bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation and cardiotoxicity: A retrospective analysis of a midwest population.
Authors: Tandan Nitin , Koester Cameron , Parajuli Priyanka , Lara Garcia Odalys Estefania , Regmi Manjari Rani , Cheema Asad , Maini Ruby , Abedrabo Sabree , Sahib Hamsa , Mirihagalle Noupama , Niaz Zurain , Bhandari Bishal , Johnson Alexander , Ibrahim Abdisamad M. , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e12616

Background: The most common female malignancy diagnosed in the US is breast cancer. Early breast cancer therapy is often treated with radiation therapy; one of the unfortunate side effects of radiotherapy in the past has been cardiotoxicity, especially coronary artery disease. Recent usage of dose reduction techniques have helped reduce these effects. Here, we present our analysis of breast cancer patients that received radiation therapy and the likelihood of cardiotoxicity. Methods: An IRB-approved retrospective study was performed utilizing ICD codes to analyze patients diagnosed with biopsy-confirmed breast cancer between January 1, 2014 and December 31, 2017. 478 of 1618 de-identified patients qualified for this study. Statistical analysis was performed with SAS v9.4. Descriptive statistics were computed for all study variables. Continuous variables were described with measures of central tendency (mean, median) and dispersion (range, standard deviation). Categorical variables were summarized as frequencies and percentages. Comparisons between categorical variables were compared with the Chi-Square test (or Fisher’s Exact) where appropriate. Survival curves were estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival were assessed with Cox proportional hazards regression analyses. All significance is assumed at the p < 0.05 level. Results: Of the 478 eligible patients, heart failure (HF), HF hospitalizations, acute coronary syndrome and overall cardiac events were compared among breast cancer patients. Patients who received radiation experienced HF 6.02% compared to 4.61% without radiation (p = 0.574). HF hospitalization was recorded as 2.27% in radiotherapy compared to 1.23% in non-radiotherapy patients (p = 0.686). Patients who radiation experienced ACS 2.27% of the time as compared to 1.21% in patients who were not treated with radiation. Of note, 9.25% receiving radiation experienced cardiac events compared to 4.24% in patients without radiation (p = 0.068). While results were not statistically significant, the trend of elevated cardiac events in breast cancer patients receiving radiation is noteworthy. Conclusions: Per our study, although statistically insignificant, radiation therapy may result in higher incidence of cardiac events in breast cancer patients. Further large-scale, prospective studies should be performed to confirm the aforementioned trends with respect to survival outcomes in urban and rural populations.
Identification of CCN1 transferred by extracellular vesicles derived from breast cancer cells responsible for doxorubicin-resistance.
Authors: Yang Sujin , Tang Jinhai
Published: May 2020

e12623

Background: The anthracycline drug, doxorubicin, is one of the most frequently used chemotherapeutic drugs for breast cancer. However, not all patients respond to doxorubicin-containing combination chemotherapy due to chemo-resistance (natural or acquired). Preceding researches have shown that extracellular vesicles (EVs) can be readily harvested from peripheral blood for further biological analysis and thus perform an attractive source of tumor derived materials for identification of chemo-resistance factors. This study aims to provide a theoretical basis to use CCN1-containing EVs as new biomarkers and therapeutic targets for doxorubicin-resistance in breast cancer. Methods: A strategy combining RNA-sequencing technique and bioinformatic analysis was used to determine the level of differential expressed mRNAs in EVs samples from cellular supernatant (n = 4) and blood serum (n = 8) from chemo-resistant and chemo-sensitive patients. Serial gene expression analysis in patients (n = 203) who treated with neoadjuvant (GSE32603) were also employed to identified drug-resistance-related proteins. The expression of CCN1 was detected in doxorubicin-resistant cell lines (MCF-7/DOX),MCF-7 and their EVs by RT-qPCR and western blot. Then, we used cell apoptosis and immunofluorescence stain to confirm the ability of CCN1-containing EVs in conferring drug resistance. Immunohistochemistry stain and RT-qPCR were used to prove the expression level of CCN1 in tumor tissues from breast cancer patients (n = 80) and in serum EVs from patients treated with the whole neoadjuvant chemotherapy. Results: We combined the differentially expressed mRNAs from three datasets and found identified CCN1 as a drug-resistance-related factor in breast cancer. The expression level of CCN1 is much higher in MCF-7/DOX cells and their EVs compared with MCF-7 cells and their EVs. The addition of CCN1-containing EVs has been found significantly increase the resistance to doxorubicin in sensitive cells. Moreover, a higher expression level of CCN1 was detected in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in tissues and serum EVs. Conclusions: All These findings demonstrate that CCN1-containing EVs appear to be essential in conferring resistance to doxorubicin. More importantly, we exhibit the potential applications of CCN1-containing EVs for predicting the efficiency and outcome of patients treated with doxorubicin-based chemotherapy.
Biodynamic response prediction in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Morgan Travis , Whitacre Eric , Burak William , Manahan Eric , Goedde Timothy , Greenspan Andrew , Woods John , Nolte David , Turek John , Loesch David M. , An Ran
Published: May 2020

