bluuebunny/crossref_metadata_2025 huggingface dataset:
Variability in metabolic cross-feeding behaviors in breast cancer and response to neoadjuvant chemotherapy.
Authors: Peterson Joseph R , Cole John A , Earnest Tyler M , Hallock Micahel J , Pandey Tushar , Ritchie Katherine , Braun Eduardo
Published: May 2020

e12645

Background: Success of neoadjuvant chemotherapy (NACT) varies by intrinsic subtype of a patient’s breast cancer (e.g., Normal-like, Luminal A/B, HER2-enriched, Triple Negative). The metabolic rate of a given tumor is implicated in response to chemotherapies, as many act by killing rapidly dividing cells. Metabolic dis-regulation opens avenues for cancer cells to exploit environmental niches arising in the tumor microenvironment (TME). Focusing on the role the TME plays in defining cancer behavior, we undertook a theoretical investigation to uncover how metabolic cross-feeding affects subtype behavior and patient response. Methods: An in silico analysis of cross-feeding variability arising from metabolic differences breast cancers was undertaken. TME community models consisting of fatty, glandular, and cancerous tissues’ metabolic behaviors were created. Expression levels of metabolic enzymes for 1222 community patients in TCGA BRCA were used to create models. Models were used in 3D simulations of tumors for 300 patients from the TCIA (Clark et al., J. Digital Imaging, 2013). Cross-feeding trends within each intrinsic subtype were analyzed. Results: Predicted TME metabolic capabilities were compared to literature: LA/LB had lower amino acid consumption than TNBC/HER2+ for asparagine, glutamine (Glu), tryptophan, phenylalanine (van Geldermolsen et al. Oncogone 2016; Furuya et al. Cancer Sci. 2012). Additionally, TNBC tumors produced Glu which was consumed by adipose tissue ( Cao et al. BMC Cancer, 2014), TNBC produced methionine and proline (Kanaan et al. Can. Gen. Prot. 2014), and TNBC/HER2+ cancers consumed high density lipoprotein produced by adipose (Balabum et al. Cancer Met. 2017). The simulations revealed novel cross-feeding behaviors. In general, TNBC/HER2+ relied on glucose as the primary energy source, while LA/LB relied on the amino acids alanine, glycine and Glu. TNBC/HER2+ cancers produced high levels of lactate which was consumed by adipose tissues. Uniquely, glycine produced by cancer was consumed by fat in TNBC cancers Several environmental niches were induced in the healthy tissue by the presence of the cancer; for example, ornithine was predicted to be cross-fed from fatty to glandular tissues in TNBC/HER2+ cancers, and glutamate and inosine from glandular to fatty tissues in HER2+ cancers. Conclusions: Metabolic niches provide opportunities for cancer subtypes. These results suggest that metabolic pathway usage can lead to difference in growth, cross-feeding, and drug efficacy.
Real-world data analysis of next generation sequencing and protein expression in metastatic breast cancer patients.
Authors: Hempel Dirk , Ebner Florian , Milani Valeria , Janni Wolfgang , De Gregorio Amelie , Gaumann Andreas , Trepotec Zeljka , Garg Arun , Hempel Louisa
Published: May 2020

e13005

Background: Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. The present study shows the retrospective analysis of our experience with NGS using a panel of 324 genes in combination with protein expression in patients with metastatic breast cancer (mBC) over the last 18 months. The primary objective of this study was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Methods: We analyzed 41 patients with advanced BC using solid tumor genomic profiling test. The test was used to detect clinically relevant genomic alterations (point mutations, indels, rearrangements, CNAs, tumor mutation burden (TMB) and microsatellite instability (MSI)) and to support the selection of appropriate targeted therapy. The protein expression (hormon receptors, ERBB2 and PDL1) of tumors was analyzed by immunohistochemistry (IHC). Results: The most common BC subtypes were HR+/ERBB2- (n = 20), followed by triple-negative (n = 15), and HER2+ BC (n = 9). 41 different genetic alterations were reported. Most patients had more than one genetic alteration (n = 27), as determined by NGS. The most common alterations were PIK3CA (n = 14), out of which 11 (78%) were hormone-receptor positive/ERBB2 negative. Conclusions: The NGS of mBC supports the decision for the most promising treatment option in 58,5% of our patients with a Tier I evidence. For an appropriate treatment decision it is necessary to evaluate gene alterations und protein expression of metastases in account. For an appropriate interpretation of rare gene alterations in mBC basket trials on basis of real world data are necessary. We founded the OnkoVision alliance to bring MTB into clinically routine and to identify appropriate patients for basket trials.
Cardiotoxicity manifestations in metastatic breast cancer patients treated with trastuzumab as first line.
Authors: Sherman Shira , Barkan Tamar , Yerushalmi Rinat
Published: May 2020

