Highlights of This Issue

Concern has been expressed, based on preclinical data, that BRCA 1/2 mutation-associated ovarian cancer patients with PARP inhibitor (PARPi) resistance might also be resistant to chemotherapy including platinum. This study by Ang and colleagues provides data for the first time to indicate that this is not the case. The response rate was 40%–49% to platinum-based chemotherapy, and despite intervening PARPi treatment, the platinum-free interval remained predictive of response and prognostic of overall survival. Secondary BRCA 1/2 mutations were not detected in six cases when tumor samples were obtained at progression on PARPi, suggesting the likely importance of alternative resistance mechanisms.

Breast cancer is genetically and molecularly heterogeneous. Genome-wide transcriptional analysis identified a subset of androgen receptor (AR) positive, ER/PgR-negative breast cancer that exhibits androgen-dependent growth. In vitro studies confirmed the functional role of AR and showed that growth could be abrogated by antiandrogens (Doane et al. Oncogene, 2006). We translated this work into a multicenter phase II trial of bicalutamide in patients with AR+/ER/PgR-metastatic breast cancer (NCT00468715) and met a prespecified definition of activity. The final results, presented here, demonstrate for the first time that AR-targeted therapy may be a useful option for women with AR+ advanced breast cancer. Additional studies of newer anti-AR signaling agents should be pursued.

Stereotactic body radiation therapy (SBRT) or stereotactic ablative body radiation (SABR) is standard of care for medically inoperable early stage NSCLC patients. Despite excellent local control, regional failures after SABR are not uncommon. Meng and colleagaues present data suggesting that microRNA-31 increases invasiveness of lung adenocarcinoma and is a marker for lymph node metastases and poor survival. MiR-31 shows promise as a molecular marker predicting for the presence of lymph node metastasis in nonsurgically staged patients and thus could predict for regional failure after SABR.

Resminostat is a novel oral hydroxamate pan-histone deacetylase (HDAC) inhibitor with promising preclinical efficacy and safety profiles. In this first-in-human dose-escalation Phase I study, Brunetto and colleagues demonstrated that resminostat was safely tolerated up to the recommended Phase II dose with pharmacokinetic dose linearity, achievement of optimal on-target pharmacodynamic modulation of HDAC enzyme inhibition and histone acetylation, and signs of antitumor efficacy. Importantly, clinically significant cardiotoxicity and myelosuppression were not detected in this study. Based on these findings, resminostat is being further evaluated in numerous Phase II trials as monotherapy or in combination with other anticancer agents.