e12643

Background: Biodynamic signatures (temporal patterns of microscopic motion within a three-dimensional tumor explant) offer a phenomic biomarker that is highly predictive for therapeutic response. The purpose of this study is to evaluate predictive accuracy of a biodynamic drug response classifier in breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods: Consecutive breast cancer patients from 4 institutions were screened for enrollment in a prospective observational study (NCT03164863). Treatment-naïve needle biopsies were delivered to a central laboratory where biodynamic signatures were measured in living tumor fragments challenged by standard-of-care cytotoxins. Patients received NAC per institutional guidelines and were followed through surgical intervention. A four-point classifier was trained to predict pathologic complete response (CR) then prospectively validated. Results: Among patients completing neoadjuvant treatment and surgical intervention, 33% (24 of 72) achieved CR. The biodynamic classifier predicted CR with 96% sensitivity and 97% negative predictive value. Biodynamically “favored” (scoring ≥ 3) and “strongly favored” (scoring 4) regimens produced CR at rates of 56% (23 of 41) and 73% (19 of 26), respectively. Only 3% of patients (1 of 31) achieved CR from regimens scoring 1 or 2. Area under the receiver operating curve (AUC) was 87% (95% CI: 75% to 93%, p < .0001), with similar performance across all subtypes and therapy cohorts (range: 84% to 89%). Performance of the classifier on training and validation patients was statistically equivalent. Conclusions: Biodynamic scoring accurately predicts response in breast cancer patients receiving NAC and holds promise to substantially improve management of these patients. [Table: see text]
Risk of recurrence in patients with HER2+ breast cancer who achieved a pathological complete response (pCR) after neoadjuvant pertuzumab and trastuzumab (nPT), and received adjuvant trastuzumab (aT): Real-world evidence.
Authors: Robert Nicholas J. , O'Shaughnessy Joyce , Annavarapu Srinivas , Zhou Jie , Sussell Jesse , Cheng Anna , Fung Anita
Published: May 2020

e12648

Background: The real-world risk of disease recurrence in patients with HER2+ early breast cancer who achieved pCR after receipt of nPT-based regimens and aT is unclear. Methods: Women with HER2+ breast cancer who achieved pCR after nPT-based regimens and received aT were identified in the US Oncology Network (USON). Patients initiated nPT between 2013 –2015 and were followed until recurrence of invasive disease or censoring. Data was sourced from structured fields and review of USON patient charts. Recurrence of invasive disease was defined as any of: recurrence of ipsilateral locoregional invasive breast cancer, contralateral breast cancer, distant disease recurrence, or death. Descriptive analyses were used to assess baseline demographic and clinical characteristics and the Kaplan-Meier method was used to assess invasive disease-free survival (iDFS), with stratification by nodal status. Results: A total of 238 pCR patients’ charts were reviewed. Median patient age was 52 (range: 23-88) years and a majority were White (77%). Most patients had stage IIA (39%) or IIB (24%) disease at diagnosis, ECOG score < 1 (85%), and tumor size > 2 cm (68%). At diagnosis, the majority of patients (57%) were node positive (N+) and negative for estrogen or progesterone receptor expression (51%). Median durations of therapy for nPT and aT were 4 (range: 1-8) and 7 (range: 0.03-53) months, respectively. The median duration of follow up was 47 (range: 1-70) months. Four-year iDFS probabilities are shown in the Table. Conclusions: Consistent with previously reported clinical trial data and several pooled analyses, results from this real-world study indicate that despite achieving pCR after nPT-based regimens, patients with HER2+ BC remain at risk for disease recurrence; in addition, node+ status appears to increase that risk. Therefore, patients should receive standard pertuzumab, trastuzumab adjuvant therapy to optimize treatment outcomes. [Table: see text]
Discordance between molecular subtyping from pre- and post-neoadjuvant chemotherapy (NACT) biopsy specimens in a Brazilian breast cancer cohort.
Authors: Tavares Monique Celeste , Leite Luciana de Moura , Cesca Marcelle Goldner , de Andrade Poliana , Pirolli Rafaela , Xerfan Mariana Pinheiro , Oliveira Fernanda A. , Silva Sinara Figueiredo , Zanco Fogassa Camilla Albina , Mattos Bruna Raphaeli Silva , Campos Fernando Augusto Batista , Sanches Solange Moraes , Cordeiro De Lima Vladmir Claudio
Published: May 2020

e12649

Background: Discordance between immunohistochemistry (IHC) and molecular subtyping from pre and post neoadjuvant chemotherapy (NACT) biopsy specimens in breast cancer (BC) patients (pts) varies in the literature. This information could have prognostic and treatment implications. To evaluate the clinicopathologic characteristics and prognostic factors in pts with localized breast cancer treated with NACT who had IHC repeated in the post treatment biopsies. Methods: We retrospectively reviewed all BC pts treated with NACT at our service (2007 – 2018). Descriptive statistics were used to describe the population. Survival curves were estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: 607 consecutive pts were treated with NACT at our service. From those, 178 (29.3%) had a pathological complete response, 420 (69.2%) had residual disease and 9 (1.5%) had an unknown status. For 95 pts, the IHC was repeated in the pathological specimen, with a change in the molecular subtype in 26 (27.3%) cases. 10 luminal pts lost the hormonal receptor expression and changed to triple negative, 6 luminal B became luminal A, 3 luminal A became luminal B, 6 pts lost the her2 amplification and 1 pt gained a her2 amplification. This 95 pts cohort had a median desease free survival (DFS) of 71 months (m) and an overall survival (OS) of 137m. Pts who had a change in their molecular subtype after NACT had a DFS of 52 m vs 71m (p .26) and OS 86m, not significantly different from those who maintained the same status (p .23). Conclusions: A little more than one quarter of the pts that had repeated post NACT IHC had a change in the molecular subtype, especially with loss of hormonal receptors of luminal tumors, that became triple negative. That did not translated into significantly worse survivals.
Metabolic profile in Mexican young women breast cancer (YWBC) to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC).
Authors: Cruz-Ramos Marlid , Nambo-Venegas Rafel , Campos-Salgado Jose Yair , Ruíz-Godoy Luz , Enríquez-Carcamo Victoria , Mohar Alejandro , Villarreal-Garza Cynthia
Published: May 2020

