bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal monitoring by next generation sequencing of plasma cell-free DNA in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with ALK tyrosine kinase inhibitors.
Authors: Kwon Minsuk , Ku Bo Mi , Park Sehhoon , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: May 2020

9603 Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) NSCLC inevitably acquire resistance to ALK inhibitors. We hypothesized that longitudinal monitoring of cell-free plasma DNA (cfDNA) next generation sequencing (NGS) could predict the response and resistance of TKI therapy in ALK+NSCLC Methods: Patients with ALK+ advanced NSCLC determined by standard tissue testing and planned for TKI therapy were prospectively recruited. Plasma was collected before therapy (n = 92), two months post-therapy (n = 58), and at progression (n = 35). Plasma DNA NGS analysis was done retrospectively by Guardant360. Results: From April 2015 to July 2019, 92 patients enrolled; 81 (88.0%) received ALK TKI as first-line (crizotinib, n = 59; alectinib, n = 22), 10 (10.9%) received TKI as second-line (alectinib, n = 6; crizotinib, n = 2; ceritinib, n = 1; brigatinib, n = 1), and 1 (1.1%) was treated in third-line (lorlatinib). At the cut-off date of January 28, 2020, 56 of 92 patients had disease progression. Circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%); among these were 43 ALK fusions (62.3%) and 1 ALK G1202R without fusion (1.4%). Fusions included EML4-ALK v1 (n = 19), EML4-ALK v3 (n = 14), CLTC-ALK (n = 1), TPM3-ALK (n = 1), GCC2-ALK/CLIP4-ALK (n = 1), and other EML4-ALK fusions (n = 7). Eight patients developed ALK resistance mutations after crizotinib therapy: L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Two patients developed ALK resistance mutations after ceritinib: G1202R (n = 1), and co-occurring G1202R and T1151R (n = 1). The absence of detectable ctDNA at baseline was associated with longer progression-free survival (PFS; median 36.1 vs 11.6 months, HR 0.432, p = 0.004) and overall survival (OS; median not reached vs 27.9 months, HR 0.418, p = 0.034). Patients with clearance of ctDNA at two months (n = 29) had significantly longer PFS (median 25.4 vs 13.9 months, HR 0.343, p = 0.030) and OS (median not reached vs 25.7 months, HR 0.173, p = 0.035) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 9) showed shorter PFS (median 7.0 vs 12.5 months, HR 3.596, p = 0.0154) than those without TP53 alterations (n = 35). Conclusions: NGS of cell-free plasma DNA is useful not only for the detection of ALK fusions and resistance mutations but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK TKI.
Establishment of the first international large-scale, genomic screening platform to identify patients with rare oncogene drivers in non-small cell lung cancer (NSCLC) in East Asia.
Authors: Matsumoto Shingo , Zhou Caicun , Kuo Chih-Hsi , Yoh Kiyotaka , Kato Terufumi , Nishino Kazumi , Furuya Naoki , Zhang Shucai , Lin Dongmei , Han Yuchen , Wang Chin-Chou , Ikeda Takaya , Zenke Yoshitaka , Goto Koichi 
Published: May 2020

9605 Background: A rapidly increasing number of oncogenic drivers have been identified in non-small cell lung cancer (NSCLC), and most of them occur in less than 5% of patients. Large-scale genomic screening to identify patients with rare driver alterations is thus necessary to enable precision medicine and to support the development of novel targeted therapies and companion diagnostics (CDx). Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 with 206 institutions in Japan and 5 in Taiwan currently participating. A separate genomic screening project with similar structure was established in China (LC-IRICA-China) in collaboration with LC-SCRUM-Asia in 2019 (3 institutions enrolling, 17 about to open, 63 undergoing review). Samples are analyzed by a multi-gene PCR panel and targeted next-generation sequencing. The target is to enroll 70000 NSCLC patients (20000 from LC-SCRUM-Asia and 50000 from LC-IRICA-China) by 2022. Results: From March 2013, a total of 9383 lung cancer patients were enrolled in LC-SCRUM-Asia, and from October 2019, 1649 pts were included in LC-IRICA-China (January 2020). The rates of genomic alterations in LC-SCRUM-Asia: EGFR (17%) of which ex20ins (2%), KRAS (13%) of which G12C (4%), ALK fusions (2%), ROS1 fusions (2%), RET fusions (2%), HER 2 ex20ins (3%), MET ex14skip (2%), BRAF V600E (1%), NRG1 fusions (0.2%) and NTRK3 fusions (0.03%). Corresponding rates in the initial 243 pts in LC-IRICA China: EGFR (45%) of which ex20ins (2%), KRAS (8%), ALK (5%), ROS1 (2%), RET (1%), HER2 (2%), MET ex14skip (1%), BRAFV600E (1%). Through the screening, 266 patients from Japan and Taiwan were enrolled into genotype-matched clinical trials of unapproved targeted drugs. In Japan, ROS1-, BRAF- and TRK-targeted therapies were successfully approved based on these clinical trials, and a NGS-based multi-gene CDx for EGFR/ALK/ROS1/BRAF targeted-therapies was approved based a concordance study using archival samples from the project. Conclusions: An East Asian international genomic screening platform has been established to enable precision medicine for patients, accelerate drug and diagnostic development in patients with very rare alterations and to help provide a deeper understanding of the underlying biology of NSCLC in East Asian patients. The screening network will be further expanded to other countries in East Asia in the near future.
Resistance to lorlatinib in ROS1 fusion-positive non-small cell lung cancer.
Authors: Lin Jessica Jiyeong , Johnson Ted , Lennerz Jochen K , Lee Charlotte , Hubbeling Harper Grace , Yeap Beow Y. , Dagogo-Jack Ibiayi , Gainor Justin F. , Shaw Alice Tsang 
Published: May 2020

