Impact of patient age on molecular alterations in left-sided colorectal tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
Benjamin Adam Weinberg ◽  
Kelsey Poorman ◽  
David Arguello ◽  
John Marshall ◽  
Mohamed E. Salem
Keyword(s):  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Distal Colon ◽  
Predictive Biomarker ◽  
Missense Mutations ◽  
Chi Square ◽  
Molecular Alterations ◽  
Nextgen Sequencing ◽  
Colon And Rectum ◽  
The Impact

3592 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. This increase is most pronounced in tumors arising from the distal colon and rectum. Since tumor sidedness has emerged as an important prognostic and predictive biomarker in CRC, we aim to explore the impact of age on the tumor biology of left-sided colon cancer (LCC). Herein, we compare profiles of LCC from younger (≤ 45 years) and older pts (≥ 65 years). Methods: LCCs (splenic flexure to rectum; n = 1,602) were examined by NextGen sequencing, protein expression, gene amplification, and microsatellite instability fragment analyses. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparisons. Results: LCCs from younger (median age 40, range 22-45 years, n = 229) and older (median age 71, range 65-89, n = 503) pts were studied. The most frequently mutated genes included APC, TP53, KRAS, PIK3CA, ARID1A, FBXW7, SMAD4, ATM, BRAF, and NRAS. Comparing younger v. older pts, there were no significant differences in the rates of APC (75.3% v. 82.9%, P = 0.139), TP53 (79.5% v. 73.1%, P = 0.261), KRAS (37.6% v. 43.0%, P = 0.403), PIK3CA (9.4% v. 14.6%, P = 0.234), ARID1A (14.3% v. 13.2%, P = 0.884), FBXW7 (11.4% v. 10.5%, P = 0.830), SMAD4 (13.1% v. 7.4%, P = 0.129), BRAF (4.8% v. 5.7%, P = 0.762), or NRAS (3.5% v. 2.6%, P = 0.680) mutations. Additionally there were no significant differences in protein overexpression. However, there was a trend towards increased HER2 amplification in younger pts (5.7% v. 2.1%, P = 0.05). MSH6 (4.8% v. 0.5%, P = 0.015), MSH2 (2.4% v. 0%, P = 0.032), POLE (2.4% v. 0%, P = 0.032), and NF1 (7.9% v. 0%, P < 0.001) mutations were observed at higher rates in younger pts. High TML (≥ 17 mutations per megabase) was seen more frequently in younger pts (8.2% v. 2.6%, P = 0.02). Conclusions: The molecular differences between LCC in younger and older pts are mostly due to mutations in mismatch repair genes. Higher TML may predict a higher response rate to checkpoint inhibitors in younger pts with LCC. The differences in tumor biology observed here warrant further study and may eventually be used to tailor therapy.

Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4558-4558
Author(s):  
Jingyuan Wang ◽  
Joanne Xiu ◽  
Anthony Frank Shields ◽  
Axel Grothey ◽  
Benjamin Adam Weinberg ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Epigenetic Modification ◽  
Gene Mutations ◽  
Mutation Rates ◽  
Missense Mutations ◽  
Chi Square ◽  
Expression Levels ◽  
Molecular Alterations ◽  
Molecular Features ◽  
The Impact

4558 Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p < .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p < .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p < .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p < .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p < .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).

Characterization of tumor mutation load (TML) in solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11517-11517 ◽  
Author(s):  
Mohamed E. Salem ◽  
Joanne Xiu ◽  
Heinz-Josef Lenz ◽  
Michael B. Atkins ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Suppressor Gene ◽  
Older Age ◽  
Patient Treatment ◽  
Missense Mutations ◽  
Driver Genes ◽  
Primary Nsclc ◽  
The Impact

11517 Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( > 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p < 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p < 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p < 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p < 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p < 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]

Colorectal cancer: Impact of primary tumor location on genetic alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3578-3578 ◽  
Author(s):  
Mohamed E. Salem ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Jimmy J. Hwang ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Location ◽  
Genetic Alterations ◽  
Hepatic Flexure ◽  
Missense Mutations ◽  
Chi Square ◽  
Molecular Alterations ◽  
Clear Cut ◽  
Comparison Results ◽  
Her 2 ◽  
The Right

