis Biomarkers. A, levels of circulating endothelial cells in patients in schedule A and B at baseline (Pre-treatment). B, circulating endothelial precursor cells (EPCs) at baseline in patients in schedule A and B. C, baseline plasma angiogenic activity (PAA) at baseline in patients in schedule A and B.

Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors.Experimental Design: Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) were assessed during cycle 1.Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3–4 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA postbaseline.Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209–17. ©2016 AACR.

BackgroundCardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC). Accumulated stress plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL).MethodsThe initial cohort included males aged 18 years and older diagnosed with PC (2005-2019). AL was modeled as an ordinal variable (0-11). Fine-Gray competing risk regressions measured the impact of precancer diagnosis AL and postdiagnosis AL in 2-year major cardiac events (MACE). The effect of AL changes over time on MACE development was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after PC diagnosis).ResultsWe included 5261 PC patients of which 6.6% had a 2-year MACE. For every 1-point increase in AL before and within 60 days after PC diagnosis, the risk of MACE increased 25% (adjusted hazard ratio [aHR] =1.25, 95% confidence interval [CI] = 1.18 to 1.33) and 27% (aHR = 1.27, 95% CI = 1.20 to 1.35), respectively. Using AL as a time-varying exposure, the risk of MACE increased 19% (aHR = 1.19, 95% CI = 1.11 to 1.27), 22% (aHR = 1.22, 95% CI = 1.14 to 1.33), 28% (aHR = 1.28, 95% CI = 1.23 to 1.33), and 31% (aHR = 1.31, 95% CI = 1.27 to 1.35) for every 1-point increase in AL before, 2 months after, 6 months after, and 1 year after PC diagnosis, respectively.ConclusionAL and its changes over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC.

Background: CDK 4/6 inhibitors (CDKI) with Endocrine therapy (ET) is mainstay treatment for hormone receptor-positive (HR+) Her2- metastatic breast cancer (MBC). Despite excellent efficacy, most patients develop resistance to CDKI limiting its utility. CDK4/6 are thought to act by upregulating VEGF causing tortuous angiogenesis and promoting cancer progression. Recent studies have shown aggressive tumors possess a higher density and tortuous vasculature. In this study, we evaluated if vascular radiomic features computationally extracted from liver CT scans pre- and post CDKI treatment could predict patient survival and treatment response. Method: From a registry of 350 patients on treatment with CDKI at institution 1(S1), 51 pts with HR+, Her2-, MBC patients with evidence of liver mets and disease progression (PFS) data were identified. 30 pts discontinued treatment due to progression or death, with a median time to progression of 195 days. Pre-treatment and first post-treatment CT exams were analyzed from 25 and 34 patients, respectively. Median time between scans was 128 days. To validate the prognostic value of our signature, a cohort of 29 patients with available OS data was identified from institution 2 (S2). A publicly available pre-trained deep learning model was applied to isolate liver metastases and vessels. Next, fast marching algorithm was applied to reduce vessels to their centerlines and divide the vasculature into constituent branches. 7 quantitative metrics were computed measuring vascularity of metastases and 3-D shape of hepatic vessels. First, the number (f1) and percentage (f2) of hepatic vessels arising from the tumor were computed. Vessel tortuosity - measuring the degree of twisting across a vessel - was computed separately for each branch. The mean (f3), standard deviation (f4), maximum (f5), skewness (f6), and kurtosis (f7) tortuosity values were calculated to summarize these measurements at patient level. The features were individually assessed at pre- and post-treatment for association with PFS at S1 in univariable Cox proportional hazards models. Features found to be associated in S1 were evaluated for association with OS in S2. Results: On the initial post-treatment scan, features of both tumor vascularization (f6 - HR=1.115 [1.039-1.196]; f7 - HR=10.646 [2.539-44.641]), as well as two features of vessel tortuosity (f3 - HR=0.011 [0.001-0.199]; f4 - HR=0.545 [0.313-0.949]) were significantly associated with PFS. Both tortuosity features were also significantly associated with OS in S2 (f3 - HR=0.085 [0.009-0.780]; f4 - HR=0.331 [0.130-0.842]). In addition the percentage (f7 - HR=6.445 [2.001-20.753]]),of vessels feeding the lesions was also significant in S2 while the number (f6 - HR=1.070 [0.966-1.184]), of vessels was not. No vessel metrics from the pre-treatment baseline exam were significantly associated with OS. Conclusions: Radiomic analysis of tumor vascularity and vessel tortuosity on CT scans post-CDK treatment was associated with patient survival and treatment response. Table 1.Association of vessel features with PFS in Institution 1(S1)and OS in Institution 2(S2)S1- Pretreatment CT (n=25)S1 - Post-Treatment CT (n=34)S2 - Post-treatment CT - Validation (n=29)f1Tortuosity - Mean0.9912702470.852294696–f2Tortuosity - St. Dev0.7563942230.273115373–f3Tortuosity - Max0.1387051870.0022517550.02931473f4Tortuosity - Skewness0.254463710.0318270370.02022882f5Tortuosity - Kurtosis0.3058266760.108967601–f6Number of vessels feeding lesions0.419096650.0025747910.19306052f7Percentage of vessels feeding lesions0.0517942660.0012205950.00179103 Citation Format: Vidya Sankar Viswanathan, Nathaniel Braman, Priyanka Reddy, Siddharth Kunte, Jame Abraham, Alberto J Montero, Anant Madabhushi. Post-treatment vascularity and vessel shape are associated with survival and response to CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer (MBC) [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 P5-13-27.