e12652

Background: YWBC is associated with aggressive biology with a higher mortality rate and recurrence risk. Similar to older patients, pCR after NAC is a surrogate marker of disease-free survival and overall survival in YWBC. However, YWBC who did not achieve pCR did significantly worse. Metabolic profile (MP) has been used for biomarker discovery to monitor chemotherapy response. Few studies focus on using metabolomics to predict pCR in BC. The study aimed to identify MP in YWBC, before NAC to predict response to chemotherapy. Methods: A targeted metabolomics approach was employed to determine the concentration of 11 AAs, free carnitine, and 30 ACCs using electrospray tandem mass spectrometry in plasma of 30 YWBC patients, before NAC to select plasma biomarkers with the most predictive power to identify pCR in YWBC. Patients were classified in responders (R) and non-responders (NR), based on pCR or not-pCR reported by the pathologist department. The differences between R and NR groups were evaluated using an analysis of Random Forest decision trees according to the distribution of the variables. To evaluate the diagnostic power of each biomarker alone, we performed univariate receiver operating characteristics (ROC) analysis on each biomarker to obtain its ROC curve, ROC area under the curve (AUC), and standard error (SE) of the AUC. Results: We observed differences in MP between R and NR YWBC. Ten metabolites contributed most to differentiating between both groups. We developed a model that included two short-chain acyl-carnitines (AC4 and AC5:1) that allowed an AUC of 0.851 (0.767-0.921) and AUC of 0.737 (0.806-0.844) respectively, and ornithine with AUC of 0.723 (0.6-0.626). Conclusions: There are different MP among Mexican YWBC patients classified as R and NR to NAC. To our understanding, this is one of the first studies that evaluate MP in YWBC in Mexico. Further studies are needed to validate a metabolic signature to predict pCR in this patient group.
Need for systematic de-escalation of care in HER2+ breast cancer patients.
Authors: Pandey Tushar , Earnest Tyler M , Cole John A , Braun Eduardo
Published: May 2020

e12657

Background: Over the last decade, there has been incredible progress in HER2-positive breast cancer patients with the adoption of targeted therapies like Trastuzumab and Pertuzumab to complement existing chemotherapies. Increasingly neoadjuvant therapy is the preferred method of therapy as it is better able to predict prognosis via pCR as well as guide adjuvant therapeutic strategy in cases with residual tumor. There are now a variety of combination therapies recommended for HER2-positive patients. As new therapies are developed, the standard-of-care shifts towards the regimen with highest pCR rate. The latest regimen being TCHP which produced pCR rates over 60% in clinical trials. While the improvement in pCR rates at a population level is encouraging, there is a growing sentiment among physicians that we may be over treating patients impacting both costs and resulting toxicity. Methods: We performed an analysis of Breast Cancer trials with pCR as the primary end point and stratification available based on HER2+ status. The cost (median insurance reimbursement) was also referenced from a recent ASCO observational study as a proxy for direct costs of drugs. Toxicities were referenced and each regimen scored (TS) from NCCN Evidence Blocks and adverse events from clinical trials. Potential savings were evaluated if a clinician had the ability to individualize regimen choice by patient. We utilized the SimBioSys TumorScope platform to perform in silico simulations to predict response to alternate therapies as it had previously used to analyze potential deescalate between AC-T vs TC in a HER2- cohort. Results: The following regimens were evaluated HP (pCR:17%,TS:1), TH (pCR: 29%,TS: 2) THP (pCR: 46%, TS: 3), TCH (pCR: 43%, TS: 4), TCHP (pCR: 64%, TS: 5), AC-TH (pCR: 43%, TS: 6), AC-THP(pCR: 55%, TS: 7). Based on an in-silico analysis and selection (where pCR was likely with multiple regimens), the lowest cost & toxicity regimen was selected. The estimated average saving per case of over $100,000 for the overall treatment plan . The calculated toxicity score was also reduced by this method to under 4 from the TCHP(5) standard of care. Conclusions: While the results above are estimates and perfection in such individualization may not be possible, an in-silico approach provides a promising solution.
Assisting decision making on the use of carboplatin for metastatic breast cancer.
Authors: Gomez Marti Juan Luis , Rosenzweig Margaret Q. , Brufsky Adam
Published: May 2020

