bluuebunny/crossref_metadata_2025 huggingface dataset:
Metastatic-free intervals and risk of breast cancer-specific mortality among patients with hormone receptor-positive breast cancer: A population-based analysis from the Surveillance, Epidemiology, and End Results registries.
Authors: Calip Gregory Sampang , Law Ernest H , Hubbard Colin , Nabulsi Nadia Azmi , Asfaw Alemseged Ayele , Lee Inyoung , Zhou Jifang , Cueto Jenilee , Mitra Debanjali
Published: May 2020

e13034

Background: Patients successfully treated for hormone receptor (HR)-positive early breast cancer remain at risk of recurrence and metastatic disease even after extended periods of disease-free years. Whether prolonged metastatic-free intervals ultimately confer a benefit to breast cancer-specific survival is not well understood. This study aimed to investigate metastatic-free intervals and risk of breast cancer-specific mortality among patients with HR-positive breast cancer after adjuvant therapy. Methods: We conducted a retrospective cohort study of women aged 18 years and older diagnosed with recurrent metastatic HR-positive breast cancer between 1990 and 2016 in the Surveillance, Epidemiology, and End Results registries. Patients with longitudinal information on primary stage I-III HR-positive breast cancer through the occurrence of metastatic disease and survival were included. Risks of breast cancer-specific mortality associated with metastatic-free intervals (defined as time from primary breast cancer diagnosis to metastasis) of ≥5 years compared to < 5 years were estimated. Fine and Gray competing risks regression models were used to calculate subdistribution hazard ratios (SHR) and 95% confidence intervals (CI). Results: Among 1,057 women with HR-positive breast cancer with a median age of 54 years at primary breast cancer diagnosis and 62 years at metastatic progression, 65% of women had a metastatic-free disease interval ≥5 years, whereas 35% had an interval of < 5 years. Overall, patients with metastatic-free intervals < 5 years had a five-year breast cancer-specific survival rate of 31% compared to 52% in women with intervals of ≥5 years. In multivariable analyses adjusted for age, race, diagnosis year, grade, treatment and sites of metastasis, patients with intervals of ≥5 years had decreased risk of breast cancer-specific mortality (SHR = 0.72, 95% CI 0.58-0.89, P = 0.002) compared to women with metastatic-free intervals of < 5 years. Conclusions: In this population-based study, rates of cancer-specific mortality among patients who experienced metastatic recurrence of HR-positive breast cancer were lower in women with metastatic-free intervals of 5 years or more. The results of this study may inform patient-clinician discussions surrounding prognosis and treatment selection among HR-positive patients.
Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.
Authors: Ji Yan , Yartsev Vitaly , Wang Yingbo , Quinlan Michelle , Serra Paolo , Samant Tanay , Rodriguez-Lorenc Karen
Published: May 2020

e13037

Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.
Prediction of early progression (EP) to CDKIs first line treatment in ER+/HER2- metastatic breast cancer (MBC) using machine learning.
Authors: Jerez Jose Manuel , Ribelles Nuria , Rodriguez-Brazzarola Pablo , Diaz Redondo Tamara , Jimenez Rodriguez Begoña , Sanchez-Muñoz Alfonso , Marquez Antonia , Carabantes Francisco , Pajares Bella , Villar Ester , Bermejo-Perez Maria-Jose , Saez Lara Enrique , Dominguez-Recio Maria Emilia , Godoy Ana , Mesa Hector , Galvez Carvajal Laura , Franco Leo , Ruíz Sofía , López Irene , Alba Emilio
Published: May 2020

e13040

Background: The treatment of luminal MBC has undergone a substantial change with the use of cyclin dependent kinase 4/6 inhibitors (CDKIs). Nevertheless, there is not a clearly defined subgroup of patients who do not initially respond to CDKIs and show EP. Methods: MBC ER+/HER2- patients who have received at least one line of treatment were eligible. The event of interest was disease progression within 6 months of first line treatment according to the type of therapy administered. The first line treatments were categorized in chemotherapy (CT), hormonal therapy (HT), CT plus maintenance HT and HT plus CDKIs. Free text data from clinical visits registered in our Electronic Health Record were obtained until the date of first treatment in order to generate a feature vector composed of the word frequencies for each visit of every patient. Six different machine learning algorithms were evaluated to predict the event of interest and to obtain the risk of EP for every type of therapy. Area under the ROC curve (AUC), True Positive Rate (TPR) and True Negative Rate (TNR) were assessed using 10-fold cross validation. Results: 610 RE+/HER2- MBC treated between November 1991 and August 2019 were included. Median follow up for metastatic disease was 28 months. 17426 clinical visits were analyzed (per patient: range 1-173; median 30). 119 patients received CT as first line treatment, 311 HT, 117 CT plus maintenance HT and 63 HT plus CDKIs. There were 379 patients with disease progression, from which 126 were within 6 months from first line treatment (54 events with CT, 57 with HT, 4 with CT plus maintenance HT and 11 with HT plus CDKIs). The model that yields the best results was the GLMBoost algorithm: AUC 0.72 (95%CI 0.67-0.77), TPR 70.85% (95%CI 70.63%-71.06%), TNR 66.27% (95% 66.08%-66.46%). Conclusions: Our model based on unstructured data from real-world patients predicts EP and establishes the risk for each of the different types of treatment for MBC ER+/HER2-. Obviously an additional validation is needed, but a tool with these characteristics could help to select the best available treatment when that decision has to be made, avoiding those therapies that are probably not to be effective.
Radiomics risk score (RRS) on CT to predict survival and response to CDK 4/6 inhibitors in hormone receptor (HR) positive metastatic breast cancer (MBC).
Authors: Kunte Siddharth , Braman Nathaniel , Bera Kaustav , Leo Patrick , Abraham Jame , Montero Alberto J. , Madabhushi Anant
Published: May 2020

