ERBB2 Mutations Research Articles

HER2 alterations and prognostic implications in all subtypes of breast cancer.

1041 Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers & is a prognostic & predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations & fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, & biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims & Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. Results: ERBB2 mutations ( ERBB2mts) were identified in 3.2% (n = 388) of tumors overall & most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p < 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p < 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- & 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p < 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p < 0.05) & D769H (0.3 vs 0.1%, p < 0.05), & the resistance mutation L755S (1.2 vs 0.6%, p < 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p < 0.001) & increased levels in HER2- samples (73 vs 35 TPM, p < 0.001). High tumor mutational burden (≥ 10 mut/Mb) & ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p < 0.001; 10.6 vs 0.8%, p < 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) & response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt & ERBB2-WT. Conclusions: ERBB2mts & fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.

Auxiliary diagnosis of periampullary carcinomas by comprehensive next-generation sequencing.

e16221 Background: Periampullary carcinoma, originating from ampulla, head of pancreas, common bile duct and duodenum, is a group of highly heterogeneous tumors with similar clinical presentations and anatomical sites but totally different prognosis. This study aims to investigate the potential diagnostic value of molecular testing in patients with periampullary carcinomas. Methods: This study retrospectively recruited patients diagnosed with periampullary, common bile duct, head of pancreas and duodenum cancers whose tumor tissue or circulating free DNA samples were sent to perform parallel hybridization-based next-generation sequencing of cancer-related genes ranging from 59 to 1021. Differentiated mutated genes were compared between different cancers using Fisher’s exact test and p < 0.05 was significant. Results: A total of 199 patients were enrolled in this molecular analysis, including 74 periampullary carcinomas, 43 duodenal cancers, 31 cancers of the common bile duct and 51 pancreatic head carcinomas. The top five most commonly mutated genes in these cancers were listed in the table. Fisher’s exact test suggested that ARID1A and LRP1B mutations were more frequently identified in duodenal cancer compared to periampullary cancer (p = 0.016 and 0.010, respectively). Compared to common bile duct carcinoma, periampullary cancer had more APC mutations and less ERBB3 mutations (p = 0.017 and 0.027, respectively). Strikingly, there was no APC mutation identified in pancreatic head cancer. Conclusions: Many common mutations were detected in periampullary, common bile duct, head of pancreas and duodenum cancers, such as TP53, KRAS and CDKN2A. However, APC mutation was not detected in pancreatic head carcinoma that is characterized by the worst prognosis. Genetic testing may facilitate distinguish the prognosis of periampullary carcinoma and assist in the differential diagnosis of pancreatic head carcinoma.[Table: see text]

Deciphering genomic characteristics of ERBB family members potentially involved in the recovery of anti-cancer immunity for intrahepatic cholangiocarcinoma patients.

