bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of palbociclib after everolimus in hormone receptor-positive, HER2-negative advanced breast cancer.
Authors: Kovac Anja , Grasic Kuhar Cvetka , Ovcaricek Tanja , Matos Erika , Mencinger Marina , Borstnar Simona
Published: May 2020

e13030

Background: Palbociclib and other selective cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy (ET) have become the standard of care in the treatment of patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). Their role in the first and second line of therapy is well established, whereas their use in subsequent lines and after treatment with everolimus remains unclear. Methods: We performed retrospective observational study of all patients who initiated treatment with palbociclib at the Institute of Oncology Ljubljana between March 8, 2018 and March 8, 2019 and received at least two prior lines of treatment for ABC. We collected individual patient data from electronic medical records. Patients were divided in two groups – everolimus-pretreated (group A) and everolimus-naïve (group B). The primary study outcomes were clinical benefit rate (CBR), time to treatment failure (TTF) and overall survival (OS). Results: Overall, 65 patients´ data was evaluated. The majority of patients (n = 50, 76.9%) received palbociclib in combination with fulvestrant, others (n = 15, 23.1%) with aromatase inhibitors. There were 25 (38.5%) patients in group A and 40 (61.5%) in group B. Patients´ and previous treatment characteristics are shown in table. CBR was the same, 40%, in both groups. The median follow-up time was 14.9 months. The median TTF was 5.28 months for the whole group, 5.0 months for everolimus-pretreated and 5.5 months for everolimus-naïve group (p = 0.7). The median OS was 18.1 months for the whole group, 14 months for everolimus-pretreated and 18.1 months for everolimus- naïve group (p = 0.7). Conclusions: Patients with HR+, HER-2-negative ABC benefit from addition of palbociclib to ET after two lines of prior systemic therapy. The benefit remained unchanged if the patients were previously treated with everolimus. [Table: see text]
CDK4/6 inhibitors beyond second line, is it worthy? A real-world data experience.
Authors: Falcón Alejandro , Salvador Bofill Javier , Montaño Alvaro , Benavent Marta , Gonzalez Rosario , Ruiz Borrego Manuel
Published: May 2020

e13033

Background: CDK4/6 inhibitors as Palbociclib, Ribociclib and Abemaciclib has become the first or second line in advanced or metastatic luminal breast cancer HER2 negative. We only have data about the use of Abemaciclib in monotherapy beyond second line. Methods: We have analyzed 200 patients treated in our center with CDK4/6 inhibitors since 2017. All of them belong to clinical practice, out of clinical trial context. The effect of CDK4/6 inhibitors was analyzed using logistic regression analyses. Results: 34 patients were treated beyond second line of treatment with a medium follow-up of 18 months. CDK4/6 inhibitors were used as fourth line as medium (range 3-9), median age of 45 years, 1 male. 52% patients had visceral disease and 8.8% were primary hormone resistance. 64.6% were treated with palbociclib, 26.5% with ribociclib and 8.8% with abemaciclib. 52.9% were asociated with Fulvestrant, 44.1% with Letrozol and 2.9% with tamoxifen. Clinical benefit of 67.6% and response rate of 32.3%. Similar toxicities to previosly published trials were observed. Median progression-free survival was 14.2 months and median overal survival was 26.6 months. Non statistical difference were observed by luminal subtype, number of prior lines, type of hormonal therapy or CDK4/6 inhibitor used. Conclusions: Despite of the small population, we can summarized that CDK4/6 inhibitors associated to hormonal therapy is a good option for patients previosly treated in the metastatic setting. We need further investigation to understand which patient will benefit from treatment with this drugs in advanced lines.
Real-world hematologic toxicities in patients > 70 versus < 69 with ER positive metastatic breast cancer on CDK 4/6 inhibitors: Single-institution retrospective study.
Authors: Olazagasti Coral , Liu Wingsze , Lee Chung-Shien , Decina Taylor , Pappas Karalyn , Cheng Kit
Published: May 2020

e13039

Background: Since 2015, 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. Pooled analysis of prior randomized trials did not show hematologic toxicity between younger and older adult age groups. We sought to review generalizability of these findings to our community population. Methods: We conducted a retrospective single institution retrospective study on patients who were treated with CDKi from 2015 to 2019. Patients were stratified according to age > 70 years and < 69 years. 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. Our primary objective was to assess any difference in grade of hematologic toxicities in the different age groups. Our secondary objective was to analyze the association between hematologic toxicities with the presence or absence of bone metastasis and/or prior chemotherapy exposure. Results: A total of 220 patients were reviewed, 140 were < 69 years and 80 > 70 years. There was no significant effect of time (p = 0.91) with respect to the outcome of hematologic toxicity adjusting for age (p = 0.16). Seventy-seven percent (171/220) of patients had evidence of bone marrow (BM) involvement. There was no significant difference in the grade of any hematologic toxicities over time (p = 0.97) and underlying BM disease (p = 0.20). On the other hand, 50% (111/220) patients had previously received an average of one line of chemotherapy. There was significant positive correlation between lines of therapy and grade of neutropenia (rS= 0.25, p = 0.0028). Overall, the estimated median progression free survival (PFS) was 19.1 months. The median overall survival could not be estimated. Conclusions: Our single institution experience does not show significant hematologic toxicity between patient age groups nor evidence of bone metastasis. However, prior exposure to chemotherapy can have a significant effect in the grade of neutropenia. Our study revealed that there is no difference in PFS according to dosing or age which correlates with current literature.
Palbociclib in hormone positive metastatic breast cancer: A real world multicenter Indian experience.
Authors: Rauthan Amit , Patil Poonam , Somashekhar S.P. , Jacob Linu Abraham , D Lokanatha , Kumar Kishore , Keechilat Pavithran , Vijayakumar DK , Patil Shekar , P Shashidhara H , Zaveri Shabber , Yashas Nitin
Published: May 2020

