scholarly journals 631 Deep, durable response to PD-1 inhibitor monotherapy in microsatellite-stable, tumor mutational burden-high colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A661-A661
Author(s):  
Samuel Schellenberg ◽  
Leeseul Kim ◽  
Young Kwang Chae
Keyword(s):  
Colorectal Cancer ◽  
Carcinoembryonic Antigen ◽  
Immune Checkpoint ◽  
Treatment Initiation ◽  
The United States ◽  
Genomic Profiling ◽  
Durable Response ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

BackgroundImmune checkpoint inhibitors have revolutionized care for a number of different cancer types. For colorectal cancer (CRC), a leading cause of cancer-related death in the United States, programmed cell death protein 1 (PD-1) inhibition is a treatment option for certain subsets of patients. High microsatellite instability (MSI-H) tumors are immunogenic, and thus PD-1 inhibition is first-line treatment. Anti-PD-1 therapy is generally not utilized for microsatellite stable (MSS) patients. Tumor mutational burden (TMB) is another predictive biomarker for immunotherapy response in all solid tumors. Here we present the case of a patient with MSS, TMB-H CRC resistant to multiple lines of chemotherapy, who responded to anti-PD-1 monotherapy.MethodsCase presentation.ResultsA 64-year-old man with a family history significant for colon cancer was diagnosed with colorectal cancer, revealed to be moderately differentiated mucinous adenocarcinoma (stage IIIC) on biopsy. A tissue-based comprehensive genomic profiling of the cancer showed KRASG12D and ERBB2 amplification, microsatellite-stable, and TMB of 11mut/mB (FoundationOne). The patient progressed on multiple lines of therapy with multiple metastatic sites, and was briefly put under home hospice with diffuse abdominal pain and weight loss. The patient was started on pembrolizumab monotherapy, around 3.5 years after initial presentation. After five months on pembrolizumab, imaging showed significant improvement in pulmonary, hepatic, adrenal, and retroperitoneal metastases and the patient demonstrated partial response to treatment according to RECIST 1.1 criteria. The patient's carcinoembryonic antigen (CEA) levels had decreased from 45 ng/mL at treatment initiation to 2.8 ng/mL, and ctDNA analysis showed a blood TMB decrease from 31.58 mut/mB at treatment initiation to .96 mut/mB (figure 1), accompanied by decreases in the variant allele frequencies of the five most prevalent variants at the time of treatment initiation (Guardant 360). The patient's pain had nearly resolved by this point and pain medications were tapered off.ConclusionsThis case demonstrates the existence of a subset of CRC patients who are MSS but TMB-H and may respond to immune checkpoint blockade. Comprehensive genomic profiling must be utilized in order to not miss this subset of patients. The mechanism of response in this subset of patients is unknown but warrants further exploration. Further studies should clarify the mechanism and likelihood of response to immunotherapy in MSS, TMB-H CRC patients, as this is critical to providing effective treatment for this subset.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 631 Figure 1Carcinoembryonic antigen (CEA) and blood tumor mutational burden (TMB) levels through six cycles of treatment with pembrolizumab

Targeted therapy for HER2 driven colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3583-3583 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
Julia Andrea Elvin ◽  
Alexa Betzig Schrock ◽  
James Suh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Precision Therapy ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Upper Gastrointestinal ◽  
Colonic Adenocarcinomas

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.

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]

Adenocarcinoma (ACB), urothelial carcinoma (UCB) and squamous cell carcinoma (SCCB) of the bladder: A Comprehensive Genomic Profiling (CGP) Study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4533-4533 ◽  
Author(s):  
Joseph Jacob ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Elizabeth Kate Ferry ◽  
...  
Keyword(s):  
High Status ◽  
Genomic Profiling ◽  
Dna Repair Genes ◽  
Genomic Profile ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Repair Genes

