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Comparison of solid tissue sequencing and liquid biopsy: Identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas [Meeting Abstract]

Allison, D; Jour, G; Park, K; DeLair, D; Moreira, A; Snuderl, M; Cotzia, P
Background: Molecular screening for therapeutically targetable alterations is considered standard of care in the management of non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. This has led to the development of "liquid biopsies": Plasma-based Next Generation Sequencing (NGS) tests that use circulating tumor DNA as a substrate to identify relevant targets. In this study, we sought to determine the level of agreement between the two tests as they are used in clinical practice and to investigate the utility of concurrent plasma/tissue testing.
Design(s): We identified 47 cases of lung adenocarcinoma diagnosed over the past 2 years, who received concurrent testing (within 24 weeks) with both our institution's tissue (DNA and RNA based) NGS assay and a commercial plasma-based NGS assay. The results were reviewed to establish concordance in the identification of mutations or fusions deemed clinically relevant or for which a targeted therapy was available.
Result(s): Patients in our cohort represented both new diagnoses (31 cases, 66%) and disease progression on treatment (16 cases, 34%). The majority (83%) had stage 4 disease. Tissue NGS identified clinically relevant mutations in 39 cases (83%), including in 14 (88%) of the previously treated cases. By comparison, plasma NGS identified clinically relevant mutations in 20 cases (43%, p<0.001), including 6 treated cases (38%, p=0.01). Tissue NGS identified therapeutic targets in 55% of cases and 75% of previously treated cases; while plasma NGS identified targets in 28% and 25% respectively (p<0.001 and p=0.01 respectively). All clinically relevant mutations identified by plasma NGS were also detected by tissue NGS, while plasma NGS detected only 51% those identified by tissue NGS. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, KRAS, and ROS1 (Table 1).(Table presented)
Conclusion(s): Tissue NGS detects more clinically relevant alterations and therapeutic targets compared to plasma NGS, especially in the post-treatment setting, suggesting that tissue NGS should be the preferred method for molecular testing of lung adenocarcinoma. Additionally, all clinically relevant mutations identified by plasma NGS were also detected by tissue NGS, suggesting that tissue/plasma cotesting provides little additional benefit over tissue NGS alone. Plasma NGS can detect clinically relevant targets, and still plays an important role when tissue testing is impractical or not possible
ISSN: 1530-0285
CID: 4472632

How close is too close? molecular heterogeneity in intraprostatic collision tumors [Meeting Abstract]

Alnajar, H; Fontugne, J; Park, K; Ye, H; Beg, S; Siddiqui, J; Chinnaiyan, A; Barbieri, C; Rubin, M; Mosquera, J M
Background: Radical prostatectomy (RP) specimens often harbor multiple prostate cancer (PCa) nodules that are spatially separated. These tumor nodules can be molecularly heterogeneous. The current practice is to separate the dominant tumor nodule histologically, usually the one with highest Gleason score and/or largest size, and assign individual Grade Groups. There is no current recommendation to use ancillary studies to further differentiate theses nodules molecularly. Current assays that interrogate biopsies and RP assume that only one tumor is present in the tissue sample. The aim of this study was to establish the frequency of molecularly heterogeneous tumors within one spatially distinct nodule in RP specimens.
Design(s): 269 RP specimens - Grade Groups 1 to 5 - collected prospectively from three participating institutions of the Early Detection Research Network (EDRN) trial were reviewed. Dual ERG/SPINK1 IHC was performed on all tumor foci. The nodule with the highest Grade Group score was defined as dominant. In case of multiple nodules with the same Gleason score, the largest one was considered as the dominant. A "collision tumor" was defined as having two molecular subtypes within one spatially distinct nodule. The presence of cribriform pattern and intraductal carcinoma (IDC-P), both features associated with unfavorable outcome were also recorded.
Result(s): IHC slides from 260 RP cases were available for analysis. 25 collision tumors (9.6%) were identified (Table), of which, 48% included nodules with different grade groups. The most common collision being between the ERG+/SPINK1- and ERG-/SPINK1-(64%) (Fig. 1). The frequency of cribriform morphology and IDC-P when applicable was 15% and 12%, respectively. Finally, we found ERG+ benign-appearing glands in 8% of total cases (Fig. 2), which were present close to ERG+ tumors in only 15% of these cases. (Table presented)
Conclusion(s): Collison tumors of two molecular subclasses of prostate cancer are not uncommon, affecting the final Grade Group in about half of these cases. Ancillary studies - e.g. dual I
ISSN: 1530-0285
CID: 4472652

