Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC.

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Human papillomavirus (HPV) infection is causative for cervical cancer and has been implicated in cancers at other sites. We review the English language literature in regard to the epidemiology of HPV infection as a risk for non-cervical cancer with a focus on the molecular evidence to support HPV having an etiologic role at each anatomic site. HPV DNA is detected in and/or serology provides evidence that HPV is associated with 35-50% of penile cancers, 80-95% of anal cancers, and ~35% of oropharyngeal cancers. HPV has also been implicated for cancer of the larynx, esophagus, lung, and urinary bladder with varying levels of linkage. Molecular studies at the respective anatomic sites provide evidence of HPV integration, E6 and E7 oncogene expression coupled with tumor suppressor down-regulation consistent with a role in the pathogenesis of tumor formation. HPV-associated cancer may represent a distinct disease entity relative to non HPV-associated cancers based upon natural history and outcome studies. Thus, the disease burden of HPV associated non-cervical cancers may be significant and justifies a comprehensive investigation of the utility of global prophylactic vaccination strategies.