Tumor Genetic Profile Research Articles

RARE-23. NOVEL NF1 MUTATIONS IN TWO OCCURRENCES OF GLIOBLASTOMA MULTIFORM IN A PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare cancer predisposition syndrome in children. Its main associated tumor types include brain and CNS tumors, hematologic malignancies, intestinal polyps and colorectal tumors, and other malignancies. Tumor genesis within this population is highly complex and poorly understood. We describe a case of a patient with two occurrences of glioblastoma multiforme (GBM), each with unique NF1 mutations. The patient is a female with CMMRD who was first diagnosed with GBM of the right frontal lobe in 2015. She subsequently underwent gross total resection, radiation to the field and concomitant and maintenance therapy with Temozolomide and Everolimus, due to high suspicion for NF-1. Genetic studies didn’t show NF-1, instead revealing a diagnosis of CMMRD. Molecular testing of the GBM showed a high mutational burden and an NF1 mutation. Later, screening revealed stage IV colon cancer, for which she underwent subtotal colectomy, partial liver resection and chemotherapy. Molecular testing from the colon cancer found a hypermutant malignancy without mutations in NF1. Surveillance imaging detected a mass at the original site of her GBM, for which she had a resection. Notably, the genetic profile of the second tumor substantially different from the original tumor and the colon cancer sample, but had new mutations in NF-1. These findings highlight the significant variability in the genetic profiles of tumors in the context of CMMRD. It is also worth considering that NF1 is one of the first in a cascade of mutations leading to GBM in these patients.

S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma.

Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.

BIOM-41. GENETIC MARKERS CORRELATED WITH PROGRESSION-FREE SURVIVAL TIMES IN GLIOBLASTOMA PATIENTS UNDERGOING TREATMENT WITH TUMOR TREATING FIELDS

Abstract INTRODUCTION Despite advances in surgical approaches, followed by chemo-radiotherapy protocols, the overall prognosis for patients with glioblastoma remains poor. Clinical trials have demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall survival times when combined with standard chemotherapy. However, the response to TTFields varies across patients, and it is currently unclear why some patients show increased time to tumor progression with TTFields treatment while others do not. One possible answer lies in the biological diversity of the tumors themselves. Genetic alterations are known to impact survival times and chemotherapy sensitivity in glioblastoma, suggesting that certain markers may also predict responsiveness to TTFields. Here, we compare the genetic profile of primary glioblastoma tumors with progression times in patients receiving TTFields treatment. METHODS Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and a sample from their primary tumor resection was sent for FoundationONE CDx™ testing. Genetic alteration results, including mutation burden and copy number alterations, were then compared with clinical data and tumor progression times. RESULTS Mutations and/or copy number changes in genes that regulate cell growth/proliferation, apoptosis, and interactions with DNA were among the most common alterations observed in our cohort. For patients that recurred within 12 months, we found a common pattern of alterations that includes CDKN2A/2B co-deletion, MTAP deletion, and PIK3 mutations. This pattern was not observed in patients that recurred after 12 months. CONCLUSION The identification of genetic markers that predict treatment responsiveness may help direct patients toward optimal treatment options. Ongoing work is aimed at expanding our sample size, correlating these genetic markers with overall patient survival, and determining if this pattern of expression is specifically related to TTFields treatment response.

Invited Commentary: Radiogenomics Applied to Select Abdominal Tumors.

Invited Commentary: Radiogenomics Applied to Select Abdominal Tumors.

Genetic profiling of primary and secondary tumors from patients with lung adenocarcinoma and bone metastases reveals targeted therapy options

BackgroundPatients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens.MethodsFine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART).ResultsARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer.ConclusionOur findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.