e13008

Background: Metastatic breast cancer (MBC) is currently treated with chemotherapy, often in combination with targeted or hormonal therapies. Current guidelines indicate the use of paclitaxel in combination with HER2-targeted therapy for HER2+ disease. Platins are often used in combination with taxanes for HER2+, and rarely for HER2(-), metastatic disease. While some studies reported no benefit from carboplatin (Carbo), others showed an additive effect in combination with a taxane (Txn). At this time, it is not clear if platins are an effective course of treatment for HER2+bone only disease. Therefore, this study investigates in a real-world clinical setting the utility of Carbo after the diagnosis of a first metastasis. Methods: Clinical information was obtained using a database with MBC patients seen at Magee Women’s Hospital from 1999-2019. After a chart review, patients were initially classified according to their molecular status and first metastatic location. Overall survival (OS) and time to next therapy (TTNT) were measured (months) and compared between those who received Txn and those who received Carbo in combination with a Txn after first metastatic diagnosis. Treatment response was investigated in either bone or visceral (lung or liver) MBC. Log ranks were used to estimate survival. Results: From 1,723 patients, 36.15% developed first metastasis to bone, 8.7% to lung, 12.63% to lymph node, 9.46% to liver, 4.17% to brain, and 23.33% to other sites. We found that HER2+ patients firstly diagnosed with visceral metastasis benefited from Carbo+Txn vs Txn only (OS 53.27 vs 38.17, P = 0.034), but not those who were HER2(-) (OS 23.20 vs 25.03, P = 0.307), or with bone metastasis, regardless of HER2 status (OS 38.57 vs 37.13, P = 0.718). However, patients with bone metastasis showed an increased TTNT with Carbo+Txn vs Txn alone (13.68 vs 8.167, P = 0.007). Finally, patients with liver metastasis who received Carbo+Txn had an increased OS (51.7 vs 20.4, P = 0.01) and TTNT (17.33 vs 8.63, P = 0.02) compared to Txn only. Looking separately at HER2 status, we found a nonsignificant trend towards Carbo+Txn efficacy in both subtypes. No differences in OS were found when looking at lung as the first metastatic location (Carbo+Txn vs Txn, 30.67 vs 27.03, P = 0.75). Conclusions: Patients whose first metastasis is to the liver, and those who are HER2+ and develop visceral metastasis, might benefit from carboplatin in combination with a taxane and HER2-targeted therapies. There is no benefit from adding carboplatin for bone metastasis. Further studies with larger datasets could validate these results.
Real-word incidence and management of durable complete response in de novo metastatic HER2-positive breast cancer.
Authors: Smith Claire Elizabeth Powers , Marcom Paul Kelly , Mitri Zahi Ibrahim
Published: May 2020

e13017

Background: HER2-directed therapies enable a small number of patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long term durable responses (DR). However, clinic-pathologic factors that correlate with DRs in de novo HER2+ MBC are unknown. Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice, especially the effect on cardiotoxicity, are lacking in the literature. Methods: This is a retrospective case control study of patients with de novo HER2+ MBC who received treatment with trastuzumab at two NCI designated cancer centers between the years 2012-2017. Patients were included if ≥2 years of follow up data were available or if patients were deceased. DRs are defined as radiographic complete or partial response without progression or death at any point after diagnosis. Controls are patients with evidence of radiographic progression or death any point after diagnosis. Age at diagnosis, ER/PR status, site of metastasis, and initial treatment were analyzed. An un-paired T test for age and fisher exact test for categorical variables were used. Results: A total of 96 patients with de novo HER2+ MBC, 28 with DRs and 68 with progression, were identified. Average follow up length for patients with DR was 90 months (range 27-224 months). Patients who progressed had a mPFS of 17.5 months and a mOS of 60 months. Results are shown in Table. Additionally, six patients (6.3%) developed reduced ejection fraction, one with DR, five with progression. Nine patients have been receiving trastuzumab for over ten years with no evidence of disease. Only one patient opted to discontinue this therapy a year after complete response and is disease free five years from diagnosis. Conclusions: Nearly a third of patients with de novo metastatic HER2+ MBC in our dataset achieved DR. Factors that predict DRs include single organ involved by metastatic disease and more intensive upfront chemotherapy including trastuzumab and pertuzumab. The majority of patients with DR continued HER2 directed therapy indefinitely with minimal cardiotoxicity. In the absence of predictive biomarkers of DRs, indefinite trastuzumab administration is common practice for these patients. [Table: see text]
Cardiac complications of CDK4/6 inhibitors for breast cancer.
Authors: Master Samip R.
Published: May 2020

e13038

Background: Cardiac toxicity has largely been underestimated toxicity of CDK4/6 inhibitors. We did a retrospective analysis of data made available to public by the FDA regarding the cardiac adverse effects of CDK 4/6 inhibitors. We used data from trastuumab for comparison purpose. Methods: The FDA has made the data on adverse effects of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the cardiac toxicities of CDK 4/6 inhibitor therapies available at FDERS for the years 2018-2019. Results: A total of 27,079 advere events(AE) from CDK4/6 inhibitors namely, ribociclib, palbociclib and abemaciclib were reported during the year 2018-2019. Out the total, 805 i.e. 2.9% were cardiac AEs. The most common reported cardiac AE were atrial fibrillation (121), myocardial infarction (190), cardiac failure (85) and pericardial effusion (70). As shown in the table, percentage of cardiac AE compared to total AE reported were 2.2%, 5.4%, 7.9% and 7.2% respectively for Palbociclib, Abemaciclib, Ribociclib and trastuzumab. Conclusions: Out of the reported cases of adverse reaction to CDK4/6 inhibitors, 2.9 % were cardio toxicities. The incidence of cardiac complications was higher in ribociclib, compared to Palbociclib and Abemaciclib. [Table: see text]
Treatment patterns and clinical outcomes among patients (pts) with HER2+ advanced breast cancer (ABC) and germline BRCA1/2 mutation(s) (gBRCA1/2mut): Results from a US real-world study.
Authors: Obeid Elias , Parikh Rohan , Esterberg Elizabeth , Arondekar Bhakti , Hitchens Abigail , Arruda Lillian Shahied , Niyazov Alexander
Published: May 2020