e16003 Background: Previous studies showed that the efficacy of immune checkpoint inhibitor (ICI) is enhanced in hepatobiliary cancers harboring activating gene alterations of ERBB family members. The purpose of this study was to explore genomic characteristics of ERBB family members as well as the relationship of them with the activity of anti-cancer immunity in Chinese intrahepatic cholangiocarcinoma (ICC) patients. Methods: Fifty-four ICC patients which carried at least one gene mutation of ERBB family members were pre-selected from 508 ICC patients included in the China Pan-cancer project of OrigiMed 2020 (https://www.cbioportal.org/study/summary?id=pan_origimed_2020). Targeted sequencing was implemented with cancer-related 450-gene panel. Tumor mutation burden (TMB) and microsatellite status were evaluated. To explore the molecular mechanisms, two human cholangiocarcinoma cell lines, RBE and HuCCT1, were transfected with a lentivirus to obtain the cells with stable S310F mutation and overexpression of ERBB2. Results: The variation frequencies of EGFR, ERBB2, ERBB3 and ERBB4 were 2.8% (14/508), 3.5% (18/508), 3.3% (17/508) and 2.4% (12/508) in Chinese ICC patients, respectively. All the patients harboring ERBB family gene mutations were classified as TMB-H (cutoff = 10 Muts/Mb), when co-mutated with ACVR2A or TGFBR2. Moreover, ACVR2A and TGFBR2 were identified as driver genes in the cohort with oncodriveCLUST. TMB and the proportion of MSI-H patients were significantly elevated when ERBB family members co-mutated with ACVR2A (mutation vs wild: TMB, 38.2 ± 19.1 vs 7.0 ± 8.6 Muts/Mb, p<0.0001; MSI-H, 77.8% vs 4.9%, p<0.0001), or with TGFBR2 (TMB, 33.1 ± 8.7 vs 9.0 ± 14.4 Muts/Mb, p<0.0001; MSI-H, 83.3% vs 9.1%, p<0.001). Besides, ACVR2A and TGFBR2 were enriched in TGF-β pathway. Flow cytometry analysis revealed that ERBB2 S310F mutation and amplification were increased by approximate 3-fold and 3.5-fold in PD-L1 expression of cell line RBE ( p < 0.0001, respectively); by approximate 2-fold and 3-fold upregulation of PD-L1 expression in cell line HUCCT1 ( p < 0.0001, respectively). Western-blot results suggested that ERBB2 mutation/overexpression mediated PD-L1 upregulation through the RAS/ERK/c-JUN pathway. T cell cytotoxicity-mediated killing assay demonstrated that ERBB2 S310F mutation and overexpression induced the recovery of anti-cancer immunity by about 30% ( p < 0.05) both in RBE and HuCCT1 cells. Conclusions: The present study revealed two distinct genomic characteristics potentially involved in the recovery of anti-cancer immunity of intrahepatic cholangiocarcinoma patients: on one hand, co-mutation of ERBB family genes with ACVR2A or TGFBR2 was enriched in TGF-β pathway, contributing to MSI-H/TMB-H; on the other hand, ERBB2 might impact expression of PD-L1 by regulating the RAS/ERK/c-Jun pathways.

Driver coexistence characteristics of ALK-fusion in Chinese patients with lung cancer.

8530 Background: ALK fusions and other driver mutations are usually mutually exclusive. With the widespread application of genetic testing techniques, the coexistence of ALK fusions and other driver mutations could be detected, such as ALK fusion and EGFR driver mutations. However, there were no systematical studies about the coexistence of ALK fusions and other driver mutations. Here, we retrospectively investigated the coexistence of ALK fusions and other driver mutations. Methods: Samples with ALK fusions were extracted from a Chinese lung cancer cohort, which from OncoPanscan (Genetron Health) based sequencing of tissue. Driver mutations of EGFR, ROS1, RET, NTRK1/2/3, BRAF, MET, KRAS and ERBB2 could be detected. Results: In the cohort, 692 samples with ALK fusions contained the intact kinase domain. These samples could be classified into three forms: canonical fusions (only EML4 partner, n = 601), single non-canonical fusions (only non- EML4 partner, n = 51) and complex non-canonical fusions (two or more partners, n = 40). Among the 692 samples, only 20 samples (20/692, 2.89%) coexisted with other driver mutations, which indicated that the driver coexistence were rare. 70% (14/20) of driver coexistence were happened on canonical fusions ( EML4-ALK) samples. They were coexisting with EGFR L858R (3), EGFR L858R plus ROS1 fusion (1), EGFR L858R plus MET amplification (1), KRAS G12C/D/V (3), MET amplification (3), MET Exon14 skipping (1), ERBB2 amplification (1), and MET amplification plus ERBB2 amplification (1), respectively. 20% (4/20) of driver coexistence samples were single non-canonical ALK fusions coexisting with EGFR 19del (1) or 20ins (1) or L858R (1) or MET amplification (1). Another 10% (2/20) samples were complex non-canonical ALK fusions coexisting with EGFR G719S (1) or RET fusion (1). Most co-mutations have corresponding targeted inhibitors, maybe these patients can be treated by combined or sequential therapies. Among canonical fusions, single non-canonical fusions and complex non-canonical fusions of ALK, the frequency of the samples without coexistence of driver mutations was respectively 97.67% (587/601), 92.16% (47/51), 95.00% (38/40), without significant difference (P = 0.056). Maybe single/complex non-canonical fusions are also strong drivers as canonical fusions. Conclusions: In this cohort, very few of ALK fusion patients coexisted with other driver mutations. Among the co-existence samples, ALK fusion were mainly coexisting with the site mutations of EGFR and KRAS, amplifications of MET and ERBB2, fusions of ROS1 and RET. These samples maybe obtain more effective outcomes by combined or sequential therapies.