e13041

Background: The addition of CDK 4/6 inhibitors (CDK) to endocrine therapy (ET) is the standard of care for HR+ MBC. Currently, no robust predictive markers for CDK inhibitors exist. We hypothesized that baseline imaging features on pre-treatment CT scans using machine learning could correctly identify responders to CDK. Methods: From a retrospective pt registry, 46 pts with HR+ MBC who received palbociclib (palbo) plus ET and had liver metastases were identified, and divided at random into equally sized training and testing cohorts. Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’ (65%), and those with progressive disease within 6 months were ‘non-responders’ (35%). The median age at diagnosis was 62. All pts were ER+ and 4% were HER2+. 65% pts received palbo as 1st or 2nd line tx. 503 radiomic texture features measuring subtle differences in lesion heterogeneity on a pixel level were extracted on pre-treatment CT within the first lesion measured for RECIST assessment. An elastic net Cox proportional hazards model was constructed within the training set to derive a Radiomics Risk Score (RRS), which was evaluated for association with prognosis and response within the testing set. A risk score threshold was chosen in the training set for stratifying patients into high and low risk groups. Results: The RRS consisted of 4 radiomic features indicating intratumoral heterogeneity to be associated with poor outcome. In the independent testing set (n = 23), RRS was continuously associated with survival (p = .0027) on multivariate analysis, along with age and RECIST response (Table). Categorical risk groups were similarly associated with survival in the testing set (p = .00491, HR = 4.03, CI = 0.6772). Median survival time in low and high risk groups were 2.33 and 0.673 years, respectively. When compared against RECIST response in the testing set, RRS was found to also be predictive of response with an ROC curve of 0.675. Conclusions: Radiomics analysis was able to predict response and survival in HR+ MBC pts prior to initiation of treatment with CDK. [Table: see text]
Keeping oncologists current with CDK4/6 inhibitors in HR+ breast cancer: The impact of online education.
Authors: Parikh Kinjal , Tanzola Mindy , Peters Pamela M. , Cristofanilli Massimo
Published: May 2020

e13044

Background: CDK4/6 inhibitors have revolutionized the care of patients with hormone receptor positive (HR+), HER2-negative breast cancer, improving survival outcomes. There are multiple CDK4/6 inhibitors available that differ in their pharmacologic features, reported outcomes, therapeutic indications, and adverse event profiles. Education is needed to empower clinicians to optimally use these agents in practice and personalize breast cancer treatment. The goal of this educational initiative was to increase the knowledge, competence, and confidence of oncologists regarding clinical trial data and factors for selection of CDK4/6 inhibitor. Methods: This educational approach included a 30-minute online video discussion among 3 expert faculty, synchronized with slides to support the discussion. Educational effectiveness was assessed with repeated paired pre/post assessment in which learners served as their own controls. A chi-square test assessed differences from pre- to post-assessment. P values < .05 are statistically significant. Effect size was calculated using Cramer’s V test by determining the strength of the association between CME and the outcomes (V = .16-.26 is considerable and V > .26 is extensive). The activity launched 11/25/2019 and data are reported through 2/4/2020. Results: A total of 889 learners, including 513 physician learners, participated in the activity from 11/2019 through 2/2020. Participation in the education resulted in significant improvements in knowledge among oncologists (n = 81; p < .001; V = 0.16). On average, the proportion of learners who responded correctly to knowledge-based questions about CDK4/6 inhibitors increased from 51% at the pre-assessment to 67% at the post-assessment. Moreover, 41% of oncologists had a measurable positive change in confidence in their ability to incorporate CDK4/6 inhibitors into the treatment of HR+, HER2- advanced breast cancer. Significant improvements in knowledge were observed in the following areas: The clinical trial safety and efficacy data evaluating CDK4/6 inhibitors in the management of patients with HR+/HER2-negative breast cancer (32% vs. 51%, p < .05, V = 0.19). The potential role of patient- and tumor- specific prognostic factors in selection of individual CDK4/6 inhibitors (56% vs. 72%, p < .05, V = 0.17). Conclusions: This CME-certified online discussion resulted in statistically significant gains in oncologists’ knowledge and improved confidence surrounding the personalization of CDK4/6 inhibitor therapy in HR+/HER2- breast cancer.
Comparison of treatment-related adverse events (TRAE) of different CDK4/6 inhibitors (CDK4/6i) in metastatic breast cancer (MBC): A network meta-analysis.
Authors: Desnoyers Alexandra , Nadler Michelle , Kumar Vikaash , Saleh Ramy , Amir Eitan
Published: May 2020

