Validation of the AJCC 8th Edition Breast Cancer Prognostic Staging System in Legacy Alliance Trials (AFT-01).

BACKGROUND: The 8th edition American Joint Committee on Cancer staging system combined anatomic stage (AS) with receptor status and grade to create prognostic stage (PS). PS has been validated in single-institution and cancer registry studies; however, missing human epidermal growth factor receptor 2 (HER2) status and variable treatment and follow-up create limitations. OBJECTIVE: Our objective was to compare the relative prognostic ability of PS versus AS to predict survival using breast cancer clinical trial data. METHODS: Women with non-metastatic breast cancer enrolled in six Alliance for Clinical Trials in Oncology trials were included (enrollment years 1997-2010). AS and PS were constructed using pathological tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and grade. Unadjusted Cox proportional hazard models were estimated to predict overall survival within 5 years, with AS and PS as predictor variables. The relative predictive power of staging models was assessed by comparing Harrell concordance indices (C-indices). Kaplan-Meier-based mortality estimates were compared by stage. RESULTS: Overall, 6924 women were included (median age 53 years); 45.2% were diagnosed with ER+/PR+/HER2- tumors, 26.2% with HER2+ tumors, and 17.1% with ER-/PR-/HER2- tumors. Median follow-up time was 5 years (interquartile range 2.95-5.00). PS significantly improved predictive performance (C-index 0.721) for overall survival compared with AS (0.700) (p = 0.020). Kaplan-Meier hazard estimates suggested PS did not distinguish mortality risk between patients with IIB and IIIA or IB and IIA disease. CONCLUSIONS: PS has significantly improved predictive performance for OS compared with AS. As systemic therapies evolve, it will be important to re-evaluate the prognostic staging system, particularly for patients with intermediate-stage cancers. CLINICALTRIALS: gov Identifier: NCT02171078.

ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

Impact of environmental temperature on the survival outcomes of breast cancer: A SEER-based study.

BACKGROUND: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates. METHODS: A retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information. RESULTS: A total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7-62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90-0.95 and HR 0.93, 95% CI 0.91-0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7-62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90-0.96 and HR 0.93, 95% CI 0.90-0.96). CONCLUSIONS: Higher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Defining Priorities in Value-Based Cancer Care: Insights From the Alliance for Clinical Trials in Oncology National Cooperative Group Survey.

PURPOSE: We determine how stakeholders prioritize the importance of oncologic outcomes, patient-reported outcomes (PROs), and cancer-related health care costs. METHODS: A survey was distributed to the National Clinical Trials Network Alliance for Clinical Trials in Oncology cooperative group membership from May 14 to June 30, 2022. Respondents were asked to rate (5-point Likert scale) and rank (1-9) evidence-based value domains: overall survival, treatment toxicities/complications, quality of life (QOL), financial toxicity, access to care, compliance with evidence-based care, health system performance, scientific discovery and innovation, and cost to the health care system. RESULTS: A total of 514 members responded, including researchers (24.7%), nurses (19.5%), medical oncologists (17.9%), administrators (9.3%), surgical and radiation oncologists (9.1%), patient advocates (3.1%), and nonphysician providers (16.4%). Participants represented various practice settings including National Cancer Institute-designated cancer centers (29.8%), university-affiliated academic cancer centers (21%), hospital-owned oncology practices (21.8%), and others (27.4%). There was agreement in how respondents prioritized value domains (W = 0.39, P < .001). Respondents ranked patient QOL (mean rank: 2.6 ± 1.9) as most important above all other metrics including survival (mean rank: 3.5 ± 0.3) and access to care (mean rank: 3.5 ± 2.1; P < .001). Members engaged in direct patient care also ranked access to care of higher importance than nonclinicians (P = .026). Cost to the health care system (mean rank: 7.5 ± 2.1) and health system performance (mean rank: 7 ± 2) were ranked as least important (P < .001). Inclusion of PROs into therapeutic assessment (59.3%) was the most frequently selected priority of future cooperative group initiatives. CONCLUSION: Oncology community stakeholders deemed patient-centered value domains as most important and considered patient QOL the highest priority. Inclusion of PROs into clinical trials was endorsed as an important component of therapeutic assessment. These findings can be taken into consideration when creating a value framework for inclusion in cancer clinical trials.