9611 Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC), including in patients (pts) previously treated with crizotinib. Despite initial benefit, however, most pts experience disease progression on lorlatinib. Mechanisms of resistance to lorlatinib in ROS1+ NSCLC are poorly understood. Methods: We analyzed repeat tumor biopsies derived from advanced ROS1+ lung cancer pts progressing on lorlatinib. Next-generation sequencing (NGS, n = 17) or whole exome sequencing (n = 1) was performed to detect mutations, indels, and copy number alterations. Results: Sixteen pts underwent a total of 18 repeat tumor biopsies after progression on lorlatinib. Fourteen had received prior crizotinib; two received prior crizotinib and entrectinib. Median duration of therapy on lorlatinib was 13.5 months (95% CI, 8.3-18.4). Among the 18 cases analyzed by sequencing, 7 (38.9%) harbored a ROS1 resistance mutation, including G2032R (4/18, 22.2%), S1986F/L2000V (1/18, 5.6%), L2086F (1/18, 5.6%), and G2032R/S1986F/L2086F (1/18, 5.6%). Of note, ROS1 L2086F was a novel resistance mutation not previously reported in the literature, but analogous to ALK L1256F (a lorlatinib-resistant ALK mutation). Structural modeling studies showed that ROS1 L2086F causes steric interference with binding of lorlatinib, as well as crizotinib and entrectinib. In addition to ROS1 kinase domain mutations, NGS analyses also identified MET copy number gain in a lorlatinib-resistant case, validated by fluorescence in situ hybridization as high-level focal MET amplification (MET/CEP7 copy number ratio 6.3) without a concomitant ROS1 resistance mutation. Duration of therapy on lorlatinib was significantly shorter in pts with a post-lorlatinib ROS1 resistance mutation compared to those without (8.3 vs 18.1 months; p = 0.005). Conclusions: ROS1 resistance mutations are observed in over one-third of cases progressing on lorlatinib, including the solvent front mutation G2032R and a novel L2086F mutation. These findings underscore the importance of developing next-generation ROS1 TKIs with activity against ROS1 mutations, and the need to elucidate ROS1-independent resistance mechanisms.
Genomic characterization and outcome evaluation of kinome fusions in a large non-small cell lung cancer population.
Authors: Wu Fengying , Liu Sisi , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Zhou Caicun 
Published: May 2020

