PIK3CA exon 18 mutation in metastatic colorectal cancer with complete response to cetuximab-based therapy: a case report

PIK3CA mutations in metastatic colorectal cancer (mCRC), particularly in exons 9/20 (kinase/helical domains), are often associated with primary resistance and reduced efficacy to anti-Epidermal growth factor receptor (EGFR) therapy (for example, cetuximab) via constitutive Phosphatidylinositol-3-kinase / Protein kinase B (PI3K/AKT) pathway activation. Unlike RAS and BRAF mutations, PIK3CA alterations are not explicitly contraindicated by current guidelines, but their clinical utility remains heavily debated. The biological and clinical significance of rare PIK3CA exon 18 (C2 domain) mutations remains undefined. A 62-year-old Chinese male presented with hematochezia and ribbon stools. Colonoscopy revealed a rectal adenocarcinoma (20 cm from anal verge), with biopsy-confirmed liver metastases. Comprehensive molecular profiling via Next-Generation Sequencing (NGS) identified a rare PIK3CA exon 18 c.2702G > T (p.Cys901Phe) mutation, alongside truncating APC/KDR and pathogenic TP53/SMAD4 alterations, with MSS/low PD-L1 status. Based on the patient’s RAS/BRAF wild-type status and left-sided primary tumor location, standard first-line treatment was initiated (1 cycle of Modifi ed folinic acid (leucovorin), 5-fl uorouracil, and oxaliplatin regimen 6 (mFOLFOX6) followed by 12 cycles of cetuximab plus mFOLFOX6, then 12 cycles of maintenance cetuximab/capecitabine). Despite high-risk molecular features, the patient achieved complete metabolic resolution of hepatic metastases and deep partial response (PFS: 13 months). Treatment-related toxicities (Grade 2 rash, paronychia, steroid-induced diabetes) were managed supportively. Over a follow-up of > 25 months (up to June 2026), subsequent-line therapies were administered following disease progression. This clinical observation indicates that not all PIK3CA mutations necessarily mediate absolute resistance to anti-EGFR therapy. The favorable response observed with cetuximab-based therapy suggests that: (1) PIK3CA C2 domain mutations (for example, p.Cys901Phe) may potentially retain sensitivity to EGFR blockade, and (2) co-mutational context warrants further investigation. Refined domain-specific characterization of PIK3CA mutations is encouraged to optimize targeted therapy selection.