[DEFERRED NEPHRECTOMY IN A PATIENT WITH METASTATIC RENAL CELL CARCINOMA AFTER A NEAR-COMPLETE RESPONSE TO IMMUNOTHERAPY].

INTRODUCTION: The treatment of newly diagnosed metastatic renal cell carcinoma (mRCC) evolved dramatically with the approval of immune checkpoint inhibitors (ICI) such as nivolumab, ipilimumab, and pembrolizumab for this indication. Herein, we describe the case of a 52-year old male patient, without chronic diseases and with a 30-pack-year smoking history, who was diagnosed with mRCC (clear cell carcinoma) including enlarged lymph nodes in the mediastinum, a mass in the pleura, and numerous metastases in both lungs. The patient was treated with a combination of nivolumab and ipilimumab, followed by nivolumab monotherapy, which is still ongoing (as of December 2021). The patient had a near-complete response (near resolution of the metastatic lesions) and did not experience adverse events. After 13 months of treatment, and in light of the near-complete response, the patient underwent a radical laparoscopic nephrectomy. The postoperative period was uneventful and the patient was discharged from the hospital 3 days after surgery. Examining the excised kidney revealed no residual tumor, connective tissue, signs of inflammation and necrosis. As of December 2021 (approximately 23 months from immunotherapy initiation) the patient had no evidence of disease. This case report demonstrates a treatment approach involving deferred nephrectomy after (and during) ICI treatment. The response of the patient described herein to a combination of nivolumab and ipilimumab is consistent with the available data supporting the efficacy of this combination as a first-line therapy in mRCC. Currently, the evidence supporting deferred nephrectomy (after ICI) vs upfront nephrectomy and then ICI, or ICI alone without nephrectomy is limited to a few retrospective studies. Thus, prospective randomized studies are needed to elucidate the role of deferred nephrectomy in mRCC. Two phase 3 studies (PROBE and NORDIC-SUN) that were designed to address this issue are currently enrolling patients and their results are expected within several years.

Tissue specific DNA methylation in normal human breast epithelium and in breast cancer.

Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.