DNA Polymerase ɛ Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity.

Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase ɛ have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in POLE lead to impaired proofreading intrinsic to Pol ɛ during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol ɛ have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these POLE mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a POLE mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in POLE deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here. The Oncologist 2017;22:497-502 KEY POINTS: Clinicians should recognize that tumors with high tumor mutation burden and that are microsatellite stable may harbor a POLE mutation, which is associated with an ultramutated phenotype.Work-up for POLE deficiency should indeed become part of the routine molecular testing paradigm for patients with colorectal cancer.This subset of patients may benefit from clinical trials where the higher number of mutation-associated neoantigens and defect in DNA repair may be exploited therapeutically.

Emerging drugs for urothelial (bladder) cancer.

INTRODUCTION: Metastatic urothelial carcinoma has been associated with poor prognosis and a median survival of approximately 12-14 months with standard therapy. Treatment options for decades have been limited to platinum based chemotherapy as first line with few therapeutic options available to the majority who will ultimately progress beyond platinum. Areas covered: This review focuses on the various targeted, antiangiogenic, chemotherapeutic and immunotherapeutic agents currently being developed for the treatment of urothelial carcinoma. Expert opinion: Incorporation of systemic immunotherapy into the treatment of urothelial carcinoma has already fundamentally changed the treatment of this disease. The landscape is rapidly changing and it is likely that immunotherapy will be incorporated into therapy in earlier disease states and in novel combinations. Outcomes in urothelial carcinoma have improved and likely to improve further with ongoing and future clinical research that is discussed in this review.

MET/HGF pathway activation as a paradigm of resistance to targeted therapies.

Resistance to targeted therapeutics is a key issue limiting the long-term utility of these medications in the management of molecularly selected subsets of cancer patients, including patients with non-small cell lung cancer harboring oncogenic alterations affecting EGFR, ALK and other genes. Bypass resistance mediated by activation of MET kinase has emerged as a frequent, validated and pivotal resistance mechanism in multiple types of cancers. Biochemical understanding is accumulating to explain the unique role of MET in such bypass pathways, providing alternate downstream activation opportunities and intricate interactions during epithelial-mesenchymal transitions. Multiple diagnostic testing platforms have become available for selecting appropriate patients for MET targeting in a variety of settings. Importantly, in light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation of MET targeting as a clinically impactful strategy.

Update of systemic immunotherapy for advanced urothelial carcinoma.

PURPOSE: Until recently, therapeutic options for metastatic urothelial carcinoma (UC) were limited to cytotoxic chemotherapy. Cisplatin-based combination chemotherapy has proven benefit in the perioperative settings for muscle-invasive disease and for metastatic disease. A large proportion of patients is cisplatin-ineligible and limited to less effective chemotherapeutic options. However, treatment options have recently expanded with the development of systemic immunotherapy with checkpoint inhibitors (CPIs).Herein we review the clinical trial data supporting the use of CPIs in UC. We also describe ongoing clinical trials that are exploring CPIs in novel combinations and in a variety of disease settings. METHODS: A comprehensive literature review was performed using Medline/Pubmed and clinical trials. RESULTS/CONCLUSIONS: Based on results of the IMvigor 210 clinical trial, the anti-programmed death-ligand1 antibody atezolizumab gained regulatory approval in May 2016 for use in locally advanced and metastatic UC in patients with progression of disease despite prior platinum-based chemotherapy. Since that time, additional CPIs (avelumab, durvalumab, nivolumab, and pembrolizumab) have gained regulatory approval in the postplatinum setting. The approval of pembrolizumab was supported by KEYNOTE-045, the first reported randomized, phase III trial of a CPI in UC. Atezolizumab and pembrolizumab are also approved for first-line therapy for cisplatin-ineligible patients with locally advanced or metastatic disease. The rapid expansion of therapeutic options in UC has shifted the treatment paradigm.

FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis.

Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.