e13011

Background: Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). Its use may result in cardiotoxicity. There are no formal guidelines for left ventricular ejection fraction (LVEF) monitoring in patients with metastatic disease treated with trastuzumab. Our local guideline include an echocardiogram every 3 months for these patients. Methods: We collected data from electronic records and hard copy files of patients treated with Trastuzumab as first line, between the years 2011-2014. Results: One hundred patients met the inclusion criteria. Median treatment duration of all patients was 30 months, with an average of 12 echocardiogram follow-ups per patient. Ninety-nine patients (99%) received additional chemotherapy. Thirty patients (30%) also received Pertuzumab. Ten (10%) of the eligible 100 patients showed significant decline in EF (≥10%) to a final LVEF of < 50%. The median follow-up duration of these patients was 52 months. Median EF at the beginning of treatment was 61.5% in all patients. Cardiotoxicity occurred at an average of 23 months [median 18 months] after beginning of Trastuzumab treatment (range; 3-54 months), with an average EF decline of 14% (range; 10-18%). Three patients (30%) required treatment change due to the decline in EF. Temporary cessation of treatment was necessary in 4 (40%) of the patients for a period of time between 4 weeks to 8 months. The remaining 3 patients (30%), although developing significant decline in EF, did not require treatment cessation or change. None of the 10 patients presented any other clinical sign of cardiotoxicity. In the group with cardiac events, there were no previous reports of congestive heart failure (CHF), ischemic heart failure (IHF), myocardial infraction (MI) or diabetes. Only one patient was a smoker and another received hormone replacement therapy. The average age of this group at the time of diagnosis of metastatic disease was younger (50.6 vs. 55.8, P-value 0.5). Conclusions: Monitoring heart function by trimonthly echocardiogram does not seem to be the optimal monitoring modality in metastatic breast cancer patients who receive a trastuzumab-containing regimen as first line. This study results suggest that less frequent monitoring may be sufficient, thus diminishing patients' inconvenience and allowing better allocation of health care resources.
Distribution of oncotype recurrence scores in invasive lobular carcinomas.
Authors: Suchman Kelly , Zimmerman Brittney Shulman , Ru Meng , Cascetta Krystal Pauline , Tiersten Amy
Published: May 2020

e13025

Background: Invasive lobular carcinomas (ILC) account for approximately 10-15% of all invasive breast cancers, with the majority of cases presenting as ER/PR positive and HER2 negative. As a result, they often exhibit more robust responses to hormone therapy than adjuvant chemotherapy. Oncotype Recurrence Score (RS) RS is a 21-gene assay used to predict the rate of distant recurrence and response to chemotherapy in women with node-negative, hormone-positive breast cancers. Limited evidence exists regarding oncotype scores for ILC tumors, thus the aim of this study was to examine the distribution and risk stratification of Oncotype RS in ILC tumors. Methods: We analyzed patient and tumor characteristics of 492 patients- 417 (85%) IDC (intraductal carcinoma) and 75 (15%) ILC. Chi-square tests and Wilcoxon rank-sum tests were used to compare categorical and numerical outcomes, respectively. Results: No significant difference was found between IDC and ILC in terms of age and ER/PR positivity. The RS raw scores were also not significantly different between the two groups (both had median scores of 16). ILC patients were significantly more likely to be in the lower RS risk groups using the traditional (Paik) cutoff than ILC patients (61%, 39% and 0% in low, medium and high-risk groups as compared to 57%, 33% and 10% in IDC, p < 0.01). Of 417 patients with IDC, there were 16 recurrences (4%) with a median time from diagnosis to recurrence of 43 months (IQR: 28 Ð 58 months), while 1 in 75 ILC patients had recurrence at 50 months. Conclusions: Oncotype RS scores have the potential to guide treatment decisions in node-negative breast cancers. Though mean RS were similar between ILC and IDC patients, ILC were more likely to be distributed in low-risk groups. Our study was limited by a small sample size and a single ILC recurrence. Further research is needed to determine oncotype RS and recurrence rates. Future studies with longer term follow up can help better elucidate patterns of recurrence scores and recurrence rates based on histologic tumor type. [Table: see text]
A retrospective analysis of CDK4/6 inhibitors among adult female patients with metastatic breast cancer.
Authors: Comis Silvia , Kandasamy Thenmozhi , Perrin Alysa J , Kent Kelley , Dulawat Mahendra , Chhikara Arun , Ranjan Nitish
Published: May 2020

e13028

Background: The aim of this study is to examine the behavior pattern of cyclin-dependent kinase (CDK4/6) inhibitor combinations in adult females with de novo metastatic breast cancer as first therapy or following adjuvant hormonal therapy. Methods: Using United States open health claims and prescription data we analyzed metastatic breast cancer from 2015 Q1 to 2019 Q4, adult female patients (age ≥18). Patients were classified into 3 groups based on their first therapy: Group 1-Hormonal, Group 2-CDK4/6 Inhibitor Combinations, and Group 3-Everolimus Combination. Analysis was completed using the Chi-Squared goodness of fit test assessing the patients moving to next therapy by time period. We also compared the overall CDK4/6 group as a base for probability distribution to study the pattern of therapy change in individual groups. Results: Of 37,351 patients on CDK4/6 inhibitors as first therapy or following adjuvant hormonal therapy for advanced/metastatic diseases, the percentage of patients who moved to next therapy was 3.2% (1,200 patients). For most patients, change in therapy occurred within a 2-year period (87%) and those who remained on their first therapy continued for an extended duration. In both Groups 1 and 2 no statistically significant difference was found in the treatment pattern compared to the overall CDK4/6 inhibitor patient population. However, most patients in Group 3 (90%) compared to the overall patient population on CDK4/6 inhibitors moved to Chemotherapy within the first year of treatment (statistically significant at p-value = 0.02). Further analysis of granularity in individual patient pathways showed about 90% of patients with CDK4/6 inhibitors remained on therapy for about 1 year and, interestingly, about 2% extended beyond 2 years up to 4.5 years. Conclusions: The results show most patients on CDK4/6 inhibitors (95%) had progression free survival (PFS) for the period we analyzed. Overall, patients on CDK4/6 inhibitors behaved similarly when used as first therapy or following adjuvant hormonal therapy.
Real-world treatment patterns among metastatic breast cancer patients by BRCA status and phenotype.
Authors: Sebby Wendy , Liede Alexander , Mazumder Debasish , Ghosh Anirban , Papademetriou Eros , Potluri Ravi C. , Bach Bruce Allen , Tyczynski Jerzy Edward
Published: May 2020

