scholarly journals IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Valeria Barresi ◽  
Michele Simbolo ◽  
Andrea Mafficini ◽  
Maurizio Martini ◽  
Martina Calicchia ◽  
...  
Keyword(s):  
Giant Cells ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Molecular Profile ◽  
Wild Type ◽  
Mutational Burden ◽  
Check Point Inhibitors ◽  
Tumor Mutational Burden ◽  
Molecular Landscape ◽  
Promoter Mutations

AbstractGiant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30–49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (< 50% or ≥ 50%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival (P = 0.004). Sixteen (41%) cases had a TMB > 10 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type (P < 0.0001; P = 0.0003; P < 0.0001) and 26 IDH-mutant (P < 0.0001; P = 0.0227; P < 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.

Comprehensive molecular profiling of IDH1/2 mutant biliary cancers (BC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 479-479 ◽  
Author(s):  
Francesca Battaglin ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
Anthony Frank Shields ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Molecular Profile ◽  
Wild Type ◽  
Fragment Analysis ◽  
Genetic Changes ◽  
Mutational Burden ◽  
Idh Mutations ◽  
Rational Combination ◽  
Tumor Mutational Burden ◽  
Gi Cancers

479 Background: Isocitrate dehydrogenases (IDH) play a key role in energetic metabolism and IDH mutations (mut) promote oncogenesis via epigenetic and genetic changes. Data addressing the molecular contexture of IDH1/2 mut in BC are lacking. We aimed to characterize the molecular profile of IDH1/2 mutant (mIDH) GI cancers with a focus on BC. Methods: 27954 GI cancer samples collected between August 2000 and July 2019 were included: 2057 BC (1159 ICC, 277 extrahepatic CC, 573 gallbladder, 48 unspecified CC), 13807 colorectal, 4183 gastric/esophageal, 3060 other. Samples were analyzed using NextGen DNA sequencing, in situ hybridization, RNA sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mut. MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Results: mIDH frequency in BC was 10.3% (211/2057), with higher prevalence of IDH1 mut (8.2%). ICC showed the highest mut prevalence: IDH1 13.5%, IDH2 4%. Mut rates in other GI cancers types were < 1%, except for HCC (1.9%, 11/582) and small bowel (1.1%, 8/736). When compared to IDH wild type (WT), mIDH BC showed lower mut rates in TP53 (13 vs 43%), KRAS (8 vs 19%), CDKN2A (1 vs 9%), and SMAD4 (0 vs 9%), whereas PBRM1 mut were higher (14 vs 5%) ( P < .001 for all comparisons). There was a trend towards higher frequency of ARID1A and BAP1 in mIDH BC. HER2 expression and amplification rates were lower in mIDH vs WT BC (0.5 vs 3%, P = .048 and 0 vs 6%, P = .002). FGFR2 fusion was detected in 7% of WT vs 2% of mIDH BC. mIDH BC showed a lower TMB (0.7 vs 3.7%, P = .048) and a trend for lower MSI rates (0.6 vs 3%, P = .06) vs WT BC. Conversely, IDH mut were associated with higher TMB and MSI ( P < .001) and higher PD-L1 expression in other GI cancers. Conclusions: This is the largest and most extensive profiling study to investigate the molecular makeup of mIDH BC and GI tumors. Our data show distinct gene alteration patterns characterizing mIDH BC, involving genes related to chromatin remodeling and DNA repair, and a differential expression of immune related markers compared to other mIDH GI tumors. These findings can contribute to the development of rational combination therapies and to improved patient selection in the future.

scholarly journals OS1.4 Liquid biopsy of the CSF in a series of GBM patients: preliminary results

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii6-iii6
Author(s):  
R Rudà ◽  
F Bruno ◽  
F De Bacco ◽  
F Orzan ◽  
P Cassoni ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Point Mutations ◽  
Digital Pcr ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Molecular Profile ◽  
Genetic Profile ◽  
Radiological Features ◽  
Meningeal Involvement ◽  
Idh Mutations

