Distinct Clinicopathological Features Research Articles

Recurrent YAP1::MAML2 fusions in “nodular necrotizing” variants of myxoinflammatory fibroblastic sarcoma: a comprehensive study of 7 cases

AbstractMyxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue tumor with a predilection for the distal extremities and a tendency for local recurrence. Morphologically, MIFS consists of spindle and bizarre epithelioid cells resembling virocytes embedded in a fibrous to myxoid stroma with an abundant inflammatory infiltrate. Importantly, the molecular landscape of MIFS is wide and includes: VGLL3 amplification, BRAF fusion/amplification and OGA/TGFBR3 rearrangements. In this study, we describe a variant of MIFS showing a frequent nodular configuration associated with necrosis and recurrent YAP1::MAML2 fusions. The cohort consisted of 7 patients (4 females and 3 males) ranging in age from 21 to 71 years (median: 47 years). Two tumors (28%) occurred in acral locations while the remaining cases were more widely distributed (thigh, n = 2; arm, n = 1; neck; n = 1; chest-wall, n = 1). Tumor size ranged from 10 to 38 mm (median: 20 mm). Histologically, lesions frequently presented as nodules with central areas of necrosis, and were predominantly composed of sheets of epithelioid cells with large vesicular nuclei and prominent nucleoli (Reed-Sternberg-like cells or virocytes). The stroma was mostly fibrous and showed a polymorphous inflammatory infiltrate. Myxoid stromal changes were focally seen in one case, and pseudolipoblasts were absent. The immunophenotype was nonspecific, with only pan-keratin (AE1-AE3) and cyclin D1 expression in a subset of cases. RNA-Sequencing detected YAP1::MAML2 fusions in 3/7 cases; aCGH showed no significant gene copy number variations in 4 tested cases, and FISH analysis showed no VGLL3 amplification in 1 tested case. Follow-up was available for 6 cases, ranging from 7 to 63 months (median: 42 months). Local recurrence and metastasis were not seen and one tumor showed spontaneous regression following initial biopsy. In conclusion, we describe a novel variant of MIFS with distinctive clinicopathological and molecular features for which we propose the term “nodular necrotizing” MIFS.

AR Expression Correlates with Distinctive Clinicopathological and Genomic Features in Breast Cancer Regardless of ESR1 Expression Status.

Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression in breast cancer remains unclear. This study analyzed the clinicopathological and molecular features associated with AR negativity in both ER-positive and ER-negative breast cancer, trying to elucidate the molecular correlation between AR and ER. Our results showed that AR negativity was associated with different clinicopathological characteristics and molecular features in ER-positive and ER-negative breast cancer. Moreover, AR-positive breast cancer has better clinicopathological features than AR-negative breast cancer, especially in the ER-negative subtype. These results suggest that the role of AR in ER-negative breast cancer is distinctive from that in ER-positive breast cancer.

Evaluation of the characteristics of multiple human papillomavirus (HPV) infections identified using the BD Onclarity HPV assay and comparison with those of single HPV infection.

BackgroundHuman papillomavirus (HPV) infection is a major cause of cervical cancer and associated precursor lesions. Multiple HPV genotype infections have been reported. However, their clinicopathological characteristics still remain elusive.MethodsFor this study, 814 consecutive patients who had undergone colposcopy and HPV genotyping test using BD Onclarity HPV assay were retrospectively selected. Clinicopathological parameters of multiple HPV infections were compared with those of single HPV infection.ResultsMultiple HPV infections were found in 110 out of 814 cases (13.5%). Multiple HPV infections were associated with a significantly higher incidence of high-grade intraepithelial lesions (HSILs) compared with single HPV infection. Other high-risk HPV genotypes, in addition to HPV 16, were found more frequently in the multiple HPV infections group; these included HPV 51, 52, 33/58, 56/59/66, and 35/39/68. No specific coinfection pattern was not identified. Additionally, the number of HPV genotypes in multiple HPV infections was not associated with the progression to HSIL or squamous cell carcinoma.ConclusionsMultiple HPV infections have distinct clinicopathological characteristics (compared with single HPV infection). As their biological behavior is uncertain, close and frequent follow-up is warranted.

Intrinsic immune evasion patterns predict temozolomide sensitivity and immunotherapy response in lower-grade gliomas

BackgroundAlthough intrinsic immune-evasion is important in cancer proliferation, metastasis and response to treatment, it is unclear whether intrinsic immune-evasion patterns of gliomas can aid in predicting clinical prognosis and determining treatment.MethodsA total of 182 immune-evasion genes intrinsic to cancer were subjected to consensus clustering to identify immune-evasion patterns in 1421 patients with lower-grade glioma (LGG). The levels of each cancer hallmark were determined by the Gene Set Variant Analysis (GSVA) method, and immune cell infiltrations were quantified using two algorithms, the single-sample Gene Set Enrichment Analysis (ssGSEA) and the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) methods. IEVscore was determined by a method that combined univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression and principal component analysis (PCA).ResultsTranscriptional and genomic analysis showed that most immune evasion genes (IEVGs) were upregulated in LGGs, with aberrant expression driven by alterations in copy number variants (CNV). Based on the mRNA expression profiles of cancer-intrinsic IEVGs could be divided into three LGG subgroups with distinct prognosis, clinicopathological features and immune infiltrations. A combined scoring scheme designed to assess the immune-evasion levels of LGGs divided these 1421 patients into two subgroups that differed in IEVscores. LGG patients with low-IEVscore had a better prognosis, would be more likely to benefit from immune check-point inhibitors and would be more susceptible to temozolomide (TMZ) chemotherapy.ConclusionIntrinsic immune evasion in the tumor microenvironment (TME) has a crucial effect on glioma formation. Quantitatively assessing the IEV scores of individual LGG patients could enhance knowledge about the intra-glioma microenvironment and lead to the development of individualized therapeutic strategies for patients with LGG.

Prognostic Significance of Low HER2 Expression in Patients With Metastatic Hormone Receptor-positive Breast Cancer Treated With First Line CDK4/6 Inhibitors: A Greek Multicenter Real-world Data Analysis.

Low expression of HER2 has defined a new "HER2-low" subgroup of breast cancer with distinct clinicopathological characteristics and both prognostic and predictive implications. The impact of low HER2 expression in metastatic hormone receptor-positive HER2-negative breast cancer treated with first-line CDK4/6 inhibitors has not been studied. Using real-world patient data, we aimed to identify prognostic differences in this patient population according to HER2 expression with immunohistochemistry. We retrospectively analyzed 191 patients from 5 Oncology Department databases in Thessaloniki, Greece, with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors in the first line, for whom detailed immunohistochemical HER2 data could be retrieved. Median progression-free survival was numerically different among the different HER2 subgroups (3.35 years for HER2 0 tumors, 2.18 years for HER2 +1 tumors, 1.74 years for HER2 +2/ISH-negative tumors), but this difference was not statistically significant (p=0.477). Median PFS was statistically significantly longer in patients without visceral metastases (5.45 years) compared to patients with visceral metastases (1.61 years) (p=0.017). Median PFS was also statistically significantly longer in patients taking an aromatase inhibitor (2.99 years) compared to patients taking fulvestrant (1.33 years) (p<0.0001). There were no statistically significant differences in the other subgroups examined. CDK4/6 inhibitors are equally effective as first-line treatment agents, regardless of the exact level of HER2 expression. Numerical differences, however, do exist among the different HER2 subgroups, and merit further evaluation in future studies to better study this phenomenon.

Clinicopathologic Features and Genomic Signature of De Novo CD5 + Diffuse Large B-Cell Lymphoma : A Multicenter Collaborative Study.

De novo CD5 + diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5 + DLBCL and 60 patients with CD5 - DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5 - DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5 + DLBCL. Most patients with CD5 + DLBCL had lymph nodes with non-germinal center B-cell-like or activated B-cell-like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88 and CD79B mutations) in the CD5 + DLBCL cohort was higher than that in the CD5 - DLBCL cohort (54.2% vs. 13.0%, P =0.005). Compared with the CD5 - cohort, CD5 + DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P <0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5 + DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5 + DLBCL patients. In summary, CD5 + DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell-like and MCD subtypes with worse survival outcome.

Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease

The methionine (M)—valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.

Clinicopathologic features of de novo non-alcoholic steatohepatitis in the post-transplant setting

BackgroundNon-alcoholic steatohepatitis (NASH) has become an increasingly recognized problem in patients after orthotopic liver transplant. The aims of this study were to compare the clinicopathologic features of recurrent and de novo NASH.MethodsFrom 1995 to 2016, we performed a retrospective review of patients with a histological diagnosis of non-alcoholic steatohepatitis made more than 6 months after liver transplant at University of California, San Francisco. The cases were categorized into de novo (n = 19) or recurrent steatohepatitis (n = 37).ResultsHepatitis C virus (HCV) infection-related cirrhosis was the most common etiology of transplantation in de novo NASH (78% of cases, n = 29). There was no difference in glycogenosis or presence of grade 3 steatosis. More recurrent NASH biopsies had small ballooned hepatocytes (62.5% of cases) compared to de novo NASH (26.7%) (p = 0.03), and were less likely to show prominent portal inflammation (5% versus 40.5%, p = 0.0049). The diagnosis of recurrent NASH was made significantly sooner after transplantation than the diagnosis of de novo NASH (2.8 years versus 4.8 years, p = 0.02).ConclusionsOverall, our results support that recurrent NASH demonstrates distinct clinicopathologic features compared to de novo NASH arising in the post-transplant setting.

Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma.

Anaplastic large cell lymphoma (ALCL) can be classified genetically based on rearrangements (R) of the ALK , TP63 , and/or DUSP22 genes. ALK- R defines a specific entity, ALK-positive ALCL, while DUSP22- R and TP63- R define subgroups of ALK-negative ALCLs with distinct clinicopathologic features. ALK -R and TP63 -R produce oncogenic fusion proteins that can be detected by immunohistochemistry. ALK immunohistochemistry is an excellent surrogate for ALK- R and screening with p63 immunohistochemistry excludes TP63- R in two third of ALCLs. In contrast, DUSP22 -R does not produce a fusion protein and its identification requires fluorescence in situ hybridization. However, DUSP22- R ALCL has a characteristic phenotype including negativity for cytotoxic markers and phospho-STAT3 Y705 . Recently, we also identified overexpression of the LEF1 transcription factor in DUSP22- R ALCL. Here, we sought to validate this finding and examine models for predicting DUSP22- R using immunohistochemistry for LEF1 and TIA1 or phospho-STAT3 Y705 . We evaluated these 3 markers in our original discovery cohort (n=45) and in an independent validation cohort (n=46) of ALCLs. The correlation between DUSP22- R and LEF1 expression replicated strongly in the validation cohort ( P <0.0001). In addition, we identified and validated a strategy using LEF1 and TIA1 immunohistochemistry that predicted DUSP22- R with positive and negative predictive values of 100% after exclusion of indeterminate cases and would eliminate the need for fluorescence in situ hybridization in 65% of ALK-negative ALCLs. This approach had similar results in identifying DUSP22- R in the related condition, lymphomatoid papulosis. Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL.

Clinicopathological and molecular characterization of early gastric adenocarcinoma in Helicobacter pylori-uninfected patients: emphasis on differentiated gastric adenocarcinoma.

Recently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated. We evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS). Among 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%). Overall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations.

Further Characterization of Clinicopathologic Features of Cystic Neutrophilic Granulomatous Mastitis

Clinical and demographic features of cystic neutrophilic granulomatous mastitis (CNGM) have not been fully explored due to the rarity of the disease. Herein we studied clinicopathologic characteristics of CNGM in a sizable hospital-based cohort. A case-control study was performed to compare clinicopathologic characteristics between patients with CNGM and granulomatous mastitis other than CNGM and between CNGM with and without Corynebacterium identification. Cases of CNGM (n = 31) and non-CNGM (n = 30) were included. Compared with the non-CNGM group, patients with CNGM were statistically significantly younger (median age: 38 vs 43 years), were less likely to be smokers (9% vs 40%), were more likely to have a painful lesion (97% vs 77%) or a larger mass-like lesion (median size: 4.6 vs 1.9 cm), and tended to have a higher Breast Imaging Reporting and Data System score in radiologic studies (score ≥4: 81% vs 53%), positive Corynebacterium identification results (36% vs 0%), and a longer resolving time (12 vs 6 months; all P values for above comparisons <.05). Among CNGM cases, patients with and without Corynebacterium identification shared a similar clinicopathologic profile. Our study further demonstrated that CNGM is a unique infectious disease with distinct clinicopathologic features.

Classification of colon adenocarcinoma based on immunological characterizations: Implications for prognosis and immunotherapy.

Accurate immune molecular typing is pivotal for screening out patients with colon adenocarcinoma (COAD) who may benefit from immunotherapy and whose tumor microenvironment (TME) was needed for reprogramming to beneficial immune-mediated responses. However, little is known about the immune characteristic of COAD. Here, by calculating the enrichment score of immune characteristics in three online COAD datasets (TCGA-COAD, GSE39582, and GSE17538), we identified 17 prognostic-related immune characteristics that overlapped in at least two datasets. We determined that COADs could be stratified into three immune subtypes (IS1–IS3), based on consensus clustering of these 17 immune characteristics. Each of the three ISs was associated with distinct clinicopathological characteristics, genetic aberrations, tumor-infiltrating immune cell composition, immunophenotyping (immune “hot” and immune “cold”), and cytokine profiles, as well as different clinical outcomes and immunotherapy/therapeutic response. Patients with the IS1 tumor had high immune infiltration but immunosuppressive phenotype, IS3 tumor is an immune “hot” phenotype, whereas those with the IS2 tumor had an immune “cold” phenotype. We further verified the distinct immune phenotype of IS1 and IS3 by an in-house COAD cohort. We propose that the immune subtyping can be utilized to identify COAD patients who will be affected by the tumor immune microenvironment. Furthermore, the ISs may provide a guide for personalized cancer immunotherapy and for tumor prognosis.

Pediatric-Type Indolent B-Cell Lymphomas With Overlapping Clinical, Pathologic, and Genetic Features.

Pediatric-type follicular lymphoma (PTFL) and pediatric nodal marginal zone lymphoma (PNMZL) are rare pediatric-type indolent B-cell lymphomas (PedIBCL) that differ clinicopathologically from their adult counterparts. Accurate diagnosis is important to avoid overtreatment but is often challenging. The mutational landscape of PTFL is known and may aid diagnosis, but the genetic features of PNMZL are not well understood. We analyzed 21 cases of PedIBCL according to their clinicopathologic findings and classified them into PTFL (n=11), PNMZL (n=2), and “mixed type” tumors (n=8) showing ambiguous histology. We also analyzed 2 cases of adult B-cell lymphomas showing features of PedIBCL. Targeted sequencing of 121 lymphoma-related genes was performed. The median age of PedIBCL patients was 16 years (range: 3 to 47), and all but 1 PTFL patient were male. All patients presented with limited-stage disease, and only 1 relapsed. There were no significant differences in clinical features among the 3 PedIBCL groups. The most frequently mutated genes were MAP2K1, TNFRSF14, KMT2C, IRF8, and NOTCH2. The genetic features of all groups were similar to the established mutational landscape of PTFL. The 2 adult B-cell lymphomas cases also had MAP2K1, TNFRSF14, and IRF8 mutations, but the clinical features were not typical of PedIBCL. In summary, this study demonstrated that PTFL and PNMZL are similar diseases with overlapping clinical, pathologic, and genetic features; mixed type tumors can also occur. Atypical adult cases with similar histologic features were also observed. Therefore, the disease spectrum of PedIBCL may be much broader than is currently believed.

Clinicopathologic and genomic features of high-grade pattern and their subclasses in lung adenocarcinoma

IntroductionRecent lung adenocarcinoma (LUAD) grading system proposed by the International Association for the Study of Lung Cancer (IASLC) has emphasized the proportion of high-grade patterns (HGPs). We aimed to evaluate the clinicopathologic and genomic characteristics associated with HGP which has not yet been fully investigated. MethodsTissue samples from 174 patients who underwent surgical resection of LUAD from January to December 2015 were histologically evaluated. Proportions of HGPs, including solid, micropapillary, cribriform, and complex glandular patterns, were individually quantified. Prognostic implications of HGP proportion, both as a continuous variable and as subclasses divided by cutoffs of 20%, 50%, and 90% (low-intermediate grade [LIG], HGP <20%; high grade 1 [HG1], 20-<50%, HG2, 50-<90%; HG3, ≥90%) were evaluated. Different clinicopathologic factors and genomic alterations according to the HGP subclasses were assessed. ResultsRelative hazards of the HGP gradually elevated as its proportion increased over 20%, the cut-off value established by the IASLC grading system, and the cancer-specific overall survival (OS) of HG1 subclass was not significantly decreased compared to the LIG subclass on univariate analysis. However, further subgrouping showed significantly increased frequencies of male, advanced stage tumors, lymphovascular invasion, and spread through alveolar space in higher HGP subclasses. Also, common LUAD driver mutations, particularly EGFR mutations, were less frequent, whereas alterations in TP53 and cell cycle pathway-related genes were more frequent. Higher HGP subclasses and TP53 gene alteration were associated with shorter cancer-specific OS and RFS in multivariate survival analysis. ConclusionsHGP subclasses of LUAD displayed distinct clinicopathological characteristics and genomic alterations, including TP53 and cell cycle pathway, emphasizing the clinical value of these subclasses in LUAD. Higher HGP subclass and alteration in TP53 may be markers of poor post-operative survival.

The m7G-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Tumour Immune Infiltration in Colon Cancer.

With high morbidity and mortality, colon cancer (CC) is considered as one of the most often diagnosed cancers around the world. M7G-related lncRNA may provide a regulatory function in the formation of CC, but the principle of regulation is still unclear. The purpose of this research was to establish a novel signature that may be used to predict survival and tumour immunity in CC patients. Data about CC in TCGA was collected for analysis, coexpression analysis and univariate Cox analysis were used to screen prognostic m7G-related lncRNAs. A consensus clustering analysis based on prognostic m7G-related lncRNAs was applied, and a prognosis model based on least absolute shrinkage and selection operator (LASSO) regression analysis was established. Independent prognostic analysis, nomogram, PCA, clinicopathological correlation analysis, TMB, survival analysis, immune correlation analysis, qRT–PCR and clinical therapeutic compound prediction were also applied. 90 prognostic m7G-related lncRNAs were found, GO and KEGG analysis showed that prognostic m7G-related lncRNAs were mainly related to cell transcription and translation. The results of the consensus clustering analysis revealed substantial disparities in survival prognosis and tumour immune infiltration between two clusters. We built a risk model with 21 signature m7G-related lncRNAs, patients in the high-risk group had a considerably poorer prognosis than those in the low-risk group. Independent prognostic analysis confirmed that patients’ prognosis was linked to their tumour stage and risk score. PCA, subgroups with distinct clinicopathological characteristics were studied for survival, multi-index ROC curve, c-index curve, the survival analysis of TMB, and model comparison tested the reliability of risk model. A tumour immunoassay revealed a substantial difference in immune infiltration between high-risk and low-risk individuals. Five chemicals were eliminated, and qRT–PCR indicated that the four lncRNAs were expressed differently. Overall, m7G-related lncRNA is closely related to colon cancer and the 21 signature lncRNAs risk model can efficiently evaluate the prognosis of CC patients, which has a possible positive consequence for the future diagnosis and therapy of CC.

Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer

It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer. To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC). This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022. Standard treatment according to institutional guidelines. Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease-free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer. Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER-very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease-free survival, or overall survival were observed among patients with HR-positive tumors or TNBC. The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.

Deciphering the tumor microenvironment cell-infiltrating landscape reveals microenvironment subtypes and therapeutic potentials for nonsquamous NSCLC.

Recent studies highlighted the clinicopathologic importance of the tumor microenvironment (TME) in delineating molecular attributes and therapeutic potentials. However, the overall TME cell infiltration landscape in nonsquamous non-small cell lung cancer (NSCLC) has not been comprehensively characterized. In this study, we used consensus non-negative matrix factorization molecular subtyping to determine TME cell infiltration patterns and identified 3 TME clusters (TME-C1, -C2, -C3) characterized by distinct clinicopathologic features, infiltrating cells, and biological processes. Proteomics analyses revealed that cyclic GMP-AMP-stimulator of interferon genes immune signaling-mediated protein and phosphorylation levels were significantly upregulated in inflammation-related TME-C2 clusters. The score extracted from the TME-related signature (TMEsig-score) divided patients with NSCLC into high- and low-score subgroups, where a high score was associated with favorable prognosis and immune infiltration. The genomic landscape revealed that patients with low TMEsig-score harbored more somatic copy number alterations and higher mutation frequency of driver genes involving STK11, KEAP1, SMARCA4, and others. Drug sensitivity analyses suggested that tumors with high TMEsig-score were responsible for favorable clinical response to immune checkpoint inhibitor treatment. In summary, this study highlights that comprehensive recognizing of the TME cell infiltration landscape will contribute to enhancing our understanding of TME immune regulation and promote effectiveness of precision biotherapy strategies.