4533 Background: We performed a CGP to compare the genomic alterations (GA) in ABC, UBC and SCCB. Methods: 143 cases of ACB, 2,142 cases of UCB and 83 cases of SCCB were subjected to CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: ABC patients were younger and more often female than UBC and SCCB (P < 0.0001). UBC and SCCB had a higher GA/tumor than ABC (P = 0.01). Un-targetable GA were similar in all 3 groups involving TP53 and KRAS. APC GA were more frequent in ABC whereas TERT, CDKN2A/B and DNA-repair genes ( ARID1A and KDM6A) more frequently altered in UBC and SCCB. Targetable MTOR pathway GA ( PIK3CA, TSC1, PTEN) were more frequent in UBC and SCCB as were targetable kinase alterations ( FGFR3 and ERBB2). The UBC and SCCB had a significantly higher TMB than ABC (P < 0.0001) including mean TMB and TMB > 20 mut/Mb (P < 0.0001). CD274 (PD-L1) was amplified more frequently in SCCB than ACB or UBC (P < 0.0001). MSI high status was very uncommon in all tumor types. Conclusions: Deep sequencing reveals that ABC features a widely different genomic profile from UBC and SCCB. UBC has the highest frequencies of targetable kinase GA and high TMB. SCCB has the highest frequencies of IO efficacy predicting biomarkers including mean TMB and PD-L1 amp. Nonetheless, ABC does feature potential kinase targets such as FGFR3 and ERBB2. [Table: see text]

Analysis of HER2 mutant bladder urothelial carcinomas reveals unique mutational signature.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 460-460
Author(s):  
Luke Juckett ◽  
Russell Madison ◽  
Jon Chung ◽  
Alexa Betzig Schrock ◽  
Brian Alexander ◽  
...  
Keyword(s):  
Transitional Cell ◽  
Large Set ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Signature ◽  
Mutational Burden ◽  
Urothelial Carcinomas ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Cancer Tumor

460 Background: Early work has described the presence of HER2 alterations in metastatic urothelial carcinomas (UC), particularly the micropapillary urothelial carcinoma (MPUC) subtype. We reviewed the genomic profiles of a large set of UC cases to further characterize HER2 altered UCs and how such alterations would suggest benefit from the expanding array of anit-HER2 therapeutics. Methods: Tissue from 2,150 UCs were assayed using hybrid capture-based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly arranged in cancer. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Results: Within the UC dataset 74.6% of cases were male (1603/2150), with a median TMB of 7 mut/Mb. 383 genomic alterations (GA) of HER2 were identified in 15.5% (334/2150) of cases which exhibited a median TMB of 8.7 mut/Mb (p < 1E-5) vs patients with wildtype HER2, median TMB of 7 mut/Mb. The most frequent HER2 alterations were amplification HER2amp (45.7%, 175/383), S310F (19.8%, 76/383), and S310Y (7/6%, 29/383). Patients harbouring a HER2amp, S310 (n = 105) exhibited a median TMB of 8.7 and 12.2 mut/Mb, respectively. 42 patients presented with multiple ( > 1) HER2 GA and exhibited a median TMB of 11.3 mut/Mb (p < 0.1) vs patients with single HER2 GA, median TMB of 12.3 mut/Mb. Of patients with multiple HER2 alterations, 57% (24/42) harbored a HER2amp. The most common co-occuring HER2 alteration pair was an amplification and extracellular S310X alteration (38.1%, 16/42). Of these 16, the median TMB was 19.5 mut/Mb (average 22.7 mut/Mb). Morphological assessments were performed on the 24 cases harbouring a HER2amp and an additional HER2 GA. 8 cases displayed MPUC features 44.4% (8/18; 6 cases histology unavailable); of these MPUC cases, 75% (6/8), harboured a HER2 amp and S310 extracellular mutation. Conclusions: CGP of bladder urothelial (transitional cell) carcinomas reveals subclasses of HER2 altered cases. Drawing on recent advances in targeting HER2 alterations in breast cancer, dual HER2 blockade (e.g. combinations of mAB/TKI/mAB+ADC) may be needed for HER2amp cases. For cases with both HER2amp and S310 GA, neratinib monotherapy may be the agent of choice and thus may be effective in MPUC.