e13052

Background: CDK4/6i in combination with endocrine therapy (ET) are a standard of care in hormone receptor positive, HER2 negative MBC. Palbociclib, ribociclib and abemaciclib have all been approved and while efficacy appears similar, differences in safety and tolerability are apparent. Here we quantify TRAEs comparing the 3 CDK4/6i in a network meta-analysis. Methods: We searched PubMed and ASCO and ESMO proceedings to identify randomized trials (RCT) of CDK4/6i. Data on common and serious TRAE were extracted for each approved CDK4/6i. The odd ratio (OR) for each TRAE and the hazard ratio (HR) for progression-free survival (PFS) were calculated relative to ET alone. A network meta-analysis was then performed for each ET backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib. Results: 7 RCT were included in the analysis and comprised 2715 patients receiving CDK4/6i (palbociclib: 789 patients; ribociclib: 1153 patients; abemaciclib: 773 patients). In 4 RCT (1440 patients) ET backbone was an AI and in 3 RCT (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed lower grade 3-4 hematological toxicity, but higher GI toxicity (see table). Treatment discontinuation was higher with abemaciclib than other CDK4/6i. Efficacy of the 3 CDK4/6i was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 1.00 and for abemaciclib 1.04. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively. Conclusions: The three approved CDK4/6i show comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to gastro-intestinal toxicity. [Table: see text]
Real-world survival data of palbociclib in advanced and metastatic breast cancer: A multicenter experience in Lebanon.
Authors: Nasr Lewis , Ghoche Ahmad , Diab Saada , Nasr Fadi
Published: May 2020

e13054

Background: Approximately 70% of all breast cancer cases are hormone receptor (HR) positive. One of the most important treatment strategies for HR positive, human epidermal growth factor receptor 2 (HER2) negative subtype was endocrine treatment monotherapy by targeting estrogen receptor or aromatization and thus reducing estrogen level. However, resistance to this treatment and disease progression is universal. In the past few years, palbociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 have been approved by the FDA, as a new standard of care in the metastatic or locally advanced setting either as front line therapy or after progression. The aim of our study is to describe the real world experience with palbociclib. Methods: Eligible patients had histologically confirmed metastatic breast cancer estrogen and progesterone receptors positive and HER2 receptor negative. Palbociclib was given 125 mg orally for 21 consecutive days of a 28 day cycle. Patients were followed over one year. Primary objective was progression free survival (PFS). Tumor response and treatment tolerability were defined as secondary objectives. Results: From 2002 to 2018, we identified a total of 44 breast cancer patients. All patients were females. The median age at diagnosis was 57 years. Among all the patients, 33.3% had visceral metastasis, 35.9% had non visceral metastasis and 30.8% had the two types of metastasis. 64.1% were de novo metastatic and 35.9% were not de novo metastatic. 82.5% had less than 3 sites of metastasis. 47% of the study patients had received both chemotherapy and endocrine therapy during treatment course, and 13 % had only received prior adjuvant endocrine therapy. 28.26% took only prior systemic therapy for breast cancer. By the cutoff date for the final analysis (1/11/2018), a total of 8 events of disease progression occurred, no death events happened. The median progression free survival was 262.6 months for palbociclib combined with letrozole as first line. Conclusions: no data was published before on palbociclib in Lebanon. We are the first to describe these characteristics. Our result (PFS 26 2.6 months) is in conformity with the PFS obtain with PALOMA-2 (24 months).
EARLY real-world treatment and dosing patterns of ribociclib for metastatic breast cancer (mBC): A retrospective observational study.
Authors: Balu Sanjeev , O'Shaughnessy Joyce , Paul Mary Lisha , Baidoo Bismark , Sudharshan Lavanya
Published: May 2020

