Targetable Genetic Alterations Research Articles

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

Abstract 198: Molecular genetic characterization of primary breast cancer via clinical next-generation sequencing

Abstract Targeting appropriate driver genes is crucial in cancer precision medicine. To find oncogenic drivers, targeted next-generation sequencing is becoming widely used in the clinical field. Using targeted next-generation sequencing, we aimed to detect targetable genetic alterations and characterize mutational profiles of breast cancer. We analyzed breast cancer biopsy specimens using customized 50-gene panel. In total, 196 patients of primary operable breast cancer patients were selected from single institution in South Korea. Among the 196 patients, 22 kinds of genes were significantly mutated or amplified. They comprised 161 nonsynonymous missense mutations, 54 frameshift mutations, 29 missense mutations and 5 small indels; 64 gene amplifications and 2 deletions. The most frequently mutated gene was PIK3CA (n=81/196; 41.3%), followed by TP53 (n=62; 31.6%), AKT1 (n=21; 10.7%), GATA3 (n=17; 8.7%) and PTEN (n=14; 7.1%). The most frequently amplified gene was ERBB2 (n=25/196; 12.8%), followed by FGFR1 (n=11; 5.6%), MYC (n=9; 4.6%), FGFR2 (n=3; 1.5%) and FGFR3 (n=3; 1.5%). Targeted next-generation sequencing can be readily performed in daily clinical practice. The most commonly found targetable genetic alterations were mutations of PI3K/AKT/mTOR pathway genes and FGFR family gene amplifications. Despite the limited number of available targeted agents, our study shows the feasible application of precision medicine in breast cancer. Citation Format: Jung Ho Park, Seung Yeon Ko, Sang Hwa Kim, Ho Young Kim, Sung Hoon Ko, Lee Su Kim. Molecular genetic characterization of primary breast cancer via clinical next-generation sequencing [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 198.

Immunotherapy Alone or in Combination with Chemotherapy as First-Line Treatment of Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of metastatic and selected cases of unresectable advanced non-small cell lung cancer (NSCLC). Importantly for patients, this implies that in the absence of a targetable oncogenic driver [especially epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements] and in the presence of high programmed death-ligand 1 (PD-L1) expression (≥ 50%), they are eligible for mono-therapy with pembrolizumab thereby avoiding chemotherapy as the first line of treatment. This mono-immunotherapy approach for high PD-L1 metastatic NSCLC is associated with improved overall survival (OS) and radiological responses (RR) with lesser toxicity as compared with conventional platinum doublet chemotherapy for both non-squamous and squamous histological types.However, majority of NSCLC patients either have no or low expression of PD-L1 (< 50%) and such patients derive greater benefit from a combination of PD-1/PD-L1 ICIs with platinum doublet chemotherapy as compared with chemotherapy alone. Again, benefits are seen for both OS and RRs. However, combining immunotherapy with chemotherapy, in general, does lead to higher toxicity than those seen with either of the two alone.Additionally, for non-squamous NSCLC patients, clinicians should not initiate ICI treatment till the results of common targetable genetic alterations like EGFR mutation, ALK, and ROS1 gene rearrangement testing are known (preferably on broad next generation sequencing) and are negative (even if results of PD-L1 testing are available)-as targeted therapies remain the cornerstone of treatment for patients harboring these oncogenic drivers.It is worth mentioning that PD-1 and PD-L1 ICIs are very expensive, and their usage is associated with occurrence of immune-related adverse events (irAEs) which occasionally can be severe. Hence, it is important to discuss efficacy, toxicity, and cost-related to ICI treatment with each and every patient at diagnosis in order to help them decide if they are willing to go ahead with this form of therapy either singly (for high PD-L1 expressors) or in combination with chemotherapy (for others).

Lung cancer histology-driven strategic therapeutic approaches

: In the last decades, the dichotomic distinction between small cell (SCLC) and non-small cell lung cancer (NSCLC) has been one of the key parameters in the therapeutic management of lung cancer. However, the advent of targeted therapies based on druggable oncogenic molecular alterations and immunotherapy interfering with the PD1/PD-L1 checkpoint has overridden the role of the precise definition of tumour histologic type in the modern approach to lung cancer, particularly in NSCLC. While a better definition of histotype in NSCLC may be still helpful in selecting chemotherapy regimens in those NSCLC lacking targetable genetic alterations (i.e., EGFR and BRAF mutations, ALK and ROS1 rearrangements) and PD-L1 overexpression, the possible identification of targetable oncogenic drivers in liquid biopsy using high throughput deep sequencing methods will somehow change the paradigm of histology determination as one the mandatory step in future therapeutic strategies in lung cancer. Thus, in this review we challenge the future role of histotype as an important influencing factor in the clinical management of patients with NSCLC.

