Thymic adenocarcinoma is an extremely rare subtype of thymic epithelial tumors. Due to its rarity, there is currently no sequencing approach for thymic adenocarcinoma. We performed whole exome and transcriptome sequencing on a case of thymic adenocarcinoma and performed subsequent validation using Sanger sequencing. The case of thymic adenocarcinoma showed aggressive behaviors with systemic bone metastases. We identified a high incidence of genetic aberrations, which included somatic mutations in RNASEL, PEG10, TNFSF15, TP53, TGFB2, and FAT1. Copy number analysis revealed a complex chromosomal rearrangement of chromosome 8, which resulted in gene fusion between MCM4 and SNTB1 and dramatic amplification of MYC and NDRG1. Focal deletion was detected at human leukocyte antigen (HLA) class II alleles, which was previously observed in thymic epithelial tumors. We further investigated fusion transcripts using RNA-seq data and found an intergenic splicing event between the CTBS and GNG5 transcript. Finally, enrichment analysis using all the variants represented the immune system dysfunction in thymic adenocarcinoma. Thymic adenocarcinoma shows highly malignant characteristics with alterations in several cancer-related genes.
8576 Background: Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16 INK4A , and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. Methods: This is a phase II multicenter, open-label, single arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapy. Patients receive oral palbociclib 125mg daily for 21 days followed by a 7-day break. The primary endpoint was the progression-free survival (PFS) rate at 6 months (H0 = 30% vs H1 = 48%). Results: Between August 2017 and October 2019, 48 patients were enrolled. The median number of previous chemotherapy was 1 (range: 1-4) and 21 (43.7%) of 48 patients received thymectomy. By WHO classification, Type A (n = 1), Type B1 (n = 2), Type B2 (n = 8), Type B3 (n = 13), Type C (n = 23), and unknown (n = 1). With medial follow-up of 14.5 months (range 0.8-38.2), the median cycle of palbociclib was 10 (range 1-40). The PFS at 6 months was 60% and the median PFS was 11.0 months (95% CI: 4.6-17.4). Six of 48 patients (12.5%) achieved partial response. The median overall survival was 26.4 months (95% CI: 17.4-35.4). The most common adverse events of any grade included neutropenia (62.5%), anemia (37.5%) and thrombocytopenia (29.1%). Conclusions: Palbociblib monotherapy is well tolerable and encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy. Updated results will be presented. Clinical trial information: NCT03219554.
Abstract Purpose: Although both gBRCA1/2 mutations are known to increases incidences of breast and ovarian cancer by abruption in homologous recombination pathway, gBRCA1 mutant mainly present with a molecular subtype of triple negative breast cancer (TNBC) and gBRCA2 with hormone receptor (HR) positive which we have little understanding regarding the underlying pathophysiology. In this study, we have comprehensively analyzed clinical characteristics and somatic mutation in gBRCA1/2 mutant patients. Methods: Patients with gBRCA mutation tested (n=2720) in Samsung Medical Center between Jan 2007 to Oct 2018 were retrospectively reviewed. 386 patients were identified as gBRCA mutant and follow-up period less than 2 years (n=105), insufficient clinical data (n=22) and no surgical treatment (n=6) were excluded. Total of 259 patients, gBRCA1 (n=128), gBRCA2 (n=126) and both gBRCA1/2 mutation (n=5), were analyzed. Among the study population, 46 patients had deep target sequencing data with 40 patients also available for matched transcriptome outcome. Results: Median age was 40 years old (range 23-68). Patients were mostly under pre-menopausal status (81.2%) with invasive ductal carcinoma pathology (86.2%). Initial stage at diagnosis were stage 0 (4.7%), 1 (30.3%), 2 (40.6%) and 3 (24.4%). A novel mutation was observed in 16.9% of the study population and frameshift (44.9%) and nonsense (31.5%) mutations were predominant. Molecular subtypes were as follows: HR-positive (n=125, 49.2%), HR/HER2 positive (n=10, 3.9%), HER2 positive (n=3, 1.2%) and TNBC (n=116, 46.7%). TNBC was observed mostly in gBRCA1 mutant patients (71.9% vs. 19.1%) and HR-positive in gBRCA2 mutant patients (76.2% vs. 22.7%). Sixty-seven patients (26.4%) experienced disease recurrence and median time to recurrence were 145.0 months (95% confidential interval 107.3-170.2). Looking into co-altered somatic mutation using target sequencing (n=45), notably, alteration in other DNA-damage response pathway-related genes, such as TP53 (60%), ATR (27%), CHEK2 (20%), MSH6 (20%), were identified. Evaluated for mutual exclusivity, only gBRCA2 was significantly (P<0.05) exclusive with CDH2, KDM5A, GNA, TGFBR2, MAP3K1, MLL3, TP53. Mean tumor mutation burden was 13.05 per mega bases with no difference between gBRCA1 and gBRCA2mutant. Conclusions: From our dataset, we have witnessed similar clinical characteristics but the difference in molecular subtype between gBRCA1/2 mutant. Despite the fact that both gBRCA1/2 mutations disrupt the homologous recombination pathways, this study provides early evidence regarding the hypothesis that difference in co-occurred somatic alteration between gBRCA1/2 lead to different carcinogenesis mechanism which consequences different molecular subtype. Detail analyses using paired transcriptome result will be presented in the poster. Citation Format: Sehhoon Park, Eunjin Lee, Seri Park, Sohee Lee, Joon Young Hur, Sang Eun Yoon, Kangkook Lee, Jang Ho Cho, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Woong-Yang Park, Yeon Hee Park. Clinical characteristics and combined somatic mutation using target sequencing among breast cancer patients with germline BRCA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3502.