e13059

Background: Ribociclib and abemaciclib in combination with endocrine therapy have demonstrated survival benefit in women with HR-positive/HER2-negative mBC. This study assessed early real-world treatment and dosing patterns of ribociclib for mBC in a US community oncology setting. Methods: This was a retrospective, observational, descriptive study of female mBC patients initiating treatment with ribociclib between March 1, 2017 and September 30, 2018 within the US Oncology Network (USON) and followed through December 31, 2018. USON’s iKnowMed (iKM) EHR database was used to identify patients and medical chart data review was conducted to abstract treatment information. Descriptive analyses were performed to assess patient and treatment characteristics. Results: A total of 161 patients were selected for chart review, of which 116 patients who received ribociclib were confirmed as eligible. The mean age of patients at initiation of treatment was 66 (SD 14) years. Among patients with documented menopausal status, 90% were post-menopausal, and 10% were pre-menopausal. Among patients with documented receptor status, 99% were ER+/HER2-. Patients most commonly initiated ribociclib in the first-line setting (1L n = 52, 2L n = 30, 3L n = 9, 4L+ n = 25) and in combination with letrozole (n = 33, 28.4%). Eastern Cooperative Oncology Group (ECOG) performance score at time of ribociclib initiation was 0-1 in 60.4% of patients. Documented metastatic sites were present in bone (35.3%), lung (8.6%), and liver (6%). The most common comorbidities documented within 6 months of treatment initiation were cardiovascular disease (53.4%), diabetes (19%), and depression (18.1%). Overall, 46.6% (n = 54) of patients received prior neoadjuvant or adjuvant chemotherapy and 32.8% patients (n = 38) received prior neoadjuvant or adjuvant endocrine therapy. 95% of patients started at the full dose of 600mg. One-fourth of patients (n = 29) had a dose-hold and 27.6% (n = 32) patients experienced a dose reduction with ribociclib therapy. Conclusions: This study represents early ribociclib uptake in a real-world setting in the US. Early utilization demonstrates patients receiving ribociclib are older and sicker than those in pivotal clinical trials. Substantial heterogeneity in ribociclib initiation by LOT was observed.
Ixabepilone efficacy and tolerability in metastatic breast cancer (MBC) patients in a real-world setting.
Authors: Hyder Tara , Rosenzweig Margaret Q. , Brufsky Adam
Published: May 2020

e13067

Background: Ixabepilone is a microtubule stabilizing agent that was approved as monotherapy and in combination with capecitabine for the treatment of refractory metastatic or locally advanced breast cancer. With limited options for refractory MBC, especially in triple negative breast cancer (TNBC), ixabepilone has demonstrated an increase in progression free survival (PFS) in randomized control trials. We assess the effectiveness and safety of the drug in a real-world setting. Methods: A large, ongoing clinical database of over 1800 women (1999 to present) was used to identify 91 patients who had received ixabepilone during their treatment course. Clinical outcomes were retrospectively analyzed utilizing descriptive and comparative statistics. Results: Treatment was late in the disease course; median line of treatment was 5.3. At the time of receiving ixabepilone, the patients PFS was 3.5 months with n = 4 patients attaining a PFS > 12 months. Overall survival (OS) was 11.3 months. A subset of patients that had triple negative breast cancer (N = 37) had similar PFS, 3.6 months, and OS, 10.2 months, as the total population. Most common adverse events of any grade were fatigue (37%), nausea (32%), and peripheral sensory neuropathy (28%). Grade 3 or higher anemia was present in 10% of the patients. Conclusions: Ixabepilone has demonstrated efficacy in the treatment of patients with MBC, including the challenging population of TNBC patients in this real-world example. It is also well tolerated. These findings make ixabepilone a reasonable chemotherapeutic agent for refractory MBC and TNBC patients. [Table: see text]
Development of an artificial intelligence model to dynamically predict metastatic recurrence of early-stage breast cancer patients.
Authors: Vaidya Vivek Prabhakar , Agrawal Smita , M Sai Vinod , Nagdewani Sandeep , Chandrashekaraiah Prajwal , Bhardwaj Tapasya , Narayanan Babu
Published: May 2020