Clinical significance of next generation sequencing (NGS) in Chinese patients with relapsed/refractory Wilm’s tumor.

e22014 Background: Medical advances have been greatly improved in the five-year survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigate the genomic profiling and the incidence of germline cancer susceptibility mutationsof Chinese patients with R/R WT. Methods: Next-generation sequencing (NGS) of tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were used in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline mutations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB) were analyzed. Results: Nineteen patients with R/R WT were enrolled in this study, including 10 males and 9 females, with a median age of 4 years old (range, 0-14). All of the pathology was identified as favorable histology WT (FHWT). Somatic mutations were detected in 84.21% (16/19) of patients, and CNVs accounted for the majority of the total somatic aberrations, followed by SNVs. The most common somatic mutations were identified in the following genes, CTNNB1 , ERBB2, MCL1 , CDK2 and MDM4. Of the top 3 frequently mutated genes, the mutation frequency and their most common mutation type were CTNNB1, 26%, in-frame deletion, missense mutation; ERBB2 21%, missense mutation, amplification; MCL1 21%, amplification. It is worth noting that MCL1 mutation has never been reported in Chinese R/R WT patients before, which may be a potential valuable mechanism. Germline mutations were detected in 89.47% (17/19) of patients, and CNVs accounted for the majority of the total germline aberrations, followed by SNVs. The most common germline mutations were identified in the following genes, MCL1, RET, ALK, EPCAM, and FANCA. Of the top frequently mutated genes frequency and most common mutation type were MCL1 21%, amplification; RET 21% missense mutation, multiple mutations. There are also some suspected clinically pathogenic germline mutation of genes CDK4 , ERBB2, and MDM4 . All the mutation type were amplification. Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2 / MET/EGFR / FGFR1, and the point mutations of CHEK2/FBXW7/NF1. The median TMB was 1.47 (range, 0-7.8). Conclusions: Overall, clinical and new results were detected in 14 (73.68%) in Chinese R/R WT patients. We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.

The differential response to immune checkpoint inhibitors in colorectal and endometrial cancer patients according to different mismatch repair alterations.

3625 Background: In colorectal cancer (CRC) and endometrial cancer (EC) patients (pts), preliminary data suggest a differential response to immune checkpoint inhibitors (ICIs) according to different MMR alterations. The drivers of this difference remain unknown and no reliable predictive biomarker has been found. We explored the genomic alterations, tumor mutation burden (TMB), immune-related gene expressions and signatures, tumor microenvironment (TME), neoantigen load and median overall survival (mOS) inCRC and EC pts treated with ICIs with different MMR alterations. Methods: 13,701 CRC and 3,315 EC specimens were tested at Caris Life Sciences (Phoenix, AZ) with Next Gen Sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome). MMR/MSI status was determined by IHC of MMR protein and/or NGS. Immune cell abundance was quantified using quanTIseq. Gene expression profiles were analyzed for T cell-inflamed signature (TIS) and IFN-gamma scores. Immune epitope prediction was performed using the NetMHCpan v4.0 method in the Immune Epitope Database. Real-world mOS was obtained from insurance claims data and calculated from tissue collection or ICIs start to last contact. Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (adjusted p < 0.05). Results: In CRC, 84 (0.6%) pts had intact expression of MLH1 and PMS2 and co-loss of MSH2 and MSH6 (MutS) and 648 (4.7%) had co-loss of MLH1 and PMS2 and intact MSH2 and MSH6 (MutL). 117 (0.9%) had other MMR IHC loss. APC, KRAS, ERBB2, ERBB3 and MSH2 mutations rates were higher in MutS while BRAF mutation rate was higher in MutL. B cell, NK cell content and neoantigen load (high affinity epitopes: p < 0.05, intermediate: p < 0.01, low: p < 0.001) were higher in MutS. The mOS in MutS (N = 149) vs. MutL (N = 980) was 56 months (m) vs. 36 m (p = 0.003). In ICI-treated pts, the mOS in MutS (N = 28) vs. MutL (N = 149) was not reached (NR) vs. 32 m (p = 0.005). BRAF mutation didn’t impact survival in MutL. In EC, 48 (1.4%) pts had MutS and 915 (27.6%) had MutL. 81 (2.4%) had other MMR IHC loss. IHC-PD-L1, TMB, neoantigen load (high affinity epitopes: p < 0.01, intermediate: p < 0.0001, low: p < 0.0001), TIS, IFN-gamma scores, immune related gene expressions, TME (Macrophage M1, CD8+) were higher in MutS. The mOS in MutS (N = 94) vs. MutL (N = 1804) was NR vs. 47 m (p < 0.001). In ICI-treated pts, the mOS in MutS (N = 11) vs. MutL (N = 273) was NR vs. NR (p = 0.559). Conclusions: This is the largest study to explore differential response to ICIs in CRC and EC pts with different MMR alterations. In pts with CRC and EC, the mOS was longer in MutS compared to MutL. In ICI-treated pts, the mOS was longer in MutS compared to MutL in CRC but not in EC. Among the explored biomarkers, neoantigen load was higher in MutS compared to MutL in both CRC and EC and maybe the driving factor for differential response to ICIs.