Abstract BACKGROUND Liquid biopsy (LB) by cerebrospinal fluid (CSF) can be useful to identify circulating tumour DNA (ctDNA), thus offering information about the heterogeneity of the neoplastic genome. The aim of our study is to assess the effectiveness of LB of the CSF in detecting ctDNA which mirrors the genetic profile of the tumoural tissue, and to investigate the clinical and radiological aspects influencing the availability of ctDNA. MATERIAL AND METHODS Tumoral tissue and CSF samples of 13 GBM patients undergoing surgery was collected. CSF was withdrawn from the very proximity of the tumoural surface before the excision. DNA extracted from tissue samples was analysed by qPCR to identify typical genetic alterations such as copy number variations (EGFR, PDGFRA, CDK4, MDM2, CDKN2A), and point mutations (TP53, PTEN, IDH, NRAS, PI3K1, pTERT). CtDNA extracted from CSF was analysed by droplet digital PCR to assess the presence of the alterations found in the matching tissue. Both contrast-enhanced (CE) and FLAIR volumes of the lesions were measured in the pre-surgical MRI. Linear and logarithmic regressions were employed for the statistical analysis. RESULTS From June 2016 to February 2017 we prospectively collected 13 GBM patients. Median age was 73 years. All lesions showed CE at the MRI; other radiological findings included necrosis (84.6%), oedema (76.9%), cortical, ventricular or meningeal involvement (76.9%, 30.8%, and 15.4%). Median volumes of CE and FLAIR lesions were 28.6 and 25.5 cm3, with a median FLAIR/CE ratio of 72.9. Surgery was subtotal (<95%) in all patients. All GBM tissues were tested for the following alterations: EGFR, PDGFRA, CDK4, MDM2, CDKN2A; 76.9% were tested for TP53, PTEN, and IDH mutations; 38.5% for NRAS and pTERT mutations; 30.8% for PI3KR1 mutation. MGMT methylation was assessed in 12 cases (92.3%) and found in 7 (58.3%). Median CSF volume, ctDNA quantity and concentration were 0.45 mL, 59.64 ng, and 0.42 ng/μL. Processable DNA was found in 11 CSF specimens (84.6%), in 8 of which (61.5%) it carried the same alteration expressed by the tumoural cells of the matched tissue, while in 3 cases (23.1%) it seemed to have a different genetic profile; finally, in 2 cases it was not possible to detect any circulating DNA in the CSF. Preliminary data on 13 patients suggest that the ctDNA concentration in the CSF could be related to the FLAIR/CE ratio as measured in the MRI before surgery (p = 0.02). Other correlations between the molecular and the radiological features are still being exploring. CONCLUSION Our study confirms that LB of CSF can detect ctDNA carrying the same molecular profile harboured in the tumour. Therefore, it seems to be an accurate method to identify markers useful for the diagnosis and the monitoring of the disease. Additionally, our ongoing study is trying to demonstrate a potential correlation between radiological features of the tumour and availability of ctDNA in CSF.

scholarly journals Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 445 ◽  
Author(s):  
David Vossen ◽  
Caroline Verhagen ◽  
Martijn van der Heijden ◽  
Paul Essers ◽  
Harry Bartelink ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Head And Neck ◽  
Genetic Alterations ◽  
Hypopharyngeal Carcinoma ◽  
Advanced Stage ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Mutational Burden ◽  
Hpv Status ◽  
Tumor Mutational Burden

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.

Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8517-8517 ◽  
Author(s):  
Young Kwang Chae ◽  
Keerthi Tamragouri ◽  
Jon Chung ◽  
Alexa Betzig Schrock ◽  
Bhaskar Kolla ◽  
...  
Keyword(s):  
Small Cell Lung Carcinoma ◽  
Clinical Care ◽  
Large Cell ◽  
Smoking History ◽  
Genomic Profiling ◽  
Wild Type ◽  
Cell Lung Carcinoma ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

8517 Background: SCLC and L-LCNEC are aggressive neoplasms that are both associated with smoking history and are thought to overlap in clinical, histogenetic, and genomic features. We reviewed the genomic profiles of >1187 patients to assess the genomic similarities of these diseases. Methods: Comprehensive genomic profiling (CGP) of tumors from 300 L-LCNEC and 887 SCLC patients in the course of clinical care was performed to suggest pathways to benefit from therapy. Results: Commonly altered genes in both diseases included TP53, RB1, MYC/MYCL1, MLL2, LRP1B and PTEN; alterations in other genes occurred at somewhat differing frequencies (table). For both diseases, RB1 mutation significantly co-occurred with TP53 mutations (p<0.001), but occurred in a mutually exclusive fashion to STK11 and CDKN2A (p<0.001). RB1 was mutually exclusive with KRAS for L-LCNEC but not for SCLC. The interquartile range for SCLC and L-LCNEC TMB is 7.9 and 12.6 with the 75% quartile being 14.4 and 17.1 respectively. Cases of both diseases will be presented with radiographic response to genomically matched targeted therapy and immunotherapy, particularly in cases of high TMB. Conclusions: Given the similar overall genomic profiles and clinical behavior of a subset of these diseases, they could be conceived of as a single disease to be further classified by genomically defined classes such as SCLC-type ( TP53/ RB1mutated) and NSCLC-like (wild type for one or both). By analogy to NSLC and melanoma, benefit from immunotherapy appears most likely for only the upper quartile of cases in TMB. [Table: see text]

Difference of genomic signatures and opportunities for targeted and immunotherapies in castrate resistant TMPRSS2:ERG fusion positive and TMPRSS2:ERG wild type refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 348-348 ◽  
Author(s):  
Gennady Bratslavsky ◽  
Hugh A.G. Fisher ◽  
Timothy Byler ◽  
Joseph M Jacob ◽  
Jon Chung ◽  
...  
Keyword(s):  
High Status ◽  
Genomic Profiling ◽  
Wild Type ◽  
Genomic Signatures ◽  
Mutational Burden ◽  
Neuroendocrine Prostate Cancer ◽  
Stage Disease ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Castrate Resistant