Abstract 4264: Liquid biopsy and FFPE tissue based somatic BRCA1/2 variant screening in breast and ovarian cancer

Abstract Next generation sequencing (NGS) has widened its use since it provides highly precise and accurate genetic testing with reasonable costs in tumor genetic profiling from somatic materials such as FFPE (formalin fixed paraffin embedded) tissue and liquid biopsy [circulating cell free DNA (ccfDNA)]. It has a high value in differentiating treatment strategies especially in BRCA1/2 genomic profiling in breast and ovarian cancer. However, somatic BRCA1/2 testing still remains unclear algorithm versus germ-line testing approved in human genetics for many decades. Thus, we sum up our testing results in relation with clinical diagnosis. FFPE samples from 89 and 74 liquid biopsy samples from breast and/or ovarian cancer patients were collected and sequenced via the GeneReader NGS system for BRCA1 and BRCA2 genes. QCI-Analyze and QCI-Interpret bioinformatics tools were used for bioinformatics analyses. We detected 56 actionable variants in 48 patients (29.5%) out of 163 patients. The 46.4% (nvariant=26) of the mutations were detected in BRCA1 gene while 53.6% (nvariant=30) of them were in BRCA2 gene. The allele frequencies vary from 1.43% to 100% with an average of 43% in 89 FFPE tissue samples with the positivity rates of 30% (nsample=27) while the rate is 28.4% (nsample=21) in 74 liquid biopsy samples. Interestingly, 8 patients had more than one actionable variant and 5 of them had mutations both in BRCA1 and BRCA2 genes. To sum up, genetic testing for targeted treatments has become first-line clinical testing in cancer and taken its place in international guidelines. Thus, somatic testing to profile BRCA genes should be considered in breast and ovarian cancer algorithm since 5% percent of the patients additionally carry somatic actionable mutation with regarding 15% positivity in germ-line BRCA1/2 studies. Citation Format: Ibrahim Boga, Ozge Sonmezler, Atil Bisgin. Liquid biopsy and FFPE tissue based somatic BRCA1/2 variant screening in breast and ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4264.

Abstract A27: Fidelity of a PDX-CR model for bladder cancer

Abstract Current efforts for cancer drug discovery have predominantly been deterred by the lack of appropriate preclinical cancer models that recapitulate the characteristics of this complex disease. Patient-derived xenografts (PDXs) are widely recognized as a more physiologically relevant preclinical model than organoids and standard cell lines, and often resemble the original tumor histology, genetic profile, and gene-expression patterns. Despite these benefits, PDX models are limited by their variable engraftment rate, lack of sustained growth in vitro, low throughput for drug screening, lower amenability to experimental manipulation, and high cost. In this study, we utilized conditional reprogramming (CR) technology to generate four CR cell (CRC) lines from bladder cancer PDXs. The CR cells were then employed to evaluate the genetic status and drug sensitivity and compared with the parental PDX tumors. All the established CRC lines maintained parental mutations and allele frequencies without clonal drift. Moreover, the drug responses of the parental PDX tumors in vivo were retained in the established CRC lines in vitro. Altogether, CR technology offers the ability to generate cell lines and expand PDX cells without compromising fundamental biologic properties of the model, thereby allowing for in vitro use to reduce animal usage, variability, and study cost. Perhaps more importantly, the CR cell lines established here can be used for personalized high-throughput drug screening as well as for studying drug-resistance mechanisms. Citation Format: Abdul M. Mondal, Ai-Hong Ma, Guangzhao Li, Ewa Krawczyk, Lu Jie, Richard Schlegel, Chong-Xian Pan, Xuefeng Liu. Fidelity of a PDX-CR model for bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A27.

Plasma DNA as a "liquid biopsy" incompletely complements tumor biopsy for identification of mutations in a case series of four patients with oligometastatic breast cancer.

Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a "liquid biopsy" for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations. Blood and biopsies of 1-3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA. Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem. The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling. Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).