Background: HER2-targeted therapies have led to marked improvements in survival for patients with HER2-positive breast cancer. Despite the gains obtained with current HER2-targeted therapies, an unmet medical need remains for patients with HER2-expressing (high or low expression) advanced breast cancer that has progressed after prior treatments. Zanidatamab is a novel HER2-targeted bispecific antibody that has multiple mechanisms of action, including immune clearance of HER2-expressing tumor cells through antibody-dependent cellular phagocytosis. Zanidatamab has been shown to be well-tolerated and has demonstrated antitumor activity, both as monotherapy and in combination with chemotherapy, across HER2-expressing solid tumors in a Phase 1 study. ALX148 is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of anticancer therapies, including antibodies, with minimal added hematologic toxicity. Treatment with zanidatamab in combination with ALX148 has the potential to augment the immune clearance of HER2-expressing cancer cells by blocking the CD47-SIRPa interaction that inhibits phagocytosis of the same cancer cells. In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2-targeted therapies. Here, we describe a Phase 1b/2 study to investigate the safety and antitumor activity of a chemotherapy-free combination of zanidatamab plus ALX148 in advanced HER2-expressing cancers, including breast cancer. Methods: ZWI-ZW25-204 is a Phase 1b/2, 2-part, open-label, multicenter study to evaluate the safety and antitumor activity of zanidatamab administered in combination with ALX148 in patients with locally advanced/inoperable and/or metastatic HER2-expressing cancer. Part 1 of this study will evaluate safety and tolerability and will establish the recommended doses (RDs) of zanidatamab plus ALX148. It will include patients with either HER2-positive (defined per ASCO/CAP guidelines) or HER2-low (defined as immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization (ISH) negative) breast cancer. Part 2 will evaluate the antitumor activity of zanidatamab plus ALX148 (at their combination therapy RDs) in 3 expansion cohorts: HER2-positive breast cancer (Cohort 1), HER2-low breast cancer (Cohort 2) and other HER2-overexpressing advanced malignancies (Cohort 3). Other key eligibility criteria include: prior use of approved agents known to confer clinical benefit, disease progression on or after the most recent systemic therapy, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients will receive zanidatamab and ALX148, each administered intravenously once every 2 weeks in a 28-day treatment cycle. Response assessments will be performed every 8 weeks. Primary endpoints include safety and tolerability assessments (Part 1) and confirmed objective response rate per RECIST 1.1 (Part 2). Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139). Citation Format: Sara A. Hurvitz, Jorge Chaves, Adam Brufsky, Alberto J. Montero, Bruno Fang, Kay Yeung, Manish R. Patel, Ritesh Parajuli, Adam Omidpanah, Elaina Gartner, Abraham Fong, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204) [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 OT1-14-01.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a higher risk of locoregional and distance recurrence. Consequently, this population was considered poor candidate for breast conservation (BCT). Our study aim was to determine whether BCT plus radiotherapy (RT) was equivalent to mastectomy for TNBC after adjustment of selection bias of demographic and clinical characteristics. Methods: The National Cancer Database was queried for women diagnosed as primary unilateral invasive clinical T1-2N0-2 TNBC from 2004-2016. Patients who underwent mastectomy or breast conservation (partial mastectomy plus radiation) were included. A 1:1 propensity match with replacement was performed to compare breast conservation vs. mastectomy. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 59,599 clinical T1-2N0-2 TNBC patients, 26,325 (44.2%) underwent mastectomy and 33,274 (55.8%) were treated with BCT. BCT patients were older (median age 59 vs. 54, p Citation Format: Lifen Cao, Christopher W Towe, Megan E Miller, Alberto J Montero, Robert Shenk. Breast conservation plus radiotherapy provides superior survival benefit than mastectomy in triple negative breast cancer: A propensity matched national cancer database analysis [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 P3-18-02.

