Search

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture–based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P =.069) and GNAS (P =.071), were more common in U versus NU. Conversely, TERT (P <.01) and RB1 (P =.071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti–PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti–PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs. [ABSTRACT FROM AUTHOR]

PURPOSE: Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1 / 2 genes (g BRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1 / 2 mutations (s BRCA) or germline PALB2 mutations (g PALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g BRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). METHODS: A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record–derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. RESULTS: Of 28,920 patients with mBC, g BRCA was detected in 3.4%, whereas the population with any BRCA alteration or g PALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and g PALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g BRCA and s BRCA / gPALB2 cohorts were similar: g BRCA versus s BRCA /g PALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig– had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). CONCLUSION: Patients with s BRCA and g PALB2 derive similar benefit from PARPi as those with g BRCA alterations. In combination, HRDsig+, s BRCA , and g PALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted. This is real-world evidence supporting benefit of PARPi in sBRCA, gPALB2, and HRDsig. [ABSTRACT FROM AUTHOR]

PURPOSE: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT , FGFR2 , IDH1 , and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care. [ABSTRACT FROM AUTHOR]

PURPOSE: Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number–high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. METHODS: Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture–based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability–high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. RESULTS: PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. CONCLUSION: The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.20-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS. [ABSTRACT FROM AUTHOR]

PURPOSE: 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. [ABSTRACT FROM AUTHOR]

PURPOSE: Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS: Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS: One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P =.001). Compared with HPV-negative (HPV–) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P =.004), PTEN (14% v 2%; P <.0001), EP300 (14% v 1%; P <.0001), STK11 (14% v 1%; P <.0001), AR (5% v 0%; P =.006), and FBXW7 (10% v 3%; P =.03). In contrast, HPV– vSCCs showed more alterations in TP53 (83% v 6%; P <.0001), TERTp (71% v 9%; P <.0001), CDKN2A (55% v 2%; P <.0001), CCND1 amplification (22% v 2%; P <.0001), FAT1 (25% v 4%; P <.0001), NOTCH1 (19% v 6%; P =.002), and EGFR amplification (11% v 0%; P <.0001), as well as a higher rate of 9p24.1 (PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P =.04). CONCLUSION: Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV– vSCCs showed alterations in TP53 , TERTp , CDKN2A , CCND1 , and EGFR , and biomarkers associated with responsiveness to immunotherapy. [ABSTRACT FROM AUTHOR]

The article presents a case study of a girl in whom tumor sequencing caused identification of a new NTRK2 gene fusion in a metastatic sarcoma. Biopsy resulted in the diagnosis of Nonrhabdomyosarcoma soft tissue sarcoma which was treated by use of larotrectinib. The patient had distended abdomen with significant back pain requiring narcotics daily.

Purpose An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing or by using commercially available sequencing panels. Methods Whole-exome sequencing and RNA sequencing data of 33 solid cancer types from The Cancer Genome Atlas were analyzed to determine whether a robust immune checkpoint-activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker of response to immune checkpoint blockade therapy. Results We found that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in eight of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, and bladder-urothelial cancer. Tumors with a mutational burden higher than the threshold (iCAM positive) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma, and colon cancer, patients with iCAM-positive tumors had significantly better response to immune checkpoint therapy compared with those with iCAM-negative tumors. Receiver operating characteristic analysis using The Cancer Genome Atlas predictions as the gold standard showed that iCAM-positive tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne (Foundation Medicine, Cambridge, MA) or StrandAdvantage (Strand Life Sciences, Bangalore, India). Using the FoundationOne-derived threshold, an analysis of 113 melanoma tumors showed that patients with iCAM-positive disease have significantly better response to immune checkpoint therapy. iCAM-positive and iCAM-negative tumors have distinct mutation patterns and different immune microenvironments. Conclusion In eight solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays. [ABSTRACT FROM AUTHOR]

Purpose: 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., Competing Interests: Hatim HusainConsulting or Advisory Role: AstraZeneca, Foundation Medicine, PierianDx, Janssen, Blueprint Medicines, NeoGenomics Laboratories, Turning Point TherapeuticsSpeakers' Bureau: AstraZeneca, JanssenResearch Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), Regeneron (Inst), Lilly (Inst)Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine Dean C. PavlickEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Bernard J. FendlerEmployment: Foundation MedicineStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: The method to estimate the tumor fraction, used in the paper submission, currently has a patent pending. The original submission was on 26.11.2020. The submission number can be provided if needed. Russell W. MadisonEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Brennan DeckerEmployment: Foundation MedicineStock and Other Ownership Interests: Roche, VaccitechConsulting or Advisory Role: Foundation Medicine, Avidea TechnologiesPatents, Royalties, Other Intellectual Property: Foundation Medicine Ole GjoerupEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Christine A. ParachoniakEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Molly McLaughlin-DrubinEmployment: Foundation Medicine, Precision for Medicine (I)Stock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Foundation Medicine Rachel L. ErlichEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation MedicineResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Contributed to several patents and patents pending at Foundation MedicineTravel, Accommodations, Expenses: Foundation Medicine Alexa B. SchrockEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, Roche Garrett M. FramptonEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Meghna Das ThakurEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechResearch Funding: Roche/GenentechPatents, Royalties, Other Intellectual Property: Method of treating a proliferative diseaseTravel, Accommodations, Expenses: Roche/Genentech Geoffrey R. OxnardThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: Foundation MedicineStock and Other Ownership Interests: Roche Hanna TukachinskyEmployment: Foundation MedicineStock and Other Ownership Interests: RocheNo other potential conflicts of interest were reported.

Purpose: 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., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erik A. WilliamsEmployment: Foundation Medicine, Inc. Stock and Other Ownership Interests: F. Hoffmann-La RocheRadwa SharafEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheBrennan DeckerStock and Other Ownership Interests: Avidea Technologies Consulting or Advisory Role: Foundation Medicine, Avidea TechnologiesMeagan MontesionStock and Other Ownership Interests: RocheEthan S. SokolEmployment: Foundation Medicine Stock and Other Ownership Interests: Roche (Parent of FMI)Dean C. PavlickStock and Other Ownership Interests: RocheNikunj ShahEmployment: Foundation MedicineKevin Jon WilliamsStock and Other Ownership Interests: Hygieia, Gemphire Therapeutics Consulting or Advisory Role: Gemphire Therapeutics Research Funding: Novo NordiskJeffrey M. VenstromEmployment: Genentech, Foundation Medicine Leadership: Genentech Stock and Other Ownership Interests: Genentech Research Funding: Genentech, Roche, Foundation Medicine Travel, Accommodations, Expenses: GenentechBrian M. AlexanderEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Eli Lilly (Inst), Puma (Inst), Celgene (Inst) (OPTIONAL) Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summaryJeffrey S. RossEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics Research Funding: Foundation MedicineLee A. AlbackerEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheDouglas I. LinEmployment: Foundation MedicineShakti H. RamkissoonEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineJulia A. ElvinEmployment: Foundation Medicine No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)