Integration of Tumor Mutation Burden and PD-L1 Testing in Routine Laboratory Diagnostics in Non-Small Cell Lung Cancer.

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved “precision” drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.

Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).

9064 Background: Development of targeted therapy for SCLC based on a large-scale genomic screening is an innovative challenge. Gedatolisib is a highly potent dual inhibitor of PI3K/mTOR and is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. SCLC harboring this pathway alterations is rare. Thus, we conducted a phase II study based on a nationwide genomic screening network in Japan (LC-SCRUM-Japan) to develop novel targeted therapies. Methods: SCLC pts with targetable genetic alterations were screened at 154 institutions in Japan. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of gedatolisib in advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The primary endpoint was objective response rate (ORR). The planned sample size was 19 (threshold and expected ORR of 20% and 50%, one-sided alpha of 5%, and power of 80%). Results: 930 SCLC pts were screened from July 2015 to January 2020. Targetable genetic alterations were identified in 148 pts (16%), including 53 PI3K/AKT/mTOR (6%), 81 MYC family (9%), 10 EGFR (1%) and 15 KRAS (2%). A total of 12 pts with genetic alterations in the PI3K/AKT/mTOR pathway (5 PIK3CA, 6 PTEN, and 1 AKT1 mutation) were enrolled in the phase II study. The median age was 67 years (range 58-79), 7 pts were male and 5 pts received 2 or more prior chemotherapy (range 1-4). The ORR was 0% and disease control rate was 25%. The median progression-free survival (PFS) was 0.9 months (95% CI, 0.4 to 3.0). The median overall survival was 5.8 months (95% CI, 1.1 to NR). Treatment-related G3 adverse events (hypertension, hypoalbuminemia, oral mucositis, ALT increased and creatinine increased) were observed in 4 pts. One patient with PTEN I8fs mutation had a long duration of stable disease (PFS; 6.7 months). Conclusions: This Large-scale nationwide genomic screening network was effective to identify rare targetable genetic alterations and had a potential role to develop targeted therapies in SCLC. This phase II study didn’t show promising clinical benefit of gedatolisib for advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The safety profile of gedatolisib was similar to that reported previously. Clinical trial information: UMIN000020585.

Different response to ALK inhibitors in EML4-ALK positive mediastinal cancer of unknown primary.

104 Background: With the development of next-generation sequencing (NGS) and precision medicine, targeted therapy especially molecule-driven therapy irrespective of tumor site may play an important role in cancer patients with druggable targets. Cancer of unknown primary (CUP) especially mediastinal CUP (MCUP) has poor prognosis with empirical chemotherapy but may harbor targetable genetic alterations. In the study, we evaluate the response to ALK inhibitors in ALK-positive MCUP. Methods: We queried the cancer database of the Second Xiangya hospitalfrom 2018.10 to 2019.12 for patients with ALK-positive cancers regardless of tumor site.Then we selected ALK-positive MCUP patients treated with ALK inhibitors, on which both NGS and programmed death-ligand 1 (PD-L1) testing were performed. Results: Forty-eightpatients with ALK-positive cancers were registered in the database. Two MCUP patients were found and showed different response. The first MCUP patient obtaining remarkable response to alectinib harbored ALK/TP53 co-mutation and TERT wild type accompanied by low PD-L1 expression, while the second one showing stable disease with crizotinib carried ALK/TP53/TERT co-mutation and high PD-L1 expression. Conclusions: We reveal for the first time that ALK inhibitors are applied to MCUP as first-line therapy and alectinib is firstly reported to treat MCUP patients. ALK inhibitor alectinib is expected to improve outcomes of patients with ALK-positive MCUP. NGS and PD-L1 testing should be recommended for MCUP to get more information about therapy and efficacy. [Table: see text]