e13076

Background: g BRCA1/2mut ABC represents ~5% of all breast cancer (BC) including pts with HER2+ BC. While HER2-targeted therapy remains an effective tx for those pts, limited information is available on the use and effectiveness of PARP inhibitors (PARPi) for pts with HER2+ g BRCA1/2mut ABC. Recently, NCCN updated its guidelines (v1.2020) to support the use of PARPi in pts with g BRCA1/2mut metastatic BC regardless of subtype. In order to establish a baseline reference point, we assessed real-world tx patterns and clinical outcomes among pts with g BRCA1/2mut HER2+. Methods: Oncologists retrospectively reviewed charts (July-Oct 2019) of randomly selected pts ≥18 y, with g BRCA1/2mut HER2+ABC who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan 2013-April 2018. Descriptive analysis was performed for 1st line ABC tx patterns. Clinical outcomes (1st line ABC PFS rates) were estimated using the Kaplan-Meier method. PARPi clinical outcomes data was immature given its recent launch. Additional analyses evaluating outcomes in pts receiving PARPi are planned. Results: Of the 225 pts with g BRCA1/2mut ABC included in the study, 48 (21%) female pts had HER2+ disease. Of the g BRCA1/2mut HER2+ pts, 77% were white with a median age of 58 y. Clinical characteristics: 42% HR+/HER2+, 56% HR-/HER2+, 2% had unknown HR/HER2+ ABC. Txs in the 1st line setting for HR+/HER2+ ABC pts (n = 20) included: CT (75%), CT + HER2-targeted therapy (25%) (Table). First-line txs used for HR-/HER2+ ABC pts (n = 27) included: CT + HER2-targeted therapy (78%), CT (15%), other (7%) (Table). 12-month PFS for 1st line HR+/HER2+ pts was 73% and for HR-/HER2+ pts was 69% (Table). Later line tx patterns will be presented. Conclusions: In this analysis of pts with g BRCA1/2mut HR+/HER2+, unexpectedly low rates of HER2-targeted therapy were observed. As expected, high rates of HER2-targeted therapy with CT were observed among g BRCA1/2mut HR-/HER2+ pts. Clinical outcome findings demonstrate the need for more efficacious tx options. Studies assessing clinical outcomes among g BRCA1/2mut HER2+ ABC pts receiving PARPi +/- HER2-targeted tx are warranted. This is a limited sample size; additional data collection including median PFS is ongoing. [Table: see text]
A phase Ib/II study of eribulin with cyclophosphamide (EC) in patients (pts) with advanced breast cancer (ABC).
Authors: Gumusay Ozge , Renslo Jonathan R. , Wabl Chiara A. , Chien Amy Jo , Melisko Michelle E. , Majure Melanie Catherine , Rahmaputri Siti D. , Moasser Mark , Park John , Rugo Hope S.
Published: May 2020

e13079

Background: Eribulin is an effective microtubule inhibitor for the treatment of ABC. Based on encouraging efficacy with docetaxel/cyclophosphamide, we hypothesized that eribulin combined with cyclophosphamide (EC) would be effective with tolerable toxicity. The aim of the study was to determine the maximum tolerated dose (MTD) of EC, followed by a dose expansion study to estimate the clinical benefit rate (CBR) of EC in pts with ABC. Methods: Study eligibility included pts with histologically confirmed ABC with any number of prior lines of therapy. Pts were treated using a dose escalation strategy with cohort expansion once MTD was determined. Dose level 0 (DL0): E 1.1 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. DL1: E 1.4 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. Phase II expanded enrollment at DL1. The primary objective of the phase II study was CBR [(complete response (CR), partial response (PR), and stable disease (SD)]. Secondary objectives were response rate (RR), duration of response (DOR), time to progression (TTP), and safety. Using a 2-stage design, responses in 3 of the first 22 pts allowed continued enrollment to a planned 40. Results: No dose limiting toxicities (DLT) were identified in phase Ib (n = 6). 3 pts were treated at DL0 and 3 at DL1, the MTD. 44 pts with ABC were enrolled at the MTD and are included in the analysis. 31 pts had HR+/HER2- disease, 12 pts had triple negative disease (TNBC), 1 pt had HR+/HER2+ disease. Median age was 56 yrs, prior treatment (rx) for ABC included a median of 1 line of hormone rx (range 0-6) and 2 lines of prior chemorx (range 0-7). CBR was 79.5% (35/44; 7 PR, 28 SD) and median PFS 16.4 wks (95%CI:13.8-21.1 wks). Longer PFS was observed in those with HR+ disease vs TNBC (18.1 vs 10.8 wks; P = 0.067). Adverse events (AE) of any grade included fatigue (68.2%, n = 30), neutropenia (ntp) (59.1%, n = 26), nausea (56.8%, n = 25), constipation (50%, n = 22), peripheral neuropathy (47.7%, n = 21), dyspnea (40.9%, n = 18), headache (36.4%, n = 16), and anorexia (36.4%, n = 16). The most common grade 3/4 AE ntp (47.7%, n = 21); 3 pts had febrile ntp. Dose reductions due to ntp were required to 500 mg/m2 C (n = 17) and to 1.1 mg/m2 in eribulin (n = 12). Conclusions: EC in heavily pretreated ABC resulted in an encouraging CBR of 79.5% and PFS of 16.4 wks, comparing favorably to single agent E (PFS 14.8 wks). Dose reduction and delays were due primarily to ntp. EC is an effective combination therapy with manageable toxicity in ABC. Clinical trial information: NCT01554371 .
Expression of CD44 and CD133 markers in regional metastases from breast cancer.
Authors: Sagakyants Aleksandr B. , Ulianova Elena P. , Zlatnik Elena Yu. , Novikova Inna A. , Shulgina Oksana G. , Karnaukhov Nikolay S. , Kuznetsova Marina A. , Petriashvili Inna R. , Gaysultanova Yakha S. , Vladimirova Liubov Yu , Shatova Iuliana S. , Vashchenko Larisa N. , Lisutin Aleksandr E. , Kit Oleg I.
Published: May 2020

