Purpose: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes. Experimental Design: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy^based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status.Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test. Results:The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor^positive and/or progesterone receptor^positive tumors) as well as by PIK3CA mutation status (P < 0.0001 for both).AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with earlystage estrogen/progesterone receptor^positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors. Conclusions: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.

PURPOSE An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. CLINICAL CONTEXT An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection. PROVISIONAL CLINICAL OPINION Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel–based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker–linked options relative to other approved or investigational treatments. Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines .

While targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, patient bene t with OXPHOS inhibitors in the clinic has yet to be achieved. Based on promising preclinical data, we advanced IACS-010759, a highly potent and selective small-molecule inhibitor of mitochondrial complex I, into two phase I trials in patients with acute myeloid leukemia (NCT02882321) or advanced solid tumors (NCT03291938). Clinical ndings revealed that IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities that included elevated blood lactate and neurotoxicity, obstructing efforts to maintain target plasma exposure. Consequently, only modest on-target inhibition and limited antitumor activity were observed. Follow-up reverse translational studies uncovered that IACS-010759 reduced oxygen consumption rates in neurons and damaged myelin. Further, IACS-010759-treated mice displayed behaviors indictive of neuropathy, which were minimized with the co-administration of a histone deacetylase 6 inhibitor. Our ndings urge caution in the continued development of complex I inhibitors as antitumor agents.

Purpose: The Stimulator of Interferon Genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited anti-tumor activity. This Phase Ib, multi-center,dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanised IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and methods: Patients were treated with weekly intratumoral injections of MIW815(50–3200 μg) on a 3-weeks-on/1-week-off schedule or once every four weeks, plus a fixed dose of spartalizumab (400mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n=23; 22%), injection site pain (n=21; 20%), and diarrhea (n=12, 11%). Overall response rate was 10.4%. The maximum tolerated dose was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab, was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal anti-tumor responses were seen.

ABBREVIATIONS ALK anaplastic lymphoma kinase BRAF v-Raf murine sarcoma viral oncogene homolog B CDx Companion Diagnostic CGDB Clinico-Genomic Database CI confidence interval CLIA Clinical Laboratory Improvement Amendments CNS central nervous system COSMIC Catalogue of Somatic Mutations in Cancer CPS Combined Positive Score CR complete response CRC colorectal cancer CTCAE Common Terminology Criteria for Adverse Events CUP carcinoma of unknown primary DCR disease control rate dMMR deficient mismatch repair DOR duration of response