MAP3K8 and ALK alterations in pediatric patients with atypical Spitz tumors and Spitz melanoma.

e21569 Background: Pediatric atypical Spitz tumors and Spitz melanoma (AST/SM) are characterized by structural variants (rearrangements/truncations) of various kinase genes more commonly involving MAP3K8 and ALK. The clinical features associated with these genomic abnormalities have not been well characterized. Methods: We reviewed the clinical characteristics and outcomes of children and adolescents with AST/SM who were enrolled on our institutional comprehensive registry for melanocytic lesions MACMEL (Cancer 127:3825, 2021) and abstracted clinical and outcome data for patients with MAP3K8, ALK, and other less common genomic aberrations. Results: Table shows the characteristics and outcomes of patients with AST/SM who had MAP3K8, ALK, and other genomic aberrations. There were 49 patients of whom 21 had MAP3K8 rearrangements/ truncations (n = 11;22%) or ALK rearrangements (n = 10;20%). The remaining 28 patients had fusions involving ARAF (1), ROS1 (2), NTRK1 (3), ERBB2 (1) or rare mutations (ATM = 1) or copy number changes (n = 14) or no identifiable genomic abnormality (n = 6). Female sex was more common in all three groups (32 female and 17 male). The median age for the entire cohort was 7.5 years. Most lesions arose in the extremities (n = 32; 65%). About half had stage III disease. 40 patients underwent sentinel node biopsy (SLNB), 25 had at least one positive node (7/9 MAP3K8, 5/8 ALK, 13/23 other), Forty-four patients had FISH analysis for CDKN2A and homozygous loss was seen in 9/11 MAP3K8-rearranged, 2/6 ALK-rearranged, and 11/27 other tumors. No TERT promoter mutation was detected in any of the 45 tumors that were analyzed. Two patients experienced local recurrence, one with a MAP3K8-STX fusion and one with a FLOT2-ARAF fusion and activating RAC1 mutation. All patients are alive and currently disease free (median follow up of 2.33 years). There were no statistically significant associations between gene mutations and tumor site, gender, or stage. Conclusions: Approximately 40% of patients with AST/SM harbored ALK or MAP3K8 alterations in our pediatric melanoma registry. We found no significant association between the individual genes and any specific clinical features in this limited cohort.[Table: see text]

Racial differences in the mutational landscape of serous endometrial cancer.