There is a male predominance of acute myeloid leukemia (AML) incidence, but survival data are conflicting. The objective of this study is to carry out a comprehensive analysis of sex differences in AML, and to investigate the impact of sex disparities in survival.The cohort included patients ≥18 years diagnosed with AML (2010-2022). Demographics, treatment patterns, treatment adverse events, and survival were analyzed. The population was described and compared by sex, and sex-based risks and associations were obtained via Cox proportional-hazards regression.In total, 1020 AML patients were analyzed (57.4% males), with lower risk of death for females (aHR = 0.41, 95% CI 0.26-0.66). Among females, BMT (aHR = 0.51, 95% CI 0.27-0.97), hospitalization record (aHR = 0.65, 95%CI 0.45-0.93), and higher appointment completion rates (aHR = 0.98, 95% CI 0.98-0.98) were associated with lower risk of death. Overall, and similarly in males, higher age at diagnosis (aHR = 1.03, 95% CI 1.02-1.04) and a TP53 mutation (aHR = 2.24, 95% CI 1.69-2.97) were associated with higher risk of death.Sex differences exist in both AML incidence and overall survival. Treatment and health care factors should be addressed by caregivers and public policies developed to reduce mortality rates and mitigate existing sex differences.

Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [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 GS3-01.

It was suggested that stereotactic radiation (SBRT) is an "alternative if no surgical capacity is available" for non-small cell lung cancer (NSCLC) care during the COVID-19 pandemic. The purpose of this study was to compare the oncologic outcomes of delayed surgical resection and early SBRT among operable patients with early stage lung cancer.The National Cancer Database was queried for patients with cT1aN0M0 NSCLC who underwent surgery or SBRT (2010-2016) with no comorbidity. Patients with any comorbidities or age80 were excluded. The outcome of interest was overall survival. Delays in surgical care were modeled using different times from diagnosis to surgery. A 1:1 propensity match was performed and survival was analyzed using multivariable Cox regression.Of 6720 healthy cT1aN0M0 NSCLC patients, 6008 (89.4%) received surgery and 712 (10.6%) received SBRT. Among surgery patients, time to surgery30 d was associated with inferior survival (HR 1.4, P ≤ 0.013) compared with patients receiving surgery ≤14 d. Relative to SBRT, surgery demonstrated superior survival at all time points evaluated: 0-30 d, 31-60 d, 61-90 d, and90 d (all P 0.001). Among a propensity-matched cohort of 256 pairs of patients, delayed surgery (90 d) remained association with better overall survival relative to early SBRT (5-year survival 76.9% versus 32.3%, HR = 0.266, P 0.001).Although longer time to surgery is associated with inferior survival among surgery patients, delayed surgery is superior to early SBRT. Surgical resection should remain the standard of care to treat operable early stage lung cancer despite delays imposed by the COVID-19 pandemic.

