This patient’s squamous cell carcinoma possessed a mutation in the ERBB3 (aka HER3) gene which encodes a receptor belonging to the human epidermal growth factor receptor (HER) family. Dysregulation of the HER family of receptors is most commonly implicated in breast cancer. Although studies of cancer involving the skin are limited, overexpression of ERBB3 has been demonstrated in squamous cell carcinoma, basal cell carcinoma, and melanoma [2, 3]. One preclinical study has shown that deletion of the ERBB3 gene provided significant skin cancer protection in mice, suggesting an important role for ERBB3 in skin carcinogenesis .
Signal transduction of HER receptors requires dimerization with another receptor within the family. ERBB3 has little ability to transduce signal via homodimerization, thus it relies on pairing with others, most notably ERBB2 (aka HER2). This combination of receptors has been found to be coexpressed more frequently in non-melanoma skin cancers when compared to normal skin . The ERBB2 and ERBB3 heterodimer appears to be the most oncogenic dimeric combination . The strength in this pairing lies in ERBB2′s potent stimulation of the mitogen-activated protein kinase (MAPK/ERK) pathway, and ERBB3′s stimulation of the phosphatidylinositol 3-kinase (PI3K) to AKT cell-survival pathway . These findings suggest that this oncogenic heterodimer may be involved the carcinogenesis of skin cancers and could be a target of therapy.
Lapatinib is a dual tyrosine kinase inhibitor of ERBB1 (aka EGFR) and ERBB2 which is FDA-approved for the treatment of ERBB2 positive metastatic breast cancer. In vitro, this drug was shown to be more efficacious than other drugs (e.g. trastuzumab) when a given to cancer cells with ERBB3-activating somatic mutations, similar to the mutation described in this patient . Our patient was given lapatinib which led to marked clinical improvement, exhibited by a significant decrease in tumor size, pain, and the return of his hearing.
Although the exact mechanism of this patient’s clinical response is unknown, we postulate that synergistic tumor destruction mechanisms enhanced the immune activation of anti-PD1. As in melanoma, it is likely that tumor recognition and destruction are dependent on the development and recognition of neo-antigens. Not all mechanisms that increase tumor destruction generate viable tumor antigens, for example, in a mouse model, cryotherapy with liquid nitrogen generated nearly 3 times as many tumor specific T cells as radiofrequency ablation [7, 8]. In our patient, we suspect that adjunctive measures, including tumor debulking surgery and liquid nitrogen cryotherapy, also contributed to his remarkable clinical response. Of note, it was difficult to identify a surgeon willing to perform debulking surgery for this patient even though debulking procedures are well known to provide palliation and augment systemic therapy in other tumor types .
Cutaneous SCC is the second most common malignancy and although surgery may be curative in local disease, effective therapy for metastatic disease remains elusive. The metastatic rate for primary tumors on sun-exposed skin is 5.2% and overall metastatic rate is 11%. Overall 5-year survival rate is 26.8% from all cutaneous sites . Future study of HER2 targeted therapies may provide an effective treatment strategy for cutaneous squamous cell carcinoma patients with mutations in the HER2/3 pathway, including those with advanced disease.