Abstract IA19: The Drug Rediscovery Protocol: Getting the most out of approved drugs

Abstract Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anticancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Therefore, we initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anticancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. We use a stepwise approach per cohort of first 8 patients, and when at least one patient experienced clinical benefit that cohort expands to 24 patients. Presently, we have reviewed >1,100 submitted patient cases and included and treated >500 patients. We found an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 29% although the formal analysis is per cohort. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab or durvalumab, and tumors with HRD treated with olaparib. Our results have led to a personalized reimbursement model for nivolumab in patients with MSI tumors that is supported by all regulatory parties. The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Citation Format: Emile E. Voest. The Drug Rediscovery Protocol: Getting the most out of approved drugs [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr IA19.

Molecular matching and treatment strategies for advanced stage lung cancer at Dartmouth-Hitchcock Medical Center: A three-year review of a Molecular Tumor Board

Matching of actionable tumor mutations with targeted therapy increases response rates and prolongs survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population.Tumor DNA was sequenced using a 50-gene targeted next-generation sequencing panel. Cases were evaluated by a multidisciplinary MTB who suggested a course of treatment based on each patient’s molecular findings.During a three-year period, 21 lung cancer patients were presented at the MTB. All patients lacked common activating EGFR mutations and ALK rearrangements. One patient had Stage IIIb disease; all others were Stage IV; 18 patients had received ≥1 prior line of therapy (range 0–5). Suggestions for treatment with a targeted therapy were made for 19/21 (90.5%) patients, and four patients (21%) underwent treatment with a targeted agent, two as part of a clinical trial. Identified barriers to treatment with targeted therapy included: ineligibility for clinical trials (n ​= ​2), lack of interest in study/distance to travel (n ​= ​2), lack of disease progression (n ​= ​2), poor performance status (n ​= ​5), decision to treat next with immunotherapy (n ​= ​3), and unknown (n ​= ​1).For the majority of lung cancer patients, the MTB provided recommendations based on tumor genetic profiles. Identified barriers to treatment suggest that presentation to the MTB at earlier stages of disease may increase the number of patients eligible for treatment with a genetically informed targeted agent.

Genomic profiling of sporadic liver metastatic colorectal cancer.

Sporadic colorectal cancer (sCRC) is the third leading cause of cancer death in the Western world. Approximately, a quarter of sCRC patients present metastatic dissemination at the moment of diagnosis, the liver being the most frequently affected organ. Additionally, this group of CRC patients is characterized by a worse prognosis. In the last decades, significant technological developments for genome analysis have fostered the identification and characterization of genetic alterations involved in the pathogenesis of sCRC. However, genetic alterations involved in the metastatic process through which tumor cells are able to colonize other tissues with a different microenvironment, still remain to be fully identified. Here, we review current knowledge about the most relevant genomic alterations involved in the liver metastatic process of sCRC, including detailed information about the genetic profile of primary colorectal tumors vs. their paired liver metastases.

Concordance of next-generation sequencing between tissue and liquid biopsies in non-small cell lung cancer.

e21547 Background: While genetic profiling has become standard of care for patients diagnosed with non-small cell lung cancer (NSCLC), next-generation sequencing (NGS) provides a wealth of information about targetable mutations. Advances in genetic testing have led to sequencing platforms that utilize tissue itself or extracellular circulating tumor DNA in the blood, known as a “liquid biopsy.” Methods: We identified 55 patients with NSCLC who had undergone both tissue and liquid biopsy, using Foundation One and Guardant 360 at the University of Miami / Sylvester Comprehensive Cancer Center between January 2016 and December 2018, and performed retrospective analysis to determine patient characteristics as well concordance between different NGS platforms. Results: In our patient population, 34% of patients had never smoked prior to diagnosis, while 22% had more than a 30 pack-year smoking history. 64% of patients had no treatment prior to initial NGS. 40% of patients had both testing done essentially simultaneously, while 60% of patients had one test done after disease progression. Of these patients, therapy was changed as a result in 73%. Median number of days between tests was 21 days, with 56% of testing done within 90 days of the previous testing. Nine patients had an additional Foundation One tissue NGS performed. Concordance across all genes tested in both platforms was 98 ± 0.2%. Concordance with consideration of genetic alterations detected in both assays was 24.5 ± 3.0%. The median number of gene alterations determined by Foundation One testing was 4 (range 1-9), while the median for gene alterations detected by Guardant 360 was 3 (range 1-13). The median number of variants of unknown significance (VUS) was 10 (range 5-25). Conclusions: Our analysis indicates a role for both tissue-based and circulating tumor DNA-based NGS for determination of targetable mutations and thus appropriate treatment regimens. Low levels of concordance are potentially related to post-treatment changes in the tumor genetic profile as well as evolution in the testing itself.