5600 Background: Tumor comprehensive genomic profiling (CGP) identifying genomic alterations (GA) that have diagnostic, prognostic and are potentially therapeutically targetable is essential to precision oncology. 2022 NCCN Uterine Neoplasm guidelines recommend tumor genetic evaluation as part of initial evaluation. As racial disparities in endometrial cancer outcomes have been widely reported, we analyzed our CGP results from a large series of serous endometrial cancer patients treated in a nationwide cancer network to identify GA differences that may contribute to worse prognosis and help inform better therapy selection. Methods: 86 Pts with serous endometrial underwent hybrid-capture based CGP for up to 324 cancer-related genes of archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 07-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Statistical analysis performed with Fisher Exact test comparing Black and White women. Results: Median age was 63 years (range, 38-85), 37% were White, 58% were Black and 5% were Asian. GA were identified in 94% (81/86) of these patients. TP 53 mutations which is characteristic of serous cancer were present in 80 of 86 patients (93%). GA predicted to activate PI3-Kinase pathway signaling ( PIK3CA, PIK3R1, PTEN) were significantly more common in White women occurring in 13 of 32 (41%), compared with 8 of 50 (16%) of Black women (p. < 0.02). An important, but not statistically significant trend of greater percentage of CCNE1 amplification in Black women is also noted, see table below: Mutation frequencies were similar between Black and White women for the following genes: PPP2R1A 23%; MYC 19%; FBXW7 14%; ARID1A 9%. Conclusions: In this 86 patient series of women with Serous Endometrial Cancer we note that PIK3CA mutations, an important resistance factor in anti-HER2 therapy, were significantly more common in White women (41%) compared with Black women (16%) (p. < 0.02) and ERBB2 mutations occurred in 19% of White women and only 10% of Black women. This study cohort also identified a larger percentage of black women with CCNE1 amplification. Increased CCNE1 amplification has been linked to the racial disparities in cancer outcomes and may explain the disparities seen with endometrial cancers. [Table: see text]

Real-world frequency of non-small cell lung cancer with ERBB2 exon 20 insertion (Exon20ins) mutations by site of insertion.

e15026 Background: ERBB2 Exon20ins mutations are in-frame insertions or duplications clustered around 2 key regions of Exon 20: the α-C helix (amino acid [AA] 770-774), the loop following the α-C helix (amino acid [AA] 775-783). The site of insertion can influence the outcome to selective EGFR/ERBB2 tyrosine kinase inhibitor therapy; ERBB2 exon 20 insertion mutation remains an unmet clinical need. The next-generation sequencing technology is a powerful tool to investigate the detailed ERBB2 mutations sites. Methods: We used real-world HaploX genomic data from patients (pts) with non-small cell lung cancer (NSCLC) to determine the frequency of ERBB2 Exon20ins mutations by site of insertion.The tumor tissue or serial blood sample was collected for each individual and the next-generation sequencing was performed using customized target captured HapOncoCDx panels. Results: From HaploX genomic data, 284/18205 pts (1.56%) with NSCLC had ERBB2 Exon20ins mutations: 72.2% were located in the helix, 27.8% in the loop (Table). The top 3 most frequent sites of insertion were Y772_A775dup (71.5%), G776delinsVC (11.3%), and G778_P780dup (6.0%). Conclusions: This real-world databases identified the helix as the most frequent insertion region of Exon 20 (∼72%). Exon20ins mutations were found less frequently in the loop (∼28%).[Table: see text]

Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets

Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%); in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%). When compared to non-SRCC histology (N = 3522), CRC-SRCC (N = 37) more frequently had mutations in BRCA1 (11% vs 1%, P < 0.001) and less frequently mutations in APC (19% vs 78%, P < 0.001), KRAS (22% vs 51%, P = 0.001) and TP53 (47% vs 73%, P = 0.001). Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, compared to non-SRCC (N = 540). Our data suggest that SRCCs harbor a similar molecular profile, regardless of the tumor location. Tailored therapy may become available for these patients.

Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients.

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.

Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer.

