Discussion
Hypopharyngeal SCCs account for <10% of HNSCCs and are difficult to visualize at early stages.1 Patients diagnosed with hypopharyngeal SCCs are predominantly males in their early 60s with a history of smoking and heavy alcohol use. These risk factors are a key determinant of clinical suspicion since tumors are associated with non-specific early symptoms.
BRCA2 mutations in HNSCC have been reported in the context of genetic variants in some patients with Fanconi Anemia, which is associated with hypopharyngeal SCC. These patients are typically young adult females with history of hematologic malignancies who develop HNSCCs in their third and fourth decade.2 One other truncating BRCA2 mutation has been linked to hypopharyngeal SCC, however, lung SCC is the most common with this mutation and breast cancer is rare.3 In some studies of families with aBRCA2 mutation, a significant increased risk of laryngeal and pharyngeal cancer has been identified.3
BRCA2 mutations can result in many cancer phenotypes due to the vital role of the BRCA2 protein in DNA homologous recombination repair. The BRCA2 gene is involved in the Fanconi Anemia (FA)/BRCA pathway for double-strand DNA break repair, which has been implicated in tumor development for both sporadic and Fanconi Anemia-related HNSCC.3-4 In this pathway, BRCA2 and other FA/BRCA proteins form a complex for DNA cross-link repair through homologous recombination (HR). Mutations at genes involved in the HR complex can impair DNA repair and potentiate cancer formation.
BRCA2 mutations may have management implications by enhancing platinum-based chemotherapy response in cancer cells from deficient DNA repair leading to increased platinum-DNA adducts.4This interaction could explain the excellent chemoradiation response observed in our patient and has been supported for HNSCCs previouslyin vitro .4 In other malignancies including ovarian, prostate and pancreatic cancers, germline BRCA2mutations have been associated with clinically distinct tumor phenotypes that respond better to agents targeting the FA/BRCA HR pathway.5 Genetic screening to direct use of platinum-based therapies, immunotherapy and PARP inhibitors is currently underway for these malignancies suggesting similar targeted therapy potential in HNSCC.