e13046

Background: BRCA1/2 mutations account for 5-10% of breast cancer (BC) patients. BRCA1 mutations are associated with aggressive tumors, often triple negative (TNBC) (HER2, estrogen-receptor [ER], progesterone-receptor [PR] negative) and are mainly treated with combination chemotherapy or platinum agents. This study aimed to compare real world treatment patterns in breast cancer patients who were BRCA-mutation positive (BRCA+) and those who were BRCA-mutation negative (BRCA-), focusing on hormone-receptor positive (HR+) and TNBC subgroups. Methods: Optum’s Humedica electronic health records (EHR) database was used to identify a cohort of women with 1) confirmed BC ICD-9/ICD-10 diagnosis between 2008 and 2018, 2) at least 12 months of history in EHR, 3) at least one distant metastasis diagnosis (per ICD-9/ICD-10 or physician notes), and 4) no previous diagnosis of other primary cancers in previous 12 months. HR and HER2 test results were used to create relevant subgroups. Distinct lines of therapy (LOT) in the post-metastatic period were established using business rules. Treatment patterns and duration of treatment were analyzed. Results: Among 65,934 metastatic BC patients identified, 7941 were BRCA+, of whom 5366 (68%) were HR+ and 1323 (17%) had TNBC phenotype, while 4027 were BRCA-, of whom 2859 (71%) were HR+ and 561 (14%) had TNBC phenotype. Seventy-one percent of BRCA+ women underwent drug treatment, compared to 65% of BRCA- women. Drug treatments included hormonal treatment (+/-other agents), targeted therapy, and chemotherapy only, and varied across the different cohorts (Table). Mean (median) duration of treatment in LOT1 in the BRCA+ and BRCA- cohorts was 117 (73) and 117 (72) days, respectively. Conclusions: Real-world evidence on treatment patterns in BC patients revealed substantial differences across important biomarker and hormonal status BC phenotypes. As a preponderance of women with TNBC are still being treated exclusively with chemotherapy, these data highlight how the need for development of effective treatment options for TNBC remains high. [Table: see text]
A single institution retrospective study of the effect of starting doses in patients with ER-positive metastatic breast cancer on CDK 4/6 inhibitors.
Authors: Liu Wingsze , Olazagasti Coral , Lee Chung-Shien , Decina Taylor , Pappas Karalyn , Cheng Kit
Published: May 2020

e13056

Background: CDK4/6 inhibitors (CDKi) have become part of standard of care in the treatment ER-positive, Her2Neu negative of metastatic breast cancer (MBC). Hematologic toxicity from CDKi are common which can lead to dose interruption or dose reduction. There is limited data to compare those who started on full dose and those who started on a reduced dose CDKi. We sought to investigate the impact of reduced starting dose of CDKis. Methods: We conducted a single institution retrospective study on patients (pts) who were treated with CDKi from 2015 to 2019. In this subgroup analysis, we sought to determine the percentage of pts that started on reduced dose CDKi. Pts who were started on reduced dose were compared to those started on standard FDA dose CDKi. Rates of hematologic toxicities, dose interruptions, further dose reductions, progression-free survival and overall survival were compared between the two groups. Data from absolute neutrophil count, hemoglobin and platelet count on Days 1 and 15 of the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: Out of 220 pts, 175 (79.6%) pts started on standard starting dose CDKi and 45 (20.5%) pts started on reduced dose CDKi. 30.86% of pts on the standard dosing group and 28.9% of pts on the reduced starting dose group had a dose interruption. The association between starting dose and dose interruption is not statistically significant (p < 0.86). The estimated 12-month survival rate is 95% (95% CI: 89% - 97%) for the pts on standard dose CDKi and 85% (95% CI: 67% - 93%) for the group reduced dose group. The estimated 12-month progression-free survival rate is 72% (95% CI: 64% - 78%) for the standard dosing group and 35% (95% CI: 21% - 50%) for the reduced dose group. Conclusions: Our study showed a significant survival rate and progression-free survival rate difference between patients who were started on standard FDA starting dose compared to those started on reduced dose CDKi.
A prospective, open-label, multicenter, phase IV clinical study on the safety and efficacy of lobaplatin in the treatment of metastatic breast cancer.
Authors: Xu Binghe , Yan Min , Ouyang Quchang , Han Guohui , Cheng Ying , Wang Dewei , Li Ran , Zhao Da , Sun Tao , Bai Yuju , Yu Hao
Published: May 2020