3578 Background: Recent data show that patients with left sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences. Methods: Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square was used for comparison. Results: When compared to LT, RT carried a significantly higher rate of BRAF (25% vs 7%; p < 0.0001), PTEN (5.4% vs 1.3%; p = 0.008), and ATM (4% vs 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs 5%; p < 0.0001) and PD-1 overexpression (58% vs 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs 42%; p = 0.07) or NRAS mutations (2.2% vs 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs 3%; p = 7E-07), PIK3CA (22% vs 11%; p = 0.001), CTNNB1 (3% vs 0.3%; p = 0.02); ATM (3% vs 1%; p = 0.04), PTEN (5% vs 1%; p = 0.004), and BRCA1 mutations (4% vs 0%; p = 0.02), and a lower rate of TP53 (56% vs 71%; p = 0.001) and APC (53% vs 66%; p = 0.003) mutations. When compared to RC, LT showed higher rates of BRAF (6.7% vs 3.2%; p = 0.04) and CTNNB1 (2.1% vs 0.3%; p = 0.04) mutations, and a higher rate of MSI-high tumors (4.6% vs 0.7%; p = 0.04), whereas RC had a higher rate of KRAS mutation (50% vs 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC, respectively (RT vs RC; p = 0.01). There was a correlation between TML and PD-L1 (p = 0.04) and PD-1 (p = 0.01). Conclusions: Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences.

Molecular variances between rectal and left-sided colon cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 522-522 ◽  
Author(s):  
John Marshall ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Wafik S. El-Deiry ◽  
Jeffrey Swensen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Recent Analysis ◽  
Missense Mutations ◽  
Chi Square ◽  
Primary Tumors ◽  
Colon Cancers ◽  
Nextgen Sequencing ◽  
Disease Biology ◽  
Infiltrating Lymphocytes

522 Background: Recent analysis of CALGB 80405 showed that left sided colon tumors (LT) respond differently to biologics compared with right-sided tumors, likely due to molecular differences. Molecular variations between LT and rectal tumors remain undefined. Herein, we report our exploration of these variations. Methods: Tumors with origins clearly defined as splenic flexure to descending colon (SFT), sigmoid colon (SgT), or rectum (RT) were included. Protein expression, gene amplification and NextGen sequencing was tested. Microsatellite instability (MSI) was measured by PCR. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 1,457 primary tumors (SFT 125; SgT 460, and RT 872) were examined. When compared with SFT, RT had a higher frequency of TP53 (71% vs. 57%, p = 0.03) and APC (66% vs. 49%, p = 0.01); a lower frequency of PIK3CA (11% vs. 22%, p = 0.02), BRAF (3% vs. 15% p = 0.0001), GNAS (0.9% vs. 4%, p = 0.04), HNF1A (0.7% vs. 5%, p = 0.01), and CTNNB1(0.3% vs. 4%, p = 0.003); and a higher expression of TOPO1 (52% vs. 31%, p = 0.0001), ERCC1 (29% vs. 15%, p = 0.03), and MGMT (64% vs. 53%, p = 0.048). When compared with SgT, RT had higher expression of TLE3 (33% vs. 23%, p = 0.007), TOPO1 (52% vs. 35%, p < 0.001), TUBB3 (41% vs. 28%, p = 0.003), and MGMT (64% vs. 54%, p = 0.003). There were no differences between SFT, SgT, and RT in the frequency of PD-L1 expression (5%, 2%, and 2%) on tumor cells, PD-1 expression on tumor-infiltrating lymphocytes (54%, 42%, and 42%), or Her-2 expression (1%, 2%, and 3%) and amplification (3%, 3%, and 5%). MSI was seen in 7% of SFT, 4% of SgT, and 0.7% of RT (total LT vs. RT, p = 0.01). Mean TML was 23, 6.5, and 7 mutations (mut)/MB (332 tumors), and the portion of tumors carrying a TML of > 17mut/MB was 9%, 1.6%, and 4% for SFT, SgT, and RT, respectively. In all 3 cohorts, a TML > 17 mut/MB was highly concordant with MSI. There was a correlation between PD-1 and TML in RT (p = 0.04) but not in SFT or SgT. There were no correlations between PD-L1 and TML. Conclusions: Tumors arising in the rectum may carry genetic alterations that are distinct from LT. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine

Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2627-2627 ◽  
Author(s):  
Sushma Jonna ◽  
Ari M. Vanderwalde ◽  
Jorge J. Nieva ◽  
Kelsey Anne Poorman ◽  
Michelle Saul ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Cytotoxic Chemotherapy ◽  
Missense Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Significant Difference ◽  
The Impact

2627 Background: Higher non-synonymous tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) is associated with a higher likelihood of response to checkpoint inhibitors. Tissue samples subject to TMB analysis may be obtained after exposure to cytotoxic chemotherapy or radiation therapy – both of which introduce somatic mutations in DNA and can influence the number of identified mutations. The role of TMB as a potential predictive marker for immunotherapy is evolving, and the impact of prior therapy on TMB could influence interpretation. Methods: Eligible cases were from patients with confirmed NSCLC, available clinical annotation and tumor molecular profiling including TMB analysis at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) using the Illumina NextSeq platform. TMB was calculated using only missense mutations that had not been previously reported as germline alterations. Treatment history was obtained for each patient under an IRB approved protocol to determine whether patients had had received chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. Data analysis was performed using the chi-square test of deviance to evaluate whether TMB was statistically significantly different between groups, correcting for smoking status. Results: Out of 1,118 patients identified, 459 cases met all eligibility criteria and were evaluated. 76 patients (17%) received either chemotherapy or radiation prior to tissue collection. Samples acquired prior to any therapy had a median TMB of 10 mut/Mb vs. 11 mut/Mb in samples acquired after any therapy. After adjusting for smoking, there was no significant difference in TMB between these cohorts (p = 0.41). Secondary pair wise analysis showed no statistically significant difference in TMB from chemotherapy-naïve and chemotherapy-treated samples (p = 0.28). The same was true for radiation (p = 0.75). Collection of clinical data is ongoing and further analysis, including additional cases will be presented. Conclusions: Though cytotoxic chemotherapy and radiation therapy can introduce somatic mutations, prior exposure to either was not associated with a significant difference in TMB.

Molecular correlates of PD-L1 expression in patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
Hira Rizvi ◽  
Chaitanya Bandlamudi ◽  
Adam Jacob Schoenfeld ◽  
Jennifer L. Sauter ◽  
Kathryn Cecilia Arbour ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Tissue Sample ◽  
Predictive Biomarker ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
A Minor ◽  
The Impact ◽  
Generation Sequencing

9018 Background: PD-L1 expression is the only FDA-approved predictive biomarker for patients with NSCLC treated with immune checkpoint inhibitors. The impact of tumor molecular profiling on tumor PD-L1 expression is not known. We hypothesized that somatic mutations and copy number alterations may be associated with distinct patterns of PD-L1 expression in patients with NSCLC. Methods: We examined patients with NSCLC in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) were performed on the same tissue sample. PD-L1 expression was determined by IHC using the E1L3N antibody clone and categorized as PD-L1 high (≥ 50%), intermediate (1-49%), or negative ( < 1%) expression. The association of PD-L1 with individual genes, pathways, tumor mutation burden, whole genome duplication (WGD), and aneuploidy (fraction of genome altered (FGA)) were evaluated. P-values < 0.05 and q-values < 0.15 were considered significant for individual genes. Results: 1023 patients with NSCLC had PD-L1 testing and MSK-IMPACT performed on the same tissue sample, 18% (n = 180) had high, 21% (n = 218) had intermediate, and 61% (n = 625) had negative PD-L1 expression. High PD-L1 expression was significantly enriched in metastatic vs primary lesions (p < 0.001). There was a minor correlation between PD-L1 and TMB (spearman rho = 0.195) and PD-L1 and FGA (spearman rho = 0.11). Similar rates of WGD were found among patients with high, intermediate, and negative PD-L1 expression (p = 0.38). Mutations in KRAS and TERT were significantly enriched in PD-L1 high compared to other groups (p = 0.001, q = 0.14; p < 0.001, q = 0.003). By contrast, mutations in EGFR and STK11 were associated with PD-L1 negativity (p < 0.001, q = 0.001; p = 0.001, q = 0.14). Pathway analysis showed DNA repair (p < 0.001), TP53 (p < 0.001), and SWI/SNF (p = 0.04) pathways significantly associated with PD-L1 high compared to PD-L1 negative expression. Conclusions: The genetic features of NSCLC are associated with distinct patterns of PD-L1 expression. This data may provide insight to how the molecular phenotype can interact with the immunologic phenotype of tumors.