The aim was to examine the real-world cost-effectiveness of breast-conserving surgery (BCS) plus hormonal therapy with radiotherapy, compared to hormonal therapy alone among women 66 and older with hormone receptor positive early-stage breast cancer in the United States (US).This study was conducted from a U.S. Centers for Medicare and Medicaid Services perspective and an eight-year time horizon. Both costs (2020 US$) and health utilities (quality-adjusted life years, QALYs) were obtained from retrospective studies using the SEER linked with Medicare and Medicare Health Outcomes Survey, respectively. The incremental cost-effectiveness ratio (ICER) of the addition of radiotherapy to hormonal therapy versus hormonal therapy alone after BCS was estimated by an unbiased doubly robust estimator. Sensitivity analyses were conducted through bootstrapping to estimate credible intervals.The addition of radiotherapy to hormonal therapy after BCS yielded the highest clinical benefits (2.66 QALYs) and costs ($19,424.27) compared to its hormonal therapy alone after BCS (0.77 QALYS; $2,028.58). The ICER was estimated to be $9,174.94/QALY. Sensitivity analyses did not change the direction of the findings.The results implicated that the combination of radiotherapy and hormonal therapy is cost-effective in the US.

PURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

The Institute of Medicine defines quality in healthcare as the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge. This concept is highly relevant for cancer care that involves patients with complex diseases in the setting of rapidly evolving treatment landscape that requires provision of appropriate services in a patient-centric and technically competent manner. This chapter uses the Donabedian model to review the structural, process, and outcome-based quality domains that lay the foundation for a robust system to measure, monitor, and improve quality of care at cancer centers. The infrastructure and personnel, systems, and culture needed for ensuring provision of high-quality cancer care are reviewed.

Background: Routine sentinel lymph node biopsy (SLNB) has been recommended against by Choosing Wisely© Foundation due to its low value in clinical node negative, hormone receptor positive breast cancer patients age≥70 years old. We used the National Cancer Database (NCDB) to examine the effect of SLNB omission and outcomes in this population. We hypothesized that SLNB would be beneficial in this population.Methods: The National Cancer Database was queried for women diagnosed with primary unilateral invasive clinical stage T1N0M0 hormone receptor positive, HER-2 negative breast cancer from 2012-2017. Patients age ≥ 70 years old with Charlson Score ≥1 who underwent partial mastectomy and received hormonal therapy were included in the study cohort. Patients received neoadjuvant therapy or underwent upfront axillary lymph node dissection (ALND) were excluded. A 1:3 propensity match with replacement was performed to compare SLNB omission vs. SLNB group controlling age, race, comorbidities, insurance and facility. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 14,150 patients, 1,928 (13.6%) omitted SLNB and 12,222 (86.4%) underwent SLNB, including 1,545/12,222 (12.6%) who proceeded to ALND. Central portion tumor location (OR=1.77, P=0.001), clinical T1c (OR= 2.49, P Citation Format: Lifen Cao, Megan E Miller, Luke D Rothermel, Alberto J Montero, Christopher W Towe, Robert Shenk. Less is not necessarily more: A propensity matched national analysis on effect and outcome of sentinel lymph node biopsy omission [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 PD7-08.