e13087

Background: High incidence and mortality of breast cancer (BC) require a constant search for the most informative and effective methods of diagnosis and treatment evaluation. The purpose of the study was to analyze phenotypic characteristics of cancer stem cells in tumor tissues and regional metastases of breast cancer (BC). Methods: The study included 20 BC patients with regional metastases (lymph nodes) aged 32-74 years, mean age 56.1±3.3 years. IHC analysis was performed on sections from paraffin blocks of tumors using monoclonal mouse antibodies to CD44 (156-3C11 Thermo Scientific) at a dilution of 1:2500 and polyclonal rabbit antibodies to CD133 (Cloud-Clone Corp.) at a dilution of 1:700 using the Thermo Scientific automated stainer. Membrane staining and staining intensity were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong staining. CD44 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells. CD133 expression was considered positive when staining was detected in more than 5% (cut-off) of the tumor. Results: CD44 + expression was detected in 80% of breast tumor tissues (16 samples), while in 20% this marker was not determined. The average CD44 expression was 27.2±13.9%. The expression of CD44 in regional metastases (RM) from BC was 35% (from 0 to 30%), on average 17.0±6.8%. When distributed according to the χ2 criterion in the tumor and RM, an association between factorial and resultant signs was statistically significant (8.286, at p < 0.004). CD133+ expression in tumor tissues was detected in 80%, with an average expression level of 56.0±14.6%, with a predominance of positive cytoplasmic staining in 60%. Determination of this marker in BC RM gave a positive result in 15% (3 samples), with expression fluctuations from 0 to 60%, the average level was 33.0±15.4%. When distributed according to the χ2 criterion in the tumor and RM, an association between factorial and resultant signs was statistically significant (16.942, at p < 0.001). Conclusions: Determination of tumor cells with the stem phenotype directly in the tissue of primary BC tumors and in tissues of regional metastases demonstrated that the percentage of CD44+ and CD133+ cells in the primary BC tumor was higher.
Enzymatic tissue disintegration leads to the loss of immunophenotype of breast cancer stem cells.
Authors: Sagakyants Aleksandr B. , Sitkovskaya Anastasia O. , Shamova Tatiana V. , Filippova Svetlana Yu. , Bondarenko Elena S. , Zlatnik Elena Yu. , Novikova Inna A. , Vashchenko Larisa N. , Kechedzhieva Emma E. , Ausheva Tatiana V. , Andreyko Elena A. , Saforyan Natalya S. , Dashkova Irina R. , Shatova Iuliana S. , Vladimirova Liubov Yu , Lisutin Aleksandr E. , Kit Oleg I.
Published: May 2020

e13089

Background: Cancer stem cells (CSC) are a population in the complex hierarchy of tumor tissue responsible for growth, metastasis and resistance to chemotherapy and radiotherapy. The purpose of the study was to reveal the effect of the enzymatic disintegration of breast cancer (BC) tissue on the CSC immunophenotype. Methods: BC tumor samples obtained during surgery were placed for 2 hours in a sterile Hanks’ solution immediately after collection. Samples were fragmented to 1 mm in diameter, the fragments were evenly distributed into 4 Petri dishes with (6 cm diameter) and placed in DMEM medium (Gibco, USA) without collagenase and with the addition of collagenase (Biolot, Russia) to a final concentration of 150, 300 and 450 units/ml. Samples were cultured for 48 hours at 37°C and 5.5% CO2. On day 2, the samples incubated in collagenase were grinded by passing through tips of decreasing diameter; the reference sample was grinded in the Medimachine system (BD, USA). The effect of enzymatic tissue disintegration on the preservation of BC SC immunophenotype (CD24low/-CD44+) was evaluated using the BD FacsCanto II flow cytometer (BD, USA) and PE Mouse Anti-Human CD24 (clone ML5; BD, USA) and FITC Mouse Anti-Human CD44 (clone G44-26; BD, USA) antibodies. Results: The total number of isolated cells increased almost exponentially with increasing collagenase concentration. The trypan blue test showed that cell viability did not change significantly with an increase in collagenase concentration and was approximately 50%, being an order of magnitude higher compared to mechanical dissociation (4%). However, 48 h incubation in a collagenase solution led decreased the number of CD44+ cells in proportion to the enzyme concentration by 3 to 10 times in comparison with the control. Similarly, inhibition of CD24 expression was observed compared with the control, inevitably leading to a decreased purity of the isolated subpopulation with the CD24low/-CD44+ phenotype. Conclusions: Despite an increase in the yield of viable cells, prolonged incubation in a collagenase solution leads to a loss of the immunophenotype of BC SC.
Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer.
Authors: Nuncia Cantarero Miriam , Serrano-Oviedo Leticia , Nieto Jiménez Cristina , Tébar García David , Burgos Lozano Miguel , Morcillo García Sara , Perez Peña Javier , Corrales-Sanchez Veronica , Gyorffy Balazs , Ocana Alberto , Galan-Moya Eva María
Published: May 2020