9620 Background: Lung cancer is the leading cause of cancer death worldwide. Kinase fusion represents an important type of somatic alterations which promote oncogenesis and serve as a diagnostic marker in lung cancer. This study aims to identify the landscape of kinase fusions in lung cancer and expand our understanding of druggable fusions, together providing valuable information for therapeutics decision making. Methods: We performed genomic profiling of tumor/plasma biopsies of a total of 18,839 Chinese lung cancer patients using next generation sequencing (NGS) by targeting 425 cancer-relevant genes. Patients’ clinical characteristics and treatment history were retrospectively studied. Results: A total of 1,048 patients (5.56%, 1,048/18,839) were identified with kinase fusions, including 815 adenocarcinomas (ADCs) and 34 squamous cell carcinomas (SCCs). Briefly, a total of 198 unique gene fusion events have been observed, including 37 recurrent fusions and 114 novel fusions which have previously not been documented. ADC patients with kinase fusions were relatively younger than SCC patients (median: 53 vs 61 years old, p< 0.01). The most frequently observed fusion was EML4-ALK for both ADCs (50.0%) and SCCs (32.4%), followed by FGFR3-TACC3 (29.4%) in SCCs and KIF5B-RET (11.8%), CD74-ROS1 (9.2%), CCDC6-RET (3.9%) and SLC34A2-ROS1 (2.3%) in ADCs, retrospectively. A total of 14 recurrent fusions including FN1-ALK, MEMO1-ALK, CUX1-ALK, KIF13A-RET and PHF20-NTRK1 were also identified at low frequencies. Of note, EML4- or STRN- ALK fusion events mainly rearranged in the intron 19 of ALK, but the breakpoints of VCL-ALK were mostly located upstream of ALK exon 18. Meanwhile, CD74-, SLC34A2- and TPM3- ROS1 rearrangement mainly occurred in the ROS1 introns 31, 33 and 34. In addition, among patients with novel fusions, RORB- ALK and AFF2-RET may potentially function as oncogenic drivers in lung cancer and have demonstrated clinical benefit from crizotinib treatment. Conclusions: Our data have depicted a comprehensive overview of the landscape of kinase fusions in lung cancer, which helps recognize potentially druggable fusions and translate into therapeutic applications.
Difference in clinicopathological characteristics between pure and mixed invasive micropapillary breast carcinomas from eastern China.
Authors: Wang Rong , Li Nani , Jia Wang Xiao , Cao Wen-Ming 
Published: May 2020

e12500 Background: Invasive micropapillary carcinoma of the breast (IMPC) is a rare pathologic subtype of breast cancer with frequent lymph node metastases. Since the differences in pathological features between pure and mixed IMPCs are not fully understood, we aimed to investigate the difference in clinicopathological characteristics between pure and mixed IMPC. Methods: Overall 121 IMPC cases were included from Zhejiang Cancer Hospital, China during May 2010-August 2018. The clinicopathological features and survival estimates between the pure IMPC and mixed IMPC groups were compared. Targeted sequencing was performed to investigate the genomic profile of paired primary breast cancer and metastatic tissue samples from two pure IMPC and four mixed IMPC. The copy number variations (CNVs) and the tumor mutation burden (TMB) from metastatic tissues were analyzed. Results: Overall 48 cases were pure IMPC and 73 were mixed IMPC. The pure group had significantly higher proportion of luminal B compared to the mixed group (37.5% vs.15.1%), but lower proportion of luminal A (33.3% vs. 45.2%). The pure group had similar HER2 overexpression rate (31.2% vs. 32.9%) and mean age at diagnosis (51.0 vs. 50.2 years), compared to the mixed group. The pure group had significant higher proportion of stage ⅢC cases compared to the mixed group (38.3% vs.17.8%). We found no significant difference in 3-year disease-free survival (DFS) between the two groups (83.7% vs. 80.0%), but the mixed group had a better overall survival (OS), compared to the pure group (HR = 0.28 (0.091-0.868), P = 0.047). Conclusions: We found that pure IMPC had more aggressive behavior with locally advanced disease and higher proportion of luminal B than mixed IMPC. Mixed IMPC had a longer OS compared to pure IMPC, but no significant difference in 3-year DFS between two groups.
Paclitaxel-induced peripheral neuropathy in early-stage breast cancer patients.
Authors: Liu Jacqueline , Sorooshian Hormozan 
Published: May 2020