p110α is a catalytic subunit of phosphoinositide 3-kinase (PI3K), a major downstream effector of receptor tyrosine kinase ErbB2, that is amplified and overexpressed in 20-30% of breast cancers, 40% of which have an activating mutation in p110α. Despite the high frequency of PIK3CA gain-of-function mutations, their prognostic value is controversial. Here, we employ a knock-in transgenic strategy to restrict the expression of an activated form of ErbB2 and p110α kinase domain mutation (p110αHR) in the mammary epithelium. Physiological levels of transgene expression under the control of their endogenous promoters did not result in a major synergistic effect. However, tumors arising in ErbB2/p110αHR bi-genic strain metastasized to the lung with significantly reduced capacity compared to tumors expressing ErbB2 alone. The reduced metastasis was further associated with retention of the myoepithelial layer reminiscent of ductal carcinoma in situ (DCIS), a non-invasive stage of human breast cancer. Molecular and biochemical analyses revealed that these poorly metastatic tumors exhibited a significant decrease in phospho-myosin light chain 2 (MLC2) associated with cellular contractility and migration. Examination of human samples for MLC2 activity revealed a progressive increase in cellular contractility between non-invasive DCIS and invasive ductal carcinoma. Collectively, these data argue that p110αHR mutation attenuates metastatic behavior in the context of ErbB2-driven breast cancer.

PD14-09 ANALYZING DIFFERENCES IN SOMATIC MUTATIONS IN LOCALIZED BLADDER CANCER PATIENTS BY RACE AND SEX: AN ANALYSIS OF DATA FROM THE CBIOPORTAL FOR CANCER GENOMICS

You have accessJournal of UrologyCME1 May 2022PD14-09 ANALYZING DIFFERENCES IN SOMATIC MUTATIONS IN LOCALIZED BLADDER CANCER PATIENTS BY RACE AND SEX: AN ANALYSIS OF DATA FROM THE CBIOPORTAL FOR CANCER GENOMICS Kelsey Baker, Yaw Nyame, Mary Redman, Robert Montgomery, Petros Grivas, and Jonathan Wright Kelsey BakerKelsey Baker More articles by this author , Yaw NyameYaw Nyame More articles by this author , Mary RedmanMary Redman More articles by this author , Robert MontgomeryRobert Montgomery More articles by this author , Petros GrivasPetros Grivas More articles by this author , and Jonathan WrightJonathan Wright More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002546.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Disparities in bladder cancer outcomes exist by race/ethnicity and sex. However, limited data exists on differences in tumor biology by these factors. We hypothesize that social, environmental, and biologic differences that exist by race and sex are likely to drive different biologic phenotypes in bladder cancer. This study aimed to evaluate if these differences existed in a large, multi-institutional cohort. METHODS: Nine urothelial cancer studies and 122 genes (113 actionable, 31 DNA damage repair (DDR)) that are commonly associated with bladder cancer were identified in the cBioPortal platform. Patients were excluded if they had low-grade disease or had no demographic data. Multivariable logistic regression, adjusted for age and disease stage, was performed to evaluate the association between mutation status and race/sex. P < 0.05 was used for statistical significance. No adjustments were made for multiple comparisons. RESULTS: Mutation and demographic data for 880 patients was included for analysis. The median age in this cohort was 67 years (range: 25-98), with 216 (25%) female, 423 (48%) White, 74 (8%) non-White, and 383 (44%) unknown race. Muscle-invasive disease was present in 78% of cases. The median total mutation count was 74 (IQR: 11-186). At least one actionable gene mutation and at least one DDR gene mutation was found in 832 (95%) and 392 (45%) patients, respectively. Somatic mutated gene prevalence differed by sex and race (Table 1). Males in this cohort were more likely to have ARID1A, ATM, CHD6, ERBB2, NCOR1, and FLT4 mutations. White race was associated with higher likelihood of having ARID1A, EP300, and TP53 mutations and lower likelihood of having HRAS mutations. CONCLUSIONS: Differences in somatic mutations existed by both race and sex in a large cohort of patients with bladder cancer. These findings are limited by poor representation of females, non-White patients, limited demographic data collection, and retrospective design. Intentional efforts are needed to build representative patient cohorts and more complete demographic data collection to assess the role of social, environmental, and sex-specific biologic drivers of bladder cancer. Source of Funding: This study was supported by institutional funding through the MXD Championships (JLW) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e259 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kelsey Baker More articles by this author Yaw Nyame More articles by this author Mary Redman More articles by this author Robert Montgomery More articles by this author Petros Grivas More articles by this author Jonathan Wright More articles by this author Expand All Advertisement PDF DownloadLoading ...

ERBB2 S310F mutation independently activates PI3K/AKT and MAPK pathways through homodimers to contribute gallbladder carcinoma growth.