e13062

Background: Platinum-based chemotherapy is an important treatment for anthracycline- and taxane-resistant metastatic breast cancer(MBC), especially for triple-negative breast cancer(TNBC). Here, we presented the results of a phase IV clinical study of the third-generation platinum compound lobaplatin (LBP) in the treatment of MBC. Methods: Patients(Pts) diagnosed with MBC who had previously received chemotherapies containing anthracycline and/or taxane were recruited. The chemotherapy regimen was decided by the investigator but must include LBP. The primary endpoint was safety, the secondary study endpoints included PFS, OS, ORR, and DCR. Results: 1181 pts were enrolled from 34 research centers, 252 pts of them were TNBC. The main treatment regimens included LBP plus paclitaxel (134, 11.4%), LBP plus docetaxel(263,22.3%), LBP plus gemcitabine(235,19.9%) and LBP plus vinorelbine (404, 34.3%).The overall incidence of AE and grade III/IV(G3-4) incidence of AE were 95.00% and 58.10%, respectively. The most common AE were leukopenia (79.9%, G3-4: 39.5%), neutropenia(75.4%, G3-4: 43.8%), anemia(67.4%, G3-4: 17.8%), and thrombocytopenia(51.1%, G3-4: 17.8%). Creatinine clearance rate (Ccr) was the main influence factor for thrombocytopenia, the incidence of G3-4 thrombocytopenia in pts with Ccr < 60 ml/min were higher than that in pts with Ccr≥60 ml/min. Median follow-up was 36 months. The ORR and DCR were 36.8% and 76.9%, respectively. The mPFS and mOS were 5.5 months and 15.4 months, respectively. The efficacy of LBP combined with taxanes was significantly better than that of other regimens. Different sites of metastasis, ECOG score, clinical stage and age were the main factors influencing for efficacy. Conclusions: LBP-based regimens are effective and safe, and these regimens provide an alternatively treatment option for Chinese MBC pts. Clinical trial information: ChiCTR-ONC-13003471. Clinical trial information: ChiCTR-ONC-13003471 .
Development and validation of a nomogram for predicting survival of advanced breast cancer patients in China.
Authors: Lin Shaoyan , Mo Hongnan , Li Yiqun , Guan Xiuwen , Chen Yimeng , Wang Zijing , Yuan Peng , Wang Jiayu , Luo Yang , Fan Ying , Cai Ruigang , Li Qiao , Chen Shanshan , Zhang Pin , Li Qing , Ma Fei , Xu Binghe
Published: May 2020

e13064

Background: The prognosis of patients with advanced breast cancer (ABC) varied according to different prognostic factors. This study aimed to establish a nomogram to predict the overall survival (OS) of ABC patients in China. Methods: Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC patients with complete relevant information were included in this study, which were further randomized 3:1 and divided into training ( n = 1706) and validation ( n = 557) cohorts. The nomogram was built based on independent predictors identified by univariate and multivariate analyses. Harrell′s concordance index (C-index) and calibration plots were used to assessed the discriminatory and predictive capacities of the nomogram. Results: With a median OS of 45.4 months, the 2-year and 3-year OS rates of ABC patients were 75.2% and 60.2%, respectively. Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) performance status, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly associated with OS (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year and 3-year OS of ABC patients. The C-indexes of the nomogram were 0.700 (95% confidence interval [CI]: 0.683-0.717) and 0.686 (95% CI: 0.652-0.719) for the training and the validation sets, respectively. The calibration curves revealed satisfactory agreement between actual survival and nomogram prediction in both the internal and external validations. The nomogram was able to stratify patients into different risk groups. Conclusions: We developed and validated a nomogram that might serve as an efficient tool to provide individual prediction for ABC patients and guide the physicians to make personalized treatment decisions for individual ABC patients.
Effect of ARID1a oncogenic loss of function mutations on overall survival in metastatic breast cancer patients.
Authors: Mariotti Veronica , Soliman Hatem Hussein
Published: May 2020

e13068

Background: ARID1a (AT Rich Interactive Domain 1A) is part of the SWI/SNF complex, which regulates gene transcription. Its inactivation has been shown to determine resistance to endocrine therapy via enrichment of basal-like gene expression features [Xu G., 2020]. We recently reported that ARID1a lower gene expression might be associated with worse overall survival (OS) [Mariotti V., 2019]. The aim of this study was to analyze the effect of ARID1a mutations on survival in metastatic breast cancer patients (pts). Methods: Breast cancer patients prospectively consented for inclusion in the ORIEN genomic database with known metastatic disease were analyzed using cBioPortal. Predicted biologic effect of mutations from RNASeq data was determined by OncoKB. OS was calculated from initial breast cancer diagnosis to death from any cause. OS analysis using Kaplan Meier and descriptive statistics were performed on SPSS. Results: We identified 644 pts with metastatic breast cancer. Of these, 88 (12.8%) pts harbored an ARID1a mutation. 62 (70.5%) mutations were missense (biologic effect unknown), the remaining 26 (29.5%) were oncogenic loss of function (OLF) changes (frame-shift, deletion, insertion, or nonsense). Median OS was significantly better in patients harboring missense mutations compared to OLF and wild type mutations [median OS 58.2 months (95% CI 44.5-71.8) with missense mutations vs 22.8 months (95% CI 10.8-34.7) with OLF mutations and 27.48 months (95% CI 24.5-30.3) with wild type]. Demographics, tumor features and chemotherapy use were generally equally distributed among the subgroups (table). Conclusions: In our study the median OS was worse in metastatic breast cancer pts harboring OFL ARID1a mutations compared to pts with wild type ARID1a or harboring missense ARID1a mutations. Further studies are warranted to assess how specific ARID1a mutations might affect survival in metastatic breast cancer pts. [Table: see text]
Effect of tailored and supervised therapeutic exercise in metastatic breast cancer patients: A prospective study.
Authors: Ruíz Sofía , Pajares Bella , Bermejo-Perez Maria-Jose , Roldán Jiménez Cristina , Cuesta Vargas Antonio , Alba Conejo Emilio
Published: May 2020