Correlation of pathogenic POLE mutations with clinical benefit to immune checkpoint inhibitor therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Benjamin Garmezy ◽  
Jinesh S. Gheeya ◽  
Kyaw Zin Thein ◽  
Patrick Glen Pilie ◽  
Wanlin Wang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cancer Center ◽  
Chi Square ◽  
Dna Polymerase Epsilon ◽  
Number Variation ◽  
Md Anderson ◽  
Chi Square Analysis

3008 Background: Mutations in DNA polymerase epsilon ( POLE) may induce DNA replication errors, increasing neoantigen load and potentially enhancing clinical benefit to immune checkpoint inhibitors (ICI). We present a clinicopathologic analysis of patients (pts) with advanced cancers harboring POLE mutations and their response to ICI therapy at MD Anderson Cancer Center. Methods: We used targeted exome sequencing via CLIA-certified next generation sequencing assays to identify pts with POLE-aberrant tumors and their co-occurring mutations. The pathogenicity of each POLE mutation was annotated utilizing InterVar and ClinVar databases. Chi-square analysis was performed. Results: Tumors from 12,947 pts were analyzed and 448 (3.5%) pts had a mutation or copy number variation in POLE (3.5%), comparable to the TCGA PanCancer Atlas (4.0%). Clinical data were available for 293 pts; the most common cancers were colorectal (14.7%), non-small cell lung (13.7%), cholangiocarcinoma (13.3%) and melanoma (10.2%). There were 267 unique co-mutations, including KRAS (23.0%), ARID1A (21.5%), BRCA2 (18.7%), ATM (18.4%), CDKN2A (17.5%), BRAF (15.3%), EGFR (15.3%), ATRX (12.6%), CREBBP (11.7%), APC (11.3%), ATR (11.0%), BRCA1 (11.0%) and CDK12 (10.4%). POLE variants were annotated in all pts: pathogenic/likely pathogenic (n = 34, 11.6%), benign/likely benign (61, 20.8%), and variant of unknown significance (198, 67.6%). 104 (35.8%) of 293 pts with POLE mutations received PD-1/L1 inhibitors as monotherapy or in combination. 93 (88.4%) of 104 pts were evaluable for response: Radiological CR 4.3% (n = 4), PR 26.9% (n = 25), SD 22.6% (n = 21), PD 46.2% (n = 43), for a clinical benefit rate (CR + PR + SD) of 53.8%. Pathogenic status of POLE mutation was associated with clinical benefit to PD-1/L1 inhibitors (p = 0.04). TMB (p = 0.44), PD-L1 (p = 0.11), and MSI (p = 0.66) status were not associated with pathogenic status. MSI-H status was not over-represented in pts with ICI clinical benefit (p = 0.36). Conclusions: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutations as a predictive biomarker. Multiple co-occurring DNA damage response mutations were found, which may contribute to ICI clinical benefit.

Association between PD-L1 variants and PD-L1 expression: A pan-cancer analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13661-e13661
Author(s):  
Xiang Wang ◽  
Ding Zhang ◽  
Guoqiang Wang ◽  
Anqi Duan ◽  
Xiang Ruan ◽  
...  
Keyword(s):  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Positive Rate ◽  
Cancer Genome Atlas ◽  
Copy Number Amplification

e13661 Background: Programmed cell death-1 (PD-L1) expression has become a predictive biomarker of response to immune checkpoint inhibitors (ICIs) in several types of solid tumors. Patients with high expression of PD-L1 can benefit more from immunotherapy. However, whether PD-L1 variants would influence the PD-L1 expression has not been fully studied. Methods: Patients with both mutation and immunohistochemistry results for PD-L1 expression from our dataset was analyzed. Patients with both mutation and RNA expression data were obtained from The Cancer Genome Atlas (TCGA) and also analyzed. Results: In our dataset, 10002 patients were included in the analysis. 101 (1%) patients harbored PD-L1 variants, including 24 with single nucleotide variant (SNV), 1 with fusion, 3 with copy-number reduction, 59 with copy-number gain, and 16 germline SNV. The PD-L1 positive rate was 42% in patients with SNV, 100% in fusion, 0% in copy-number reduction, 78% in copy-number gain, 19% in germline SNV and 39% in patients without PD-L1 variants. 32 studies of 10071 patients from TCGA were included for analysis. 244 (2.22%) patients harboring PD-L1 variants, including 2 with frame shift mutations, 3 with nonsense mutations, 38 with missense mutations, 2 with splices, 3 with fusions, 83 with copy-number reduction and 118 with copy-number amplification. The PD-L1 expression in patients with PD-L1 variants was significantly higher than patients without PD-L1 variants (P < 0.001). Further analysis among PD-L1 variants groups showed that PD-L1 fusion and amplification were associated with higher PD-L1 expression. Conclusions: Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.