A molecular comparison of intraductal carcinoma of the prostate, associated invasive high grade prostatic carcinoma, and lymph node metastases by copy number alteration analysis [Meeting Abstract]

Park, K; Robinson, B; Ho, M; Viswanathan, K; Gogineni, S; Miguel, Mosquera J; Barbieri, C; Lotan, T; Loda, M; Mathew, S; Borczuk, A; Khani, F
Background: Intraductal carcinoma of the prostate (IDC-P) is considered a harbinger of aggressive disease and is associated with poor clinical prognosis. It is believed to represent retrograde spread of high grade invasive carcinoma into the prostatic ductular system, although there is minimal molecular evidence to support this theory. We aimed to further study the molecular evolution of IDC-P and how it relates to invasive carcinoma and tumor metastases.
Design(s): Radical prostatectomy specimens where the dominant tumor nodule had an abundant IDC-P component (>20%) were identified. Cases were reviewed by GU pathologists to annotate areas of IDC-P and high grade (> Grade Group 3) invasive carcinoma (HGIC) in ten selected cases. Five cases also had lymph node metastases. DNA was extracted from each macrodissected area and subjected to copy number alteration (CNA) analysis using the OncoScan Assay (Affymetrix). CNA was performed using the Oncoscan Nexus Express software v3.0. FISH was utilized to validate particular key findings with centromeric probes for chromosomes 8, 10, and 12.
Result(s): Similar 8p and 10q losses were seen in both the IDC-P and high grade invasive carcinoma in all 10 cases, and 8q gains were also seen in both areas in 7 cases. In 3 of 10 cases, the IDC-P component showed copy number gains spanning the entire genome in the regions without chromosomal losses, and in one of these cases, the HGIC area showed similar whole genome gains. In addition, those non-amplified regions of chromosomal loss are common to the HGIC and IDC-P components, including both deletion and uniparental disomy. In 2 of 5 cases, the lymph node metastases also showed a copy number profile that was more similar to IDC-P than it was to HGIC, including one case with whole genome gain. Whole genome gains were further validated by FISH, which showed a mixed population of cells containing a range of 2-5 copies of each of the selected chromosomes.
Conclusion(s): IDC-P and invasive high grade carcinoma are clonally related, as evidenced by similar focal chromosomal gains and losses. Whole genome gains are seen in IDC-P, and share the same loss pattern with HGIC. This suggests a clonal evolution from invasive carcinoma to IDC-P in some cases. The copy number alteration pattern of the lymph node metastases is sometimes more similar to IDC-P than it is to HGIC, suggesting that the tumor clones present within IDC-P have metastatic potential
ISSN: 1530-0285
CID: 4472692

Concordance of p53 immunohistochemistry and tp53 mutation status in endometrial cancer [Meeting Abstract]