e13075

Background: The safety, feasibility and benefit of physical activity is robust in adjuvant breast cancer, but as far as we know, there is little information on the feasibility and benefit of exercise in women with advanced breast cancer. The objective of our study is to analyze the feasibility and impact on fatigue, quality of life and functionality of an individualized, prospective and supervised exercise program in a group of patients with metastatic breast cancer. Methods: A prospective study on 30 metastatic breast cancer patients who were recruited as volunteers between February 2018 and April 2019 by Medical Oncologists from the Medical Oncology Unit at University Clinical Hospital Virgen de la Victoria (Malaga, Spain). Participants included in this study were patients aged between 34 and 71 years old and all had metastatic breast cancer, not amenable to curative treatment. The intervention was a twelve-week Therapeutic Exercise and Education Programme delivered by a physiotherapist. The intervention was preceded by a physical assessment of the musculoskeletal system. The outcomes were cancer-related fatigue, quality of life and functional outcomes (patient- reported and other measured by investigators). Results: Of the 30 patients initially recruited, only 11 of them completed the program with an attendance greater or equal to 17 sessions (75% of assistance). Most of patients who dropped (19), did it because of personal matters, not related to disease progression. Regarding patients who completed the completion of physical activity program (n = 11), the majority were treated on first line of treatment with hormonal receptors positive tumors and bone metastasis. After the intervention, no major changes were observed in cancer-related fatigue, quality of life and several patients-reported outcomes, although an improvement in functionality was observed, in investigator-measured parameters (30-STS and adapted burpees). Conclusions: Our study shows that a supervised and individualized tailored physical activity program in metastatic breast cancer patients is safe and feasible, although more studies are needed to analyse its impact on improving functional parameters, fatigue and quality of life.
Impact of absolute lymphocyte count on the efficacy of eribulin and capecitabine in patients with metastatic breast cancer.
Authors: Ueno Ayako , Maeda Reina , KIM Kyeongduk , Ito Mitsuya , Kawasaki Kensuke , Ohtani Shoichiro
Published: May 2020

e13082

Background: In a phase 3 trial (Study 301), which compared eribulin and capecitabine for metastatic breast cancer did not show the superiority of one to the other on overall survival. Recently, a post-hoc analysis has revealed that efficacy of eribulin was greater in patients with high levels of absolute lymphocyte count (ALC), probably because the drug has immunologic mechanisms of action. Here we investigated whether the favorable impact of high ALC levels on the efficacy was specific to eribulin or shared with capecitabine. Methods: A total of 275 patients with metastatic breast cancer who were treated with eribulin (n = 125) or capecitabine (n = 150) in our hospital between July 2011–April 2019 were retrospectively analyzed. Progression-free survival (PFS) was compared between patients with higher ALC levels (≥1500/μL) and those with lower ALC levels ( < 1500/μL) in each treatment group. Then, we investigated how hazard ratio (HR) of PFS (eribulin vs. capecitabine) changed when we excluded patients with low ALC levels one by one; a scatter plot was made (X = cut-off value of ALC, Y = adjusted HR). PFS was compared by using the Cox proportional hazards model and covariates included age, hormonal and HER2 status, presence/absence of liver and other visceral metastasis, the number of involved organs and the number of previous chemotherapy regimens. Results: In eribulin group, PFS was significantly better in patients with higher ALC than those with lower ALC (adjusted HR, 0.50 [95% confidence interval (CI), 0.29–0.85]; p = .010). Contrarily, in capecitabine group, PFS was not significantly different between the two groups (adjusted HR, 0.86 [95% CI, 0.58–1.28], p = .456). According to the scatter plot, as the cut-off value of ALC (X) was increased, the hazard ratio of PFS (Y) changed biphasically, being almost flat when X was less than 1500, and a linear decrease when X was 1500 or more. Adjusted HR were (i) 1.07 [95% CI, 0.64–1.82], (ii) 0.79 [95% CI, 0.29–2.11] and (iii) 0.67 [95% CI, 0.18–2.41] when inclusion criteria of patients were (i) ALC ≥1500/μL, (ii) ALC ≥1900/μL and (iii) ALC ≥2200/μL, respectively. Conclusions: The efficacy of eribulin was significantly better in patients with higher ALC levels, whereas that of capecitabine was not significantly different. “The more, the better” relationship between ALC and the efficacy of eribulin (vs. capecitabine) was recognized when ALC was 1500/μL or more.
Recruitment and retention in a self-directed “walking” intervention: Feasibility study in women with metastatic breast cancer during active treatment.
Authors: Shachar Shlomit S. , Deal Allison Mary , Nyrop Kirsten A. , Damone Emily , Wagoner Chad William , Muss Hyman B.
Published: May 2020

e13084

Background: Health related quality of life (HRQOL) and physical function are greatly impacted by the diagnosis and treatment of metastatic breast cancer (MBC). This study investigates the ability of women with MBC to engage in moderate walking during active treatment, with exercise monitored through a FitbitTM activity tracker. Methods: This is a single-site feasibility study of a home-based, self-directed physical activity intervention for women with MBC who could have had up to three lines of treatment. Questionnaires were completed at baseline, 12 weeks, and 24 weeks. Results: Sixty patients were consented, with mean age 55 (SD 11.1), 21% non-white, and 56% ECOG = 0. 36% were in their 3rd or 4th line of chemotherapy treatment. 65% had metastases to the bone, 46% to the lung, and 33% to the liver; mean number of metastasis sites was 2 (range 1 to 4). N = 52 completed all baseline measurements; N = 40 remained in the study at 3 months, and N = 29 at 6 months. Of the N = 31 (52%) lost to attrition, N = 6 were due to death, N = 5 due to deterioration, and N = 20 due to patient withdrawal from the study. Mean walking steps per day of at least 4000 was achieved in months 1, 2 and 3 by 41%, 50%, and 41% of participants. In months 4, 5 and 6, these percentages were 45%, 51% and 39%. On a scale from 1 = very confident to 10 = not at all confident about “continuing to walk or be physically active after completing the study”, confidence scores were 2.8 (SD 2.8) at 3 months and 2.9 (2.9) at 6 months. Conclusions: Forty-nine percent of women with MBC who signed up for a home-based walking program during active treatment were able to complete the 24-week intervention, with high proportions of these women walking more than 4000 steps per day. Moderate walking is feasible for women with MBC on active treatment.
Gemcitabine with carboplatin in metastatic breast cancer: Characterizing outcomes in a modern, real-world population.
Authors: Higgins Jordyn Paige , Lalonde Chloe , Byers Kristina F. , Davis Christine , Horne Kandra , Goyal Subir , Chen Zhengjia , Meisel Jane Lowe , Kramer Joan L. , Barbee Meagan Spencer
Published: May 2020

