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  • 1
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    Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 5 ( 2021-05), p. e002680-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 5 ( 2021-05), p. e002680-
    Abstract: Several studies have shown clinical outcomes data that support the use of CD274 (PD-L1 ) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI). Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry. Methods We analyzed all cases that underwent comprehensive genomic profiling (CGP) testing at Foundation Medicine between August 2014 and June 2020. CD274 CN changes were correlated with PD-L1 expression in tumor types where there were Food and Drug Administration approved companion diagnostic (CDx) claims and the CDx assay was used to assess PD-L1 expression. Results In all, 244 584 samples representing 290 solid tumor types were included in the study. Overall, 17.6% (42 983/244 584) had CD274 CN gains ( 〉 specimen ploidy), 44.6% (108 970/244 584) were CD274 CN neutral, and 37.9% (92 631/244 584) had CD274 CN loss. Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4% (42 636/244 584); ploidy +2, 6.2% (15 183/244 584); ploidy +3, 2.2% (5375/244 584); ploidy +4, 1.1% (2712/244 584); and ploidy +8, 0.2% (434/244 584). The prevalence of CN changes and CN positivity varied based on tumor type. CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5. 3.8, 8.4, 1.4, respectively; p 〈 0.05) and with microsatellite instability status in only clinically relevant tumor types (gastric adenocarcinoma, colorectal adenocarcinoma, uterine endometrial adenocarcinoma, esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma (OR: 5.2, 1.9, 3.2, 3.7 and 6.5, respectively; p 〈 0.05)). Conversely, CD274 CN changes were not significantly correlated with tumor mutational burden in almost all the tumor types. Conclusion CD274 CN changes and PD-L1 expression were highly correlated in multiple tumor types. These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-002680
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 2
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    Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 292-292
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 292-292
    Abstract: 292 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (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: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p 〈 .0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in only 2.3% of the ccRCC cases with 37% of the GA predicted to be germline. chrRCC did not reveal somatic or germline FLCN GA. GA/tumor were slightly higher in ccRCC vs chrRCC (3.6 vs 2.4; NS). GA more frequent in chrRCC included TP53, RB1 and PTEN. GA more frequent in the ccRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Putative biomarkers of immune checkpoint inhibitor (ICPI) response were infrequent in both groups with only a slightly higher, but still low, mean TMB in ccRCC vs chrRCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chrRCC group. Conclusions: FLCN mutations that are associated with the familial incidence of chrRCC were not associated with sporadic chrRCC. Sporadic chrRCC has substantially different genomic profile from ccRCC and may harbor a few ‘targetable’ GA. The prediction of response to ICPI in RCC remains challenging with chrRCC featuring slightly higher PD-L1 expression and ccRCC featuring higher PBRM1 GA and higher TMB.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.292
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Genomic classification of clinically advanced major genito-urinary cancers (GUca) based on methylthioadenosine phosphorylase ( MTAP ) genomic loss.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 164-164
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 164-164
    Abstract: 164 Background: Novel treatments for clinically advanced GUca including castrate resistant prostate ca (PC), bladder urothelial ca (BUC) and clear cell renal ca (ccRCC) are widely needed. Recently, the targeting of cancer cells with arginine accumulation caused by MTAP loss has emerged as a new synthetic lethality-based anti-cancer program. Methods: 8,436 mCRPC, 2,683 BUC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (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 up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Dako 22C3). Results: 1.3% of PC, 24.2% of BUC and 5.5% of ccRCC featured MTAP loss. There were no significant age or gender differences associated with MTAP loss. CDKN2A/B loss ranged from 94% in ccRCC to 〉 99% in PC and BUC. The GA/tumor frequencies were similar when CDKN2A/B GA are excluded. In PC, GA in TP53, PTEN and BRCA1 were more frequent, while GA in AR, CDK12, RB1 and BRCA2 were less frequent in cases with MTAP loss. In BUC, GA in TSC1 and FGFR3 were more frequent and GA in RB1and TP53 were less frequent in cases with MTAP loss. In ccRCC, GA in NF2 were more frequent in cases with MTAP loss, while GA in VHL and PBRM1 were less frequent in cases with MTAP loss. “Targetable” kinase GA were rare in all groups, except for FGFR3 GA in MTAP loss BUC. Immunotherapy (IO) putative biomarkers varied among tumors, with MSI-high status less frequent and TMB ≥ 10 mut/Mb more frequent in BUC MTAP-intact than BUC with MTAP loss. PD-L1 expression was similar except for high PD-L1 expression more frequent in MTAP-intact BUC. Conclusions: When compared with PC and ccRCC, the clinical development of novel drugs, such as PRMT5 and MTA2 inhibitors in GUca will likely be focused on BUC given the 24% frequency of MTAP loss in that tumor type. CGP of PC, BUC and ccRCC reveal significant differences in GA in MTAP-intact and tumors with MTAP loss, which may impact future combinatorial clinical trial designs.