Highlights of This Issue

HER2 activating mutations occur in 2% to 3% of HER2-nonamplified breast cancers with a higher incidence in lobular cancers. Ma and colleagues demonstrate the pan-HER inhibitor neratinib is active in this setting with a clinical benefit rate of 31% in advanced disease. Retrospective analysis of plasma-circulating tumor DNA (ctDNA) showed a high specificity and good sensitivity for detecting HER2 mutations. An early decrease in ctDNA HER2 mutation variant allele frequency correlated well with clinical responsiveness. This study therefore establishes ctDNA sequencing as a noninvasive approach to HER2 mutation diagnosis, simplifying patient eligibility assessment, and potentially disease monitoring.

Despite a considerable risk of recurrence, a widely accepted adjuvant treatment for early-stage melanoma is lacking. Notwithstanding the advent of immune checkpoint inhibitors, distant recurrences will still prove fatal for many patients. Koster and colleagues show that local low-dose CpG-B administration provides an adjuvant treatment option for early stages of melanoma that selectively activates lymph node-resident dendritic cells, boosts loco-regional and systemic T-cell immunity, and can offer durable protection against recurrence with minimal side effects. This one-off and generally applicable intervention could eventually preempt the need for often toxic and costly systemic treatment with immune checkpoint inhibitors.

Cisplatin, a commonly prescribed chemotherapeutic, can lead to persistent and debilitating neurotoxicity. Dolan and colleagues show that cisplatin-induced peripheral neuropathy (CisIPN) symptoms are common, significantly correlated with weight gain since treatment, and inversely correlated with self-reported health and physical activity. Furthermore, the authors identified age, tobacco use, excess drinking, and hypertension as significantly associated with CisIPN. They found high trait heritability, indicating that genetic variants likely explain a large proportion of variability in the CisIPN phenotype. The authors found RPRD1B, a DNA repair gene, to be protective against neuropathy induced by various drugs, indicating that it might play a broad neuroprotective role.

It is widely accepted that tissue tumor mutational burden can help predict response to checkpoint inhibitor immunotherapy. In assessing peripheral blood circulating tumor DNA of patients with a wide variety of malignancies, Khagi and colleagues found that bright line cutoffs for total and variant of unknown significance (VUS) alteration number predicted response rate, progression-free, and overall survival to checkpoint inhibitor-based immunotherapy. This analysis demonstrates a correlation between high alteration number in blood-derived circulating tumor DNA and favorable outcome, providing the impetus to potentially utilize liquid biopsy as a noninvasive predictive biomarker for checkpoint inhibitor response across various histologies.