The landscape of chromosome 11q13 amplification in Chinese solid tumor patients and hyperprogressive disease (HPD) clinical example.

e15222 Background: Multiple biomarkers are thought to be effective guides in selecting immune checkpoint inhibitors, such as Tumor mutational burden (TMB), PD-L1 and MSI/dMMR. Immunotherapy may be miraculous effective in some patients but many other patients experienced poor prognosis and even tumor overgrowth after immunotherapy in real practice. Previous studies have reported that 11q13 (CCND1, FGF3, FGF4, and FGF19) amplifications were associated with HPD. However, the characterization of chromosome 11q13 amplification in Chinese solid tumor patients are not clear. Methods: A total of 10167 Chinese solid tumor patients’ FFPE and matching blood samples sequenced by next-generation sequencing (NGS) targeting 450 cancer genes were included in this study. Genomic alterations including single nucleotide variants (SNV), insertions and deletions, copy number variations and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: Chromosome 11q13 amplifications were identified in 679 (6.7%) Chinese solid tumor patients. The top six tumor types with 11q13 amplification were esophageal carcinoma 43.8%, melanoma 17%, urothelial carcinoma 16%, breast carcinoma 13.4%, head and neck carcinoma 13.1% and hepatocellular carcinoma 9.4%. In 2257 patients with TMB-H (10muts/Mb) / PD-L1 expression / MSI samples, chromosome 11q13 copy number gain were identified in 184 (8.2%) patients. Chromosome 11q13 amplification and MSI were independent events and didn't occur simultaneously. In TMB-H patients, the detection rate of 11q13 amplification was 8.5%, while in PD-L1 positive patients, the amplification rate of 11q13 was 7.4%. In patients with TMB-H and PD-L1 positive, the detection rate of 11q13 amplification was 9.4%. In our clinical practice, we saw example of HPD exist in a lung squamous cell carcinoma patient who was treated with multiple lines of therapy and then used the Nivolumab. The patient underwent genetic testing and was found to be chromosome 11q13 amplified. Conclusions: The proportion of 11q13 amplification was different in different types of solid tumor. Esophageal carcinoma, melanoma and urothelial carcinoma were top three types of solid tumors with 11q13 amplification. The 11q13 amplification did not coincide with MSI but it overlapped with PD-L1 expression or TMB-H. Together, these results may provide immunotherapy guidance in clinical practice.

The Genetic Multiplicity- Multiple Endocrine Neoplasia type I

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome emerging from characteristic mutations of MEN1 gene with concurrently enunciated multiple endocrine and tumours and associated non-endocrine neoplasm. Previously designated as Werner’s syndrome, MEN1 syndrome denominates genomic mutation within chromosome 11q13 or a tumour suppressor gene with a distinctive protein product nomenclated as “menin”. MEN1 syndrome demonstrates an autosomal dominant pattern of disease inheritance where genomic mutations delineate a comprehensive (100%) disease penetrance. MEN1 gene was initially identified in 1997 upon chromosome 11q13. Although twelve genetic mutations were primarily identified, currently beyond eighteen hundred genomic mutations are scripted1, 2. MEN1 syndrome is comprised of diverse combination of twenty or more endocrine and non-endocrine tumours exemplifying a classic triad of pituitary, parathyroid and pancreatic neoplasm. Diverse non endocrine tumours enunciated with MEN1 syndrome are denominated with meningioma, ependymoma or angiofibroma1, 2. Endocrine tumours are discerned on account of excessive hormonal secretion engendered from various neoplasm or on account of neoplastic evolution. Approximately 10% instances can occur due to a de-novo genomic variant. Offspring of an individual with MEN1 syndrome quantifies a 50% possibility of inheriting the genomic variant. Cogent prenatal diagnosis can be determined in instances where specific genomic variant of a particular family is known. Physical, psychological and social restrictions are prevalent with MEN1 syndrome. Heterozygotes with MEN1 genetic variant are denominated as carriers and manifest a two- fold possible mortality1, 2.

Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.

4036 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.