Metachronous brain-only oligorecurrence in patients with non-small cell lung cancer (NSCLC) is a rare event with favorable prognosis, but the clinical outcome has not been fully determined. We retrospectively analyzed clinical outcomes and prognostic factors in metachronous brain-only oligorecurrence in patients with NSCLC who underwent definitive treatment.We reviewed 4,437 NSCLC patients without oncogenic driver mutations who underwent definitive treatment between 2008 and 2018. Among them, we identified 327 patients who developed 1 to 5 brain metastases with or without systemic metastasis. Of the 327 patients, 71 had metachronous brain-only oligorecurrence without extracranial progression and were treated with local therapy to the brain. Overall survival (OS), progression-free survival (PFS), and prognostic factors affecting OS were analyzed.The median OS was 38.9 months (95% confidence interval [CI], 21.8 to 56.1 months) in 71 patients. The 2-year OS rate was 67.8% and the 5-year OS rate was 33.1%. The median PFS was 25.5 months (95% CI, 12.2 to 14.4 months). The longest surviving patient had a survival period of 115 months. Through multivariate analysis, Eastern Cooperative Oncology Group ≥ 1 (hazard ratio, 5.33; p=0.005) was associated with poor survival. There was no significant difference in OS between patients with local therapy and those with local plus systemic therapy (18.5 months vs. 34.7 months, p=0.815).Metachronous brain-only oligorecurrence NSCLC patients who underwent definitive treatment experienced long-term survival with local therapy, highlighting the unique patient population. The role of systemic chemotherapy in this patient population requires further investigation.
Background Immune checkpoint inhibitors (ICIs) are an essential treatment for non-small cell lung cancer (NSCLC). Currently, the tumor-related intrinsic factors in response to ICIs have mostly been elucidated in tissue samples. However, tissue immune status and changes in the immune microenvironment can also be reflected and monitored through peripheral blood. Methods Single-cell RNA and T cell receptor (scTCR) sequencing were conducted using peripheral blood mononuclear cells (PBMCs) from 60 patients with stage IV NSCLC. Those samples were prospectively acquired from patients treated with anti-PD(L)-1 therapy for advanced lung cancer. Based on the clinical outcomes, samples were classified as durable clinical benefit (DCB) and non-durable clinical benefit (NCB). The samples constituted paired longitudinal samples, consisting of pre-treatment and on-treatment. Additionally, PBMC samples from 60 healthy donors from the Asian Immune Diversity Atlas project were used as a control. Results The dynamic changes in major cell types between pre-treatment and on-treatment PBMCs were associated with an increase in proliferating T cells and NK cells in both DCB and NCB groups. Among T cell subtypes, effector memory CD8 + T cells (CD8 + T EM _GZMK_PDCD1) were increased after ICI treatment in both DCB and NCB. From the lineage trajectory analysis, effector memory CD8 + T cells resided at the bifurcation point, which has the potential to differentiate into lineages with precursor exhausted CD8 + T cells (CD8 + T CM cells) assumed to be related to the ICI response. From the scTCR-seq, effector memory CD8 + T cells along with T cells recognizing unknown antigen expanded and composed of novel clones skewed toward dysfunctional status, especially in on-treatment samples of the DCB group. The extent of immunophenotype conversion capabilities of the TCR with effector memory CD8 + T cells showed remarkable variation in the on-treatment sample in the DCB group. Conclusion A transitioning T cell subtype identified in PBMCs might be related to the prolonged ICI response. From our study, expansion of effector memory CD8 + T cells with novel TCRs in PBMCs after ICI treatment could contribute to a better clinical outcome in patients with NSCLC. This proof-of-concept research strengthens the use of non-invasive PBMCs in studying systemic changes of immune reactions related to the ICI treatment.
<p>Figure S5. Heatmap plot of gene expression profile between samples from patients with gBRCA1 and gBRCA2 mutations showing the top 20 ranked genes.</p>
<div>Abstract<p>gBRCA1/2 mutations increase the incidence of breast cancer by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 breast cancer have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 breast cancer. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 (<i>n</i> = 128) and gBRCA2 (<i>n</i> = 126) mutations were analyzed. Within this population, deep target sequencing and matched whole-transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of patients with breast cancer with wild-type gBRCA was used to compile a target sequencing (<i>n</i> = 195) and WTS (<i>n</i> = 137) reference dataset. Three specific mutation sites, p.Y130X (<i>n</i> = 14) and p.1210Afs (<i>n</i> = 13) in gBRCA1 and p.R294X (<i>n</i> = 22) in gBRCA2, were comparably frequent. IHC subtyping determined that the incidence of triple-negative breast cancer was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor–positive breast cancer was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with <i>PIK3CA</i> somatic mutations (<i>P</i> < 0.05), and gBRCA1 frequently cooccurred with <i>TP53</i> somatic mutations (<i>P</i> < 0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of <i>AR, ESR1</i>, and <i>PGR</i> was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 breast cancer have similar clinical characteristics, but they have different molecular subtypes, coaltered somatic mutations, and gene expression patterns.</p>Implications:<p>Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.</p></div>
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