e13057

Background: Palbociclib, a selective CDK4/6 inhibitor, in combination with hormonal therapy has become the standard of care in the treatment of hormonal positive (HR+) metastatic breast cancer (MBC). There is limited efficacy and safety data in Indian patients. Methods: This is a multicenter retrospective study of real world experience of patients with HR+, Her 2 neu negative MBC who received Palbociclib in 5 centers of south India between Oct 2016 and Aug 2019. Endpoints were overall response rate (ORR), progression free survival (PFS) and toxicity. Results: 133 patients received Palbociclib; 83 (62.4%) in the first line setting (hormone naïve MBC) and 50 (37.6%) in the second line (MBC progressed on at least one line of hormonal therapy). Median age was 56 years (range 48-76). All patients started with 125mg/day. In the 83 first line patients, 46 (55.4%) had denovo MBC, 37 (44.6%) had post-adjuvant relapse. 38 (45.8%) had bone only and 45 (54.2%) had visceral metastases. Letrozole was the companion drug in 76%, Fulvestrant in 18%, Exemestane in 6%. 5 (6%) patients achieved complete response (CR), 54 (65%) partial response (PR), 12 (14.5%) stable disease (SD) and 12 (14.5%) had progressive disease (PD). ORR was 71%. At a median followup of 18 months, the median PFS was not reached (maximum ongoing followup 38 months). The median PFS in the denovo metastatic disease versus relapsed disease was not reached versus 18 months (p = 0.021). The median PFS was significantly better in bone only versus visceral metastases (not reached versus 28 months, p = 0.007). In the 50 second line patients, 15 (30%) had bone only and 35 (70%) had visceral metastases. Companion drug was Fulvestrant in 64%, Letrozole in 20%, Exemestane in 16%. 60% received prior chemotherapy. Best response was CR 3 (6%), PR 23 (46%), SD 4 (8%), PD 17 (34%), not assessed 3 (6%). ORR was 52%. The median PFS was 14 months. PFS in bone only versus visceral disease was 14 months versus 13 months (p = 0.382). Neutropenia was present in 75.2%, thrombocytopenia in 19.5%, anaemia in 18%. Neutropenia was grade 1 in 26%, grade 2 in 51%, grade 3 in 23%; with no febrile neutropenia. 30% had dose delays and 8.2% had dose reduction. Conclusions: Palbociclib has resulted in similar efficacy and safety in Indian patients as the PALOMA trials. Neutropenia was the commonest side effect, which was uncomplicated and easily managed with dose delays. Using CDK4/6 inhibitors with hormonal therapy has become the standard of care in HR+ MBC Indian patients.
Metaplastic breast cancer: A retrospective analysis over 14 years.
Authors: Bhasin Pooja Gogia , Desai Gopal R
Published: May 2020

e13066

Background: Metaplastic breast carcinoma (MBC), a rare entity, is known to be an aggressive form of breast cancer. With few published reports and scant literature, there are no current guidelines for this type of cancer. The aim of the study is to describe the patient characteristics, pathologic features, treatment and clinical outcomes of the patients with MBC at our institution. Methods: A retrospective analysis of patient charts with histologically confirmed MBC from 2001 to 2014 was done. Clinical information was abstracted from the medical records. Medical records were reviewed for patient age, tumor size, nodal status, tumor grade, hormone receptor status, treatment, recurrence rates and survival characteristics. Results: Twenty-three patients were identified with a median age at diagnosis of 59 years (range 42-91 years). The median tumor size was 2.1 cm (range 0.4-4.5 cm). Most tumors were grade 3 (73.9 %). None of the patients had metastatic disease at presentation. 17 patients were node negative (74%). 13 patients (56.5 %) were triple negative. 6 patients (26 %) underwent mastectomy and 17 underwent lumpectomy. 16 out of 23 patients underwent post-operative radiation therapy. The 5-year disease free survival was 73.9 % and 5-year overall survival was 82.6%. The tumor size was more than or equal to 2.4 cm in all the patients with recurrence. 60 % of the patients with recurrence were triple negative and 20% were Her2 neu positive. 33.33 % patients were poorly differentiated on histology. Conclusions: Based on our analysis and review of literature, MBC has higher tumor grade, hormone receptor negativity and lesser nodal involvement on presentation. Various studies have shown that tumor size is often large on presentation. In our study, tumor size was modest on presentation. Hence, our survival rates are better than seen with other studies. As per our analysis and as demonstrated by other studies, tumor size is an independent risk factor for recurrence. Other ominous factors for recurrence are triple negative hormone status and poorly differentiated tumor as seen in our case. Further studies and clinical trials comparing with infiltrating ductal carcinoma are needed to understand this rare breast cancer.
Asymptomatic versus symptomatic metastatic breast cancer: Potential effects on prognosis and quality adjusted life years (QALYs).
Authors: Yamanouchi Kosho , Maeda Shigeto , Kuroki Tamotsu
Published: May 2020