e13078

Background: Models that can dynamically predict risk of metastatic breast cancer (MBC) recurrence based on cumulative historical clinical data could help guide patient care & surveillance decisions. The objectives of this study were to predict risk of MBC recurrence dynamically from any point after 1 year of initial diagnosis in a BC patient’s journey. We show representative results for predicting 4 year risk post 1 year of date of diagnosis. There are established models to predict risk of distant recurrence at the time of diagnosis but we have not found much work on dynamic risk scores. Methods: We used a set of 3807 patients from the Concerto HealthAI database of oncology EMR data that includes clinical data from CancerLinQ Discovery to build this model that were further enriched by expert nurse curators. The average age at diagnosis was 58 & the average follow up period for this cohort of patients was 6.6 years. The cohort included patients of all breast cancer subtypes. 628 patients had metastatic recurrence within 4 years post 1 year of date of diagnosis. We used 60% of the data for training, 20% for hyper-parameter tuning & 20% for testing & tried out various machine learning (ML) algorithms including Linear Regression, Lasso, Random Forest, Extremely Random Forests, & XGBoost. Extremely Random Forest built using 330 features had the best performance. Results: The performance of various ML algorithms for predicting metastatic BC recurrence within 4 years post 1 year from date of diagnosis is provided in the table below with sensitivity held constant at 0.7. Key variables influencing the results in each model are also indicated. The Extremely Random Forest model for predicting risk of metastatic recurrence within 1 year from 1 year post diagnosis yielded an AUC of 0.814 & a balanced accuracy of 0.719. Conclusions: An AI model to predict risk of metastatic recurrence in breast cancer patients built using a real world dataset yielded promising results. Furthermore, analysis of input variables provided insights not only into the key features driving metastatic recurrence risk such as previous surgery, tumor subtype, stage & age at diagnosis etc. Such a model could be a useful for assessing patient risk & treatment options at various points in a breast cancer patients journey as well as stratify patients for different levels of surveillance. [Table: see text]
Prognosis of breast cancer patients with initial bone metastasis: A population-based study.
Authors: LIU Deyue , Wu Jiayi , Zhu Li
Published: May 2020

e13081

Background: Metastatic breast cancer (MBC) is a highly heterogeneous disease and bone is one of the most common metastatic sites. This retrospective study was conducted to investigate the clinical features, prognostic factors and benefits of surgery of breast cancer patients with initial bone metastases. Methods: From 2010 to 2015, 6860 breast cancer patients diagnosed with initial bone metastasis were analysed from Surveillance, Epidemiology, and End Results (SEER) database. Univariate and Multivariable analysis were used to identify prognostic factors. A nomogram was performed based on the factors selected from cox regression result. Survival curves were plotted according to different subtypes, metastatic burdens and risk group differentiated by nomogram. Results: Hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) positive patients showed the best outcome compared to other subtypes. Patients of younger age ( < 60 years old), white race, lower grade, lower T stage ( < = T2), not combining organ metastasistend to have better outcome. About 37% (2249) patients received surgery of primary tumor. Patients of all subtypes can benefit from surgery. Patients of bone-only metastases (BOM), bone and liver metastases, bone and lung metastases also showed superior survival time if surgery is performed. While patients of bone and brain patients cannot benefit from surgery (p = 0.05). The C-index of nomogram is 0.68. A cutoff value of nomogram point was identified by ROC curve as 93 points, which divided all patients into low-risk group and high-risk group. Patients of both groups showed better overall survival when receiving surgery. Conclusions: Our study has provided population-based nomogram in patients with initial bone metastatic breast cancer. The finding of potential benefit of surgery to overall survival will cast some light on the treatment tactics of this group of patients.
Feasibility of real-time serial comprehensive tumor analytics: Pilot study of olaparib and durvalumab in metastatic triple negative breast cancer (mTNBC).
Authors: Li Allen , Labrie Marilyne , Vuky Jacqueline , Lim Jeong Youn , Johnson Brett , Sivagnanam Sam , Betts Courtney , Coussens Lisa , Corless Christopher L. , Bergan Raymond C. , Gray Joe W. , Mills Gordon B. , Mitri Zahi Ibrahim
Published: May 2020

e13092

Background: Longitudinal analysis of serial tumor biopsies is an under-utilized approach to studying adaptive mechanisms of resistance. We have established a comprehensive analytic platform to evaluate real-time trial sample analysis to inform precision oncology combinations in mTNBC. The primary endpoint of the study is feasibility of completing all CLIA assays within 28 days of biopsy. Methods: Following a pre-treatment biopsy and 4 weeks of olaparib monotherapy mTNBC patients underwent an on-treatment (tx) biopsy and durvalumab was added to their therapy. Pre- and on-tx biopsies underwent comparative analysis using CLIA assays (immunohistochemistry-IHC, whole exome seq, RNAseq and phospho-proteomics) as well as research assays (multiplex IHC-mIHC, cyclic immunofluorescence-IF, and reverse phase protein array-RPPA). Results: Serial biopsies were obtained from all 3 enrolled patients, and the primary endpoint was achieved for all patients (Table). Treatment was well tolerated, and 2 patients achieved clinical benefit > 6 months. In one patient with a prolonged CR ( > 18 months), the on-tx sample exhibited dramatic changes in protein network rewiring by protein data analysis (RPPA, cyclic-IF), and an increase in immune infiltrate by mIHC. Conclusions: This pilot confirmed the feasibility of rapid real-time analysis to inform treatment decisions. This led to the development and initiation of biomarker driven olaparib combination trials in mTNBC at our institution. Clinical trial information: NCT03544125 . [Table: see text]
Blocking pro-invasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NASs).
Authors: Eteshola Elias , Landa Karenia , Hwang Eun-Sil Shelley , Nair Smita , Sullenger Bruce
Published: May 2020