Exploring the Cancer Genome Atlas (TCGA) for the molecular profile of young onset colorectal cancers.

3548 Background: Colorectal cancer (CRC) incidence and mortality has been declining, in part due to increased implementation of screening, but the incidence among patients under 50 (young onset, YO) is increasing at a rate of 2% per year. The cause of this increasing incidence remains poorly understood, but differences in mutation profiles can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Genomic and clinical data for 488 TCGA CRC patients was used to evaluate differences in genetic alterations between YO and patients over 50. Chi-squared tests were used to determine differences in somatic mutation frequency in critical pathways implicated in CRC: DNA MMR, P53, WNT, RAS-MAPK, PI3K/AKT/mTOR, and TGF-B pathways. For 85 of the patients, proteomic data via RPPA was also available and analyzed. Results: The average age of included patients was 66 (SD 12.8). 76 (12.2%) were under 50 at time of diagnosis. When comparing YO with those over 50, there were no differences in microsatellite instability, histologic type (adeno or mucinous), location (colon or rectal), tumor size, or metastasis. YO patients were more likely to have nodal involvement (p = 0.007) and higher histological grade (p = 0.022). YO patients were more likely to have mutations in the MMR pathway (43% vs 23%, p = 0.002) and the PI3K/AKT/mTOR pathway (70% vs 54%, p = 0.024). Specifically, YO were more likely to have mutations in MSH2 (7% vs 1%, p = 0.001), MSH6 (24% vs 7%, p = 0.000); ATM (46% vs 30%, p = 0.015); FZD10 (7% vs 2%, p = 0.007); ERBB2 (15% vs 7%, p = 0.027); PIK3R1 (20% vs 9%, p = 0.014), PTEN (61% vs 35%, p = 0.000), and TGFBR2 (13% vs 4%, p = 0.004). When looking at proteomic data, YO were more likely to have decreased expression of MSH2 (p = 0.003) and MSH6 (p = 0.005). Conclusions: Patients with YO CRC are more likely to have somatic mutations in genes involved in the MMR pathway and the PI3K/AKT/mTOR pathway. Specifically, in MSH2, MSH6, ATM, FZD10, ERBB2, PIK3R1, PTEN and TGFBR2. When including proteomic data, significant differences were only seen in expression of MSH2/6. Some of these genes (e.g. ERBB2/HER2) are targets for existing therapies, and others are being actively investigated as potential therapeutic targets. Establishing differences in tumor genetic profiles is a first step towards understanding the increase in YO CRC, and simultaneously identifies targets for therapy. However, because of post-transcriptional changes (e.g. RNAi, methylation), genetic profiling alone cannot always reliably establish differences in protein expression, and thus therapy targets.

Distinct genomic profiles of 589 Chinese early-stage breast cancer.