Genetic Profile of Young Chinese Patients with Lung Adenocarcinoma

背景与目的全球肺癌的发病率正呈逐年上升趋势，其中腺癌所占的百分比日益升高。据统计，全球的肺癌平均初诊年龄在70岁左右，虽然肺癌仍以老年患者居多，但发病年龄的年轻化趋势愈加明显。结合现有研究数据，我们已知在非小细胞肺癌中，年轻患者疾病的发生有其独特的生物学特点。但年轻肺腺癌患者的基因组学特性和临床特征仍有待确定。本研究采用高通量测序（next-generation sequencing technology, NGS）技术对中国年轻肺腺癌患者的基因突变状态进行了研究。方法共收集了89例年龄≤45岁的肺腺癌患者组织标本，所有患者均知情同意。使用NGS检测用于确定癌组织中驱动基因突变。此外，对同期行NGS检测的95例 > 45岁肺腺癌患者的基因组和临床病理特征进行回顾性分析。结果根据年龄分类对184例肺腺癌患者的驱动基因突变频率进行了分析，揭示了年龄≤45岁的年轻组患者的独特基因特征。其中间变淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因和人表皮生长因子受体-2（human epidermal growth factor receptor 2, HER2）基因的突变频率较高。而鼠类肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene, KRAS）、丝氨酸/苏氨酸蛋白激酶11（serine/threonine kinase 11, STK11）和表皮生长因子受体（epidermal growth factor receptor, EGFR）20外显子突变的趋势则相反，这些突变在年龄 > 45岁的老年组中更为常见。此外，年轻组EGFR基因突变同时伴有肿瘤蛋白p53（tumor protein p53, TP53）基因突变较老年组更为普遍（81.6% vs 44.9%），这可能使其应用EGFR酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor, EGFR-TKI）后疗效较差。结论NGS分析显示年轻腺癌患者具有独特的基因突变特点。在年轻患者中发现EGFR/TP53共突变的频率较高，这些独特的基因组学特征对临床治疗有重要的指导意义。

Abstract P6-10-07: Activating HER2 missense mutations in HER2-negative metastatic breast cancer

Abstract Background: Activating HER2 missense mutations can develop in HER2-negative metastatic breast cancer, particularly in ER-positive disease. These mutations may be targeted with anti-HER2-directed therapy, providing a novel therapeutic option for women with HER2-negative metastatic breast cancer. The clinical behavior and significance of these mutations in the era of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) for ER-positive breast cancer are unknown. Methods: We examined patients enrolled onto an ongoing single institution prospective study entitled Individualized Molecular Analyses Guide Efforts (IMAGE) II. The purpose of IMAGE II was to identify potentially targetable tumor genetic alterations, and the purpose of this analysis was to identify HER2 missense mutations. Patients eligible for IMAGE II had metastatic breast cancer of any subtype that had progressed on at least one standard-of-care therapy. Genetic profiling of blood was performed using the FoundationOne Liquid platform; metastatic tumor tissue profiling was performed using one of several commercially available next-generation sequencing platforms. All assays were capable of detecting common point mutations in the ERBB2 gene. Results: As of June 1, 2019, 54 patients were enrolled onto IMAGE II and had available genetic profiling results. Approximately half had ER+HER2- disease (n=29, 54%), one-third had triple negative breast cancer-TNBC (n=18, 33%), and the rest had HER2-positive disease (n=7, 13%). Six patients had activating HER2 missense mutations, with the same mutation(s) found in both tissue and blood in all patients. Five of these patients had ER+HER2- disease and the prevalence of HER2 mutations among patients with ER+HER2- disease was 17% (5/29) in our cohort. All five patients had received CDK4/6i with endocrine therapy in the metastatic setting prior to enrollment on IMAGE II. Four patients had markedly rapid tumor progression with this therapy. The median time to progression on CDK4/6i and endocrine therapy was 3.7 months (range 2.4-14.7) among patients with ER+HER2- disease and a HER2 missense mutation, compared to 9.4 months (range 2.3-40.9) among patients with ER+HER2- disease without a missense mutation. A summary of the patients with a HER2 missense mutation is shown in Table 1. Three patients with a HER2 missense mutation received HER2-directed therapy with trastuzumab and pertuzumab. One patient has an ongoing clinical response at 9.4 months, one patient has a clinical response after 1.8 months of therapy, and one patient recently began treatment with no follow-up data available yet. Conclusions: The frequency of HER2 missense mutations in patients with ER+HER2- metastatic breast cancer in our small cohort was higher than previously reported, and patients with this mutation had early tumor progression on CDK4/6i therapy regardless of endocrine therapy pairing. We hypothesize that activating HER2 missense mutations may be important drivers of resistance to CDK4/6i therapy. Testing patients who progress rapidly on CDK4/6i therapy for activating HER2 missense mutations may provide a novel therapeutic option. PatientSubtypeHER2 Mutation(s)Found whereReceived CDK4/6iLineWith which endocrine therapyTime to progression (in months)1ER+HER2-L755STissue/bloodYes2ndfulvestrant14.82ER+HER2-V777LTissue/bloodYes1sttamoxifen3.73ER+HER2-L755PTissue/bloodYes1stfulvestrant3.34ER+HER2-L755S, V697LTissue/bloodYes2ndfulvestrant4.15ER+HER2-L869RTissue/bloodYes1stletrozole2.46TNBCD769YTissue/bloodNoNANANA Citation Format: Mirat Shah, Jennifer Ensminger, Chenguang Wang, Siraj Ali, Jon Chung, Josh Lauring, Ben Ho Park, Vered Stearns. Activating HER2 missense mutations in HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-07.