Primary tumor (p-bx) versus metastatic tumor (m-bx) tissue versus liquid biopsy (lb) in intrahepatic cholangiocarcinoma (IHCC): A comparative comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4579-4579
Author(s):  
Jeffrey S. Ross ◽  
Ethan Sokol ◽  
Dean Pavlick ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
...  
Keyword(s):  
Drug Response ◽  
Soft Tissues ◽  
Metastatic Tumor ◽  
Genomic Profiling ◽  
Tissue Samples ◽  
Upper Gi ◽  
Metastatic Lesions ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

4579 Background: Genomic alterations (GA) characteristic of IHCC are well known. We queried whether GA from Pbx would differ from Mbx and Lbx in IHCC. Methods: Hybrid-capture based CGP was performed on 1,268 tissue samples of advanced stage IHCC using Pbx in 1,048 cases and Mbx from 220 cases and 364 Lbx cases (solid tissue: 318-327 genes, Lbx: 72 genes). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC. Results: Mbx sites included: lymph nodes (63), soft tissues (47), peritoneum (34), lung/pleura (27), omentum (15), bone (10), abdomen (7), GYN tract (5), liver (4), brain (2), Upper GI (2), colon (2), bladder (1), and adrenal (1). The GA/sample and biomarkers of immuno-oncology (IO) drug response were similarThe KRAS mutation frequency including G12C alterations was doubled in Mbx compared to Pbx and Lbx (p < 0.001). Frequencies of untargetable GA were similar overall. IDH1 (p < 0.001) and FGFR2 GA known to be enriched in IHCC were less frequent in Mbx than Pbx. Both IDH1 and FGFR2 were identified in Lbx. GA in STK11 (p < 0.001) and SMAD4 (p = 0.0016) were more frequently identified in Mbx. Conclusions: GA found in Pbx vs Mbx and Lbx in IHCC are significantly different; the Mbx cohort features greater KRAS and lower IDH1 and FGFR2 GA. Lbx detected more IDH1 GA than Mbx. This suggests that the Mbx group may contain non-IHCC cases whose metastatic lesions were actually derived from other primary sites and incorrectly assigned the diagnosis of IHCC. [Table: see text]

Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 426-426
Author(s):  
Joseph Jacob ◽  
Oleg Shapiro ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Ethan Sokol ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Metastatic Disease ◽  
Clear Cell ◽  
High Status ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Histologic Subtypes

426 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 126 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (27%) adenocarcinomas (UrthAC) and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Ages were similar in all groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher TMB and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. MSI high status was absent throughout. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials.[Table: see text]

The emerging target KRAS G12C in genitourinary malignancies.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 434-434
Author(s):  
Petros Grivas ◽  
Andrea Necchi ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clear Cell ◽  
Ffpe Tissue ◽  
Genomic Alteration ◽  
Genomic Profiling ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Urothelial Bladder ◽  
Bladder Carcinomas

434 Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (<1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p<0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]

Metastatic renal cell carcinoma (mRCC) in young patients: A comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 727-727
Author(s):  
Gennady Bratslavsky ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Statistical Evaluation ◽  
Clear Cell ◽  
Collecting Duct ◽  
Young Patients ◽  
High Status ◽  
Genomic Profiling ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Male Preponderance

727 Background: We studied the genomic alterations (GA) in patients with mRCC under 40 years of age (<40) and patients 40 years of age or older (>40). Methods: 2,128 mRCC underwent hybrid-capture based CGP. Clear cell (ccRCC), papillary (pRCC), sarcomatoid (sRCC), NOS (nosRCC), chromophobe (chrRCC), medullary (medRCC) and collecting duct (cdRCC) were separately evaluated. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Male preponderance in all subsets increased in the >40 patients. The GA/tumor increased significantly in the >40 cohorts except for in medRCC. The relatively low TMB was higher in all >40 and MSI high status was infrequent in all groups. PD-L1 expression was generally low, the 44% high positive PD-L1 in sRCC was noteworthy. Significant differences in GA in <40 vs >40 RCC included increased PBRM1 and SETD2 GA in >40 vs <40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in >40 vs <40 pRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in >40 vs <40 sRCC; increased TP53, VHL and TERT in >40 vs <40 nosRCC. Changes in GA in <40 vs >40 chrRCC, medRCC and cdRCC were noted but insufficient cases prevented statistical evaluation. Conclusions: When evaluated by age, CGP of mRCC demonstrates significant differences in the genomic landscapes with >40 cases featuring increasing male preponderance and higher GA/tumor, TMB and increases in TP53, CDKN2A/B and TERT GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of mRCC.[Table: see text]

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