e13073

Background: After radical surgery for breast cancer, routine laboratory or imaging studies for metastases screening are not indicated in the absence of clinical signs and symptoms suggestive of recurrence. While the goal of therapy is the extension of survival and maintenance of quality of life (QOL), therapies themselves could induce adverse events, resulting in deterioration of QOL. We evaluated quality adjusted life years (QALYs), which is survival adjusted by QOL, of the patients with recurrent breast cancer retrospectively and adequate follow-up measures. Methods: Fifty seven patients with recurrent breast cancer who died already were included. Survival curves were partitioned into two health states: time with ≥ grade 2 chemotherapy-related toxicity (TOX) and time without toxicity (TWiST). QALYs were acquired as follows: QALYs = TWiST + 0.7 * TOX. We compared clinical factors in the patients between with (symptomatic group, n = 32) and without symptoms (asymptomatic group, n = 25). Results: The median age of the patient at diagnosis of recurrence was 57 years. Luminal (hormone receptors (HR) - and human epidermal growth factor receptor-2 (HER2) -), HER2 (HER2 +), triple negative (TN) (HR - and HER2 -), and unknown were 29, 7, 15, and 6 cases, respectively. The proportion of HER2 and TN was significantly higher in the symptomatic group than that in the asymptomatic group (58.6, 21.7 %, p < 0.05). 44.6 % of the patients had visceral metastases at diagnosis of recurrence and the proportions were not different between the groups. Although post recurrent survival (PRS) was shorter significantly in the symptomatic group (22.5, 42,0 months, p < 0.01), overall survival from diagnosis of primary breast cancer (OS) was identical (60.5, 91.0 months). Additionally, QALYs after recurrence was shorter in the symptomatic group (23.0, 41.1 months, p < 0.01) and QALYs from diagnosis of primary breast cancer was identical (58.7, 91.0 months). Conclusions: Although there was no significant difference in OS between the both groups, the duration of therapy received was longer in the symptomatic group. In the present study, we acquired limited information due to retrospective manner. Prospective evaluation of QALYs, including patient reported outcome and symptoms derived from cancer itself, would turn out adequate measures of follow-up after radical surgery for primary breast cancer.
Apatinib to prolong overall survival from recurrence to death in metastatic breast cancer: A single-center experience from east China.
Authors: Shi Lei , Chen Zhanhong , Wang Xiaojia
Published: May 2020

e13090

Background: To observe the efficacy and side effects of apatinib in patients with metastatic breast cancer in non-clinical trial setting. Methods: Patients with metastatic breast cancer who were treated in Zhejiang Cancer Hospital from January 2014 to September 2019 were collected from the hospital information system. According to whether patients were treated with apatinib, they were divided into apatinib group and control group. There were significant differences in baseline data such as the age of onset between the two groups, and the propensity score match was used to ensure balance. The survival time from the first recurrence to death was compared between the two groups. The progression-free survival, the incidence of side effects and the types of side effects of apatinib were observed. The prognostic factors of apatinib were also analyzed. Results: There were 297 patients who met the criteria, of whom 40 received apatinib treatment. After propensity score match, the balance of the two groups was guaranteed. Compared with the control group, the hazard ratio of apatinib group was 0.111 from first recurrence to death (95% confidence interval: 0.022 to 0.556, p = 0.007). The median progression-free survival of apatinib was 8 months. Patients often received apatinib at the end of the disease. And 67.5% (27/40) of patients received apatinib at the end line. 52.5% (21/40) of patients had adverse reactions, and common adverse reactions included myelosuppression (7/40), fatigue (6/40), hypertension (6/40), proteinuria (5/40), skin and mucosal reactions (5/40) and so on. Three of them had grade Ⅲ to Ⅳ adverse reactions, including hypertension, myelosuppression and skin ulceration. Severe adverse reactions increased the risk of progression-free survival with apatinib. Its hazard ratio is 10.103 (95% confidence interval: 1.149 to 88.825, p = 0.037). Conclusions: As the choice of multi-line therapy for metastatic breast cancer, apatinib can prolong the survival time after recurrence. The adverse reactions are common, so it is necessary to guard against the severe adverse reactions that lead to poor prognosis.
Depressive factors associated with breast cancer.
Authors: Tostes Alexandre Alberto Mendes , Freitas Carla Simone Moreira de , Soares Aleida Nazareth
Published: May 2020

