ESMO 2017: Subtypes of Thymic Carcinomas Show Different Genomic Alterations and Tumour Mutational Burden

Comprehensive genomic profiling identifies varied genetic alterations in thymic gland carcinoma that may be treated with targeted and immunotherapy therapies

Comprehensive genomic profiling (CGP) may be used to identify genomic alterations in the highly variable histologic subtypes of thymic gland carcinoma that may also inform treatment decisions, according to findings presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

It is known that thymic gland carcinomas include a variety of histologic subtypes of variable clinical aggressiveness that respond differently to local and systemic therapies, leading Dr. Jeffrey S. Ross, Medical Director, Foundation Medicine and the Pathology Department, Albany Medical Center in Albany, USA and colleagues to investigate whether these subtypes could be refined using CGP to identify actionable genomic alterations for targeted therapies and immunotherapy for patients with relapsed and metastatic disease.

The investigatorssequenced FFPE sections obtained from 174 consecutive patients with metastatic thymic tumours using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >500X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. Total mutational burden (TMB) was determined on 1.1 Mb.

Clinically relevant genomic alterations found in thymic gland carcinoma subtypes

All of the patients had metastatic thymic gland tumours. Twice as many men as women had thymic tumours, and the incidence of thymic tumours peaked in late middle age.

Forty percent of samples were squamous (TSCC), 31% were non-neuroendocrine undifferentiated (TNOS), 17% neuroendocrine (TNEC), 4% adenocarcinomas (TAC), 3% basaloid (TBC), 3% lymphoepitheliomatous (TLEC), and 2% were sarcomatoid (TSRC) carcinomas.

The samples had an average of 4 genomic alterations per case. Genomic alterations were most often found in the TSRC, TSCC, TNOS, and subtypes with an average of 4.8, 4.1, 4.1, and 4.0 genomic alterations, respectively

Clinically relevant genomic alterations (CRGA) were defined as genomic alterations (GA) that could be linked to drugs currently on the market or being evaluated in mechanism driven clinical trials. The investigators found an average of 0.9 CRGA per case. The TSCC and TSRC subtypes had the most CTGAs at an average of 1.0 each.

KIT and PIK3CA were the most frequently altered genes

It was determined that the KIT and PIK3CA genes were most commonly identified molecular targets; altered KIT occurred most often in the TAC, TNEC, TSCC, and TSRC subtypes, whereas PIK3CA was found most often in the TNOS and TSCC subtypes.

Other targets included PDGFRA, FGFR3, PTCH1, FBXW7, BRCA2, IDH1, ERBB2, and ERBB3.

The more frequently occurring subtypes included TNEC, TSCC and TNOS, which also tended to have more genomic alterations, with KIT targets identified in approximately 10% of cases.

The metastatic thymic tumour samples demonstrated low TMB, with just 6% of cases showing more than 10 mutations/Mb and only 3% had more than 20 mutations/Mb. The TMB was highest in the TAC subtype, where 14% of samples showed TMB greater than 10 mutations per Mb. Nine percent of TSCC samples had TMB greater than 20 mutations per Mb.

Conclusions

The thymic gland carcinoma histologic subtypes showed varying genomic alterations and TMB status, with the TSCC, TNEC and TNOS subtypes featuring more genomic alterations. These subtypes plus the TAC subtypes had more CRGA that included KIT mutations and higher TMB.

The authors concluded that CGP shows promise to guide both targeted and immunotherapy selection for patients with thymic gland carcinomas.

Disclosure

No external funding was reported. Dr. Ross is the employed Medical Director of Foundation Medicine, Inc.

Reference

1701O – Ross JS, et al. Comprehensive Genomic Profiling (CGP) of Thymic Gland Carcinomas.