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

ADCC's Improving Goal Concordant Care Initiative: Implementing Primary Palliative Care Principles.

BACKGROUND: High-quality, timely goals of care communication (GOCC) may improve patient and caregiver outcomes and promote care that is consistent with patient preferences. PROBLEM: Cancer patients, and their loved ones, appreciate GOCC; however, oncologists often lack formal communication training, institutional support and structures necessary to promote the delivery, documentation, and longitudinal follow-up of GOCC. PROPOSED SOLUTION: The Alliance of Dedicated Cancer Centers (ADCC), representing 10 U.S. academic cancer hospitals, undertook the Improving Goal Concordant Care Initiative (IGCC). This national, 3-year implementation initiative was designed in Fall 2019 by a workgroup of quality, oncology, and palliative care leaders, as well as patient and family advisory committee members (PFAC). IGCC addresses systemic gaps by requiring four core components for participation: 1) Implementation of a formal communication skills training (CST) program, 2) Structured GOCC documentation in the electronic medical record that is visible to all clinicians, 3) Expectations regarding the timing and patient populations for GOCC, and 4) Implementation of a measurement framework. METHOD: Dyads of palliative and oncology leaders committed to attend regularly scheduled, ADCC-led, virtual meetings during the design and implementation phase, incorporating PFAC feedback at every stage. Using the RE-AIM framework, we describe process and outcome evaluation measures defined by implementation and measures workgroups and collected routinely, including: CST completion; trainee evaluation response rate, trainee-reported quality of CST, trainee changes in self-efficacy and distress; percent of high-priority patients participating in GOCC, and patient-reported response to the "Heard and Understood" scale (HU). IGCC's impact will be assessed using claims-based utilization metrics near the end of life (EOLM) and followed longitudinally. Qualitative evaluations near the completion of IGCC will provide insight into perceived barriers, enabling factors, and sustainability. OUTCOMES: Implementation of all IGCC components has begun at all sites. ADCC-wide, 35% of MD/DOs have completed CST (range by site: 8%-100%). CST is highly rated; in Quarter 3, 2022, 93%-100%, 90%-100% and 87%-100% of respondents reported above average to excellent CST quality, likelihood to use the skills and likelihood to recommend CST to others, respectively. Clinician self-efficacy and distress ratings are expected in late 2023. All sites have identified patient populations and continue to refine automated triggers and timelines; uptake of GOCC documentation has been slow. Eight of 10 sites have submitted patient-reported HU data. EOLM data are expected for all sites in early 2024. LESSONS LEARNED: Flexibility in implementation with shared definitions, measures, and learnings about approaches optimizes the ability of all centers to collaborate and make progress in improving GOCC. Flexibility adds to the complexity of understanding intervention effectiveness, the critical intervention components and the fidelity necessary to achieve specific outcomes.

Impact of Environmental Temperature on the Pathological Complete Response and Survival Outcomes of Breast Cancer: A NCDB and SEER study.

Background: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate with an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates have higher odds of achieving pathologic complete response (pCR) and better survival outcomes than patients living in colder climates. Methods: A retrospective population-based analysis was conducted on Stage I-III breast cancer patients utilizing data from National Cancer Database (NCDB) from 2010-2018 with 892,092 patients and Surveillance, Epidemiology and End Results (SEER) from 1996-2017 with 270,496 patients. The average annual temperature (AAT) was calculated based on data from the National Centers for Environmental Information. Results: In the SEER cohort, patients residing at AAT ≥47.5°F had a 16% higher overall survival (OS) (HR 0.84, 95% CI 0.81-0.88, p <0.001) and 15% higher disease specific survival (DSS) (HR 0.85, 95% CI 0.80 - 0.90; p <0.001). Similarly, 4% higher OS (HR 0.96, 95% CI 0.95-0.97, p <0.001) and DSS (HR 0.96, 95% CI 0.94-0.97, p <0.001) was noted with every 5°F increment in AAT. In the NCDB cohort, patients in regions with AAT ≥ 60.9°F had 9% greater odds of achieving a pCR, odds ratio (OR 1.09, 95% CI 1.05, 1.13, p <0.001) and a 5% higher OS (HR 0.95, 95% CI 0.93 - 0.97, p<0.001). Conclusions: Higher environmental temperatures are associated with significantly better OS and DSS, as well as higher odds of achieving pCR in these patients. Future research is warranted to confirm this observation using large datasets, to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

The influence of anatomic stage and receptor status on first recurrence for breast cancer within 5 years (AFT-01).

