Cell-free DNA (cfDNA) variant analysis is used to guide treatment decisions for men with metastatic prostate cancer (mPC) and to enroll patients on clinical trials.¹ Two poly(ADP) ribose polymerase inhibitors (PARPi) were recently granted US Food and Drug Administration (FDA) approval for use in selected patients with mPC based on DNA repair gene status: rucaparib for patients with BRCA1 or BRCA2 variants and olaparib for patients with ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD51L variants.² Following these biomarker-guided approvals we expect cfDNA testing will sharply increase for patients with mPC because it offers the convenience and simplicity of testing on a blood sample in the advanced disease setting.^1,3,4 Thus, there is an urgent need to understand cfDNA testing performance and sources of test interferences.

Microsatellite instability (MSI) is now being used as a sole biomarker to guide immunotherapy treatment for men with advanced prostate cancer. Yet current molecular diagnostic tests for MSI have not been evaluated for use in prostate cancer. We evaluated two next-generation sequencing (NGS) MSI-detection methods, MSIplus (18 markers) and MSI by Large Panel NGS (> 60 markers), and compared the performance of each NGS method to the most widely used 5-marker MSI-PCR detection system. All methods were evaluated by comparison to targeted whole gene sequencing of DNA mismatch-repair genes, and immunohistochemistry for mismatch repair genes, where available. In a set of 91 prostate tumors with known mismatch repair status (29-deficient and 62-intact mismatch-repair) MSIplus had a sensitivity of 96.6% (28/29) and a specificity of 100% (62/62), MSI by Large Panel NGS had a sensitivity of 93.1% (27/29) and a specificity of 98.4% (61/62), and MSI-PCR had a sensitivity of 72.4% (21/29) and a specificity of 100% (62/62). We found that the widely used 5-marker MSI-PCR panel has inferior sensitivity when applied to prostate cancer and that NGS testing with an expanded panel of markers performs well. In addition, NGS methods offer advantages over MSI-PCR, including no requirement for matched non-tumor tissue and an automated analysis pipeline with quantitative interpretation of MSI-status.

Purpose: The WEE1 tyrosine kinase regulates G2–M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders. Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740–8. ©2018 AACR.

In 2011, an association between somatic mosaic mutations in the p53-inducible protein phosphatase gene PPM1D in peripheral blood mononuclear cells (PBMCs) in patients with breast cancer and ovarian cancer (OC) was reported.¹ All PPM1D mutations were truncating mutations in the last exon, were thought to be activating, and were absent from matched cancers. Akbari et al² confirmed these findings and suggested that somatic PPM1D mutations reveal an OC predisposition that warrants risk-reducing salpingo-oophorectomy. Somatic mosaic PPM1D mutations have also been reported in lung cancer.³ Whether PPMID mutations reflect an underlying cancer predisposition or consequence of cancer therapy is unclear. Here we investigated whether PPM1D somatic mosaic mutations reflect a previously unrecognized association with prior chemotherapy and whether similar mutations also occur in other genes associated with OC.

Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate