The prognostic role of microsatellite status, tumor mutational burden, and protein expression in CRC.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 572-572 ◽  
Author(s):  
Sarit Schwartz ◽  
Yuan Tian ◽  
Fabiola Cecchi ◽  
Andrew Nguyen ◽  
Yeoun Jin Kim ◽  
...  
Keyword(s):  
Protein Expression ◽  
Treatment Options ◽  
Molecular Profiling ◽  
Clinical Samples ◽  
Rank Test ◽  
P16 Protein ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Patient Subgroups ◽  
P16 Expression

572 Background: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by WGS and RNA-seq; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as > 4.5 somatic mutations per megabase; p16 as > 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p < 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Further analyses of clinical correlates will be presented. Conclusions: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.

scholarly journals Immunohistochemical Analysis of BRAF (V600E) Mutation and P16 Expression in Malignant Melanoma in Lagos, Nigeria: A 10-Year Retrospective Study

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
O. Obadofin ◽  
K. Badmos ◽  
N. Orsi ◽  
M. Bipin ◽  
O. Rotimi ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Protein Expression ◽  
Immunohistochemical Analysis ◽  
Braf V600e Mutation ◽  
Breslow Thickness ◽  
University Teaching ◽  
Braf V600e ◽  
Clark Level ◽  
P16 Protein ◽  
P16 Expression

Background. In Blacks, malignant melanoma (MM) is associated with greater morbidity and mortality compared to Caucasians. MMs with BRAF V600E mutation as well as those with loss of p16 protein expression are associated with aggressive behavior and worse prognosis. Objectives. We determined BRAF (V600E) mutation status and loss of p16 expression in MM cases in Lagos, Nigeria, and correlated these with histopathologic parameters and patients’ age. Methods. Forty-five cases of MM received between January 2005 and December 2014 in the Anatomic and Molecular Pathology Department of Lagos University Teaching Hospital were subjected to immunohistochemical studies to determine BRAF V600E mutation and p16 protein expression. These included cutaneous (n=37), musosal (n=3), and ocular MM (n=2) as well as lymph node metastatases (n=3). Results. BRAF (V600E) mutations were detected in 5/45 (11%) while 31/45 (69%) of the cases had loss of p16 expression. No statistically significant association was found between the BRAF (V600E) mutation, loss of p16 expression, and histologic parameters such as histologic variant, Clark level, Breslow thickness, and ulceration. Conclusion. BRAF (V600E) mutation was detected only in a small proportion of cases while loss of p16 expression occurred in most cases which also had high Clark level, high Breslow thickness, and ulceration.

Gene-specific features (MLH1, MSH2, MSH6, PMS2) of mismatch repair (MMR) protein expression and somatic mutations (muts), microsatellite instability (MSI) and tumor mutational burden (TMB) in MSI-H and MMR-mutated tumor genomic profiles (TGPs).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Michael J. Hall ◽  
Joseph Nicholas Bodor ◽  
Joanne Xiu ◽  
Rebecca Feldman ◽  
Axel Grothey ◽  
...  
Keyword(s):  
Protein Expression ◽  
Somatic Mutations ◽  
Germ Line ◽  
Tumor Biomarker ◽  
Dna Repair Genes ◽  
Mmr Genes ◽  
Mutational Burden ◽  
Response Table ◽  
Tumor Mutational Burden ◽  
Repair Genes

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]

scholarly journals OA05 Tumor Mutational Burden Standardization Initiative: Establish a Consistent Methodology for TMB Measurement in Clinical Samples

2018 ◽  
Vol 13 (12) ◽  
pp. S1045-S1046
Author(s):  
A. Stenzinger ◽  
J. Allen ◽  
J. Maas ◽  
M. Stewart ◽  
D. Merino ◽  
...  
Keyword(s):  
Clinical Samples ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals A novel NCOR2-NTRK1 fusion detected in a patient of lung adenocarcinoma and response to larotrectinib: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lei Zhang ◽  
Huanhuan Liu ◽  
Ye Tian ◽  
Huina Wang ◽  
Xueying Yang
Keyword(s):  
Targeted Therapy ◽  
Lung Adenocarcinoma ◽  
Ct Scan ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Molecular Profiling ◽  
Case Presentation ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Breakpoint Location

Abstract Background The identification of NTRK fusions in tumours has become critically important due to the actionable events predictive of response to TRK inhibitor. It is not clear whether the NTRK breakpoint location is different for response to targeted therapy and NTRK fusions affects the efficacy of immunotherapy. Case presentation Here we reported a 60-year-old female diagnosed with advanced lung adenocarcinoma. NGS-based molecular profiling identified a novel NCOR2-NTRK1 fusion and high tumor mutational burden (TMB) (58.58 mutations/Mb) in this case. Additionally, program death-ligand 1 (PD-L1) expression was detected in 20–30% of the tumor cells by immunohistochemical (IHC) staining. The patient received treatment with anti-PD-1 immune checkpoint inhibitor of camrelizumab. After two cycles of treatment, the CT scan showed some tumor nodules were still enlarged, indicating disease progression. She was then changed to TRK inhibitor larotrectinib. One month later, the CT scan showed the volume of some lesions started to decrease, and no metastasis lesions were found. The patient then continued the administration of larotrectinib, and some lesion sizes were significantly reduced or even disappeared in the next few months. Currently, this patient is still alive. Conclusions Altogether, this report provided a new driver of lung adenocarcinoma expanded the mutational spectrum of NTRK1 fusion variants and suggested using larotrectinib as the targeted therapy is more effective than anti-PD-1 inhibitor in lung adenocarcinoma harboring with NTRK fusion, positive PD-L1 expression, and high TMB simultaneously.

Loss of p16 in recurrent malignant mixed müllerian tumors of the uterus

2006 ◽  
Vol 16 (3) ◽  
pp. 1354-1357
Author(s):  
B. Robinson-Bennett ◽  
R. Z. Belch ◽  
A. C. Han
Keyword(s):  
Tumor Suppressor ◽  
Protein Expression ◽  
Tumor Suppressor Genes ◽  
Antigen Expression ◽  
Genetic Profile ◽  
P16 Protein ◽  
Recurrent Tumors ◽  
Changes Over Time ◽  
P16 Expression ◽  
Over Time

Uterine malignant mixed müllerian tumors (MMMTs) are rare and highly aggressive malignancies with poor clinical prognoses. We examined for differences in the oncoprotein profiles of primary versus recurrent MMMTs. Five cases of recurrent uterine MMMT were examined by paraffin immunohistochemistry for the expression of p53, p16, P-cadherin, and Cerb-B2. P16, p53, and P-cadherin were each expressed in 100%, 80%, and 60% of the primary cases, respectively. Three cases expressed all three oncoproteins. All five cases were negative for Cerb-B2. No difference in antigen expression was seen in the epithelial versus sarcomatous components. Primary and recurrent tumors were concordant for p53, P-cadherin, and Cerb-B2. However, three cases of recurrent tumors were negative for p16 expression. P53, p16, and P-cadherin are common tumor suppressor genes expressed in uterine MMMT. Interestingly, p16 protein expression was lost in some cases of MMMTs when they recurred. This suggests that the oncoprotein and possibly genetic profile of p16 changes over time. We did not observe any difference in antigen expression between areas of epithelial or sarcomatous differentiation, which would support a single pluripotential malignant clone in the histogenesis of these tumors.

scholarly journals p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Nonoropharyngeal Head and Neck Squamous Cell Carcinoma

2014 ◽  
Vol 32 (35) ◽  
pp. 3930-3938 ◽  
Author(s):  
Christine H. Chung ◽  
Qiang Zhang ◽  
Christina S. Kong ◽  
Jonathan Harris ◽  
Elana J. Fertig ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Human Papillomavirus ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Hpv Infection ◽  
P16 Protein ◽  
Hazard Ratios ◽  
Hpv Status ◽  
P16 Expression

Purpose Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx. Patients and Methods p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics. Results p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes. Conclusion Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

scholarly journals Response to anti-PD1 immunotherapy in patients with metastatic cutaneous sarcoma: case reports and literature review

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Aline Cristini Vieira ◽  
Thais Baccili Cury Megid ◽  
Raissa Melo ◽  
David Muniz ◽  
Alessandra Corte Real Salgues ◽  
...  
Keyword(s):  
Case Reports ◽  
Treatment Options ◽  
Surgical Excision ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Targeted Agents ◽  
Mutational Burden ◽  
Metastatic Setting ◽  
Tumor Mutational Burden

Abstract Dermal sarcomas represent a group or rare malignancies of mesenchymal origin. Although surgical excision with wide margins can be curative, in the advanced/metastatic setting, treatment options are limited and the benefit from anthracycline-based chemotherapy or targeted agents is usually short-lived. Tumor mutational burden and PD-L1 expression scores can be used as predictive biomarker for response to immunotherapy in some metastatic cancers. The role of immune-checkpoint blockade for sarcoma patients remains investigational. Here we present three cases of dermal sarcomas with high TMB and PD-L1 expression and responses to anti-PD1 agents in two of them.

scholarly journals PD-L1 and Tumor Mutational Burden Are Not Predictive of Thrombosis in a Cohort of 1,221 Patients with Solid Organ Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1055-1055
Author(s):  
Rajat Thawani ◽  
Thomas Kartika ◽  
Benjamin Elstrott ◽  
Elizabeth Batiuk ◽  
Lilian Chen ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Subgroup Analysis ◽  
Clinical Samples ◽  
Solid Organ ◽  
Primary Malignancy ◽  
Thrombotic Risk ◽  
Mutational Burden ◽  
Multivariable Logistic Regression ◽  
Tumor Mutational Burden ◽  
Solid Organ Malignancy

Abstract Introduction: Malignancy is a well-known risk factor for thrombosis. While many clinical risk factors for cancer-associated thrombosis have been described, it remains unknown how certain tumor specific observations (such as programmed death ligand 1 expression (PD-L1) and tumor mutational burden (TMB)) correspond to thrombotic risk. To determine the relationship between PD-L1 and TMB quantification and thrombosis in patients with solid tumors, we evaluated a large cohort of clinical samples from an NCI designated cancer center, correlating tissue sample pathology with the development of venous or arterial thromboembolism. Methods: We performed a retrospective cohort study of patients between the ages of 18-89 who underwent histopathologic examination and next generation sequencing for a diagnosis of a solid organ malignancy at the Knight Cancer Institute between June 2019 and Feb 2021. Medical records were reviewed to document clinical and demographic information as well as for the development of thrombosis after cancer diagnosis. Multivariable logistic regression was performed to assess if PD-L1 expression and TMB are independent predictors of thrombosis. Subgroup analysis was then performed to evaluate whether this relationship differed by the organ of the primary malignancy. All analyses were conducted in R (R Core Team 2019). Results: We identified 1,221 patients with solid organ malignancies (mean age 62, 53.6% male). The most common malignancies in the cohort were lung cancer (13.8%), pancreatic cancer (12.3%) and colon cancer (12.3%). Thrombotic events occurred in 206 patients (16.8%) after diagnosis of their malignancy (100 deep vein thrombosis, 42 pulmonary embolism, 46 visceral vein thromboses, 6 superficial vein thromboses, and 11 arterial events). The mean time from initial biopsy to thrombosis was 224 days. TMB (mean 8.5 mutations/Mb) was evaluated in all patients in the cohort, while PD-L1 expression testing (mean 23.0%) was available for 255 patients. On multivariable logistic regression adjusting for age and patient sex, neither TMB (ORadj: 0.97, CI: 0.92-1.03) nor PD-L1 expression (ORadj 1.00, CI: 1.00-1.02) were significant predictors of thrombotic events. Subgroup analysis by primary malignancy type did not demonstrate any specific primary sites for which TMB or PD-L1 were predictive of thrombosis. Discussion: Our analysis found no predictive relationship between TMB and PD-L1 expression with thrombotic events in patients with solid organ malignancy. Further analysis is needed to determine if specific treatment protocols, such as the use of immunotherapy in patients with varying levels of PD-L1 and TMB, alter thrombosis risk. Disclosures Shatzel: Aronora Inc,: Consultancy.

scholarly journals The prognostic role of microsatellite status, tumor mutational burden and protein expression in CRC

2018 ◽  
Vol 29 ◽  
pp. v103
Author(s):  
J. Lam ◽  
Y. Kim ◽  
F. Cecchi ◽  
S. Woo ◽  
A. Chambers ◽  
...  
Keyword(s):  
Protein Expression ◽  
Prognostic Role ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Molecular profiling of appendix-derived pseudomyxoma peritonei (PMP).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 571-571 ◽  
Author(s):  
Elizabeth Gleeson ◽  
Rebecca Feldman ◽  
Sherri Z. Millis ◽  
Beth Mapow ◽  
Lynn Mackovick ◽  
...  
Keyword(s):  
Protein Expression ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Tumor Infiltrating Lymphocytes ◽  
Molecular Profiling ◽  
Low Frequencies ◽  
Rare Malignancy

571 Background: PMP is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. Cytoreductive surgery and intraperitoneal chemotherapy offers optimal outcomes for most patients; however, for patients that progress, there are few treatment options. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. Methods: 54 patients with appendix-derived PMP were included in the study and tested centrally at Caris Life Sciences (Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Targeted sequencing of 47 genes detected variants in KRAS (79%), GNAS (73%) and SMAD4 (18%). Mutations were found at low frequencies (n = 1-2) in APC, ATM, BRAF, PIK3CA, MLH1 and TP53. GNAS and KRAS co-occurrence was found in 38%. High rates of protein overexpression were found in EGFR (83%), cMET (59%), cKIT (58%) and PDGFRA (58%), respectively. Immune checkpoint expression was found in 36% (PD1-positive tumor infiltrating lymphocytes) and 9% (PDL1 tumor expression). Expression of surrogate markers of cell proliferation were found at low rates (TLE3 27%, TOP2A 22%), consistent with the slow-growing biology of PMP. PTEN was intact (wild type [100%] and positive IHC [80%]) in the majority of PMP. Patients exhibit stable microsatellite status and mismatch repair proficiency in 93% of patients. Importantly, multidrug resistance protein expression was found at high levels (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1) and irinotecan (TOPO1) chemo-sensitivities were found to be favorable in 93%, 87%, 77% and 65%, respectively. Conclusions: Molecular profiling by multiple platforms identified potential therapy options in the non-targetable setting of a KRAS-mutated population. The role of cMET-targeted therapies and immune checkpoint inhibitors merit further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate responses to systemic treatment.

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