Abstract 5776: Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas

Abstract Optimized surgery and radioactive iodine (131I, RAI) are the cornerstone of treatment for papillary thyroid carcinoma (PTC). Although standard treatment is curative for most, 5-20% of PTC patients develop RAI refractory disease – the main cause of thyroid cancer-related deaths. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. We performed whole-exome sequencing (at a median depth of 198x) on 158 patient-matched primary PTCs and germline DNA. Clinical data was used to categorize RAI avidity in the PTC cohort. Whereby, 66 RAI refractory and 92 RAI avid tumors were identified. Clinical data and somatic variants were analyzed to compare the clinicopathological presentation, genomic landscape and mutational signatures between RAI refractory and avid PTCs. RAI refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (65.5% versus 26.7%; p=0.016) and the presence of lymph node metastases at primary diagnosis (62.5% versus 30.1%; p=0.012); higher nonsilent tumor mutation burden (p=0.011); and the enrichment of APOBEC-related single base substitution (SBS) COSMIC mutational signatures 2 (p=0.03) and 13 (p&amp;lt;0.001). APOBEC mutational signatures were not associated with BRAFV600E mutation. Notably, using multivariate logistic regression analysis only the SBS13 (odds ratio 13.01, 95% confidence intervals 1.20-140.94) APOBEC mutational signature was revealed to be an independent predictor of RAI refractoriness in PTC (p=0.035). Furthermore, using Cox proportional hazards SBS13-positive tumors (hazard ratio 3.52, 95% confidence intervals 1.79-6.91) were also significantly associated with poorer progression-free survival (p&amp;lt;0.001), albeit only in univariate analysis. This study highlights distinct clinical and genomic features in RAI refractory PTC, but above all proposes the APOBEC SBS13 mutational signature as an independent predictor of RAI refractoriness in a more aggressive subgroup of PTC. Where detection of RAI refractory disease following standard surgical PTC removal, and more suitable therapeutic interventions may potentially improve patient outcomes. Citation Format: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Khawla S. Al-Kuraya. Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5776.

Abstract 5265: Novelmolecular subtypes of papillary thyroid carcinoma (PTC) driven by BRAFV600E-,RAS- and RET-mutations linked to distinct clinicopathological features and tumor immune microenvironment