e13096

Background: Breast cancers remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. Triple-negative breast cancer (TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Inflammation-driven tumorigenesis has been shown to correlate with cell-free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. We showed that nucleic-acid scavengers (NAS) can block pro-inflammatory signals elicited by DAMP-activation of innate immune sensors (e.g. toll-like receptors). Treatment with the NAS PAMAM-G3 drastically reduced liver metastatic burden in an immunocompetent murine model of pancreatic cancer. Methods: TNBC cells lines were treated with a cocktail of standard-of-care chemotherapeutic agents and the conditioned media (CM) from these cells served as an in vitro DAMP source. Downstream function of TLR activation was tested via a HEK293-TLR reporter cell line measuring absorbance at 655nm. The in vitro invasive phenotype was tested and quantified using a Transwell-Matrigel invasion assay. Cytokine secretion was measured using a BioLegend cytokine array. Results: TNBC CM greatly increased TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of human monocytes (THP-1) with TNBC CM elicited a strong pro-inflammatory response with elevated levels of IL-8, IL-6, CCL2, and IL-1β. Other biologically immune responders including human PBMCs will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. Conclusions: To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to capture and characterize DAMPs and do in vivo live imaging experiments to gain insight into NAS PK/PD properties. This insight into NAS capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.
Evaluating progression-free survival in black and white women with triple-negative breast cancer in pooled clinical trials from a synthetic control database (SCD) and real-world electronic medical records (EMR).
Authors: Watson Mark Layton , Holcomb Kevin , Newman Lisa , Andrews Janna , Ensign Lisa , Galaznik Aaron , Fields Bryant , Diamond Sheila , Pollard Nicole
Published: May 2020

e13102

Background: Previous studies have shown a lower survival rate in Black women with breast cancer compared with other ethnic groups, largely explained by the increased incidence of triple negative breast cancer (TNBC). In this study we further explore relative survival by race within a TNBC population. By using pooled clinical trial data, we seek to control for variation in patient assessment on outcomes. We further use a real-world electronic medical records (EMR) data source to compare the representativeness of pooled trial findings to patients receiving care not on trial. Methods: Phase II and III open-label breast cancer studies having completed their primary analysis were selected from the Medidata Enterprise Data Store (MEDS), comprised of over 19,000 historical clinical trials, for de-identified aggregate analyses. The Synthetic Control Database (SCD) for this study contains 749 patients with TNBC enrolled in second line and higher treatment trials between 2010 and 2017. De-identified Oncology EMR data was sourced from the Guardian Research Network (GRN) of integrated delivery systems from 2010 to 2018, and contained 1877 patients. Baseline characteristics were assessed between pooled trial and real-world data cohorts. Patients were stratified by race. Progression-free survival (PFS) was assessed using a Kaplan-Meier analysis. We conducted further analysis to assess the impact of additional factors that may influence the aggressive progression of TNBC response in Black women and TNBC disparity. Factors included, but were not limited to: age, stage at diagnosis, baseline benign neutropenia, Body Mass Index (BMI) and genetic factors (BRCA). Results: The TNBC SCD population was 73.0% White, 6.8% Black, and 20.2% Non-White Non-Black (NWNB). The real-world distribution, by contrast was 79%, 10%, and 11%, respectively, with patients predominantly stage 2 at diagnosis. Median BMI at diagnosis was 28.6, 32.6 and 27.1. Unadjusted progression-free survival (PFS) was directionally lower in Black patients in a Kaplan-Meier assessment with a Median PFS of 105 days vs 144 days for all others. Conclusions: A representative pool of cross trial TNBC patients demonstrated lower PFS in Black patients compared to their non-Black counterparts. Based on these findings, further investigation to explore potential biological and treatment factors associated with racial disparity in TNBC is warranted.
Dual TGF-β and AURKA targeting enhances chemosensitivity in triple-negative breast cancer.
Authors: Faruqi Fahad Ahmed , Jalalirad Mohammad , D'Assoro Antonino Bonaventura , Haddad Tufia C. , Carter Jodi M , Boughey Judy Caroline , Wang Leiwei , Goetz Matthew P. , Ingle James N.
Published: May 2020