e13091

Background: In Brazil, the estimated cancer for the 2019 was approximately 420 thousand new cases. In Minas Gerais, the estimate was 5,360 new cases. Objective is to relate comorbid humor disorders with breast cancer in patients treated at a cancer hospital. Methods: Cross-sectional and descriptive study with a sample of 100 patients with Breast Cancer (BC), chosen at random. Data were collected at a Muriaé cancer hospital in, from January to June 2019. Semi-structured sociodemographic and clinical suervey and the Beck Depression Inventory (BDI-II) to check for signs and symptoms of depression. Data analysis was performed using the statistical packages SPSS. To check if there was a difference between groups in continuous variables, Shapiro-Wilk test; the data considered normal the Student's t test (parametric test) and the data considered non-normal the Mann Whitney test (non-parametric test). For categorical variables, the chi-square test, Fisher's exact test or Monte Carlo simulation. As for the interpretation of Beck's inventory, the scores were analyzed and demonstrated according to the standardized by the inventory, that is, the result obtained was the sum of the individual items, reaching a maximum score of 63 points. The classification of the levels of depression varies between minimum, mild, moderate and severe, thus indicating the intensity of the depression. The study was developed according to Resol. 466/12, of the National Health Council. Results: Average age of women with BC in both groups was 55 years, with low education (43%), married (48%), and, 50% of them have one or more children and, 70% do not work. Regarding the use of drugs and/or medication and smoking, it was higher in group B (with depression) (64.6%). In the other variables (family relationship, self-preservation of health, affected daily life, family/social isolation, living with other women with BC, perspective of life after treatment, type of follow-up), the proportion was always higher in group B compared to group A (without depression). The time of diagnosis, staging, type of surgery and edema in the upper limb did not show significant difference between the two groups analyzed. Regarding the type of treatment, there was a significant difference, mainly showing that proportionally the Surgery + Chemotherapy treatment is higher in the group without depression while the and Surgery + Chemotherapy + Radiotherapy + Hormone therapy are proportionally higher in the group with depression. Conclusions: Women with BC have depressive symptoms frequently and should be investigated and treated so that the negative impacts can be minimized.
Very long term follow-up of high dose chemotherapy followed by autologous stem cell transplantation in high risk locally advanced triple negative breast cancer.
Authors: Al-Share Bayan A , Assad Hadeel , Abrams Judith , Deol Abhinav , Alavi Asif , Ratanatharathorn Voravit , Uberti Joseph P. , Ayash Lois Jeanne
Published: May 2020

e13094

Background: The role of High Dose Chemotherapy (HDC) with Autologous Stem Cell Transplantation (ASCT) in treatment of high risk locally advanced breast cancer remains unclear. This modality stopped being used for breast cancer treatment when trials in early 2000s reported Disease Free Survival (DFS) benefit but no Overall survival (OS) benefit. However, subgroup analyses of these studies reported OS benefit in young and Triple Negative Breast Cancer (TNBC). We report very long-term outcomes of high risk locally advanced TNBC treated with HDC-ASCT at our institution between 1995 and 2001. Methods: We reviewed our BMT database for women with stage IIB or III TNBC treated with HDC-ASCT. We excluded women with hormone positive, Her2/Neu positive/Unknown and metastatic disease prior to transplant per updated AJCC 7th edition. The majority of patients underwent surgery followed by adjuvant Anthracycline and Taxane based induction chemotherapy followed by HDC-ASCT for consolidation. The HDC regimen consisted of Carmustine 600 mg/m2, Cyclophosphamide 5.6gm/ m2 and Cisplatin 165mg/ m2 (STAMP 1 regimen). Four patients received induction regimen as neoadjuvant and HDC-ASCT as adjuvant treatment per the same protocol. All patients received loco-regional radiation after ASCT. Results: 29 patients had locally advanced TNBC treated with HDC-ASCT. Median age at diagnosis was 43 years (IQR 40-51). 28 had at least 4 positive lymph nodes. Median time from diagnosis to ASCT was 5 months. Median overall survival was 17 years (95% CI, 3-19 years), and median DFS was 14 years (95% CI, 1-19). There was no treatment related mortality (TRM) at 30- and 100-days post ASCT. 12 patients (41%) were alive at median of 16 years (95% CI, 12-19) post ASCT. Conclusions: This single institution study of locally advanced high risk TNBC patients who received HDC-ASCT as part of treatment demonstrates a high long term OS exceeded historical controls. This supports a potential role for HDC-ASCT in this cohort of high risk TNBC. Considering the low TRM associated with this approach, prospective evaluation of this strategy is warranted.
Outcomes of transarterial chemoembolization (TACE) of the liver in patients with metastatic triple-negative breast cancer (TNBC).
Authors: Storozhakova Anna E. , Vladimirova Liubov Yu , Kit Oleg I. , Kolesnikov Evgeniy N. , Snezhko Aleksandr V. , Chernyak Maksim N. , Snezhko Tatiana A. , Samaneva Natalia Yu. , Svetitskaya Yana V. , Kalabanova Elena A. , Kabanov Sergey N. , Tishina Anna V. , Teplyakova Maria A. , Lisutin Aleksandr E.
Published: May 2020

