The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute ‘gain of function’ mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested.

BackgroundImmune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys.Case presentationA 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient’s kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab.ConclusionImmune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect.

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

Squamous cell carcinoma of head and neck (SCCHN) is a group of cancer arising from mucosal surfaces of the head and neck. Optimal management of SCCHN requires a multidisciplinary team of surgical oncologists, radiation oncologists, medical oncologists, nutritionist, and speech-language pathologists, due to the complexity of anatomical structure and importance of functional outcome. Human papilloma virus (HPV)-related SCCHN represents a distinct subset from HPV negative SCCHN which is associated with carcinogen exposure such as cigarette smoking, betel nut use and alcohol. HPV related SCCHN responds better to concurrent chemoradiation and has better overall prognosis, compared to HPV negative SCCHN. Radiation therapy has been introduced to the treatment of SCCHN, administered concurrently with systemic chemotherapy for locoregional SCCHN, as well as a palliative measure for recurrent and/or metastatic (R/M) SCCHN. Recently, immune checkpoint inhibitors have been shown to improve overall survival in R/M-SCCHN and have been incorporated into the standard of care. Combination approaches with immune therapy and targeted therapy for biomarker enriched population based on genomics are being actively investigated and will shape the future of SCCHN treatment.

Although none of the treatment options were found to be significantly superior with respect to survival, neoadjuvant chemotherapy might halt the progression of the disease until cystectomy and lead to downstaging. At our institution, the best outcomes were observed in patients who received neoadjuvant platinum-based chemotherapy combined with radical cystectomy.