Selected Articles from This Issue

Cervical cancer is among the most common malignancies worldwide. A significant proportion of patients present with locally advanced disease (FIGO stage IB-IVA) that is treated with chemoradiotherapy with curative intent. Tumor hypoxia is associated with poor response to radiotherapy; despite advances in radiotherapy techniques, many women with cervical cancer develop recurrence. The authors previously demonstrated that metformin can decrease tumor hypoxia and consequently increase radiation response in vivo. Here, Han and colleagues present data from a phase II, window-of-opportunity trial that investigated if metformin decreased tumor hypoxia in patients with locally advanced cervical cancer. In this trial that selected for patients with hypoxic tumor, metformin decreased cervical tumor hypoxia without significant toxicity. The additional FAZA-PET scans and tumor biopsies limited study accrual, and more pragmatic ways of measuring and selecting tumor hypoxia are needed for future studies.

Poor-risk cytogenetics are associated with inferior outcomes in patients with AML treated with conventional therapies. TP53 mutations frequently co-occur with poor-risk cytogenetics. The phase III VIALE-A study showed that patients treated with venetoclax + azacitidine had higher remission rates and superior overall survival (OS) than patients treated with azacitidine alone. Pollyea and colleagues evaluated the efficacy of venetoclax + azacitidine in patients with poor-risk cytogenetics and TP53 mutations (TP53^mut) or TP53 wild-type (TP53^wt). Patients with poor-risk cytogenetics and TP53^mut receiving venetoclax + azacitidine had higher response rates but similar durations of remission (DoR) and OS than treatment with azacitidine alone. However, patients with poor-risk cytogenetics and TP53^wt who received venetoclax + azacitidine had remission rates, DoR, and OS that were superior to patients receiving azacitidine alone and comparable with those of similarly treated patients with intermediate-risk cytogenetics. Thus, in the absence of TP53^mut, poor-risk cytogenetics may not be an adverse risk factor for venetoclax + azacitidine.

Fibroblast activation protein (FAP) is a pan-tumor target expressed by cancer-associated fibroblasts in the tumor microenvironment. Many FAP-targeted therapies, including anti-FAP CAR-T cells, have been developed but tools to predict and monitor responses are limited. To design a biomarker of FAP CAR T-cell therapy, Lee and colleagues evaluated the use of radiolabeled FAP inhibitor, [18F]AlF-FAPI. The probe demonstrated high specificity for FAP in preclinical tumor models and was able to monitor the clearance of FAP⁺ cells following FAP CAR T-cell therapy. This work highlights the potential role of [18F]AlF-FAPI PET in informing patient selection and monitoring response to FAP-targeted therapies.

Clinical radiotherapy treatments do not currently consider tumor genetic features. Gopal and colleagues developed new computational and functional genomic tools to facilitate the profiling of individual genetic alterations (i.e., single nucleotide variants) in cells at scale. The results show that many genes can regulate the vulnerability of cells to ionizing radiation. In addition, the authors observed significant inter- and intragene mutant variation in the magnitude of conferred sensitivity or resistance. These results represent a pivotal step toward the development of information capabilities that can provide consistent and accurate predictions of tumor responses to radiotherapy.