e13107

Background: TACE is widely used in oncology in patients with metastasis in liver from GI tumors, meanwhile its opportunities in management pts with TNBC are unknown. The purpose of the study was to analyze the results of TACE of the liver metastases from TNBC. Methods: The study included 60 TNBC pts with unresectable liver metastases. 34 pts of the main group underwent chemotherapy including taxanes in standard regimens. After 6-12 chemotherapy cycles, the main group received 1-2 TACE procedures (doxorubicin 30 mg/m², 5-fluorouracil 600 mg/m², 10 ml of lipiodol and 1-2 ml of 300-500 µm HepaSphere microspheres). The control group (n = 32) received only 6-12 cycles of taxane-containing chemotherapy. Pts were aged 32-66 years, mean age in the main group 49.4, in controls 55 years. Primarily advanced breast cancer with unresectable liver metastases was diagnosed in 6 (17.6%) pts of the main group and in 5 (15.6%) controls. Progression after previous treatment was observed in 91.2% (31) main group and 90.6% (29) controls. Sizes of metastatic foci were 2.7-7.3 cm, average number 7.5. Bilobar metastases were most common. Liver metastases were own accompanied by metastases to the bones, intrathoracic lymph nodes, lungs and pleura. Obtained data were processed with software package “Statistica 7.0”. Results: Main group received a total of 46 TACE procedures performed for a maximal number of metastatic lesions, especially for those progressing after systemic therapy and the largest ones, when possible. Post-embolization syndrome after performing TACE, was observed in 60.86% (28) of cases, managed with conservative therapy for 2-7 days. Icterus was not observed. The tumor response rate was 94.1% in the main group vs. 80.6% in controls, with significant differences in PR (44.1% and 15.3% respectively, p < 0.05). Median of duration treatment response was 13.4 months in the main group and 9.3 months in control group (p < 0.05). CR was not achieved. Median follow-up was 17 months. 3-year disease-free survival was 63.2% in the main group and 43.8% in controls (p = 0.039). Conclusions: TACE resulted in better response to the therapy as well as improved disease-free survival in pts with TNBC. TACE is possible to be used to consolidate the achieved effect of the chemotherapy.
Staging the cancer ecosystem: Survival data from a registry study of patients with active cancer.
Authors: Cunningham James R. , Rittenbach Jon , Dodd Cheryl , Clemens Mitch
Published: May 2020

e13505

Background: Predicting cancer evolutionary trajectories remains an unmet goal for current cancer staging systems. Understanding the influence of selection pressures operating in the host-cancer environment and capable of effecting neoplastic evolution may be a means of informing such predictions. Methods: An IRB-approved cancer ecology registry study was begun, recruiting subjects whose cancer required active treatment. A set of 22 clinical and laboratory parameters obtained at time of entry onto the registry were compiled into eight separate profiles ( tumor microenvironment, inflammation, energy balance, psychosocial stress, GI microbiome, endocrine, skeletal remodeling, mutagenic) to help define a subjects’ ecological landscape. Parameters were chosen based on previous evidence of selection influence and scored using a trichotimzation of data (0, 1, 2). Resulting quantitative profiles from each subject were then aggregated using a geometric figure, an octomer, (an ‘ecogram’), length of vertices representing individual profile scores and whose net area, bounded by the ecogram, it is hypothesized will reflect strength of net selection pressure occurring at the level of the whole-patient. Survival data from the enrolled registry subjects was then correlated with ecogram area. Results: Complete ecological assessments were obtained in 15 subjects participating in the registry. Resulting ecograms demonstrated considerable variation among participants both in derived ecogram area of over 12-fold (range 0-12.7 arbitrary units, mean 4.7±2.9) as well as in morphologic appearance suggesting sensitivity and specificity for strength and character of active selection pressures. Overall survival for registry participants ranged from 14-198 months (median 47 mos.). For 12 subjects with advanced stage disease, survival from time of initial cancer diagnosis demonstrated a moderate degree of inverse correlation with ecogram area (r = -.38, R2= 0.144). Conclusions: A method for making a quantitative ecological assessment of patients with active cancer demonstrated both sensitivity and specificity for differences among participants in a cancer ecology registry study. Overall survival among subjects with advanced disease demonstrated inverse correlation with ecogram area supporting further study to predict cancer evolutionary tendency.
Towards cancer mega-cohorts: A novel homogenization algorithm applied to diverse breast cancer RNA-Seq datasets.
Authors: Ahmed Talal , Carty Mark , Wenric Stephane , Pelossof Raphael
Published: May 2020

e13507

Background: Recent advances in transcriptomics have resulted in the emergence of several publicly available breast cancer RNA-Seq datasets, such as TCGA, SCAN-B, and METABRIC. However, molecular predictors cannot be applied across datasets without the correction of batch differences. In this study, we demonstrate a homogenization algorithm that allows the transfer of molecular subtype predictors from one RNA-Seq cohort to another. The algorithm only uses cohort-level RNA-Seq summary statistics, and therefore, does not require joint normalization of both datasets nor the transfer of patient information. Using this approach, we transferred a breast cancer subtype (Luminal A, Luminal B, HER2+, Basal) predictor trained on SCAN-B data to accurately predict subtypes from TCGA. Methods: First, we randomly split the TCGA cohort (n = 481 Luminal A, n = 189 Luminal B, n = 73 Her2+, n = 168 Basal) into two sets: TCGA-train and held-out TCGA-test (n = 455 and n = 456, respectively). Second, the SCAN-B cohort (n = 837) was homogenized with the TCGA-train set. Third, a molecular subtype predictor, based on a logistic regression model, was trained on homogenized SCAN-B RNA-Seq samples and used to predict the subtypes of TCGA-test RNA-Seq samples. For baseline comparison, a similar predictor trained on the non-homogenized SCAN-B cohort was tested on the TCGA-test set. The experimental framework was iterated 250 times. Reported P-values reflect a paired one-sided t-test. Results: To quantify model performance, we measured the average F1 score for each tumor subtype prediction from the held-out TCGA test set with and without cohort homogenization. The average F1 scores with vs. without homogenization were: Luminal A, 0.88 vs. 0.85 ( P< 1e-69); Luminal B, 0.74 vs. 0.51 ( P< 1e-183); Her2+, 0.73 vs. 0.53 ( P< 1e-99); Basal, 0.98 vs. 0.97 ( P< 1e-53). Overall, homogenization significantly outperformed no homogenization. Conclusions: We developed a novel homogenization algorithm that accurately transfers subtype predictors across diverse, independent breast cancer cohorts.
Family aggregation of pulmonary ground-glass nodules: Identification of multiple candidate risk loci.
Authors: Fu Rui , Zhang Jia-Tao , Chen Rongrong , Tai Zai-Xian , Lin Hao-Xiang , Su Jian , Chu Xiang-Peng , Zhang Chao , Tang Wen-Fang , Lin Jun-Tao , Nie Qiang , Yang Xue-Ning , Wu Yi-Long , Zhong Wenzhao
Published: May 2020