543 Background: Early validation studies using the Oncotype DX recurrence score (RS) in NSABP B20 demonstrated that women with node negative breast cancer and RS >31 had significant survival benefit from the addition of adjuvant chemotherapy to endocrine therapy (CET). Consequently, in the prospective TAILORx trial, node negative women with RS >26 received CET. These studies did not clearly delineate the magnitude of benefit of adjuvant chemotherapy for post-menopausal node negative women. A recently published well-designed adjuvant trial (RxPONDER) demonstrated that adjuvant chemotherapy was not beneficial in post-menopausal pts with ER+/HER2- breast cancer, 1-3 positive nodes, and RS 26 compared to endocrine therapy (ET) alone, given that CET is more beneficial in women 50 with ER+/HER2- pT1-2N0M0 breast cancer with RS >26, to assess real world utilization. We separated women into two groups based on adjuvant treatment: ET alone or CET. Chi-square and logistic regression analysis determined difference between different systemic treatment groups. OS was analyzed using a multivariable Cox model. Results: A total of 16,745 eligible women who underwent surgery and received ET were identified in the NCDB—4,740 (28.3%) received ET alone and 12,005 (71.7%) received CET. We observed that CET use increased over time. Women were more likely to receive CET if their tumors were moderately differentiated (OR = 1.853, p < 0.001), poorly/undifferentiated tumors (OR = 3.875, p < 0.001), or associated with lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates in this cohort were significantly superior in women receiving CET compared to ET alone (95.4% vs 92.0%, Hazard Ratio = 0.680, p < 0.001). Conclusions: Utilizing the NCDB to represent real world outcomes, we observed that women > 50 years with pT1-2N0M0 ER+/HER2- breast cancer, and RS > 26 had a significantly superior 5-year OS when receiving adjuvant chemotherapy provides a measurable OS benefit for post-menopausal women in this setting and should be discussed with patients.

1100 Background: EMERALD demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for elacestrant vs standard of care endocrine therapy (SOC) in patients with ER+/HER2- mBC following progression on prior endocrine and CDK4/6 inhibitor therapy. Benefit was observed in the overall study population and in patients with ESR1 mutations (mESR1). Here, we report a subgroup analysis from EMERALD in patients with no prior chemotherapy. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled patients with ER+/HER2− mBC who had 1–2 lines of endocrine therapy, mandatory pretreatment with a CDK4/6 inhibitor, and ≤1 chemotherapy. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SOC (investigator’s choice of fulvestrant or aromatase inhibitor). Primary endpoints were PFS in all patients and patients with mESR1. In this analysis, we compared PFS between elacestrant and SOC in patients without prior chemotherapy. Results: Among the 477 patients enrolled in the trial, 77.8% (n = 371) had not received prior chemotherapy for mBC (median age = 64). Among patients without prior chemotherapy, treatment with elacestrant was associated with significantly prolonged PFS compared to SOC in both the overall population (hazard ratio [HR] = 0.68 [95% CI, 0.52-0.89] P = 0.004; median PFS 3.7 vs 2.0; 6-mo PFS 38% vs 23%; 12-mo PFS 27% vs 12%), and patients with mESR1 (HR = 0.54 [95% CI, 0.36-0.80] P = 0.002; median PFS 5.3 vs 1.9; 6-mo PFS 44% vs 24%; 12-mo PFS 31% vs 12%). Key treatment-related adverse events (AEs) in the no prior chemotherapy elacestrant group were nausea (25.9%), fatigue (12.7%), and hot flush (11.1%). There were no treatment-related deaths in either group. Conclusions: Among patients with ER+/HER2− mBC without prior chemotherapy, elacestrant significantly prolonged PFS compared to SOC endocrine therapy and showed favorable outcomes in this subgroup. Clinical trial information: NCT03778931.

540 Background: Based on the results of the RxPonder trial, post-menopausal women over age 50 with estrogen receptor (ER)+ breast cancer, 1-3+ nodes, and a 21-gene Oncotype DX recurrence score (RS) score of 20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age < = 50: HR = 0.334, P = 0.002; age > 50: HR = 0.521, P = 0.019). Conclusions: Among women with ER+/HER2- breast cancer with 1–3 positive nodes, and RS of 20-25, in contrast to the RxPonder trial we observed that CET was associated with an OS benefit in women regardless of age.