Genomic instability and mutability are a prominent character of tumor. The whole-exosome sequence reveals that ERBB2 mutations are the representative mutations of gallbladder carcinoma, which takes potential targets for gallbladder carcinoma therapy. However, the roles of ERBB2 mutations are unclear in gallbladder carcinoma. We identified S310F mutation is the hottest mutation of ERBB2 mutations from TCGA PanCancer Altas data with 10,967 samples and our previous study with 157 gallbladder carcinoma samples. S310F mutation located in ERBB2 extracellular domain, promoted ERBB2 homodimerization and consequent auto-phosphorylation to activate the downstream PI3K/AKT and MAPK pathways, which was independent on ERBB1, ERBB3, and ERBB4. ERBB2 S310F mutation up-regulated aerobic glycolysis and promoted gallbladder carcinoma growth. Our study reveals the roles of ERBB2 S310F mutation, which is beneficial to ERBB2 S310F mutant gallbladder carcinoma therapy.

Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review

Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer.

BackgroundClinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics.MethodsThere were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher’s exact test compared each pair of genes. A similarity score was constructed with the resulting P-values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients.ResultsGene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (ADGRA2, ZNF703, FGFR1, KAT6A, and POLB) was significantly associated with PR status; gene cluster 2 (COL1A1, AXIN2, ZNF217, GNAS, and BRIP1) and gene cluster 3 (FGF3, FGF4, FGF19, and CCND1) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively.ConclusionThis study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.

The efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer patients with different driver gene mutations

Objective: To explore the efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer (NSCLC) patients with different driver gene mutations. Methods: Medical records of advanced NSCLC patients who harbored driver gene mutations (EGFR, KRAS, ALK and etc.) and received PD-1 inhibitors in Henan Cancer Hospital from April 2016 to May 2021 were collected. Treatment patterns, progression free survival (PFS), overall survival (OS) and prognostic factors of patients with driver gene mutations were estimated. Results: A total of 120 patients were included. There were 70 males and 50 females, with a median age [M(Q1,Q3)] of 57 (50, 65) years. Of these, 52 patients harbored KRAS mutations, 42 patients harbored EGFR mutations, 16 patients harbored ERBB2 mutations, 5 patients harbored MET mutations or amplifications, 5 patients harbored ROS-1 mutations, 2 patients harbored BRAF mutations, and the last 2 patients harbored ALK and RET mutations, respectively. The PFS and OS [M (95%CI)] were 6.4 (5.1-7.8) and 31.2 (22.0-40.3) months in 120 participated patients. Patients with KRAS mutations showed the greatest survival benefit from Immune checkpoint inhibitors (ICIs) with the PFS of 9.7 (4.8-14.6) months and OS of 31.2 (19.4-50.6) months. They mostly received the first-line (34.6%, 18/52) and second-line (38.5%, 20/52) ICIs. The PFS and OS of EGFR mutant patients were 3.9 (1.8-6.1) months and 18.0 (12.1-23.8) months, respectively. They tended to receive ICIs after resistance to EGFR-tyrosine kinase inhibitors (TKIs), and the proportion of second-, third-, fourth or further-line drugs was 38.1% (16/42), 11.9% (5/42), and 47.6% (20/42), respectively. PD-L1 expression level (negative vs ≥50% positive: HR=3.710, 95%CI: 1.372-10.031, P=0.010; 1%-49% positive vs ≥50% positive: HR=2.738, 95%CI: 0.841-8.912, P=0.094), age (every additional year: HR=0.957, 95%CI: 0.933-0.982, P=0.001) and different driver mutations status (EGFR vs KRAS: HR=2.676, 95%CI: 1.317-5.436, P=0.006; ERBB2 vs KRAS: HR=3.411, 95%CI: 1.493-7.792, P=0.004; other mutations vs KRAS: HR=0.727, 95%CI: 0.322-1.643, P=0.444) were prognostic factors for PFS. While PD-L1 expression level (negative vs ≥50% positive: HR=2.305, 95%CI: 0.748-7.103, P=0.146; 1%-49% positive vs ≥50% positive: HR=1.286, 95%CI: 0.337-4.913, P=0.713), and treatment lines of ICIs (first-line vs ≥ third-line: HR=0.322, 95%CI: 0.114-0.914, P=0.033; second-line vs ≥ third-line: HR=0.375, 95%CI: 0.178-0.789, P=0.010) were prognostic factors for OS. Conclusions: KRAS mutant NSCLC patients mostly receive ICIs at the front line, and have best survival benefits from immunotherapy. While EGFR mutant NSCLC patients tend to receive ICIs at the back line, and obtain reasonable survival benefits. PD-L1 expression level, age, and different driver mutations status are prognostic factors for PFS, and PD-L1 expression level and treatment lines of ICIs are prognostic factors for OS.