e13512

Background: Lung cancer with family history have been emerging gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGNs with lung cancer family history remains baffling. Methods: This prospective study was registered at clinicaltrials.gov (number NCT04220268) and enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, especially presenting as GGNs. We collected blood and tumor samples from 29 GGNs patients with family history to investigated germline and somatic mutations by whole exome sequencing (WES). As the first part of our study, we focused on 107 nonoverlapping susceptibility loci for lung carcinogenesis identified by recent genome-wide association studies (GWAS) to identify novel rare causal variants. Potential causal variants were further verified in other patients from the families when possible. Results: A total of 461267 single neocleotide variants (SNVs) and 132268 insertion-deletions (InDels) were detected from the 29 index patients. By focusing on exome profiles of the 107 target loci, we identified three key rare mutations, namely MSH5 p.Ala702Thr, ADGRG6 p.Asn338Ile and CCDC147 p.Arg619Trp in two index patients respectively. The minor allele frequency (MAF) of these three variants was extremely low in the general population, which is 1/5008, 2/5008 and 6/5008 respectively in the 1000 Genomes database, and 2/31406, 5/31346, and 5/31394 respectively in the GnomAD database. There three mutations were predicted as probably damaging or disease-causing variations by SIFT or Polyphen. Mutations of MSH5 and CCDC147 were also detected in other patients from the two families. Conclusions: With the identification of highly disruptive risk-conferring MSH5, ADGRG6 and CCDC147 mutations, we confirmed the probably heritable and risk loci exists in the GGNs patients with lung cancer family history in East Asians. Exome sequencing has great potential to identify novel rare causal variants, and more analyses on more patients are still ongoing.
Incidence of mutated DNA damage response pathway and clinically actionable alterations in Chinese patients with unknown primary tumor revealed by comprehensive genomic profiling.
Authors: Wang Shibao , Yu Ruoying , Ou Qiuxiang , Wu Xue , Bao Hua , Shao Yang , Wei Suju
Published: May 2020

e13523

Background: Carcinoma of unknown primary(CUP) is a clinically aggressive disorder with early tumor dissemination. Without drugs specifically approved for CUP, the outcome of standard chemotherapy is generally poor. Identifying molecular traits of CUP can be beneficial not only for better therapy approach but also potentially for all patients with metastatic dissemination. Methods: From January 2015 to July 2019, 36 unique cases were diagnosed as CUP. DNA was extracted with formalin-fixed paraffin-embedded specimens(FFPEs) or plasma samples and sequenced with 400+ gene panels. Results: In this cohort, identified sites of tumor dissemination included lymph node(36%), bone(19%), liver(8%), lung(5%), gut(5%). More than half of patients were male(65%) with a median age of 62 years old(range:42-82). 83% of CUP patients harboured at least one altered DNA damage repair(DDR) gene including TP53(74%), ATM(19%), ARID1A(11%), ATR(11%). Patients with altered homologous recombination repair (HRR) pathway(42%) showed significantly increased tumor mutational burden(TMB) compared to patients with intact HRR(p = 0.025). MYC gene displayed the most copy number variation (gain, 22%) followed by CDKN2A(loss, 15%) and ZNF217(gain, 15%). Clinically actionable mutations were identified in ten patients including KRAS G12C(3), PIK3CA E545K(2), PIK3CA E542K(1), BRAF V600L(1), EGFR L861Q(1), EML4- ALK(1), ALK L1196M(1). One SCC patient with lymph node metastasis had a PIK3CA mutation E545K and a resistant ALK mutation L1196M without prior ALK TKI treatment, suggesting this patient might benefit from PI3K inhibitors. Unfortunately, He progressed on paclitaxel and cisplatin and died in 2019. The other ADC patient with lymph node metastasis achieved SD on pemetrexed disodium and oxaliplatin. He harboured a KRAS G12C mutation (allele frequency 77.75%), indicating target therapy with KRAS inhibitor might be a better treatment option. Conclusions: Majority of CUP patients showed impaired DDR pathway. TMB of CUP patients with altered HRR pathway is significantly higher than ones with intact HRR. Comprehensive genomic profiling revealed the potentiality of target therapy in CUP patients with clinically actionable mutations.
Distinct genomic and immune microenvironment between thymomas and thymic carcinomas.
Authors: Wang Kaicheng , Lin Suxia , Hou Xue , Liu Yongdong , Li Meichen , Chen Jing , Wang Na , Wang Fang , Bai Jing , Xu Yaping , Chen Likun
Published: May 2020