552 Background: Extensive efforts by The Cancer Genome Atlas (TCGA) Network had provided much of our current understanding of the molecular profile of various solid tumors including breast tumors; however, Asian patients were underrepresented in this cohort. In this study, we aimed to elucidate the comprehensive genetic alteration profile of early-stage breast tumors among Chinese patients. Methods: Surgical tissue samples from 589 Chinese women with stage I-III breast cancer with various histology and molecular subtype consecutively diagnosed at Guangdong Provincial People’s Hospital were sequenced using a panel targeting 520 cancer-related genes spanning 1.64Mb of the human genome. Clinical and genomic data from our cohort was compared with publicly-available data from 1,046 stage I-III breast cancer patients from the TCGA dataset. Results: Based on the analysis of the genetic alteration profile from our cohort, at least one genetic alteration was observed from 98% of the tumor samples, with TP53 (47%), PIK3CA (45%), ERBB2 (30%), and CDK12 (18%) as the most commonly altered genes. The most common genetic alteration types were copy number amplification (43.6%) and missense mutations (36.8%). As compared with the TCGA dataset, our cohort is mostly composed of women 50 years and younger (59.1% vs. 30.4%, P< 0.001), with significantly fewer patients with lobular carcinoma histology (2.4% vs. 19.0%, P< 0.001), and significantly more patients with pathologic stage I tumors (23.3% vs. 17.3%, P= 0.012). Consistently, genetic alterations detected from our cohort affected genes involved in PI3K (63% vs. 56%, P= 0.009) and cell cycle (23% vs. 35%, P< 0.001) pathways, with statistically different genetic alteration rates as compared with the TCGA dataset. Comparison of genetic alteration profile between the two cohorts revealed that our cohort had more frequent genetic alterations in genes including PIK3CA ( P< 0.001), TP53, particularly in hotspot mutations Q192* ( P< 0.001) and A307V/del ( P= 0.02), and ERBB2 amplification ( P< 0.001). Conclusions: Our study contributes to the understanding of the key pathways and specific genetic alterations harbored by Chinese patients with early-stage breast cancer that could potentially be developed as markers of treatment response to targeted therapeutics.

Investigation of triple negative breast cancer rates in women diagnosed with breast cancer in Trinidad and Tobago.

e19005 Background: According to the WHO/PAHO, Trinidad and Tobago (T&T) has the 2nd highest breast cancer mortality rate in the Caribbean region. In T&T, citizens of African descent make up about 36.8% of the T&T population, with 24.8% being of East Indian ancestry, and 32.4% identifying as having mixed heritage. In the United States, it has been showed that African American women, despite being diagnosed less often, have an earlier onset of breast cancer with less favorable clinical outcomes. One of the factors studied has been the higher frequency of triple negative breast cancer (TNBC) in African American women particularly when these patients are diagnosed at a younger age. Notably, a large proportion of breast cancer cases in T&T appear to occur at a young age, with nearly 36% of them being diagnosed under the age of 50. However, breast cancer tumor phenotypes have not been well studied. Therefore, we sought to investigate the distribution of tumor hormone receptor markers in the T&T breast cancer population. Methods: At the National Radiotherapy Center, T&T’s main oncology unit, we investigated breast cancer patients born in T&T using paper chart reviews. We collected information about their demographics, personal breast cancer diagnosis, tumor hormone receptor status and germline genetic testing results. Results: So far, we reviewed 90 patient charts, and in our sample, 33.3% (30/90) had TNBC. This is higher than the rates in the US where TNBC accounts for 10-20% of breast cancer patients, and of those TNBC cases, 10.6% have BRCA 1 or BRCA 2 mutations. In our T&T sample, of those with TNBC, 23.3% (7/30) had a HBOC mutation (5 BRCA, 1 TP53 and 1 PTEN). Average diagnosis age of TNBC cases reported in our sample was 45.7 years. In our sample, 52.2% (47/90) identified as having African ancestry, 37.8% (34/90) identified as having East Indian ancestry and 10% (9/90) identified as Mixed. Of the patients with TNBC, 63.3% (19/30) were of African ancestry, 30.0% (9/30) were of East Indian ancestry and 6.7% (2/30) identified as Mixed. Conclusions: Therefore, our sample results suggest that there is a significant portion of the breast cancer cases being TNBC in the T&T population, particularly in citizens with African ancestry. As we continue to finalize the incoming data, we hope to draw associations between tumor pathology, clinical presentation and genetic profiles. However, these initial results demonstrate the need to study tumor pathology within the T&T population, as this could lead to improved clinical and screening guidelines specific to T&T citizens.