Abstract Background: PTC is the most common type of thyroid cancer and offers excellent prognosis. However, recurrence PTC remains relatively common, especially PTC with BRAF V600E mutation. PTC is often characterized by RET, RAS or BRAFmutations. RAS, RET and BRAF V600E mutations tend to be mutually exclusive. In this study, we investigated whether these oncogenic driver mutations could propose a molecular classification of PTC into distinct tumor immune microenvironment. Methods: Surgical tissue samples from 252 patients with stage I-III PTC consecutively diagnosed between 07/2020 to 08/2021 at Sun Yat-sen Memorial Hospital (SYMH) were sequenced using a panel targeting 18 cancer-related genes. Clinical and genomic data from SYMH cohort was compared with 499 stage I-III PTC patients (PTCs) from TCGA. Results: Based on the analysis of the genetic alteration profile from SYMH cohort, 252 PTCs can be classed into three major subgroups, BRAFV600E-(83.7%), RAS-(6.0%), and RET-(3.6%) driven PTCs. These three subgroups covered 93.2% of SYMH cohort and 77.6% in TCGA cohort. (Thyroid peroxidase) TPO status was strongly correlated with BRAF V600E (p=0.003), RET (p=0.005) mutations. Median age of RET- driven PTCs was lower than that of BRAFV600E-, RAS- driven PTCs (p=0.034), which was in concordance with TCGA cohort (p=0.0021). In both cohorts, prevalence of lymph node metastasis in RET-driven PTCs (SYMH, 88%; TCGA, 76%) was higher than that in RAS-(SYMH, 20%; TCGA, 21%) driven PTCs (SYMH, RET vs. RAS, P=0.018; TCGA RET vs. RAS, p &amp;lt;0.001). The TPO positive rates in RET- (p=0.034) and RAS- (p &amp;lt;0.01) driven PTCs were higher than BRAF V600E- driven PTCs in SYMH cohort. In TCGA cohort, RET-driven PTCs had longer disease-free survival (DFS) than RAS- driven PTCs, but not statistically significant. Tumor immune microenvironment study in TCGA cohort revealed a more anti-inflammatory tumor state for RAS-driven PTCs, with decreased levels of pro-inflammatory mediators DC cells, Eosinophils, M1 Macrophages, B cells, and CD4 memory T cells, and increased level of anti-inflammatory M2 macrophages. RAS-driven PTCs also had the decreased level of pro-inflammatory cytokines IL-1, IL-2, IL-12, IL-17, IL-18, IFN-γ, and TNF-α. In contrast, significantly increased level of tumor-infiltrating Tregs was observed in BRAFV600E -driven PTCs (p&amp;lt;0.005). BRAF V600E - driven PTCs had higher degree of NKT cells infiltration than RAS-driven PTCs (p&amp;lt;0.05). Conclusion: PTCs can be classified into BRAF V600E-, or RAS-, or RET-driven subgroups with district clinicopathological features and tumor immune microenvironmental differences, which implication for clinical treatment decision. Citation Format: Miaoyun Long, Yunfang Yu, Lili Lin, Yue Zhu, Langping Tan, Yisikandaer Yalikun, Wenhao Ouyang, Shuai Ni, Xi Li, Ting Hou, Wenjie Sun, Zhange Chen. Novelmolecular subtypes of papillary thyroid carcinoma (PTC) driven by BRAFV600E-,RAS- and RET-mutations linked to distinct clinicopathological features and tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5265.

TRIM29 is differentially expressed in colorectal cancers of different primary locations and affects survival by regulating tumor immunity based on retrospective study and bioinformatics analysis.

In colorectal cancer (CRC) patients, different primary tumor locations caused distinct prognosis and clinicopathological features. It is necessary to identify specific tumor markers according tumor site. Our previous work has identified differentially expressed genes between CRC and adjacent normal tissues, in which only TRIM29 was differently expressed between right colon cancer (RCC) and left colon cancer (LCC) patients. Rectal cancer (RECC) was not included in this latter study and the effects of TRIM29 on the survival with RCC and LCC patients were not investigated. This study further verified TRIM29 expression through Gene Expression Omnibus (GEO) database and our retrospective study. The role of TRIM29 on survival according tumor sites was also explored. Furthermore, the molecular mechanisms of TRIM29 were explored. The GEO dataset was used to confirm the differential expression of TRIM29 in proximal and distal cancers. Moreover, TRIM29 were assess using immunohistochemistry (IHC) in 227 cases to observe the correlation between TRIM29 and tumor site. The relationship between TRIM29 and the clinicopathologic features was investigated according tumor sites. Furthermore, the disease-free survival (DFS) and overall survival (OS) was analyzed using the Kaplan-Meier method to assess the prognostic value of TRIM29. Finally, bioinformatics analysis was used to explore the molecular mechanisms. The Tumor-Immune System Interactions and Drug Bank database (TISIDB) was used to analyze the correlations between TRIM29 expression and tumor immune functions. The correlation of TRIM29 with tumor infiltrating lymphocytes or mismatch-repair-proficient/mismatch-repair-deficient (pMMR/dMMR) status was also investigated. TRIM29 expression was significantly higher in patients with RCC (P<0.001). RCC patients with high TRIM29 tended to be older, male, in stage III-IV, with N+ staging, and intestinal obstruction (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.010, respectively). High TRIM29 expression was associated with an increased risk of recurrence/metastasis and death, only in RCC patients (P=0.020 and P<0.001). Functional annotations and immune activity analysis showed that TRIM29 is related to tumor infiltrating lymphocytes and immune dysfunction. TRIM29 plays varying roles in patients with different tumor sites. TRIM29 is correlated with the clinicopathological features and prognosis in RCC patients. Indeed, TRIM29 may serve as a new biomarker for RCC patients.