Genomic Profiling and Clinicopathological Characteristics of Neuroendocrine Tumors of the Lung in East Asian Patients.

In recent years, the genomic landscape of neuroendocrine tumors (NETs) of the lung has been investigated. However, more data are necessary to elucidate the heterogeneous nature of NETs, especially in East Asian patients. A total of 64 patients who underwent surgical resection for lung NETs [26 typical or atypical carcinoid tumors, 21 large-cell neuroendocrine carcinomas (LCNECs), and 19 small-cell lung carcinomas (SCLCs)] were enrolled, and samples from 46 patients were subjected to targeted next-generation sequencing. Co-mutations of tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) were detected in 15%, 42%, and 93% of carcinoid tumors, LCNECs, and SCLCs, respectively. Oncogenic or targetable genetic alterations identified in this study included mutations of KRAS proto-oncogene (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), ALK receptor tyrosine kinase (ALK), mitogen-activated protein kinase kinase 1 (MAP2K1), and isocitrate dehydrogenase 1 (IDH1), as well as amplifications of erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), CD274 molecule (CD274), and MYCN proto-oncogene (MYCN). These alterations were more frequently found in high-grade NETs than in carcinoid tumors (33.3% vs. 7.7%). Programmed cell death-ligand 1 expression was strongly associated with the LCNEC subtype among NETs (p=0.002). The mutational status of TP53 and RB1 was significantly associated with NET subtypes in East Asian patients. Targeted therapy or immunotherapy may serve as a treatment option in a subset of patients with high-grade NETs.

A Transcriptionally Definable Subgroup of Triple-Negative Breast and Ovarian Cancer Samples Shows Sensitivity to HSP90 Inhibition.

We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis. Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro. The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi. Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro, and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA. Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage.

BET bromodomains' functions in bone-related pathologies.

Throughout life, bones are subjected to the so-called 'bone-remodeling' process, which is a balanced mechanism between the apposition and the resorption of bone. This remodeling process depends on the activities of bone-specialized cells, namely the osteoblasts and the osteoclasts. Any deregulation in this process results in bone-related pathologies, classified as either metabolic nonmalignant diseases (such as osteoporosis) or malignant primary bone sarcomas. As these pathologies are not characterized by common targetable genetic alterations, epigenetic strategies could be relevant and promising options. Recently, targeting epigenetic regulators such as the bromodomains and extraterminal domains (BET) readers have achieved success in numerous other pathologies, including cancers. In this review, we highlight the current state of the art in terms of the diverse implications of BET bromodomain proteins in the bone's biology and its defects. Consequently, their role in bone-related pathologies will also be developed, especially in the context of the primary bone sarcomas.

Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC)

In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype.

Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.

PurposeEpidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) are ‘must-test’ biomarkers in the molecular diagnostics of advanced-stage lung cancer patients. Although single-gene assays are currently considered the gold standard for these genes, next-generation sequencing (NGS) tests are being introduced to clinical practices. We compared the results of current diagnostics and aimed to suggest timely effective guidance for their clinical use. Materials and MethodsPatients with lung cancer who received both conventional single-gene assays and subsequent targeted NGS testing were enrolled, and the results of their tests were compared. ResultsA total of 241 patients were enrolled, and the EGFR real-time polymerase chain reaction, ALK fluorescence in situ hybridization (FISH), and ROS1 FISH assays exhibited 92.9%, 99.6%, and 99.5% concordance with the NGS tests, respectively. The discordant cases were mostly false-negatives of the single-gene assays, probably due to technical limitation. Of 158 cases previously designated as wild-type, EGFR, ALK, and ROS1 alterations were identified in 10.1%, 1.9%, and 1.3%, respectively, and other targetable alterations were identified in 36.1% of the cases. Of patients with additionally identified actionable alterations, 32.6% (31/95) received matched therapy with a clinical benefit of 48.4% (15/31). ConclusionEven though the conventional and NGS methods were concordant in the majority of cases, NGS testing still revealed a considerable number of additional EGFR, ALK, and ROS1 alterations, as well as other targetable alterations, in Korean advanced-stage lung cancer patients. Given the high frequency of EGFR and other targetable mutations identified in the present study, NGS testing is highly recommended in the diagnosis of Korean lung cancer patients.

377P - NGS in advanced NSCLC in a developing country: Ready for prime time?

BackgroundThe increasing availability of targeted therapies has made genomic testing an integral part of management of patients with lung cancer. The guidelines are moving towards upfront molecular profiling of all advanced non-small cell lung cancers (NSCLC) with Next Generation Sequencing (NGS). Whether this translates into a clinically meaningful benefit in these patients, especially in a resource constrained country is yet to be determined. MethodsPatients with advanced adenocarcinoma of lung who underwent tissue NGS testing after a negative EGFR, ALK and ROS1 report between April 2017 and March 2019 were included. We retrospectively analyzed the testing outcomes and any change in clinical decision making after the NGS report in such patients. ResultsOverall, NGS was done on tissue of 50 patients with advanced adenocarcinoma of lung. The median age was 58 years (range 27-82 years) and there were 31 males (58%). Most of the patients were never smokers 38(72%). The average turnaround time for the assay was 23 days (SD ± 15 days). One or more genomic alterations were found in 43 patients (86%) with most common genes affected being p53(43%), KRAS (19%), NOTCH1(13%), EGFR(6%), ROS1(4%), BRAF(8%) and HER2(8%). Seven (14%) of the patients were found to have mutations that were targetable by an FDA approved therapy and 9(18%) more patients had an off label available drug. So there was a potential for change of treatment in 16(32%) patients. Out of the 38(76%) patients who continued treatment at our institute, the NGS results led to a change in treatment in only 6(15%) patients. This was mostly due to limited availability of drugs, limited access to clinical trials and high cost of therapy. ConclusionsNGS is an important tool in the detection of targetable genetic alterations and results could potentially alter therapy. However, it is an expensive investigation and its clinical utility is questionable in a developing country like India. Single gene testing for common mutations is both rapid and cost-effective, and change in therapy after further NGS testing is possible in a very small percentage of patients. However, it may be considered after a detailed discussion with the patient in view of limited access to clinical trials or targeted therapies. Legal entity responsible for the studyNil. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

EP1.01-31 PET CT Radiogenomic Depiction in PDL1 Expression in Lung Cancer in Indian Population

Non small cell lung cancer (NSCLC) represents an area of paramount importance wherein patients undergo testing for targetable genetic alterations. Association between the imaging and molecular phenotypes needs to be explored highlighting the growing importance of classifications based on radio genomic characterization. This study was conducted to evaluate the correlations between the radiologic and molecular phenotypes in patients with NSCLC. 211 patients with lung cancers during the study period of one year from October 2017 till November 2018 in our institution and undergoing both radiologic (PET-CT) and molecular investigations [Programmed death ligand 1 (PDL1)] were included in the study. Both quantitative and qualitative CT findings were evaluated and correlated with the molecular findings. Quantitative data included SUV max obtained from PET component of CT and maximum diameter of lesion according to the RECIST criteria. Qualitative data recorded included location, pleural tail, pleural effusion, pericardial effusion, opacity, margins, calcifications, obstructive changes, pleural nodules, lung nodules, invasion, air bronchogram, emphysema, pulmonary fibrosis, mediastinal lymph nodes and distant metastasis. Statistical analysis was performed to evaluate the association of the qualitative features with the molecular expression. Receiver operating characteristic curves (ROC) were drawn and the corresponding area under curve (AUC) was calculated. P-values <0.05 were considered significant. PDL1 expression was observed in 69 patients and 13/14 females and 29/34 non-smokers showed the expression (p-value <0.0001). A total of 1, 19, 22 and 27 patients had <1%, 1-10%, 10-50% and >50% PDL1 expression. SUV max was 11.7 ± 3.7 in the group with PDL1 expression. Correlations were observed between PDL1 expression and location (p-value <0.0001), pleural tail (p-value <0.0001), pleural effusion (p-value <0.0001), obstructive changes (p-value 0.001), pleural nodule (p-value 0.001), lung nodules (p-value <0.0001), air bronchogram (p-value <0.0001), emphysema (p-value <0.0001), mediastinal nodes (p-value <0.0001) and distant metastasis (p-value <0.0001). PDL1 expression correlated with pulmonary fibrosis (p-value 0.001). In ROC curves, in case of PDL1 expression, the AUC was 0.728 on the basis of length. The correlation between CT findings and molecular findings highlights the importance of newer radio genomic based characterization for patients with NSCLC for better diagnostic and prognostic approaches.