Clinical, genetic, and pathologic determinants of prostate cancer brain metastasis.

5536 Background: Prostate cancer (PCa) brain metastasis (BM) is a rare event occurring in 0.16-0.63% of PCa patients. Current clinical data on this phenomenon is limited to small retrospective cohorts and our understanding of it is incomplete. We sought to identify clinical and molecular predictors of PCa BM in a large retrospective cohort treated at our institution. Methods: Men diagnosed with Pca from 1995-2017 with ≥6 months of follow-up were included. Data was collected on clinical and tumor characteristics at diagnosis, PCa treatment, brain and bone metastasis, and tumor genetic profile based on Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) analysis. Results were examined using Kyoto Encyclopedia of Genes and Genome (KEGG) pathway. Genes altered in ≥5% of patients were included. Time to brain metastasis (TTBM) and overall survival (OS) were analyzed with univariable (UVA) Fine-Gray competing risks regression and Cox proportional hazards. TTBM and OS were landmarked at 6 months after PCa diagnosis. False discovery rate (FDR) adjustment accounted for multiple comparisons. Results: 27,887 men met inclusion criteria; 74 developed BM. Clinical variables associated with increased hazard of TTBM in UVA were high-clinical and pathologic-* (p<.001) T stage, node-positive disease* (p<.001), primary* and total* Gleason (p<.001), receipt of abiraterone* (HR 52.51 (95% CI 7.1-389.8), p<.001), and receipt of leuprolide* (HR 3.0 (95% CI 1.7-5.4), p<.001). Tumor alterations associated with BM include mutations in BRCA2 (HR 2.94 (95% CI 1.1-8.0), p=.04), MYC (HR 3.41 (95% CI 1.2-9.5), p=.02), PTEN (HR 2.90 (95% CI 1.2-6.9), p=.02), RB1 (HR 3.09 (95% CI 1.2-8.0), p=.02), and pathways involving homologous recombination (HR 2.70 (95% CI 1.1-6.4), p=.02), Fanconi anemia* (HR 4.22 (95% CI 1.8-10.0), p<.001), Ras signaling* (HR 4.6 (95% CI 1.5-13.9), p=.006), mTOR signaling (HR 2.88 (95% CI 1.1-7.9), p=.04), VEGF signaling* (HR 3.60 (95% CI 1.5-8.8), p=.005), and GnRH signaling* genes (HR 3.93 (95% CI 1.6-9.6), p0.003). Variables associated with increased hazard of BM after FDR adjustment are denoted with an asterisk. Variables associated with reduced OS after FDR adjustment were neuroendocrine or blastoma histology, node-positive disease, high-T stage, high initial PSA, receipt of leuprolide, and alterations in AR, TP53, and CDK12 genes. Conclusions: PCa BM is significantly associated with high-stage and grade disease, receipt of androgen deprivation agents such as abiraterone and leuprolide, and alterations in the Fanconi anemia, Ras, VEGF, and GnRH pathways.

Genetic profile of advanced thyroid cancers in relation to distant metastasis.

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit-related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor-metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Current Perspectives on Circulating Tumor DNA, Precision Medicine, and Personalized Clinical Management of Cancer.

Circulating tumor DNA (ctDNA) has recently emerged as a minimally invasive "liquid biopsy" tool in precision medicine. ctDNA-genomic DNA fragments that are released into the bloodstream after the active secretion of microvesicles or tumor cell lysis reflects tumor evolution and the genomic alterations present in primary and/or metastatic tumors. Notably, ctDNA analysis might allow the stratification of patients, the monitoring of the therapeutic response, and the establishment of an opportunity for early intervention independent of detection by imaging modalities or clinical symptoms. As oncology moves towards precision medicine, the information in ctDNA provides a means for the individual management of the patient based on their tumor's genetic profile. This review presents current evidence on the potential role for ctDNA in helping to guide individualized clinical treatment decisions for patients with melanoma, castration-resistant prostate cancer, breast cancer, metastatic colorectal cancer, and non-small cell lung cancer.