e13085

Background: The specifics of the salvage regimen gemcitabine/carboplatin (G/C) in metastatic breast cancer (MBC) are not well-characterized and are limited to the clinical trial setting, which often excludes heavily pretreated patients with high disease burden and velocity. The primary objective of this study is to assess real-world outcomes in patients with MBC treated with G/C. Methods: A retrospective chart review was conducted on adults with MBC who received >1 dose of G/C at Emory Healthcare / Winship Cancer Institute from December 1, 2005 to April 30, 2019 (n = 109). Patients were stratified by receptor status (hormone receptor (HR), triple-negative (TN), and human epidermal growth factor receptor-2 (HER2)). Results: Patients were heavily pretreated (median 2 lines, range 0-11) and had extensive metastatic disease (median 3 sites, range 1-6). The median starting doses were carboplatin AUC 2 (range: 1.5-5) and gemcitabine 1000 mg/m2 (range 400-1100). The median cycle length was 21 days (range 14-28). The median progression-free survival (mPFS) was 3.7 months and median overall survival (mOS) was 7.7 months. OS at 24 months was 23.1%. Previous immunotherapy, radiation for palliation, or historical receipt of neoadjuvant/adjuvant cytotoxic therapy was significantly associated with improved survival outcomes, while possessing lung, liver, or bone metastases was significantly associated with worse survival outcomes. The presence of brain metastases did not correlate with outcomes. Side effect/intolerance led to dosing and scheduling adjustments in 38.5% and 49.5% of patients, respectively, and resulted in treatment discontinuation in 21% of patients. Hospitalization occurred in 51.4% of patients on treatment. Conclusions: G/C is a safe and effective regimen in real-world MBC patients regardless of receptor subtype. Even low doses of G/C may provide some CNS penetration and control. Improved survival outcomes associated with previous immunotherapy and radiation for palliation may be due to disease control or carry over effect and warrant further study. [Table: see text]
The role of circCNIH4 in the adipocyte's effects on metastasis of breast cancer cells.
Authors: Chen Xiu , Tang Jinhai
Published: May 2020

e13086

Background: Obesity is associated with the risk of breast cancer(BCa) incidence and development. However, biological changes in obesity BCa individuals are still uncertain. Nowadays, circCNIH4, one of novel non-coding RNAs, was found to be a non-invasive biomarker in cancers. Methods: We verified the cancer-promoting role of obesity in BCa patients by comparing BMI indexes of 33 BCa and 44 benign tumor patients. Then we cocultured viscera adipose cells(HPA-v) and BCa cells(MCF-7/H and MDA-MB-231/H) to confirm the function of adipocytes on metastasis of BCa cells through wound healing, transwell assays. In vivo experiments were also performed. We analyzed the expression level of circCNIH4 in MCF-7/H, MDA-MB-231/H and different subtypes of BCa cells by quantitative polymerase chain reaction. Simultaneously, we identified inhibited effects of circCNIH4 on metastasis of BCa cells by wound healing, transwell assays and verified the location of circCNIH4 by FISH. Luciferase Assay was used to detect harbored miRNA. Rescue experiments were then applied. Results: We found the BMI of BCa patients(24.37±2.51) was much higher than benign patients(22.97±2.91). Metastasis of BCa cells were obviously promoted after in vitro and in vivo experiments. Then we found the expression of circCNIH4 in MCF-7/H and MDA-MB-231/H were down-regulated 0.71 and 0.52 than that in MCF-7 and MDA-MB-231. Also, circCNIH4 was positively correlated with less aggressive types of BCa cells. Overexpression of circCNIH4 in MDA-MB-231 could suppress cell invasion and migration, while silencing of it in MCF-7 promoted cell invasion and migration. The FISH assay demonstrated that circCNIH4 mainly located in the cytoplasm and might function as a “sponge” for miRNA. MiR-135b functioned as a tumor promoter gene from data of 93 BCa patients (HR = 2.27; 1.01 − 5.12), and it could be captured by circCNIH4 via luciferase and rescued assays. Conclusions: In this study, we revealed that BMI or viscera adipocytes could deteriorate prognosis of BCa and circCNIH4 could be a novel biomarker for non-invasive BCa. In details, circCNIH4 mainly suppressed the adipocyte's pro-metastasis effects on BCa by capturing miR-135b.
DNA and RNA next generation sequencing for personalizing cancer treatment: A single-center experience.
Authors: Rebollo Joseba , Sureda Manuel , González-Manzano Ramón , Martínez Elena Ma , Rostagno Roman , Mata Juan José , Monedero Elena , Ortega Jose , Brugarolas Antonio
Published: May 2020