e12503 Background: Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and can persist for up to two years after completing treatment, greatly affecting both the course of chemotherapy and quality of patients. Few studies have characterized the side effect profiles of two commonly used paclitaxel-based adjuvant regimens, dose-dense biweekly paclitaxel with growth factor support (ddP, 175 mg/m2 biweekly for four cycles) and weekly paclitaxel (wP, 80 mg/m2 weekly for 12 cycles). Conflicting results exist regarding the incidence of paclitaxel-induced neuropathy related to either administration scheme. Methods: This is a data-only retrospective cohort study that consisted of adult patients with early-stage breast cancer who received either ddP or wP at Kaiser Permanente Diablo Service Area (Walnut Creek and Antioch Medical Centers) between January 1, 2010 and January 1, 2019. The primary endpoint was the proportion of patients with dose-limiting chemotherapy-induced peripheral neuropathy (DL CIPN). Results: 244 patients were included in the final analysis with 159 and 85 patients receiving wP and ddP, respectively. Baseline demographics were well matched between the two groups. There was no significant difference in the proportion of patients who experienced DL CIPN with wP (17.6%) compared to ddP (19.1%) (p = 0.647). Grade 3 or 4 adverse events occurred in 8.9% of patients who received wP and 10.6% of patients who received ddP. No significant difference was observed (p = 0.650). Conclusions: The results of this study support the current National Comprehensive Cancer Network (NCCN) guidelines, which recommend dose-dense doxorubicin and cyclophosphamide (ddAC) followed by either sequential wP or sequential ddP with growth factor support as preoperative and/or adjuvant therapy for the treatment of early-stage breast cancer. The selection of an appropriate paclitaxel schedule is provider preference and largely based on the consideration of patient tolerability. These findings suggest that the concern for paclitaxel-induced peripheral neuropathy, including DL CIPN, may potentially play a smaller role in helping guide clinicians who are choosing between the two paclitaxel-based adjuvant regimens.
Differential expression of micro-RNAs in breast cancer with relapsed disease: A clinical data base study.
Authors: Pandey Yadav , Chen Zhongning , Makhoul Issam 
Published: May 2020

e12514 Background: Micro-RNAs (miRNAs) are small, noncoding RNA molecules that play important role in RNA silencing and post-transcriptional regulation of gene expression that are dysregulated in cancer. miRNAs are divided into oncogenic and tumor suppressor miRNAs. Both of these subtypes are known to regulate breast cancer development and progression. We studied the expression of these miRNAs before and after treatment in patients with breast cancer with relapsed disease. Methods: Data was obtained from the TCGA database. 11 patients with biopsy proven diagnosis of invasive ductal adenocarcinoma of the breast receiving adjuvant chemotherapy with relapsed disease who had tissue biopsy post-treatment were included in the study. miRNA expression was assessed in the pre- and post-treatment tissue samples. A total of 178 miRNA were analyzed after filtering out miRNA expression counts < 10. A pair-wise comparison of the differential expression of miRNA before and after treatment with adjuvant chemotherapy was analyzed using a quasi-likelihood F test implemented by bioconductor package, edgeR. This package is well documented for analyzing RNA-seq data due to adjustment for biological variations and measuring error using a negative binomial distribution. The expression of miRNA |Log2FC| > 1 and P value < 0.05 were obtained. Results: Out of 11 female patients, 10 were Caucasian. 9 out of 11 patients’ tumors were Estrogen Receptor positive; 8 patients had progesterone Receptor positive and 1 patient had Human epidermal growth factor receptor2 positive cancer. Of the 178 miRNAs of interest, we found 14 miRNA that are differentially expressed. The miRNA that are up-regulated post-treatment were hsa-miR-148a, hsa-miR-126, hsa-miR-142, hsa-miR-210, hsa-miR-374a, hsa-miR-192. The miRNA that were down-regulated were hsa-miR-197, hsa-miR-155, hsa-miR-149, hsa-miR-365a, hsa-miR-365b, hsa-miR-484, hsa-miR-339 and hsa-miR-3653. Among the miRNA up-regulated post-treatment, miR-148 and miR-126 are known major tumor suppresser miRNA whereas miR-210 and miR-374a are major oncogenic miRNA in breast cancer. Among the miRNA down-regulated post treatment, miR-155 is major oncogenic miRNA whereas miR-365 is major tumor suppressor miRNA in breast cancer. Conclusions: There is mixed expression profile of tumor suppressor miRNA and oncogenic miRNA molecules between before and after treatment in patients with breast cancer with relapsed disease. Further studying these miRNA molecules can help us better understand about the tumor progression and disease relapse.
Genomic testing in early breast cancer (EBC) for low middle income countries (LMIC): Is it worth the cost?
Authors: Shrivastav Gunjan , Arya Devavrat , Chaturvedi Aditi , Garg Charu , Jain Shubham , Mukhiya Sheetal , Chaturvedi Harit Kumar , Rohatgi Nitesh 
Published: May 2020