348 Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]

scholarly journals Intraventricular Meningiomas: Clinical-Pathological and Genetic Features of a Monocentric Series

2022 ◽  
Vol 29 (1) ◽  
pp. 178-185
Author(s):  
Serena Ammendola ◽  
Michele Simbolo ◽  
Chiara Ciaparrone ◽  
Paola Chiara Rizzo ◽  
Maria Caffo ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Copy Number Variations ◽  
Low Grade ◽  
Check Point ◽  
Mutational Burden ◽  
Genetic Features ◽  
Tumor Mutational Burden ◽  
Life Threatening ◽  
Grade Ii ◽  
Generation Sequencing

Intraventricular meningiomas (IVMs) are rare (0.5–5%) and usually low-grade (90% grade I) brain neoplasms. Their recurrence rate is lower than that of extra-axial meningiomas, but their surgical resection can be burdened with life-threatening complications, which represent the major cause of the reported 4% mortality. The aim of this study is to characterize the molecular portrait of IVMs to identify potential therapeutic targets. For this, we explored mutations and copy number variations (CNV) of 409 cancer-related genes and tumor mutational burden (TMB) of six cases, using next-generation sequencing. Five IVMs were grade I and one was grade II; none recurred, in spite of partial surgical resection in one case. NF2 mutation was the only recurring alteration and was present in three of the six IVMs, in association with SMARCB1 mutation in one case. None of the cases was hypermutated (TMB > 10 mutations/Mb). NF2-mutant progressing or recurring IVMs could potentially be treated with targeted therapies applied to other NF2-mutant tumors, as an alternative to surgery or radiosurgery, while in view of their low TMB they are unlikely candidates to immune check-point inhibition.

Large cell neuroendocrine carcinoma of the urothelial tract (LNEC): The MSKCC experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4526-4526
Author(s):  
Brendan John Guercio ◽  
Jatin Gandhi ◽  
Min Yuen Teo ◽  
Michael Lattanzi ◽  
Samuel Aaron Funt ◽  
...  
Keyword(s):  
Large Cell ◽  
First Line ◽  
Mutational Burden ◽  
Epigenetic Modifiers ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Tumor Mutational Burden ◽  
Promoter Mutations ◽  
Pathologic Response Rate

4526 Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (<ypT2N0) after NAC was 25% for LNEC and 50% for SNEC-only (p =.13); the ypT0N0 rate was 25% for LNEC and 40% for SNEC-only (p =.52). Perioperative chemo did not improve OS compared to surgery alone in LNEC, adjusting for age and concurrent SNEC (HR 1.46, 95% CI 0.12-17.5, p =.76), but was associated with longer OS among SNEC-only pts (n = 98; HR 0.39, 95% CI 0.22-0.69, p =.001). Two M1 LNEC pts received immunotherapy (IO) in the first-line: 1 atezolizumab, 1 atezolizumab + chemo. Both remained free of progression on IO at a follow-up of 20 and 12 mos, respectively. Of 18 sequenced LNEC tumors, 89% had TERT promoter alterations (alts), similar to 85% seen in 52 SNEC tumors. All LNEC tumors had alts of TP53 or RB1, and 10 (56%) had both. Median tumor mutational burden (TMB) was 14 (IQR 8-38) in LNEC and 30 (IQR 15-55) in SNEC. Epigenetic modifiers were altered in 78% LNEC and 79% SNEC. Two LNEC pts had ERCC2 alts and received platinum chemo; both were alive at last follow-up from NEC diagnosis of 30.7-39.1 mos. Conclusions: LNEC pts experienced longer OS compared to pts with SNEC-only in this cohort, but did not appear more chemo-sensitive. Genomic profiles of LNEC and SNEC-only tumors were similar; TERT promoter mutations suggest a potential urothelial precursor. Further investigation of IO for LNEC is warranted.[Table: see text]

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation

2021 ◽  
Author(s):  
Kristina Schenck ◽  
Michael Masetti ◽  
Nicole Pfarr ◽  
Sylvie Lorenzen
Keyword(s):  
Immune Checkpoint ◽  
Genetic Alterations ◽  
Chemotherapeutic Agents ◽  
Neuroendocrine Neoplasm ◽  
Cancer Drug ◽  
Standard Chemotherapy ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Cell Death Protein ◽  
The U.S

Introduction: In the last decade immune checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017 the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability (MSI), regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden (TMB), likewise benefit from immune checkpoint therapy. Case report: Here we present two cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab. Conclusion: Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype especially in patients that are refractory to standard chemotherapy.

Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14280-e14280
Author(s):  
HaiTao Wang ◽  
Huina Wang ◽  
Rongyun Guo ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Cell Cancer ◽  
Objective Response ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tumor Type ◽  
Mutational Burden ◽  
Esophagogastric Cancer ◽  
Tumor Mutational Burden

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.

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