In a meanwhile, epidermal growth factor receptor (EGFR) signaling promotes aerobic glycolysis through the phosphoinositide 3-kinase/AKT or RAS/ mitogen-activated protein kinase pathway , and EGFR TKI erlotinib reverted aerobic glycolysis in cancer cell line . Against this backdrop, phase II clinical trials evaluating the efficacy and safety of the combination of GSK2838232A bevacizumab plus erlotinib (AVATAR trial, “type”:”clinical-trial”,”attrs”:”text”:”NCT01130519″,”term_id”:”NCT01130519″NCT01130519) and the combination of vandetanib plus metformin (“type”:”clinical-trial”,”attrs”:”text”:”NCT02495103″,”term_id”:”NCT02495103″NCT02495103) are underway. plus erlotinib. Median age at diagnosis was 41 years, and five of the patients had received the combination as first- or second-line treatments. The ORR was 50% and the median PFS and OS were 13.3 and 14.1 months, respectively. Most adverse events were predictable and manageable by conventional measures, except for one instance where a patient died of gastrointestinal bleeding. Conclusion This is the first real-world outcome of the treatment of advanced HLRCC-associated RCC. Bevacizumab plus erlotinib therapy showed promising activity with moderate toxicity. We should be increasingly aware of HLRCC-associated GSK2838232A RCC and bevacizumab plus erlotinib should be a first-line treatment for this condition, unless other promising data are published. strong class=”kwd-title” Keywords: Hereditary leiomyomatosis and renal cell carcinoma, Bevacizumab, Erlotinib, Renal cell carcinoma, Fumarate hydratase, Non-clear cell Introduction Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a genetic syndrome resulting from germline mutations in GSK2838232A fumarate hydratase (FH) . This autosomal dominant condition is characterized by cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive form of type 2 papillary renal cell carcinoma (RCC) [2,3]. Although RCC arising in HLRCC syndrome has been described as type 2 papillary RCC, the recently updated World Health Organization (WHO) 2016 genitourinary cancer classification added RCC in HLRCC as a new entity, HLRCC-associated RCC . More than 180 families with FH germline mutations have been reported  but the Rabbit polyclonal to Src.This gene is highly similar to the v-src gene of Rous sarcoma virus.This proto-oncogene may play a role in the regulation of embryonic development and cell growth.The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase.Mutations in this gene could be involved in the malignant progression of colon cancer.Two transcript variants encoding the same protein have been found for this gene. exact incidence of HLRCC syndrome or HLRCC-associated RCC remains unknown as this entity has had a low awareness among urologists, medical oncologists, and pathologists until today. A considerable proportion of patients with HLRCC-associated RCC might have been diagnosed and treated as having sporadic papillary RCC and even after correct diagnosis, there has been no specific treatment option for advanced HLRCC-associated RCC. The most commonly used treatment might be mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs), similar to the treatment of non-clear cell RCC . With the accumulation of pathobiological knowledge underlying HLRCC-associated RCC, there have been attempts at mechanism-based treatment for HLRCC-associated RCC. FH-deficient kidney cancer is characterized by impaired Krebs cycle and oxidative phosphorylation, thus depends on glucose for adenosine triphosphate generation by aerobic glycolysis (Warburg effect). Increased oxidative stress and/or increased levels of fumarate inhibit hypoxia-inducible factor (HIF) prolyl hydroxylase which facilitates ubiquitinmediated degradation of HIF, resulting in HIF stabilization. Accumulation of HIF leads to increased transcription of vascular endothelial growth factor (VEGF) . Bevacizumab can inhibit VEGF-mediated tumor vasculature. In a meanwhile, epidermal growth factor receptor (EGFR) signaling promotes aerobic glycolysis through the phosphoinositide 3-kinase/AKT or RAS/ mitogen-activated protein kinase pathway , and EGFR TKI erlotinib reverted aerobic glycolysis in cancer cell line . Against this backdrop, phase II clinical trials evaluating the efficacy and safety of the combination of bevacizumab plus erlotinib (AVATAR trial, “type”:”clinical-trial”,”attrs”:”text”:”NCT01130519″,”term_id”:”NCT01130519″NCT01130519) and the combination of vandetanib plus metformin (“type”:”clinical-trial”,”attrs”:”text”:”NCT02495103″,”term_id”:”NCT02495103″NCT02495103) are underway. An interim analysis of the AVATAR trial of bevacizumab plus erlotinib showed an impressive objective response rate (ORR) of 65% in patients with HLRCC-associated RCC  and a median progression-free survival (PFS) of 24.2 months. This promising result led to the recommendation of bevacizumab plus erlotinib for the treatment of HLRCC-associated RCC in the 2018 National Comprehensive Cancer Network (NCCN) guidelines . In Korea, however, HLRCC-associated RCC has only recently been recognized by physicians and, to our knowledge, there are currently no formal reports on Korean patients with this disease. Therefore, the outcome of bevacizumab plus erlotinib therapy in Korean patients is not known. For this good reason, we GSK2838232A retrospectively gathered data on individuals with HLRCC in Korea also to evaluate the effectiveness and safety from the bevacizumab plus erlotinib mixture treatment. Methods and Materials 1. Individual selection We retrospectively evaluated consecutive individuals identified as having HLRCC-associated RCC and treated between July 2014 and July 2018 in three educational hospitals (Asan INFIRMARY, Gil INFIRMARY, and Seoul Country wide University Medical center) in South Korea. The choice criteria for evaluation were the following: analysis of HLRCC-associated RCC, advanced stage (repeated, advanced unresectable locoregionally,.