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.164
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase ( MTAP ) deletion.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9116-9116
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9116-9116
    Abstract: 9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P 〈 .0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P 〈 .0001) and RB1 and a lower frequency of SMARCA4 (P 〈 .0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9116
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 5
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    Expanding the use of targeted therapy for urothelial bladder cancer (UBC): Non- FGFR3 receptor tyrosine kinase (RTK) gene rearrangements (ReAr) and fusions (fus).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 550-550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 550-550
    Abstract: 550 Background: After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC. We queried a large database of advanced UBC to study the landscape of RTK ReAr and Fus to categorize additional targets beyond FGFR1-3 that have potential to further personalize treatment of this disease. Methods: We analyzed data from 8,233 UBC cases, which underwent hybrid capture-based comprehensive genomic profiling (CGP). 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 in tumor cells was assessed by IHC (Dako 22C3). Results: A total of 1,210 (14.7%) UBC featured known and likely large-scale (LS) internal ReAr with 414 (5%) ReAr in RTK genes. The ReAr/fus were distributed among ABL1 (3), ALK (3), BRAF (29), CDK12 (44), CDK8 (1), EGFR (10 ), ERBB2 (3), FGFR1 (2), FGFR2 (16 ), FGFR3 (231), FLT3 (1), MAO2K4 (4), NTRK1 (7 ), NTRK2 (5), NTRK3 (7), RAF1 (31 ), RET (8) and ROS1 (9). LS ReAr were divided into LS ReAr-associated gene deletions (1%), truncations (1%), rearrangements (61%) and fusions (37%). FGFR3 fus accounted for 81% of RTK fus with BRAF and RAF1 both at 2%. The greatest frequencies of kinase ReAr were in CDK12 (29%), FGFR3 (16%), RAF1 (13%) and BRAF (12%). Additional noteworthy ‘targetable’ RTK ReAR and fus included NTRK1-3 (19 cases), ROS1 (9 cases), RET (8 cases) and ALK (1 case). 407 (98.4%) of the RTK ReAr/fus-positive UBC had only 1 RTK ReAr/fus GA and 7 (1.6%) had 2 ReAr ReAr/fus, 6 (85.7%) of which involved FGFR3. Compared with LS ReAR negative UBC, the LS ReAR UBC cases revealed similar gender and age characteristics, MSI status, similar frequencies of TMB ≥ 10 mut/Mb and PD-L1 expression in tumor cells ≥1% and ≥50%. Conclusions: At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors ( CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 6
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    Genomic landscape of MSH6 -mutated clinically advanced castrate-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 5062-5062
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 5062-5062
    Abstract: 5062 Background: Loss-of-function genomic alterations (GAs) in MSH6 have been associated with a unique subtype of hypermutated mCRPC that is often microsatellite stable (MSS) and may occur in either a sporadic or familial Lynch Syndrome-like clinical setting. Methods: 5,617 mCRPC cases were sequenced to evaluate all classes of GA using a hybrid capture-based FDA-approved comprehensive genomic profiling (CGP) assay. Tumor mutational burden (TMB) was determined on 0.8 Mb of sequenced DNA and microsatellite instability high (MSI-High) was determined on 95 loci. MSI-low status was not assessed. Results: 78 (1.4%) mCRPC were MSH6 mut (Table). MSH6 mut mCRPC included 73.1% short variant mutations, 23.1% biallelic deletions, 2.6% genomic rearrangements, and 1.3% multiple GAs/sample. Co-mutation of MSH2 was found in 28% of MSH6 mut cases vs. 2% in MSH6 wt cases (P 〈 .0001) and was most frequently caused by biallelic co-deletion of both genes (73% of co-mutated cases). MSI-High status was present in 46% of MSH6 mut mCRPC, which was significantly greater than the 2% seen in MSH6 wt cases (P 〈 .0001). An MMR single nucleotide mutational signature was observed in 65% of MSH6 mut cases, compared to 3% MSH6 wt cases (P 〈 .0001). Among MSH6 mut cases with neither MSI-High nor MMR mutational signature, 87% did not have biallelic loss of MSH6 or any other MMR gene, confirming that monoallelic pathogenic