e13509

Background: Personalized multidrug therapies improve outcomes in patients with drug resistant cancer. For 8 years we have been using microarray-based gene expression profiling (360 procedures) to improve drug selection (Rebollo J et al, 2017; Sureda M et al, 2018). Recently, we have adopted Ion Torrent DNA and RNA Next Generation Sequencing (NGS) to improve the target detection ability. Methods: Since March 2018 DNA (95 analyses) and whole trancriptome RNA (78 analyses) NGS have been performed using Ion Torrent GeneStudio S5 System in fresh-frozen (RNA and DNA sequencing) and paraffin-embedded (DNA sequencing) biopsies obtained from tru-cut or surgical excision procedures from patients with metastatic cancer. Favourable chemotherapy drug profile, treatable (available inhibitory drugs) targets and potentially favourable immunologic signature have been investigated. Results: All biopsies were valid for DNA sequencing but in five patients were invalid (less than 30% viable tumor cells required) for RNA sequencing. Combined DNA and RNA sequencing have been studied in sixty patients with advanced cancer biopsies. Histologies have been NSCLC (12 patents), Breast (9), STS (6), NHL (4), NET (4), Pancreas (4), CRC (4), Ovary/Fallopian tube (3), Prostate (2), Cholangiocarcinoma (2), H&N (2), Esophagus, Bladder, Uterus, Melanoma, SCLC, Anal, Kidney and Cervix (1 each). Most of the patients had been previously treated with systemic therapies. Biopsies have been taken from Lymph nodes (18 patients), Liver (16), Soft Tissues (14), Lung (8), Peritoneum (3) and Adrenal Gland (1). RNA sequencing has predicted favourable chemotherapy drug profile (Median 3 drugs, Range 1-9) in 54 (90%) patients. In addition, treatable targets (Median 3 targets, Range 1-6) have been found in 40 (67%) patients. Favourable immunologic signature has been found in 22 (37%) patients. DNA sequencing has shown treatable (drug available) targets in 14 (23%) patients. In 12 (20%) patients, no targets have been found in any of the sequencing protocols (DNA and RNA). Conclusions: Tumor RNA and DNA sequencing provide potential useful information in personalized cancer treatment decision in a vast majority of advanced cancer patients independent of treatment status.
Genomic characterization of sub-centimeter pulmonary nodules.
Authors: Peng Muyun , Xing Guanlan , Zhang Bingyu , Xu Yaping , Yu Fenglei
Published: May 2020

e13530

Background: There has been a dramatic increase in the detection of indeterminate pulmonary nodules (IPNs), many of which are 10 mm or less in diameter. The management of subcentimeter pulmonary nodules remains controversial. Deciphering the genomic landscape of subcentimeter pulmonary nodules will provide critical insights to the mechanisms of carcinogenesis and pave the way for the early prevention and interception of lung cancer. Methods: We subjected 439 IPN samples including 249 subcentimeter pulmonary nodules (≤10 mm in diameter) and 190 larger pulmonary nodules (>10 and ≤30mm in diameter) to deep next generation sequencing by using customized panels of 1021 genes. Clinical parameters of these IPNs were collected. The genomic landscape of subcentimeter pulmonary nodules and differences from that of larger pulmonary nodules were defined. Results: The proportions of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (ADC) in the subcentimeter group and the larger nodule group were 2.81% vs 0.00%, 13.25% vs 0.80%, 28.92% vs 4.82% and 55.02% vs 70.68%, respectively. The most commonly mutated genes in subcentimeter group were in EGFR, ERBB2, BRAF, MED12 and MAP2K1. Compared with the larger nodule group, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and SMARCA4 ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF, MAP2K1, and TSC1 ( p< 0.05). In the subset of ADC, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and PIK3CA ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF ( p< 0.05). Clonal index analysis of driver genes in lung adenocarcinoma showed that the larger nodule group had more driver mutations, but the clonality index of BRAF was higher in the subcentimeter group ( p= 0.0014). Furthermore, in the subcentimeter nodule group, the mutation frequency of BRAF was significantly higher in pre-invasive group (AAH/AIS) than that in the invasive group (IAC). And BRAF and EGFR were significantly mutually exclusive ( q< 0.001) in subcentimeter nodules, which showed the subgroup with BRAF mutations was a special subtype. Conclusions: Our results provided the distinct mutation pattern of subcentimeter nodules and showed that BRAF could play different roles in early phase of lung carcinogenesis. It would be helpful for understanding the genomic evolution mechanisms underlying the progression and invasiveness of early lung adenocarcinoma.
Expression profile and co-expression analysis of ADH1A in human solid tumors.
Authors: Huang Wenqi , Yang Mi , Wu Xixi , Yuan Lu , Wu Yuting , Hwang Jihong , Guan Jian , Liu Laiyu
Published: May 2020