e13106

Background: Chemotherapy resistance remains a significant barrier in the effective treatment of patients with triple negative breast cancer (TNBC). TGF-β signaling is a well characterized oncogenic pathway in TNBC that promotes chemoresistance by inducing epithelial to mesenchymal transition (EMT) and tumor stemness. Aurora-A kinase (AURKA) is a serine/threonine kinase responsible for chromosomal stability during mitosis. Significantly, aberrant expression of AURKA induces breast cancer progression. We hypothesized that aberrant activation of TGF-β and AURKA signaling pathways contributes to chemoresistance in TNBC by promoting EMT and tumor stemness and that dual-targeting of these oncoproteins will enhance chemosensitivity. Methods: RNA-Seq data were analyzed from patient derived xenografts (PDx) established from patients with Stage I-III TNBC who received pre-operative taxane and anthracycline based chemotherapy. Chemoresistance was defined as an RCB score of 1-3, and chemosensitivity was defined as an RCB score of 0. Unique TNBC cell lines developed from brain metastasis PDxs (TNBC M14, TNBC M25) were treated in vitro with 10nM docetaxel (DTX), 50nM LY2157299 (TGF-β inhibitor) and 50nM MLN8237 (AURKA inhibitor). EMT reprogramming was determined by measuring the expression of vimentin, ALDH activity and mammosphere growth. Apoptotic cells following drug treatment were labeled with Red Annexin-V marker and monitored in real time using the IncuCyte instrument. Results: RNA-Seq revealed that there was no baseline difference in expression of AURKA between chemoresistant and chemosensitive TNBC PDxs. However, there was a 2.7-fold increase in AURKA expression in the post-treatment PDx models compared to pre-treatment PDx models. In vitro treatment of the M14 and M25 cell lines with DTX demonstrated no significant increase in apoptotic cells compared to control, whereas treatment with the combination of DTX, LY2157299 and MLN8237 resulted in a two-fold increase in apoptosis compared to treatment with DTX alone (p = 0.0068 M14, p = 0.003 M25). Dual-targeting with LY2157299 and MLN8237 reduced the expression of vimentin and ALDH activity. Conclusions: TGF-β and AURKA play a central role inducing EMT and a stem-cell-like phenotype in TNBC that confers chemoresistance. AURKA is up-regulated after exposure to chemotherapy in chemoresistant TNBC PDx models. LY2157299 and MLN8237 reduce TNBC stemness in M14 and M25 cell lines and enhance DTX chemosensitivity. Dual-targeting of TGF-β and AURKA is a potentially promising approach in chemoresistant TNBC.
Deoptimized influenza virus for treatment of TNBC and induction of anticancer immunity in the EMT6 mouse model.
Authors: Stawowczyk Marcin , Stauft Charles Brandon , Wang Ying , Mueller Steffen , Coleman John Robert
Published: May 2020

e13109

Background: Triple negative breast cancer (TNBC) is resistant to classical hormone-based therapy, prone to relapse and aggressive metastasis. Oncolytic viruses (OVs) when injected into the tumor, can promote local lysis of tumor cells and drive presentation of tumor antigens, thereby making tumors visible to the immune system. CodaLytic is a re-coded influenza A virus that has a high frequency of disfavored codons and codon pairs which attenuate the virus yet preserve all antigens and immune stimulation properties of the wild type influenza virus. CodaLytic is produced from the same master virus seed as CodaVax, a universal influenza vaccine candidate currently in Phase I clinical trials under a US IND. Methods: BALB/c mice were implanted with EMT6 mouse TNBC cells into a mammary fat pad. Six days post-implantation, when tumors became palpable, treatment was initiated by intratumoral administration of PBS (mock) or CodaLytic (108 PFU in 50 µL). Mice were treated three times a week for a total of three weeks. Tumor growth was monitored daily for 33 days and animals were euthanized if the tumor volume exceeded 500 mm3. Survivors were challenged via flank or intravenous (IV) injection of EMT6 cells. Two weeks after IV challenge, lungs were removed and compared to the lungs of control mice. Results: At the end of the initial experiment (day 33), 80% of CodaLytic-treated mice were alive with 70% of survivors being tumor-free as compared to mock, of which none survived. Survivors on day 33 had a median decrease in tumor size of 75%. CodaLytic stimulated lasting anti-tumor immunity as 100% of CodaLytic-treated survivors failed to establish tumors following challenge with EMT6 cells via flank injection. To model metastasis, surviving treated mice were also challenged with EMT6 cells delivered 2x104 cells IV. IV challenged mice had over 10-fold fewer nodules in their lungs as compared to naïve controls and 40% of the animals remained tumor free, whereas 100% of the control animals developed tumors. Additionally, CodaLytic-treated survivors showed no weight loss after IV re-challenge compared to controls which lost an average of 12% body mass. Conclusions: CodaLytic OV treatment of TNBC increased survival, led to complete tumor clearance in the EMT6 mouse model, and induced systemic anti-tumor immunity that has potential for preventing and treating metastatic disease.
Triple-negative and non–triple-negative breast cancer in a south Indian cohort.
Authors: Warrier Narayanankutty Edavalath , Sankar Uma V , P S Sreedharan , Sherif Ajmal
Published: May 2020