TPS10618 Background: Coronavirus disease 2019 (COVID-19), caused by betacoronavirus SARS-CoV-2, is associated with an increased risk of severe infection or death in cancer patients compared to the general population. The CANVAX trial recently demonstrated that short term immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer— particularly those who receive myelosuppressive chemotherapy. Because little is known regarding longitudinal antibody or T-cell responses in cancer patients who receive cytotoxic chemotherapy or non-myelosuppressive targeted systemic therapy, the aim of this longitudinal study is to assess immune B and T cell responses to SARS-CoV-2 over a 12-month period in solid tumor patients who receive chemotherapy or non-immunosuppressive therapy compared to healthy individuals without cancer. Methods: This is an ongoing prospective non-interventional clinical trial (NCT05238467). Approximately 100 patients will be enrolled into three different arms. Accrual began in May 2021 and 37 patients have been enrolled. Eligible patients must not have prior COVID-19 infection < 6 months from study enrollment and have a diagnosis of a solid tumor (breast, genitourinary, or gastrointestinal cancers), who either: received myelosuppressive chemotherapy within 60 days prior to initial or booster COVID vaccination, or who started on chemotherapy within 30 to 60 days after the initial or booster COVID vaccination (Arm A); or received non-immunosuppressive treatments (Arm B); or have no history of cancer or prior history of cancer but beyond 12 months from completion of curative cancer treatment (Arm C, control cohort). Whole blood will be collected in accordance with standard operating procedures. Blood samples analyzed for the presence of antibodies against the major antigenic components of SARS-CoV-2 including the spike glycoprotein (S), receptor binding domain (R) and nucleocapsid phosphoprotein (N). Antibody levels will be quantified utilizing quantitative ELISA. T-cell responses will also be quantified. The primary endpoint is seroprotection rate with an antibody titer protective (1:40) at any point: baseline, 2, 6, and 12 months. The secondary endpoint is to evaluate differences in longitudinal immunological responses to SARS-CoV-2 over a 12-month period. The difference of the seroprotection rate among 3 cohorts of participants will be examined using chi-square test. Moreover, the effect of treatment (chemotherapy, endocrine, TKIs) on seroprotection will be estimated using multivariable logistic regression controlling the effects of confounders, such as age, gender and cancer type. COVID antibody titers measured over time (baseline, 8 weeks, 6, 9, 12 months after the second vaccination) will be analyzed using mixed-effect models. Clinical trial information: NCT05238467.

BACKGROUND: Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells promoting anti-tumor immune responses. DNA plasmid-based IL-12 delivered to accessible tumors by intratumoral injection and electroporation (TAVO-EP) has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that has limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Early clinical data indicate similar potential for eliciting strengthened immunogenic responses in TNBC. KEYNOTE-890 (OMS-I141) is a Phase 2 study in patients with metastatic TNBC to evaluate the safety and efficacy of TAVO-EP + pembrolizumab in the second-line or later (2L+) treatment setting (Cohort 1) or TAVO-EP + pembrolizumab + chemotherapy in the first-line (1L) setting (Cohort 2). Cohort 1 data are presented in a separate abstract. Enrollment in Cohort 2 is ongoing. METHODS: Cohort 2 of this Phase 2, open-label, multicenter study will be assessing the safety and efficacy of TAVO-EP in combination with pembrolizumab and chemotherapy as a first-line treatment for metastatic TNBC. Eligible patients are adults with metastatic TNBC (ER and PR staining Citation Format: Melinda Telli, Bianca Devitt, Katharine Cuff, Shaveta Vinayak, Rita Nanda, Alberto J. Montero, Rina Hui, David A. Canton, Christopher Twitty, Sunny Xie, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141) [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 OT2-01-03.