e12521 Background: Chemotherapy is crucial for EBC management but has toxicities. Attempts are made to identify patients where chemotherapy can be safely skipped. Genomic testing offers advantage over clinico-pathological tools but given the cost, its utility in clinical practise, especially in LMIC remains questionable. Methods: 50 EBC patients who underwent risk stratification by oncotypeDX were retrospectively studied. Their clinico-pathological characteristics, Nottingham prognostic index (NPI) and PREDICT recommendation (v 2.1) were recorded. Tumor board(TB) made treatment recommendations based on age and histopathology, blinded to recurrence score(RS). The results were compared. Results: 32% patients were < 50 years, 68% were > 50 years. 32% and 68% patients were pre and post menopausal respectively. On pathological examination, T1, T2 & T3 comprised 26%, 70% and 4% respectively. 96% were node negative, 2% node positive, 2% had unknown nodal status. Tumors had Grade 1, 2 and 3 in 8%, 88% and 4% respectively. 4% had unknown estrogen receptor (ER), progesterone receptor (PR) score. ER and PR were low (Allred 3-5) in 2% and 12% respectively. NPI was low ( < 3.4) in 96% and intermediate (3.5- 5.4) in 4%. On PREDICT, all showed low benefit of chemotherapy ( < 3% at 10 years). TB prescribed chemotherapy in 58% and hormonal therapy (HT) in 42% patients. RS was low, intermediate and high in 66%, 26% and 8% patients respectively. Patients with low and high RS were supposed to receive HT and chemotherapy respectively. In the intermediate group, 4% patients were recommended HT as per age. 22% patients could not be assigned a treatment based on RS alone. In remaining 78%, TB’s decision matched RS recommendation in 38% (19) patients. In 2% (1), TB recommended HT while OncotypeDX showed high RS. In 38% (19) patients, TB recommended chemotherapy while OncotypeDX showed low RS. Despite all having low/intermediate NPI with < 3% chemotherapy benefit on PREDICT, 8% showed chemotherapy benefit on OncotypeDX. In 40%, OncotypeDX recommendation deferred from TB. In more than one third patients, when TB recommended chemotherapy, RS came low. In these patients we could avoid chemotherapy, saving ~900 USD treatment costs. As 68% patients were elderly ( > 50), genomic testing avoided chemotherapy in this subgroup, likely to suffer treatment toxicities. Conclusions: In LMIC where all patients don’t have access to hospitals with adequate infrastructure for chemotherapy administration, genomic testing has significant implications. We recommend using it more in clinical practise.
Is the toxicity of breast radiotherapy higher in patients with collagen vascular disease? A systematic review of the literature.
Authors: Liu Wei , Leung Aaron , Park Jane , Liu Brandon , Boldt Gabriel , Palma David A. 
Published: May 2020

e12527 Background: Collagen vascular disease (CVD) has been described to be a relative contraindication for radiotherapy (RT) due to increased toxicity. As a result, RT to the breast or chest wall is underutilized in patients with CVD, despite known benefits in local control and overall survival after breast conserving surgery or mastectomy. We sought to characterize the acute and late toxicity rates associated with curative-intent RT for breast cancer patients with CVD. Methods: A systematic review per the PRISMA guidelines was performed using Pubmed database (inception to July 2019), for English-language articles. Key search themes included collagen vascular disease, connective tissue disease, including specific subtypes, along with terms for radiation and cancer. Title and abstract review were followed by full-text review. Inclusion criteria were reports of toxicity of five or more patients with CVD and treatment with curative-intent RT to the breast or chest wall. Data abstracted included: type of study, CVD diagnosis, number of patients who received breast RT, acute grade ≥3, and late grade ≥1, grade ≥3, and grade 5 toxicity. Primary endpoint was late grade ≥3 toxicity for patients with pre-existing CVD. Acute and late toxicity were classified as per CTCAE version 5.0. Results: The initial search yielded 3286 unique abstracts. 34 articles were determined appropriate for full-text review. From these, a final set of 10 articles met all inclusion criteria. All studies were retrospective. In these studies, more than 30 000 patient cases were reported. 184 patients with CVD who underwent curative-intent RT to the breast or chest wall and had available toxicity data were identified, including 128 patients with CVD diagnosed before RT. In the 5 case control studies, 100 patients were matched to 225 controls. Most studies did not report the incidence of all grades of toxicity. Among patients with available data, 7/102 patients (7%) with pre-existing CVD had late grade ≥3 toxicity, including 4/6 (67%) with pre-existing scleroderma and 3/96 (3%) with pre-existing non-scleroderma CVD. 32/88 patients (36%) with pre-existing CVD and available data had late grade ≥1 toxicity. 1/142 (1%) had late grade 5 toxicity, in the form of chronic pericarditis. 6/66 patients (11%) with pre-existing CVD had acute grade ≥3 radiation dermatitis. No patients had acute grade 5 toxicity. Conclusions: Retrospective data suggest that patients with pre-existing CVD, aside from scleroderma, have acceptable acute and late toxicity rates after RT to the breast or chest wall.