Computational Pathways Analysis and Personalized Medicine in HER2-Positive Breast Cancer

Background: The heterogeneity of some diseases, such as cancer, makes the decisions on therapeutic strategy very challenging. In this context, pathway analysis can support the identification of the best treatment and indeed prevent the issues arising from the trial and error process, in terms of best overall efficacy and lowest toxicity, ultimately saving time and resources. In a pathway, each gene is represented by a node and the pathway analysis can be performed using algorithms that interpolate data from different sources (i.e. sequencing, microarray, drug efficacy and interactions). Objective: The purpose of this study was to evaluate the effects of erbb2 amplification on HER2- positive breast cancer and to predict, with a pathway based computational approach, the efficacy of a therapy with Trastuzumab and Palbociclib, alone or in combination. Methods: One of the available and most integrated algorithms is PHENSIM that was used in this study to evaluate the gene dysregulations caused by the erbb2 amplification on its related pathways and the effects of Trastuzumab and Palbociclib on these deregulations. The effects have been estimated considering the drugs alone or in a combination therapy. Results: A reduction of the number of pro-proliferative signals has been observed for both drugs alone or in combination. Regarding genes involved in MAPK signaling pathway, a total of 69 nodes were activated by the erbb2 mutation. A simulated treatment with Palbociclib reduced the number of activated genes down to 60, while with Trastuzumab the activated nodes were only 53. The combined therapy revealed an intriguing result providing a significant and remarkable reduction of the activated genes from 69 to 33. Conclusion: These results let us hypothesize that there could be an increased efficacy giving the combination therapy to subjects with HER2 positive breast cancer. Finally, pathway analysis could be specifically used to design clinical trials predicting the efficacy of combination therapies or untested drugs on a specific disease.

ERBB2 Mutations as Potential Predictors for Recurrence in Colorectal Serrated Polyps by Targeted Next-Generation Sequencing.

BackgroundFollow-up guidelines for serrated polyps (SPs) are mainly based on factors such as histology and size with limited evidence. The underlying genomic mechanism of SPs in relation to recurrence risks is utterly unknown.MethodsWe applied targeted next-generation sequencing (NGS) approach on two groups of SPs [polyp-relapsed SPs (PRSPs) vs. polyp-free SPs (PFSPs)] based on the surveillance outcomes to compare differences of DNA variants in 71 colorectal cancer-associated genes. A multicenter validation cohort was established longitudinally from 2016 to 2019 to confirm the relevant results.ResultsAmong the 96 NGS samples, at least one mutant after filtration was detected in 90 samples (94%). Molecular profiling presented BRAF, KRAS, and APC as top 3 mutated genes. FBXW7, MSH2, and ERBB2 might be recurrence-relevant, while DMD, BRCA1, and BRCA2 might be negatively correlated with recurrence. Notably, ERBB2 mutants (R678Q and V842I) (n = 5) had higher risks of polyp recurrence than the wild types (n = 85), with a median polyp-free interval of 15 months compared to 26 months [P < 0.001; hazard ratio (HR) = 4.9; 95% confidence interval (CI) = 1.9–12.8]. Furthermore, a multicenter cohort composed by 321 SPs verified that ERBB2-mutated SPs had increased risks of polyp recurrence (P < 0.001; HR = 3.7; 95% CI = 2.3–6.0) and advanced neoplastic lesion (ANL) recurrence (P < 0.001; HR = 10.0; 95% CI = 2.7–36.9) compared with wild-type SPs, respectively.ConclusionsOur results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC).

Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p&lt;0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p&lt;0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]