e13529

Background: Thymomas and thymic carcinomas which uniformly known as thymic epithelial tumors (TETs) are rare intrathoracic malignancies and a limited studies have been reported addressing the molecular biology and immune discrepancy. The main purpose of this study was to depict the genomic and transcriptomic landscape of thymomas and thymic carcinomas, as well as elucidate the differentiated immune microenvironment. Methods: Totally 15 thymomas and 7 thymic carcinomas patients were enrolled from January 2014 to July 2018. Treatment-naïve tissue samples were collected, and we also obtained matched peripheral blood mononucleocytes as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: Exome sequencing revealed that GTF2I mutation occurred in all of type A thymomas but was absent in the aggressive subtypes. The median tumor mutation burden of thymomas was 0.12/Mb, significantly lower than thymic carcinomas (median: 1.02/Mb, p = 0.001). Copy number variation was more common in thymic carcinomas than thymomas (83.3% vs 9.1%, p = 0.005). Top mutational signatures enriched in both thymomas and thymic carcinomas included age and Aristolochic acid exposure, while the APOBEC signature was more common in thymomas than thymic carcinomas (81.8% vs 16.7%, p = 0.03). As a confirmed immune escape event, loss of heterozygosity of human leukocyte antigen was identified in 9.1% of thymomas and 50% of thymic carcinomas. Via unsupervised clustering of immune infiltration, all tissue samples were classified into high- and low-infiltration subgroups. Remarkably, up to 71.4% of samples from thymic carcinomas and only 6.7% of samples from thymomas were defined as low immune cell infiltration. In consideration of specific immune cell types, macrophage ( p = 0.01) and neutrophil ( p = 0.02) were enriched in thymic carcinomas while CD56+ NK cell ( p = 0.005) was enriched in thymomas, indicating the evidential discrepancy about immune cell infiltration between two subtypes of TETs. Conclusions: This study elucidated the molecular and immune microenvironment discrepancy between two subtypes of TETs. From molecular perspective, thymomas and thymic carcinomas are entirely different diseases with different etiology and characterized by distinct immune infiltration, and thus should be managed with disparate therapeutic strategies. Findings in this study may also be useful in future targets development and exploration of immunotherapies in TETs.
A new PMS2 gene variant of unknown significance: How pathogenic is it?
Authors: Picanço-Albuquerque Clarissa Gondim , Bezerra Maria Júlia Barbosa , Silva Paulo Goberlanio de Barros , Sant'Ana Rosane Oliveira , Luciano Maria Claudia dos Santos , Silva-Fernandes Isabelle Joyce de Lima , Lima Marcos Venicio Alves
Published: May 2020

e13532

Background: The Lynch syndrome (LS) is the most common inherited syndrome associated with colorectal cancer (CRC). The hallmark of LS is DNA mismatch repair deficiency. The amount of variants of uncertain significance (VUS) in suspected LS confounds diagnosis, requiring surveillance of variant reclassifications. In this paper we describe a new and most likely pathogenic VUS in PMS2. Methods: Patient screened for personal and familial cancer and evaluated with NGS gene panels for 31 genes. The protein structure was analyzed with the software Pymol. Results: A woman diagnosed with breast cancer (BC) at 60 years and CRC at 65 years was investigated due to her extensive family history of cancer (21 maternal relatives), including 6/9 siblings [gastric n = 1, lung n = 1, BC n = 4 (one of whom with BC, endometrium and CRC)], 8/12 aunts and uncles, all of whom died of cancer (gastric n = 4, CRC n = 1, CNS n = 1, BC n = 1; uterus/gallbladder n = 1), and 7 cousins (CNS n = 3, lung n = 1, gastric n = 2, suspected ovary n = 1). The new PMS2 gene variant c.134A > G(p.Asn45Ser), which was also detected in two sisters with CRC submitted to segregation analysis, occupied the same locus as a known pathogenic variant, c.134A > C(p.Asn45Thr). The structural analysis showed that the mutated locus encodes a serine instead of an asparagine in position 45 at the enzyme’s active site. Asn 45 is a conserved amino acid that binds to ATP in protein structure (PDB = 1EA6). Interestingly, this is close to position 42-44, for which another potentially pathogenic VUS (p.Leu42_Glu44del) has been described. Conclusions: Based on our patient’s personal and family history and on the locus variant and protein structure analysis, the new PMS2 gene variant described in this paper is most likely pathogenic.
The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).
Authors: Arora Sanjeevani , Xiu Joanne , Sohal Davendra , Lou Emil , Goldberg Richard M. , Weinberg Benjamin A. , Grothey Axel , Korn W. Michael , Khushman Mohd , Shields Anthony Frank , Marshall John , Hall Michael J.
Published: May 2020

e13538

Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]
HBV-human DNA integration in non-hepatic tumors.
Authors: Liu Lei , Liu Ming , Huang Tanxiao , Liao Wenting , Fu Mimi , Duan Jingxian , Chen Shifu
Published: May 2020