e13110

Background: The heterogeneity of breast cancer explains in part the differences in the morbidity and mortality of this disease. Triple-negative breast cancer (TNBC) is a specific subset of tumors characterized by the absence of the 3 most commonly targeted biomarkers considered for breast cancer treatment: Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). TNBC accounts for 15% to 20% of all breast cancer diagnoses and usually has a more aggressive clinical course, with worse evolution within the first 3 to 5 years after diagnosis; early and higher rates of distant recurrences, typically visceral; and poor survival. Methods: To analyze the clinical, pathological, and sociodemographic aspects between triple-negative breast cancer (TNBC) and non-TNBC in a Kerala cohort and identify potential prognostic factors. This hospital-based retrospective cohort study (From January 2017 till December 2018) included 465 women with breast cancer treated at MVR Cancer Centre & Research Institute in North Kerala. Overall and disease-free survival was compared; prognostic factors were evaluated. Results: Triple-negative breast cancer corresponded to 16.3% of breast cancer diagnosis and was more prevalent among rural women. The patients with TNBC tended to present with stage III cancer, high p53 expression, lymphocytic infiltration, and multifocality and treated with radical surgery and chemotherapy. The 2-year overall and disease-free survival were 52.1% and 43.5% for TNBC and 83.8% and 73.4% for non-TNBC, respectively ( P < .001). The TNBC recurrence was associated with multicentricity, whereas lymph node involvement increased the risk of both recurrence and death. Non-TNBC worse clinical course was associated with rural women, younger age, lymph node involvement, and advanced stage. Conclusions: Triple-negative breast cancer exhibited a more aggressive behavior, earlier and more frequent recurrence, and worse survival compared with non-TNBC. While biological and social variables were associated with poorer prognosis in non-TNBC, only lymph node involvement and multicentricity were correlated with worse clinical outcomes in TNBC.
Next generation sequencing reveals the phylogenetic relationship of multi-organ metastatic colon cancer and molecular determinants of metastasis.
Authors: Hu Dandan , Chen Gong , Zhang Yaojun , Chen Minshan
Published: May 2020

e13502

Background: The clinical manifestation of metastatic colorectal cancer (mCRC) varies from patient to patient, with the underlying genetic alterations and expression profiles deceptive. We aim to investigate the phylogenetic relationships of the multi-organ mCRC and the possible biomarkers of disease progression. Methods: Whole Extron Sequencing (WES) was performed in CRC and their matched multi-organ metastases from three patients with different clinical manifestations. Sciclone calculation between individual lesions illustrated the evolutionary origins of each metastatic sites. Genomic divergence between primary and metastatic sites were identified and their potential role in the metastatic process were annotated. Following the WES results, the significantly correlated genes were validated by immunohistochemistry. Results: The evolutionary tree showed that the distant metastasis could originated from either the primary colon cancer or the other metastatic site. Organotropism exists in both mCRC and protein levels in terms of APOB, and a number of driver mutations potentially decide the disease progression. Moreover, the expressive change of APOB between primary CRC and CRC liver metastasis indicates worse long-term outcomes. Conclusions: Metastatic routes of multi-organ mCRC are highly heterogeneous. We identified previously unreported gene alterations might facilitate metastatic and organotropic progression, providing potential biomarkers for diagnosis and treatment.
Association of rs28714259 polymorphism with a risk of early-onset chronic anthracycline-mediated cardiotoxicity in patients with breast cancer.
Authors: Gvaldin Dmitry Yu. , Timoshkina Natalya N. , Omelchuk Ekaterina P. , Vashchenko Larisa N. , Ratieva Anastasia S. , Vladimirova Liubov Yu , Kit Oleg I. , Lisutin Aleksandr E.
Published: May 2020

e13504

Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to assess the prevalence of rs28714259 polymorphism and to study possible correlation with anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 173 Caucasian patients (median age 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular pathology who underwent treatment in the RRIO, Rostov-on-Don in 2019. For genotyping of SNP rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by Sanger sequencing with a Genetic Analyzer 3500 (ABI, USA). The obtained results were compared with European population (1000 Genome). Results: 13 patients (7.5%) with an early-onset of chronic AMC were founded after three courses of chemotherapy. The allelic frequency rs28714259 was 0.079, the frequency of AG genotypes was 0.135, and AA was 0.012. It was shown that the presence of this SNP leads to an increase risk of cardiovascular pathology at an early stage by more than 4 times (OR = 4.186, p = 0.006). In addition, when comparing with the European population, the highest probability of developing early-onset chronic AMC was determined for patients with the AA genotype (more than 22 times, p = 0.001). Conclusions: In this study, a statistically significant association of rs28714259 presence with developing early-onset chronic AMC was revealed, which seems promising for the early determination of the risk group in the management of cancer patients.