PIK3CA alterations in metastatic colorectal cancer.

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Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) encodes the p110 catalytic subunit of PI3K. This is a crucial kinase in the PI3K/AKT/mTOR signaling pathway and oncogenic PIK3CA mutations promote colorectal cancer (CRC) cell growth and metastasis. We aimed to assess clinicopathological features and prevalence of PIK3CA alterations in metastatic colorectal cancer (mCRC). Methods: We analyzed clinicopathological data from 339 patients diagnosed with mCRC at Southwestern Sydney Local Health District from 2014-2021. We performed next-generation sequencing using the Qiagen 30-gene panel and recorded demographic characteristics, histological features and survival outcomes from electronic medical records. Results: Of the 339 mCRC cases, 84 (25%) had PIK3CA alterations of which 56% were men and 44% women, with median age of 72 years. 74% of patients with PIK3CA alterations were Caucasian, 13% Middle Eastern, 12% Asian and 1% South American. E542K and E545K (exon 9) and H1047R (exon 20) together made up over half of all PIK3CA mutations, and 15% of tumours had more than one PIK3CA alteration identified. 51% had concurrent KRAS mutations, 15% concurrent BRAF mutations and 17% were mismatch-repair deficient. Most tumours were adenocarcinoma (89%) and the remainder mucinous adenocarcinoma. 80% of tumours were moderately differentiated, 17% poorly differentiated and 3% well differentiated. 45% were stage IV at diagnosis with median survival of 22 months (vs 24 months for patients without PIK3CA alterations). Conclusions: A quarter of mCRC patients in our study had PIK3CA mutations. Defining these patients may have therapeutic implications, including the use of aspirin or PIK3CA inhibitors. Identifying PIK3CA exon 20 mutations is also of clinical importance as these have been associated with resistance to anti- EGFR therapy in some studies.