Predictive value of tumor genetic alteration profiling for chemotherapy and EGFR-TKI treatment in advanced NSCLC.

Previous studies have suggested that a variety of tumor driver genetic alterations affected the treatment efficacy of chemotherapy and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). The present study aimed to investigate the association between the tumor genetic alteration landscape and the treatment outcome of first-line chemotherapy and EGFR-TKIs in advanced NSCLC. A total of 94 patients with advanced NSCLC were recruited. All patients received first-line chemotherapy and/or EGFR-TKIs (either first- or second-generation EGFR-TKI, or third-generation EGFR-TKI) alone or sequentially. Prior to chemotherapy and/or EGFR-TKI treatment, plasma, effusion and/or tumor tissues from the included patients were subjected to next-generation sequencing, targeting 59 genes. The results indicated that the positive genetic alteration status prior to first-line chemotherapy was associated with prolonged progression-free survival (PFS) time compared with the negative status [9.1 vs. 4.0 months; hazard ratio (HR)=6.68; 95% CI, 2.25–19.82; P=0.001). Furthermore, patients with EGFR activating mutation harboring concomitant alterations exhibited a shorter PFS (11.1 vs. 7.4 months; HR=2.14; 95% CI, 1.03–4.44; P=0.04) and overall survival (OS) time [not reached (NR) vs. 32.8 months; HR=4.30; 95% CI, 1.41–13.16; P=0.01] than those without concomitant alterations, with first- and second-generation EGFR-TKI treatment. Similarly, patients with T79M mutation harboring concomitant alterations exhibited a shorter PFS (15.6 vs. 3.6 months; HR=9.48; 95% CI, 2.29–39.28; P=0.002) and OS time (NR vs. 32.8 months; HR=4.85; 95% CI, 1.16–20.29; P=0.03) with osimertinib treatment. Taken together, the results demonstrated that positive genetic alteration status predicted greater efficacy of first-line chemotherapy, while concomitant genetic alterations were associated with poor treatment outcome for first- or second-generation EGFR-TKI and third-generation EGFR-TKI treatment.

The Lack of Evidence for an Association between Cancer Biomarker Conversion Patterns and CTC-Status in Patients with Metastatic Breast Cancer.

Circulating tumor cell (CTC) detection is a prognostic factor in the metastatic breast cancer (MBC) setting. Discrepancies in primary (PT) and metastatic tumor (MT) genetic profiles are also of prognostic importance. Our study aimed to compare the CTC statuses and prognoses between those with subtype stable MBCs and MBCs with specific biomarker conversions. The study enrolled 261 MBC patients, treated at the National Center for Tumor Diseases, Heidelberg, Germany in a five-year period. All underwent PT and MT biopsies and subsequent CTC enumeration before the initiation of systemic therapy. ER and HER2 statuses of the PTs and MTs were determined and progression free survivals (PFSs) and overall survivals (OSs) were recorded. We compared CTC statuses, CTC counts, PFSs and OSs between subgroups of patients with different receptor change patterns. Patients who had tumors that converted to triple negative MTs had the shortest median OSs, while HER2 expression was not associated with a shorter median OS. No significant differences in PFSs and OSs have been demonstrated by Kaplan-Meier curve comparisons in any of the subgroup analyses. CTC counts were similar in all subgroups. CTCs were comparably less frequently detected in patients with a stable HER2 expression. Similar proportions of CTC positives were observed in all other subtype change pattern subgroups, barring the aforementioned HER2 stable subgroup. The detection of CTCs was of no appreciable prognostic value in different receptor change pattern subgroups in our cohort.