e13544

Background: Hepatitis B virus (HBV) infection in hepatocytes may induce chronic liver damage, which further leads to hepatocellular carcinoma. HBV infection was also reported in other cell types including peripheral blood mononuclear cells (PBMCs). Moreover, epidemiological evidence suggested that HBV infection was associated with various types of cancers. In this study, we investigated whether HBV DNA integration was observed in extrahepatic tumor cells. Methods: The study enrolled thousands of Chinese patients with different types of cancers. Peripheral blood and tumor tissue samples were collected, plasma cfDNA, PBMC gDNA and tumor tissue DNA were extracted. By targeted capture and next-generation sequencing, we sequenced the cancer-related genes and identified HBV DNA integration events in these samples. Moreover, the subtype of HBV captured in the host genome was verified, and the ratio of reads mapped to the HBV genome was calculated. Results: Samples with more than 0.1% of the sequencing reads mapped to the HBV genome were identified as HBV positive cases. Thirty-two liver cancer patients were subtype-b HBV positive, among which 8 tumor samples exhibited HBV genome integration. Three colorectal cancer patients were infected by subtype-c HBV, only one tumor sample carried HBV DNA integration. Two lung cancer patients were shown to be HBV positive; one was infected by subtype-b HBV and the other carried subtype-c HBV. Subtype-b and-c HBV genome was observed in the tumor sample of two cholangiocarcinoma patients, whereas subtype-b HBV DNA was identified in the PBMC of one gastrointestinal stromal cancer patient. Conclusions: HBV genome integration was identified in the tumor cells of lung, colorectal, biliary ducts, and gastrointestinal stromal cancer. The mechanisms by which the HBV genome integrates into these tissues requires further investigation.
Community-based practice of early lung cancer screening with low-dose spiral computed tomography in Jiaxing city from Zhejiang Province.
Authors: Zhu You-cai , Wang Wen xian , Xu Chunwei , Lan Gang , Chen Huafei , Li Xiaofeng , Zhai Zhanqiang , Huang Lichao , Du Kaiqi , Fang Meiyu
Published: May 2020

e13557

Background: As one of the most frequent malignant tumors in China, the morbidity and mortality of lung cancer remain high. Early diagnosis and normative treatment is the key to improve the prognosis of lung cancer. The aim of this study is to explore the practice of early lung cancer screening with low-dose spiral computed tomography (CT) based on the current situation in community health service, with integration of superior resources of medical institutions at all levels in Jiaxing City from Zhejiang Province. Methods: From Jan. 2017 to Dec. 2019, we screened 13491 (male 8783, female 4708) individuals high-risk population in selected communities of Nanhu District, Pinghu County and Haiyan County, Zhejiang Province, for early diagnosis of lung cancer with low-dose spiral CT combined with multidisciplinary comprehensive treatment models including minimally invasive surgery, exploring the medical service network covering prevention, diagnosis, treatment, rehabilitation and follow-up. Results: Screening resulted in a diagnosis of cancer in 27 participants. Of these participants, 24 cases of primary lung cancer, 1 case of lung metastasis, 1 case of breast cancer, 1 case of thyroid cancer. The morbidity of primary lung cancer is 224.53×10-5. There were 20 cases of Stage 0-Ⅰlung cancer accounting for 83.33% of all diagnosed primary lung cancer. Conclusions: Based on community health service, screening with LDCT could improve the early diagnosis rate of lung cancer in both smokers and nonsmokers with feasibility and validity, which could be applicable in qualified eligible medical centers and communities in China. It is not reasonable to exclude nonsmokers from screening with LDCT.
Proteomic screening of saturated fatty acid-induced hepatocytes-derived exosomes.
Authors: Liu Yi-Ting , Huang Jee-Fu , Yu Ming-Lung , Wang Shu-Chi
Published: May 2020

e13568

Background: Most countries continuously westernize and industrialize, the prevalence of NAFLD is expected to increase, which will greatly increase social and economic burden. Meanwhile, the trend that NAFLD acts as a main stream of liver diseases will be much emphasized with the eradication and/or effective control of viral hepatitis in the future. There are many studies indicated that lipotoxicity of hepatocyte plays an important role in the inflammation and hepatic injury during the progression of liver steatohepatitis and HCC. However, the extracellular vesicles (EVs) participate in intercellular signaling, tissue injury and repair, and matrix remodeling still unclear. Methods: In this research, we used hepatitis liver cells (Huh 7.5.1 and Hep-G2) and LX-2 cell lines (liver stellate cells, HSCs) with palmitic acid (PA) to study the cell inflammation/fibrosis response and exosome contents. Results: The Oil red lipid droplet cell stain result found the liver cells has produced higher fatty oil droplet than HSCs cells in the same PA dose. However, the inflammation cytokines (IL-6, TNF-α, and IL-1β) and fibrosis-related protein (α-SMA and COL1A1) only significant increasing in HSCs cells but not in liver cells after the PA treatment. Isolation of exosomes from PA-treated hepatocytes presenting the same effect on the activation of HSCs, which lead to significant expression of fibrosis markerα-SMA and COL1A1. Based on the finding, we further analyzed the exosomes from PA-treated hepatocytes by LC-MS analysis and found 6 proteins (CFHR-4, A2M, HBG, APOB, IG, DCTN1) presenting compare to un-treated liver cells. Conclusions: This study provide the released Hep-EVs have important roles in hepatocyte-to-HSC communication.