Treatment of Fanconi Anemia-Associated Head and Neck Cancer: Opportunities to Improve Outcomes

Abstract

Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection toward multiple malignancies, including a greater than 500-fold incidence of head and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiotherapy to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 patients with FA-HNSCC including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, radiotherapy, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation. Although there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.

Figure 1.. The FA-BRCA Pathway.

Interstrand crosslink (ICL) stalled replication forks are recognized by FANCM and its binding partner FAAP24, allowing for precise localization of the FA core complex to damaged chromatin. The FA core complex, a multimeric ubiquitin ligase, is comprised of at least 8 subunits including FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FAAP100. Once bound to the FANCM/FAAP24 docking platform, FANCL of the core complex associates with E2-conjugating ligase UBE2T (FANCT) to monoubiquitinate a heterodimer of FANCD2 and FANCI (FANCD2-I). Ubiquitination of FANCD2-I triggers assembly of the downstream ICL repairosome, with recruitment of SLX4 (FANCP), activating various endonucleases, including ERCC4 (FANCQ), MUS81, and SLX1. Cleavage at ICL sites by these enzymes separates the DNA strands, to which the FA core complex recruits REV1, REV3, and REV7 (FANCV) to form the translesion synthesis polymerase complex (REV1–pol ζ). Pol ζ bypasses the ICL, with the nascent strand re-establishing one of the original DNA duplexes. The double-stranded break of the remaining damaged duplex is then repaired via homologous recombination. First, BRCA2 (FANCD1) and its binding partner PALB2 (FANCN) localize to the break. BRCA2 initiates the homologous strand exchange process by recruiting recombinase RAD51 (FANCR), which facilitates invasion of the cleaved strand into the intact sister chromatid. This RAD51-guided recombination filament searches for and identifies the complementary sister sequence upon which repair synthesis and ligation are completed.

Figure 2.

Suggested FA-HNSCC Treatment Pathway.