e13533

Background: The human alcohol dehydrogenase (ADH) gene family is associated with various solid cancers. It seems that the ADH1 gene cluster plays an important role in various solid tumors, so it aroused our interest in studying these genes to find out their functions and biological process within different solid tumors. Methods: Paired tumor and normal tissues gathered from 38 tumor patients, and 5 male BALB/c mice tissues were collected and Immunohistochemistry (IHC) assay was performed. The expression of ADH1A at RNA level in normal tissues and pan-solid tumors and the main functions of ADH1A in different solid tumors were analyzed by Bioinformatics mining. Results: At the RNA level, ADH1A was highly expressed in normal hepatocytes and was expressed lower in the tumor tissues than in the adjacent normal tissues or the corresponding normal tissues, suggesting the At the protein level, ADH1A was expressed to varying degrees in human alveoli, kidney, stomach, colon, and rectum. We predicted three major conserved functions of ADH1A, including angiogenesis, cell adhesion, and leukocyte migration function which might influence the prognosis of the immunotherapy and the immune response, and constructed an upstream regulation network of ADH1A and a downstream protein network. Besides, we also explored the functional differences of ADH1A in lung adenocarcinoma and lung squamous cell carcinoma and its effect on overall survival. And for investigating ADH1A, the BALB/c mice might be an option to consider in constructing an animal model of gastric cancer (GC), esophageal carcinoma (ESCA), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD). Conclusions: ADH1A has potential diagnostic and prognostic value in various solid tumors. Our findings highlight new avenues for further investigation of ADH1A biology process and provide a novel potential prognostic biomarker of immunotherapy.
Enrichment of circulating tumor DNA from cell-free DNA of hematopoietic origin.
Authors: Terrell Jason , Van den Ackerveken Priscilla , Lobbens Alison , Eccleston Mark , Hannart Clotilde , Deglasse Jean-Philippe , Turatsinze Jean-Valery , Herzog Marielle , Micallef Jake
Published: May 2020

e13534

Background: In liquid biopsy, circulating tumor DNA (ctDNA) is more fragmented than background cell free DNA, peaking at 147bp (equivalent to a mono-nucleosome) instead of 165bp (nucleosome with an additional 20bp of linker DNA). Isolation of these shorter cell free DNA fragments from longer, extracted cell-free DNA improves detection of ctDNA as demonstrated by enrichment of tumor specific mutations. Nuclease protection of the additional 20bp of linker DNA, conferred by bound linker proteins such as Histone 1, would account for the 165bp peak in host background DNA. We hypothesised that extracting intact nucleosomes with linker DNA using a novel, H1 antigen based, immunocapture approach would enrich the ctDNA fraction in the remaining nucleosomes. Methods: We expressed H1.0 protein in E. coli and following extraction, purification and chemically immobilised it to tosyl-activated magnetic beads. The beads were first used to immunodeplete mono-nucleosomes from HeLa cell digests and the level of immunocaptured nucleosomes was determined by immunoassay targeting intact nucleosomes. The level of nucleosome levels determined before and after depletion was further determined by ELISA targeting H3.1 containing intact nucleosomes. DNA was extracted from the H1 immunocaptured “long” nucleosomes and size profiles compared with the remaining nucleosomes in the supernatant by BioAnalyzer. Then, the method was applied to clinical plasma samples and the size distribution of NGS Libraries (Illumina system) prepared from five colorectal cancer and three healthy samples, their immune depleted supernatants and the immunocaptured nucleosomes were then compared. Enrichment of specific genomic regions was also evaluated. Results: We observed relative enrichment of nucleosomes with short DNA in supernatants following H1 immuno-depletion of the cancer samples as evidenced by a change in size distribution by Bioanalyzer and NGS-sequencing. We also observed potential enrichment of TSS is the H1 immunocaptured nucleosomes consistent with linker DNA positioning of TF binding sites. Conclusions: Histone 1.0 has the highest affinity of H1 mammalian isoforms and successfully immunodepleted plasma samples containing cell free circulating nucleosomes with DNA longer that 147bp. Immobilized H1.0 effectively formed a pseudo-chromatosome by binding to free linker DNA or displacing endogenous H1 and other linker associated proteins. H1 antigen based immuno-depletion offers a simple way to enrich tumour derived nucleosomes and thus cell free DNA.
A discrete choice experiment (DCE) study evaluating preferences of Asian adults for inherited cancer risk testing.
Authors: Tay Ru Jin , Zhao Pan , Chen Hao , Tan Min-Han , Chong Josephine Shuk Ching
Published: May 2020

e13550

Background: Inherited cancer genetic testing (CGT) is increasingly recommended in a wide range of settings to better evaluate and manage personal and/or family cancer risks. For individuals at risk, identification of monogenic risk factors by inherited CGT allows more appropriate advice, surveillance and targeted prevention. For cancer patients, inherited CGT provides guidance for the selection of targeted therapy treatment options. Little is known about the views of non-Western global communities, which can impact cancer prevention. We designed a DCE study to evaluate four key attributes to better target educational and policy interventions in an urban Asian community. Methods: We recruited healthy adults in the community aged between 21-60 in Singapore. Participants received basic information about cancer and cancer genetic testing, then completed a 16-task DCE survey that examined preferences for four attributes of cancer genetic testing for targeted prevention including: accuracy, waiting time for result, out-of-pocket cost and insurance claims. A conditional logit regression model was used to examine the main effect parameter, assuming all attributes have an independent influence on the participants’ preferences. Results: 93 adults were enrolled (71% female, 29% male). Attributes influencing decision to undergo inherited CGT in decreasing order of concern were accuracy (37%), out-of-pocket costs (22%), insurance claim (21%) and waiting time for result (20%). Increased out-of-pocket cost reduces the likelihood of people to go for testing (coef: -6.579e−04, p < 0.01). The impact of financial cost is less important for participants with increased monthly household income (coef: 1.791e−04, p < 0.01). Conclusions: With inherited cancer genetic testing becoming more common and relevant in terms of personal and/or family risk managements and guiding treatment options, this DCE study is helpful to guide clinicians tailor of individualized genetic counseling for non-Western communities, who may have different concerns from Western populations. Targeted policy intervention and education on these concerns may lead to greater accessibility for inherited CGT.