BACKGROUND: Risk-stratified follow-up guidelines that account for the absolute risk and timing of recurrence may improve the quality and efficiency of breast cancer follow-up. The objective of this study was to assess the relationship of anatomic stage and receptor status with timing of the first recurrence for patients with local-regional breast cancer and generate risk-stratified follow-up recommendations. METHODS: The authors conducted a secondary analysis of 8007 patients with stage I-III breast cancer who enrolled in nine Alliance legacy clinical trials from 1997 to 2013 (ClinicalTrials.gov identifier NCT02171078). Patients who received standard-of-care therapy were included. Patients who were missing stage or receptor status were excluded. The primary outcome was days from the earliest treatment start date to the date of first recurrence. The primary explanatory variable was anatomic stage. The analysis was stratified by receptor type. Cox proportional-hazards regression models produced cumulative probabilities of recurrence. A dynamic programming algorithm approach was used to optimize the timing of follow-up intervals based on the timing of recurrence events. RESULTS: The time to first recurrence varied significantly between receptor types (p < .0001). Within each receptor type, stage influenced the time to recurrence (p < .0001). The risk of recurrence was highest and occurred earliest for estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/Her2neu-negative tumors (stage III; 5-year probability of recurrence, 45.5%). The risk of recurrence was lower for ER-positive/PR-positive/Her2neu-positive tumors (stage III; 5-year probability of recurrence, 15.3%), with recurrences distributed over time. Model-generated follow-up recommendations by stage and receptor type were created. CONCLUSIONS: This study supports considering both anatomic stage and receptor status in follow-up recommendations. The implementation of risk-stratified guidelines based on these data has the potential to improve the quality and efficiency of follow-up.

Novel Prognostic Staging System for Patients With De Novo Metastatic Breast Cancer.

PURPOSE: Given the heterogeneity and improvement in outcomes for metastatic breast cancer (MBC), we developed a staging system that refines prognostic estimates for patients with metastatic cancer at the time of initial diagnosis, de novo MBC (dnMBC), on the basis of survival outcomes and disease-related variables. METHODS: Patients with dnMBC (2010-2016) were selected from the National Cancer Database (NCDB). Recursive partitioning analysis (RPA) was used to group patients with similar overall survival (OS) on the basis of clinical T category, grade, estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2, histology, organ system site of metastases (bone-only, brain-only, visceral), and number of organ systems involved. Three-year OS rates were used to assign a final stage: IVA: >70%, IVB: 50%-70%, IVC: 25 to <50%, and IVD: <25%. Bootstrapping was applied with 1,000 iterations, and final stage assignments were made based on the most commonly occurring assignment. Unadjusted OS was estimated. Validation analyses were conducted using SEER and NCDB. RESULTS: At a median follow-up of 52.9 months, the median OS of the original cohort (N = 42,467) was 35.4 months (95% CI, 34.8 to 35.9). RPA stratified patients into 53 groups with 3-year OS rates ranging from 73.5% to 5.7%; these groups were amalgamated into four stage groups: 3-year OS, A = 73.2%, B = 61.9%, C = 40.1%, and D = 17% (log-rank P < .001). After bootstrapping, the survival outcomes for the four stages remained significantly different (log-rank P < .001). This staging system was then validated using SEER data (N = 20,469) and a separate cohort from the NCDB (N = 7,645) (both log-rank P < .001). CONCLUSION: Our findings regarding the heterogeneity in outcomes for patients with dnMBC could guide future revisions of the current American Joint Committee on Cancer staging guidelines for patients with newly diagnosed stage IV disease. Our findings should be independently confirmed.

Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations.