Da, Cruz Paula A; DeLair, D; Fix, D; Soslow, R; Park, K; Chiang, S; Reis-Filho, J; Zehir, A; Murali, R; Makker, V; Cadoo, K; Mueller, J; Leitao, M; Abu-Rustum, N; Aghajanian, C; Weigelt, B
Background: For the clinical identification of the four molecular subtypes of endometrial cancer (EC), which were originally identified using whole-exome sequencing, surrogates employing immunohistochemistry (IHC) have been implemented. In this surrogate, p53 IHC is used to identify 'copy-number high'/ p53 abnormal ECs. We sought to define the concordance of p53 IHC and TP53 mutation status in ECs.
Design(s): Patients with newly diagnosed primary EC were prospectively consented to an IRB-approved protocol. ECs were subjected to p53 and DNA mismatch repair (MMR) protein IHC and to massively parallel sequencing targeting 410-468 cancer-related genes. ECs were classified based on POLE mutation status and MMR and p53 IHC into the four molecular subtypes: POLE (ultramutated), MMRdeficient, copy-number low (endometrioid) and copy-number high (serous-like). Concordance between p53 IHC and somatic TP53 mutation status was defined using Cohen's Kappa.
Result(s): 175 ECs were included in this study (116 endometrioid, 17 serous, 11 carcinosarcoma, 13 mixed, 6 clear cell, 7 dedifferentiated, 5 other). 41 (23%) ECs demonstrated aberrant p53 expression by IHC, and of these 36 (88%) harbored a somatic TP53 mutation (Table). Of the 134 ECs with normal/ wild-type p53 protein expression by IHC, the majority of ECs (115; 86%) were molecularly concordant and did not harbor a somatic TP53 mutation (Table). The agreement between the two methods was 151/175 (86%), with a Kappa of 0.726 (good agreement). The sensitivity and specificity of p53 IHC for the detection of pathogenic TP53 mutations was 66% and 96%, respectively. In total, there were 24 (14%) discrepant cases, which had aberrant p53 IHC in the absence of a TP53 mutation (n=5) or a TP53 mutation but normal p53 protein expression patterns (n=19). Of the 19 TP53-mutant ECs with normal p53 IHC, 10 harbored nonpathogenic TP53 mutations, 3 harbored subclonal TP53 hotspot mutations, 3 had subclonal TP53 loss of function mutations, and only 3 had clonal TP53 hotspot mutations (Table). Discrepancies were primarily observed in ECs of MMR-deficient (9/19) or POLE (4/19) EC subtypes. (Table presented)
Conclusion(s): Our findings demonstrate a good concordance between p53 IHC and TP53 mutation status in EC. p53 IHC is a specific and fairly sensitive surrogate for pathogenic TP53 mutations. The type and clonality of TP53 mutations explain the vast majority of discrepancies between sequencing and IHC assessment of TP53
ISSN: 1530-0285
CID: 4472722

Can Gleason Grade be Reliably Assigned Based on the Perineural Focus of Adenocarcinoma? [Meeting Abstract]

Chen, Fei; Isaila, Bogdan; Parimi (Parini), Vamsi; Ren, Qinghu; Park, Kyung; Huang, Hongying; Deng, Fangming; Melamed, Jonathan
ISSN: 0023-6837
CID: 4048352

Integrated Expression (Chromogenic in situ Hybridization) of Long Noncoding RNAs (LncRNAs) Segregate Low Grade from Clinically Significant Prostate Cancer [Meeting Abstract]

Parimi (Parini), Vamsi; Xia, Yuhe; Mezzano, Valeria; Vasudevaraja, Varshini; Selvaraj, Shanmugapriya; Loomis, Cynthia; Moreira, Andre; Lee, Peng; Levy, David; Park, Kyung; Huang, Hongying; Ren, Qinghu; Deng, Fangming; Melamed, Jonathan
ISSN: 0023-6837
CID: 4048382

Expanding Therapeutic Options for Patients with Lung Adenocarcinomas Using Oncomine Comprehensive Panel [Meeting Abstract]

Park, Kyung; Tran, Hung; Feng, Xiaojun; Rubin, Marka; Fernandes, Helen
ISSN: 0023-6837
CID: 3133682

Expanding Therapeutic Options for Patients with Lung Adenocarcinomas Using Oncomine Comprehensive Panel [Meeting Abstract]

Park, Kyung; Tian, Hung; Feng, Xiaojun; Rubin, Mark A.; Fernandes, Helen
ISSN: 0893-3952
CID: 3133702

KRAS Mutation Is Highly Prevalent and Predicts Recurrence in Patients with Primary Invasive Mucinous Adenocarcinoma of the Lung [Meeting Abstract]

Kemel, Mohamed K.; Narula, Navneet; Park, Kyung; Stiles, Brendon M.; Port, Jeffrey L.; Fernandes, Helen; Altorki, Nasser K.
ISSN: 0893-3952
CID: 3150752

KRAS Mutation Is Highly Prevalent and Predicts Recurrence in Patients with Primary Invasive Mutinous Adenocarcinoma of the Lung [Meeting Abstract]

Kamel, Mohamed K.; Narula, Navneet; Park, Kyung; Stiles, Brendon M.; Port, Jeffrey L.; Fernandes, Helen; Altorki, Nasser K.
ISSN: 0023-6837
CID: 3151812