P2.01-77 PET CT Radiogenomic Depiction with EGFR and ALK Molecular Alterations in Lung Cancer Among Indian Population

Non small cell lung cancer (NSCLC) represents an area of paramount importance wherein patients undergo testing for targetable genetic alterations. Association between the imaging and molecular phenotypes is vital highlighting the growing importance and unmet need of classifications based on radio genomic characterization. This study was conducted to evaluate the correlations between the radiologic and molecular phenotypes in patients with NSCLC. 211 patients with lung cancers during the study period of one year from October 2017 till November 2018 in our institution and undergoing both radiologic (PET-CT) and molecular investigations [Epidermal Growth Factor Receptor (EGFR), Anaplastic lymphoma kinase (ALK)] were included in the study. Both quantitative and qualitative CT findings were evaluated and correlated with the molecular findings. Quantitative data included SUV max obtained from PET component of CT and maximum diameter of lesion according to the RECIST criteria. Qualitative data recorded included location, pleural tail, pleural effusion, pericardial effusion, opacity, margins, calcifications, obstructive changes, pleural nodules, lung nodules, invasion, air bronchogram, emphysema, pulmonary fibrosis, mediastinal lymph nodes and distant metastasis. Statistical analysis was performed to evaluate the association of the qualitative features with the molecular expression. Receiver operating characteristic curves (ROC) were drawn and the corresponding area under curve (AUC) was calculated. P-values <0.05 were considered significant. Overall, EGFR mutation positivity and ALK rearrangement was observed in 114 and 37 patients, respectively whereas 60 patients had neither of these. SUV max was comparable between the groups with EGFR mutation (11.3 ± 3.9) and ALK rearrangement (12.3 ± 4.0). Correlations were observed between EGFR mutation and ALK rearrangement and location (p-value <0.0001), pleural tail (p-value <0.0001), pleural effusion (p-value <0.0001), obstructive changes (p-value <0.025), pleural nodule (p-value <0.002), lung nodules (p-value <0.002), air bronchogram (p-value <0.002), emphysema (p-value <0.002), mediastinal nodes (p-value <0.002) and distant metastasis (p-value <0.002). EGFR mutation also correlated with invasion (p-value 0.022). In ROC curves, for EGFR mutation and ALK rearrangement prediction based on mediastinal lymph nodes, the AUC was 0.661 and 0.588, respectively. The correlation between CT findings and molecular findings highlights the importance of newer radio genomic based characterization for patients with NSCLC for better diagnostic and prognostic approaches.

Cholangiolar pattern and albumin in situ hybridisation enable a diagnosis of intrahepatic cholangiocarcinoma

AimsThe histological distinction of intrahepatic cholangiocarcinoma (ICC) from metastatic adenocarcinoma remains a challenge. The primary goal was to evaluate the diagnostic value of morphology and albumin expression in the diagnosis...

Molecular profiling and molecular classification of endometrioid ovarian carcinomas

ObjectiveEndometrioid ovarian carcinomas (EOCs) comprise 5–10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. MethodsEOCs and matched normal samples were subjected to massively parallel sequencing targeting 341–468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). ResultsEOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. ConclusionsEOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.

Genetic profiling as a clinical tool in advanced parathyroid carcinoma.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy. To evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels. All patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel. The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 11 patients with advanced PC were selected to undergo molecular testing. Genetic profiles of advanced PC. Among the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients. Mutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.