PURPOSE: Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 (CD274) and PD-L2 (PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS: We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS: Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION: Our findings show that the 3'-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.

Local/Regional Recurrence Rates After Breast-Conserving Therapy in Patients Enrolled in Legacy Trials of the Alliance for Clinical Trials in Oncology (AFT-01).

OBJECTIVE: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. BACKGROUND: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. METHODS: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. RESULTS: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence ( P <0.0001). CONCLUSIONS: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

De-Escalating the Management of In Situ and Invasive Breast Cancer.

It is necessary to identify appropriate areas of de-escalation in breast cancer treatment to minimize morbidity and maximize patients' quality of life. Less radical treatment modalities, or even no treatment, have been reconsidered if they offer the same oncologic outcomes as standard therapies. Identifying which patients benefit from de-escalation requires particular care, as standard therapies will continue to offer adequate cancer outcomes. We provide an overview of the literature on the de-escalation of treatment of ductal carcinoma in situ (DCIS), local treatment of breast cancer, and surgery after neoadjuvant systemic therapy. De-escalation of breast cancer treatment is a key area of investigation that will continue to remain a priority. Improvements in understanding the natural history and biology of breast cancer, imaging modalities, and adjuvant treatments will expand this even further. Future efforts will continue to challenge us to consider the true role of various treatment modalities.

Surveillance Imaging vs Symptomatic Recurrence Detection and Survival in Stage II-III Breast Cancer (AFT-01).

BACKGROUND: Guidelines for follow-up after locoregional breast cancer treatment recommend imaging for distant metastases only in the presence of patient signs and/or symptoms. However, guidelines have not been updated to reflect advances in imaging, systemic therapy, or the understanding of biological subtype. We assessed the association between mode of distant recurrence detection and survival. METHODS: In this observational study, a stage-stratified random sample of women with stage II-III breast cancer in 2006-2007 and followed through 2016 was selected, including up to 10 women from each of 1217 Commission on Cancer facilities (n = 10 076). The explanatory variable was mode of recurrence detection (asymptomatic imaging vs signs and/or symptoms). The outcome was time from initial cancer diagnosis to death. Registrars abstracted scan type, intent (cancer-related vs not, asymptomatic surveillance vs not), and recurrence. Data were merged with each patient's National Cancer Database record. RESULTS: Surveillance imaging detected 23.3% (284 of 1220) of distant recurrences (76.7%, 936 of 1220 by signs and/or symptoms). Based on propensity-weighted multivariable Cox proportional hazards models, patients with asymptomatic imaging compared with sign and/or symptom detected recurrences had a lower risk of death if estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative (triple negative; hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.54 to 0.99), or HER2 positive (HR = 0.51, 95% CI = 0.33 to 0.80). No association was observed for ER- or PR-positive, HER2-negative (HR = 1.14, 95% CI = 0.91 to 1.44) cancers. CONCLUSIONS: Recurrence detection by asymptomatic imaging compared with signs and/or symptoms was associated with lower risk of death for triple-negative and HER2-positive, but not ER- or PR-positive, HER2-negative cancers. A randomized trial is warranted to evaluate imaging surveillance for metastases results in these subgroups.

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

BACKGROUND: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-). PATIENTS AND METHODS: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies. RESULTS: In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002). CONCLUSIONS: The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

A Presurgical-Window Intervention Trial of Isothiocyanate-Rich Broccoli Sprout Extract in Patients with Breast Cancer.

SCOPE: Dietary isothiocyanates (ITCs) from cruciferous vegetables have shown potent anti-breast cancer activities in preclinical models, but their anticancer effects in vivo in breast cancer patients remain elusive. A proof-of-principle, presurgical window of opportunity trial is conducted to assess the anticancer effects of dietary ITCs in breast cancer patients. METHODS AND RESULTS: Thirty postmenopausal breast cancer patients are randomly assigned to receive ITC-rich broccoli sprout extract (BSE) (200 µmol ITC per day) or a placebo for 2 weeks. Expression of biomarkers related to ITCs functions are measured in breast cancer tissue specimens at pre- and post-interventions using immunohistochemistry staining. First morning urine samples are collected at both timepoints for proteomic analysis. Overall, the study shows high compliance (100%) and low toxicity (no grade 4 adverse event). Trends of increase in cleaved caspase 3 and tumor-infiltrating lymphocytes (TILs) and trends of decrease in Ki-67 and nuclear to cytoplasm ratio of estrogen receptor (ER)-α are observed in the BSE arm only, consistent with the significantly altered signaling pathways identified in urinary proteomic analysis. CONCLUSIONS: Anticancer activities of ITCs are observed in breast cancer patients, supporting the potential beneficial roles of ITC-containing cruciferous vegetables in breast cancer prognosis.