Adoption of immunotherapy into real-world practice: Insights from the use of checkpoint inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14583-e14583 ◽  
Author(s):  
Jeremy O'Connor ◽  
Kathi Seidl-Rathkopf ◽  
Paul You ◽  
Nathan C. Nussbaum ◽  
Aracelis Z. Torres ◽  
...  
Keyword(s):  
Real World ◽  
Older Persons ◽  
Checkpoint Inhibitors ◽  
National Sample ◽  
Chi Square ◽  
Patients With Cancer ◽  
Fda Approval ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
The Impact

e14583 Background: Cancer research has been criticized regarding the generalizability of trials to older persons, as well as the timeliness of the impact of new trials on real-world practice. Despite growing enthusiasm about programmed death 1 checkpoint inhibitors (anti-PD1s), little is known about the speed with which these drugs are adopted into real-world practice, or whether anti-PD1 treated patients in real-world practice are older than patients treated in trials. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced melanoma (n=1,670), advanced non-small cell lung cancer (aNSCLC; n=19,536), or metastatic renal cell carcinoma (mRCC; n=2,018). Then, we determined the proportion treated with anti-PD1s in the 2nd line or later following US Food and Drug Administration (FDA) approval. Therapy lines containing study drugs were excluded. Chi-square tests were used to compare age distributions of patients treated in real-world practice to patients treated in trials that support FDA approval. Results: At 6 months following FDA approval, 71.9% of patients with melanoma undergoing treatment were receiving anti-PD1s, versus 33.0% of patients with aNSCLC and 46.0% of patients with mRCC. Within 1 year, more than half of all treated patients with these 3 cancers were receiving anti-PD1s (71.0% in melanoma; 51.4% in aNSCLC; and 51.8% in mRCC). The median ages at first receipt of anti-PD1s were ≥65 years (65.1 years in melanoma; 67.9 years in aNSCLC; 66.0 years in mRCC). Anti-PD1 treated patients were significantly older in real-world practice than patients treated in trials (Table: all p<0.001). Conclusions: In a large national sample of patients with cancer, anti-PD1s were adopted rapidly into real-world practice. Compared to patients treated in real-world practice, older patients were underrepresented in clinical trials. [Table: see text]

scholarly journals Integration of Systemic Therapy and Stereotactic Radiosurgery for Brain Metastases

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3682
Author(s):  
Raees Tonse ◽  
Martin C. Tom ◽  
Minesh P. Mehta ◽  
Manmeet S. Ahluwalia ◽  
Rupesh Kotecha
Keyword(s):  
Stereotactic Radiosurgery ◽  
Systemic Therapy ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Whole Brain Radiotherapy ◽  
Cancer Therapeutics ◽  
Optimal Timing ◽  
The Impact ◽  
Systemic Therapies

Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and resection. However, the increased availability of molecular-based therapies with central nervous system (CNS) penetration now permits the individualized selection of tailored systemic therapies to be used alongside local treatments. Moreover, the introduction of immune checkpoint inhibitors (ICIs), with demonstrated CNS activity has further revolutionized the management of BM patients. The rapid introduction of these cancer therapeutics into clinical practice, however, has led to a significant dearth in the published literature about the optimal timing, sequencing, and combination of these systemic therapies along with SRS. This manuscript reviews the impact of tumor biology and molecular profiles on the management paradigm for BM patients and critically analyzes the current landscape of SRS, with a specific focus on integration with systemic therapy. We also discuss emerging treatment strategies combining SRS and ICIs, the impact of timing and the sequencing of these therapies around SRS, the effect of corticosteroids, and review post-treatment imaging findings, including pseudo-progression and radiation necrosis.

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