e13098

Background: Triple negative breast cancers (TNBCs) are enriched in cells bearing stem-like features, i.e., cancer stem cells (CSCs), which underlie cancer progression. Thus, targeting stemness may be an interesting treatment approach. The epigenetic machinery is crucial for maintaining the stemness phenotype. Bromodomain and extra-terminal domain (BET) epigenetic reader family members are emerging as novel targets for cancer therapy, and have already shown preclinical effects in breast cancer. Here, we aimed to evaluate the effect of the BET inhibitor JQ1 on stemness in TNBC. Methods: Transcriptomic, functional annotation and qRT-PCR studies were performed on JQ1-exposed TNBC cells in culture. The results obtained were confirmed in spheroids and spheroid-derived tumours. In addition, limiting dilution, secondary and tertiary tumour sphere formation, matrigel invasion, immunofluorescence and flow cytometry assays were performed to evaluate the effect of JQ1 on CSC features. For clinical outcome analyses, the online tool Kaplan-Meier Plotter and an integrated response database were used. Results: We found that JQ1 modified the expression of stemness-related genes in two TNBC-derived cell lines, MDA-MB-231 and BT549. Among these changes, the CD44/CD24 ratio and ALDH1A1 expression level, i.e., both classical stemness markers, were found to be decreased by JQ1. Using a validated spheroid model to mimic the intrinsic characteristics of CSCs, we found that JQ1 decreased surface CD44 expression, inhibited self-renewal and invasion, and induced cell cycle arrest in G0/G1, thereby altering the stemness phenotype. We also found associations between four of the identified stemness genes, GJA1 , CD24, EPCAM and SOX9, and a worse TNBC patient outcome. The expression of another two of the stemness-related genes was found to be decreased by JQ1, ABCG2 and RUNX2, and predicted a low response to chemotherapy in TNBC patients, which supports a role for RUNX2 as a potential predictive marker for chemotherapy response in TNBC. Conclusions: We identified a stemness-related gene panel associated with JQ1 and describe how this inhibitor modifies the stemness landscape in TNBC. Therefore, we propose a novel role for JQ1 as a stemness-targeting drug. Loss of the stem cell phenotype via JQ1 treatment could lead to less aggressive and more chemo-sensitive tumours, reflecting a better patient prognosis. Thus, the identified gene panel may be of interest for the clinical management of patients with aggressive TNBC.
12-month uptake of PD-L1 testing and atezolizumab (atezo) + nab-paclitaxel (nab-pac) treatment in metastatic triple-negative breast cancer (mTNBC) following accelerated FDA-approval in the United States.
Authors: Emens Leisha A. , Craggs Christopher , Debiasi Marcio , Kent Matthew , Luhn Patricia , Hamilton Erika Paige
Published: May 2020

e13103

Background: In March 2019, atezo + nab-pac received accelerated FDA-approval for the treatment (tx) of patients (pts) with unresectable locally advanced or metastatic TNBC who express PD-L1 in immune cells (IC), based on the results from the randomized IMpassion130 clinical trial. A companion diagnostic, the Ventana SP142 PD-L1 assay, was concurrently approved. This real-world data analysis describes the uptake of both PD-L1 testing and therapy with atezo + nab-pac from the time of approval. Methods: This is a retrospective study using the Flatiron Health electronic health record (EHR) derived de-identified database, representing > 2.4 million US cancer pts from > 280 cancer clinics. Pts diagnosed with mTNBC starting any line of systemic therapy between March 9, 2019 and December 31, 2019 (to be updated in April 2020 for 12-months follow-up) were included. Two cohorts were examined: pts receiving either atezo-based tx, or tx without atezo. Demographics were described in the pt group overall and by line of therapy (LOT). Steroid tx at baseline was classified as any order/administration of a steroid within the first three administrations of a systemic therapy in a given LOT. Any record of a PD-L1 test was reported. Results: 228 pts diagnosed with mTNBC were included; 65 pts (28%) received any atezo combination, the majority in combination with nab-pac: 57% (n = 37) in first-line (1L), 25% (n = 16) in second-line (2L), and 18% (n = 12) in third-line or later (3L+). Median age at metastatic diagnosis (mDx) for atezo-treated pts was: 1L, 65 y (IQR: 49, 72); 2L, 56 y (IQR: 48, 64); 3L+, 52 y (IQR: 42, 60). Median age at mDx for non-atezo-treated patients was: 1L, 63 y (IQR: 53, 74); 2L, 59 y (IQR: 51, 65); 3L+, 61 y (IQR: 53, 71). Of 228 pts, 158 (69%) had any PD-L1 test recorded. Among atezo-treated pts, 62 (95%) had a documented PD-L1 test; of those 40 (62%) were tested using the SP142 assay. Overall, 205 tests were recorded: SP142, n = 96 (46.8%); unknown/not documented, n = 44 (21.5%); 22C3, n = 36 (17.6%); lab-developed test, n = 26 (12.7%); SP263, n = 2 (1.0%); and 28-8, n = 1, (0.5%). 37 (57%) atezo-treated pts received a steroid at baseline. Conclusions: Atezo tx and testing with SP142 is being implemented following accelerated FDA-approval. A considerable proportion of pts received steroids at baseline and had nab-pac as chemotherapy backbone in clinical practice. Clinical outcomes of atezo-treated pts in the real-world setting remain to be further explored pending longer pt follow-up times.
Genomic landscape of FGF/FGFR pathway alternations across 12,372 pan-cancer patients.
Authors: Yin Yongmei , Zuo Wei , Yan He , Zhao Zhengyi , Zhang Yuzi , Zhao Jing , Cui Longgang , Wang Guoqiang , Cai Shangli , Bai Yuezong , Li Wei , Wu Hao
Published: May 2020