Low RUFY3 expression level is associated with lymph node metastasis in older women with invasive breast cancer.

PURPOSE: Sentinel lymph node biopsy is omitted in older women (≥ 70 years old) with clinical lymph node (LN)-negative hormone receptor-positive breast cancer as it does not influence adjuvant treatment decision-making. However, older women are heterogeneous in frailty while the chance of recurrence increase with improving longevity. Therefore, a biomarker that identifies LN metastasis may facilitate treatment decision-making. RUFY3 is associated with cancer progression. We evaluated RUFY3 expression level as a biomarker for LN-positive breast cancer in older women. METHODS: Clinical and transcriptomic data of breast cancer patients were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1903) and The Cancer Genome Atlas (TCGA, n = 1046) Pan-cancer study cohorts. RESULTS: A total of 510 (METABRIC) and 211 (TCGA) older women were identified. LN-positive breast cancer, which represented 51.4% (METABRIC) and 48.4% (TCGA), demonstrated worse disease-free, disease-specific, and overall survival. RUFY3 levels were significantly lower in LN-positive tumors regardless of age. The area under the curve for the receiver operator characteristic (AUC-ROC) curves showed RUFY3-predicted LN metastasis. Low RUFY3 enriched oxidative phosphorylation, DNA repair, MYC targets, unfolded protein response, and mtorc1 signaling gene sets, was associated with T helper type 1 cell infiltration, and with intratumor heterogeneity and fraction altered. Low RUFY3 expression was associated with LN-positive breast cancer and with worse disease-specific survival among older women. CONCLUSION: Older women with breast cancers who had low expression level of RUFY3 were more frequently diagnosed with LN-positive tumors, which translated into worse prognosis.

The Impact of Radiotherapy Delay in Breast Conservation Patients Not Receiving Chemotherapy and the Rationale for Dichotomizing the Radiation Oncology Time-Dependent Standard into Two Quality Measures.

INTRODUCTION: The Commission on Cancer/National Quality Forum breast radiotherapy quality measure establishes that for women < 70 years, adjuvant radiotherapy after breast conserving surgery (BCS) should be started < 1 year from diagnosis. This was intended to prevent accidental radiotherapy omission or delay due to a long interval between surgery and chemotherapy completion, when radiation is delivered. However, the impact on patients not receiving chemotherapy, who proceed from surgery directly to radiotherapy, remains unknown. PATIENTS AND METHODS: Patients aged 18-69, diagnosed with stage I-III breast cancer as their first and only cancer diagnosis (2004-2016), having BCS, for whom this measure would be applicable, were reviewed from the National Cancer Database. RESULTS: Among 308,521 patients, the median age was 57.0 years, and > 99% of all patients were compliant with the measure. The cohort of interest included 186,650 (60.5%) patients not receiving chemotherapy, with a mean age of 57.9 years. Of these, 90.5% received external beam radiotherapy (EBRT) and 9.5% brachytherapy. Among them, 24.9% started radiotherapy > 8 weeks after surgery. In a multivariable model, delay from surgery to radiotherapy increased the hazard ratios for overall survival to 9.0% (EBRT) per month and 3.0% (brachytherapy) per week. CONCLUSION: While 99.9% of patients undergoing BCS without chemotherapy remain compliant with the current quality measure, 25% have delays > 8 weeks to start radiation, which is associated with impaired survival. These data suggest that the current quality measure should be dichotomized into two, with or without chemotherapy, in order to impel prompt radiotherapy initiation and maximize outcomes in all patients.