Background: Endocrine therapy(ET) plus CDK4/6 inhibitor (i) is the mainstay for the management of estrogenreceptor-positive (ER+)/HER2- mBC. However, most patients (pts) with ER+ mBCeventually experience disease progression, including development of ESR1mutations (mESR1). Elacestrant, an oral SERD, demonstrated preclinical activity,and clinical activity in a phase 1 trial in ER+ mBC, including responses in ptswith prior fulvestrant, CDK4/6i, and mESR1tumors (Bardia JCO 2021).. Methods: EMERALD(NCT03778931), a multicenter, international, randomized, open-label, controlledphase 3 trial, enrolled postmenopausal pts with ER+/HER2- mBC who had received 1-2prior lines of ET and ≤1 line of chemotherapy in the mBC setting and had prior progressionon a ET plus CDK4/6i. Pts were randomized 1:1 to elacestrant (400 mg orallydaily) or standard of care (SOC; investigator’s choice of fulvestrant or anaromatase inhibitor). Stratification factors included mESR1 status (by central lab), priorfulvestrant exposure, and presence of visceral disease. The study had 2 primary endpoints of progression-free survival (PFS), by blindedindependent review committee, in pts withtumors harboring mESR1 and in all pts (mESR1 or mESR1 notdetected). Secondary endpoints included: overall survival (OS), safety, tolerability,and quality of life. An alpha-value of 0.0475 was used to determine statisticalsignificance (2-sided using the truncated Hochberg procedure).. Results: EMERALD enrolled 477 pts(228 with mESR1) between Feb 2019 - Oct 2020, with 239 pts randomized toreceive elacestrant vs 238 pts to SOC. Demographics and disease characteristicswere well-balanced across treatment arms [median age: 63 yrs vs 63.5 yrs; 2prior lines: 46% vs 40.8%; prior CDK4/6i: 100% in both arms]. The study met bothprimary endpoints. There was a 30% reduction in the risk of progression ordeath in the elacestrant arm in all pts (HR=0.697 [95% CI: 0.552, 0.88]; P=0.0018),and a 45% (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005) reduction in therisk of progression or death in pts with mESR1.For both endpoints, results in key prespecified subgroups, including visceral metastases,number of prior lines of therapy, pretreatment with fulvestrant, and geographicalregion, were consistent with the overall outcome. The PFS rate at 12 months was 22.32% (95% CI: 15.24%, 29.40%)with elacestrant vs 9.42% (95% CI: 4.02%, 14.81%) with SOC in all pts, and26.76% (95% CI: 16.17%, 37.36%) vs 8.19% (95% CI: 1.26%, 15.12%) in the mESR1 subgroup. The prespecified interim OS analysis plannedat the time of the final PFS analysis (allocated2-sided alpha level of 0.0001) demonstrated a trend in favor of elacestrant inall pts (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in pts with mESR1(HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325). The final OS analysisis expected next year. Common (>10%) treatment-related adverse events (AEs) withelacestrant vs SOC included: nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%), mostlygrade 1/2. Treatment-emergent AEs leading to discontinuation of elacestrant orSOC were infrequent in both arms (6.3% and 4.4%). Grade ≥3 treatment-relatedAEs in the elacestrant arm vs SOC were 7.2% vs 3.1%, mainly driven by nausea(2.1% vs 0.9%). There were no treatment-related deaths in either group.. Conclusions:Elacestrant is the first oral SERD to demonstrate a statistically significantand clinically meaningful improvement of PFS vs SOC in a randomized phase 3study in pts with ER+/HER2- mBC in the 2nd/3rd-linesetting, including those whose tumors harbor mESR1. Elacestrant was well tolerated and hasthe potential to become the new standard of care for pts with ER+/HER2- mBC. Citation Format: Aditya Bardia, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frédéric Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Peter Vuylsteke, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Virginia Kaklamani, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, José García-Sáenz, Emilio Bria, Marina Cazzaniga, Janice Lu, Philippe Aftimos, Javier Cortes, Shubin Liu, Dirk Laurent, Maureen G. Conlan, Francois-Clement Bidard. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial [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 GS2-02.