mutations are insufficient to cause the MMR-D phenotype. For subjects whose variants could be classified, 45% (19/42) of pathogenic MSH6 alleles were germline; of these, 58% (11/19) had neither MSI-High nor an MMR single nucleotide signature. MSH6 mut cases had fewer TMPRSS2: ERG fusions (P =.01), but harbored significantly higher frequencies of GAs in AR (P =.0002), ATM (P =.04), PIK3CA (P =.0003), APC (P =.005), ERBB2 (P =.001), and CDK6 (p =.046), likely at least partially attributable to the higher TMB in MSH6 mut cases (P 〈 .0001). Conclusions: MSH6 mut mCRPC is a unique disease that often features a hypermutated genomic signature, although only 46% of cases exhibited MSI-high status. This complex phenotype highlights the potential utility of multiple rather than single biomarkers to understand tumor biology and determine patients who may benefit from immunotherapy.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.5062
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 7
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    Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UBC) genomic alteration (GA) profile.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 563-563
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 563-563
    Abstract: 563 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of 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. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.563
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 8
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    CDKN2C -Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53 / RB1 –Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  JCO Precision Oncology , No. 4 ( 2020-11), p. 955-971
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 4 ( 2020-11), p. 955-971
    Abstract: Leiomyosarcoma (LMS) harbors frequent mutations in TP53 and RB1 but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers. METHODS Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture–based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases. RESULTS Overall, 77 LMS exhibited homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare compared with the remainder of the LMS cohort (11.7% v 73.4%, 0% v 54.5%, 2.6% v 24.5%, respectively; all P 〈 .0001). CDKN2C-null LMS patient cases were significantly enriched for GAs in CIC (40.3% v 1.4%) at 19q13.2, CDKN2A (46.8% v 7.0%), and RAD51B (16.9% v 1.7%; all P 〈 .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of CDKN2C-null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort ( P 〈 .0001). In total, 99% of CDKN2C-null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative. CONCLUSION CDKN2C-null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00040
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
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    Tumor Fraction Correlates With Detection of Actionable Variants Across 〉 23,000 Circulating Tumor DNA Samples
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Precision Oncology , No. 6 ( 2022-11)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-11)
    Abstract: Profiling of circulating tumor DNA (ctDNA) is increasingly adopted in the management of solid tumors, concurrent with increased availability of more comprehensive ctDNA panels. However, variable ctDNA shed can result in variable assay sensitivity. We studied the relationship between ctDNA tumor fraction (TF) and detection of actionable alterations across cancer types. METHODS A total of 23,482 liquid biopsies (LBx) submitted between September 2020 and October 2021 were sequenced using a hybrid capture panel that reports genomic alterations (GAs) and genomic biomarkers across 324 cancer-related genes. The primary end points were the prevalence of targetable GAs by cancer type and detection in relationship to ctDNA TF. Sensitivity of detection in LBx was assessed in 1,289 patients with available tissue results. RESULTS 94% (n = 22,130) of LBx had detectable ctDNA, with a median TF of 2.2%. LBx profiling detected GAs in National Comprehensive Cancer Network category 1 genes in 37% of lung, 30% of prostate, 36% of breast, and 51% of colon cancer cases. Potential germline GAs flagged on clinical reports were detected in genes including BRCA1/2, PALB2, CHEK2, and ATM. Polyclonal mutations in genes associated with resistance such as AR, ESR1, RB1, and NF1 were detected. The sensitivity of LBx to detect driver alterations identified in tissue biopsy from the same patient ranged from 58% to 86% but was consistently at or near 100% in cases with TF ≥ 10%. CONCLUSION Elevated ctDNA shed is associated with both high sensitivity and negative predictive value for detection of actionable GAs. The presence of elevated TF suggests adequate tumor profiling and may reduce the value of subsequent reflex to confirmatory tissue testing in patients with negative LBx results.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.22.00261
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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