e13503

Background: The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway is involved in diverse biological processes and plays a crucial role in carcinogenesis. FGFR targeted therapies have shown great promise in the treatment of a multitude of malignancies. This study aimed to assess the alternations of FGF/FGFR pathway and explore the potential relationships between the genetic alternations in a pan-cancer setting. Methods: Next-generation sequencing was conducted with formalin-fixed, paraffin-embedded tumor specimens from 12,372 Chinese cancer patients with over 21 tumor types, including lung cancer (n = 3557), liver cancer (n = 1433), colorectal cancer (n = 1310), biliary tract cancer (n = 960), gastric cancer (n = 758), etc. Somatic mutations including single nucleotide variations (SNVs), amplifications, and fusions were analyzed, and microsatellite instability status was also assayed. Results: Of all patients, the frequency of genomic alterations in FGF/FGFR pathway (FGF3/4/6/10/14/19/23 and FGFR1-4) ranged from 54.1% (86/159) in esophagus cancer, 40.7% (112/275) in bladder/urinary tract cancer, 28.4% (73/257) in head and neck cancer to 5.3% (5/95) in prostate cancer and 4.0% (22/548) in kidney cancer. Amongst all, the highest mutational prevalence fell in FGFR SNV (5.13%) and FGF amplification (5.08%), followed by FGF SNV (3.90%), FGFR amplification (2.89%), FGFR fusion (0.88%), and FGF fusion (0.06%). Partial co-occurrence was observed between alternations of FGFR1 and 11q13 (FGF3/4/19) and between FGF6 and FGF23. On the other side, alternations of FGFR1, FGFR2, FGFR3, and FGFR4 were found to be mutually exclusive ( p< 0.001). In addition, microsatellite instability was found to be positively correlated with FGF/FGFR pathway mutation ( p< 0.001), while was negatively correlated with pathway amplifications ( p= 0.002). Conclusions: Our study investigated the molecular landscape of FGF/FGFR pathway alternations and the interplay between co-occurrence and mutual exclusivity between pathway genes in a large pan-cancer cohort. FGF/FGFR pathway mutations occurs in a variety of solid tumors, indicating that these patients may benefit from FGFR inhibitors.
Identification of paclitaxel resistance through a new statistical approach based on a random forest of perfect trees classifcation.
Authors: Nguyen Jean-Michel , Juin Philippe , Antonioli Daniel , Moreau-Gaudry Alexandre , Campone Mario , Jézéquel Pascal
Published: May 2020

e13513

Background: Predictors of paclitaxel sensitivity in breast cancer published ten years ago, are still pending. The authors showed that paclitaxel pathological complete response (pCR) was in one hand, encountered in aggressive breast tumor with immune response and in another hand, paclitaxel resistance in less aggressive tumor. We have developed a new analysis paradigm, mixing neurons into nodes of trees classification and news class of statistical information based on free-error trees classification. We proposed to reanalyze the Bauer et al’s dataset using this novel approach. Methods: GES22513 dataset including 14 duplicated observations and 54675 anonymized probes was analyzed. A random forest of one million trees whose nodes were composed of neurons including 15 probes, was developped. We selected probes for which a free-error classification was obtained and ranked them according to the inverse of the probability of being a confounding factor and to the inverse of the probability of interacting with another probe. We compared the sets of probes which were necessary to obtain an error-free classification between those associated with a decrease and those associated with an increase of the probability of pCR. Results: Our 15 best ranked predictors were free-error classification for all observations. This includes gene expression of TLCD2, BRCC3, CHI3L2 and PROX1. Their over-expressions were associated with an increase in the probability of pCR, and gene expression of APH1B, ARFGEF1, ARID2, BPGM, CAMK2N1, CCNY, PARM1, PHKA1, PSMD9, SUDS3 (two probes) whose over-expressions are associated with a decrease in the probability of pCR. Ten out of these probes were concordant with Bauer et al’s conclusion. Four probes ( BPGM, PHKA1, CCNY and ARFGEF1) are in contradiction with it. The limited biological information were available for TLCD2. The statistical analysis also showed that TLCD2, BBRCC3, CHI3L2 and PROX1 were altogether positively modulated by eight genes/probes ( CKS1B, ADIG, NCR3, RIN3, NIPAL1, 234422_at, DCLRE1C, SLC17A4). At the opposite, the modulation of genes associated with a decrease in the probability of pCR, was rather heterogeneous and involves many more genes. Conclusions: This preliminary work shows that our statistical approach allows a perfect classification of tumors with and without pCR. Also, it proves that the selected probes/genes are respectively associated with aggressiveness/basal and less aggressiveness/luminal phenotypes. These results need to be validated on an independent cohort.