Co-Occurring EGFR S645C and EGFR L858R in a Patient with Lung Adenocarcinoma Induced Primary Resistance to Osimertinib.

Approximately 10-20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.

Metastatic colorectal cancer as the primary phenotype in a hereditary breast and ovarian cancer patient with Germline BRCA1 mutation: a case report.

Hereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.