Purpose Late relapse (LR) of germ cell tumor (GCT) is a well recognized entity associated with poor survival. We report on our experience with LR and determine predictors of survival. Patients and Methods From 1990 to 2004, 75 patients were managed for LR of GCT at our institution. Clinical and pathologic parameters were reviewed. Estimates of cancer-specific survival were generated using the Kaplan-Meier method, and a Cox proportional hazards model was used to assess potential predictors of outcome. Results The median time to LR was 6.9 years (range, 2.1 to 37.7 years). Overall, 56 patients (75%) had LR in the retroperitoneum, including 25 (93%) of 27 patients initially managed without retroperitoneal lymph node dissection. The 5-year cancer-specific survival (CSS) was 60% (95% CI, 46% to 71%). Patients who underwent complete surgical resection at time of LR (n = 45) had a 5-year CSS of 79% versus 36% for patients without complete resection (n = 30; P < .0001). The 5-year CSS for chemotherapy-naive patients was significantly greater than patients with a prior history of chemotherapy as part of their initial management (5-year CSS, 93% v 49%, respectively). In multivariable analysis of pretreatment parameters available at the time of LR, the presence of symptoms (hazard ratio [HR] = 4.9) and multifocal disease (HR = 3.0) were associated with an inferior CSS. Conclusion The data suggest that meticulous control of the retroperitoneum is critical to prevent LR in the retroperitoneum. In multivariable analysis, patients with a symptomatic presentation and those with multifocal disease have a significantly decreased survival. Survival is greatly improved if complete surgical excision of disease is attained.
4551 Background: The current recommendation for the management of patients with the histologic finding of fibrosis or teratoma at PC-RPLND is surveillance. We evaluated men at our institution who underwent PC-RPLND for metastatic non-seminomatous germ cell tumor (NSGCT) to determine predictors of disease recurrence. Methods: From 1989 through 2003, a total of 532 men underwent PC-RPLND for metastatic NSGCT at our institution. Of these, 473 (89%) had either fibrosis or teratoma present in the RPLND specimen. Following IRB approval, clinical and pathologic data were obtained from our prospective surgical database. A Cox regression model was constructed to evaluate variables that may predict for recurrence of viable NSGCT following PC-RPLND and a prognostic index was developed. Freedom from disease recurrence was analyzed using the Kaplan Meier method. Results: Of the 473 patients with fibrosis or teratoma, all patients underwent complete resection of all residual retroperitoneal masses, however 35 (7%) did not undergo a full PC-RPLND. With a median follow-up of 41 months, 47 (10%) patients relapsed with viable NSGCT. The 2- and 5- year probability of freedom from recurrent viable GCT for the entire cohort was 90% and 89%, respectively. In our multivariable model only post-chemotherapy nodal size > 5cm (p = 0.008), clinical stage III (p = 0.002), and absence of a full PC-RPLND (p = 0.002) were independent predictors for recurrence with viable NSGCT. Based on these three adverse predictors, a prognostic index was developed with favorable patients having no risk factors, intermediate prognosis patients with one risk factor, and poor prognosis patients having 2 or more risk factors. Favorable, intermediate, and poor prognosis patients had a 2-year progression free probability of 97% (95% CI 95–99%), 90% (95% CI 85–95%), and 66% (95% CI 54–78%), respectively (p < 0.001). Conclusions: This data suggests that patients who have a high risk of reucrrence with viable GCT should undergo more frequent follow-up during the first 2-years with serum tumor markers and imaging. Additionally, this data suggests that an incomlete RPLND is not sufficient surgery for men with metastatic NSGCT. These men should undergo a bilateral RPLND. No significant financial relationships to disclose.
Recent phase 3 clinical trial showed improved radiographic progression-free survival in PTEN-deficient prostate cancers treated with combined Akt and AR inhibition. Building on this and our previous research into PI3K and AR signaling interactions, we aimed to define the mechanisms of response and resistance to Akt inhibition. We discovered that restoration of mTOR signaling was the early dominant driver of resistance to Akt inhibition. Mechanistically, this can be achieved through molecular alterations, resulting in loss of negative regulators of mTOR. Unexpectedly, we discovered that this was dominated by restoration of mTOR signaling through the nutrient sensing arm. This can be achieved by loss of the components of the GATOR/KICSTOR complexes or through cellular processes, leading to the recycling of amino acids. The addition of an mTOR inhibitor restored sensitivity to Akt inhibition and represents a precision-based strategy to overcome resistance in the clinic.
Despite the improved clinical outcomes for patients with advanced prostate cancer due to the use of second generation antiandrogens, acquired drug resistance inevitably occurs and remains the major challenge for prostate cancer therapy. While several cell-autonomous mechanisms of drug resistance have been elucidated previously, for a large number of patients the mechanism of resistance remains unclear. Recent studies point to the importance of the tumor microenvironment (TME), and cancer associated fibroblasts (CAF) in the TME, in mediating tumor progression and resistance to therapy, but whether CAFs specifically contribute to antiandrogen resistance in prostate cancer is not known. Using a preclinical model that faithfully mimics the typical progression of patients on antiandrogen therapy, we found that antiandrogen resistance develops significantly faster when cells are grown in the presence of their cognate CAFs. By carrying out biochemical purification and mass spectrometry analysis, we identified NRG1 as a CAF secreted factor, and found that it can promote antiandrogen resistance in tumor cells, via activation of HER3 in the tumor. Importantly, blocking either NRG1 or HER3 can re-sensitize tumors to antiandrogen treatment in this model. Moreover, NRG1 expression is up-regulated in CAFs after antiandrogen exposure or in androgen deprivation condition. Clinically, increased stroma-NRG1 expression was observed in patients post androgen deprivation therapy but not in hormonally intact men. Taken together, this work has revealed a novel, NRG1-mediated non-cell autonomous mechanism of antiandrogen resistance in prostate cancer, and suggests that therapeutically targeting NRG1 in the setting of metastatic, antiandrogen-resistant prostate cancer with elevated NRG1 could provide significant benefit to patients.Note: This abstract was not presented at the meeting.Citation Format: Zeda Zhang, Wouter Karthaus, Jose Mauricio Mota, Ping Mu, Chao Wu, Wassim Abida, Eliot Linton, Young Sun Lee, Eugine Lee, Ninghui Mao, Elizabeth Adams, Danielle Choi, Dana E. Rathkopf, Brett Carver, Anuradha Gopalan, Xuejun Jiang, Philip Watson, Charles Sawyers. Tumor microenvironment derived NRG1 promotes antiandrogen resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 111.
Abstract Mutational activation of the PI3K/AKT pathway is among the most common pro-oncogenic events in human cancers. The clinical utility of PI3K and AKT inhibitors has, however, been modest to date. Here, we used CRISPR-mediated gene editing to study the biological consequences of AKT1 E17K mutation by developing an AKT1 E17K–mutant isogenic system in a TP53-null background. AKT1 E17K expression under the control of its endogenous promoter enhanced cell growth and colony formation, but had a paradoxical inhibitory effect on cell migration and invasion. The mechanistic basis by which activated AKT1 inhibited cell migration and invasion was increased E-cadherin expression mediated by suppression of ZEB1 transcription via altered β-catenin subcellular localization. This phenotypic effect was AKT1-specific, as AKT2 activation had the opposite effect, a reduction in E-cadherin expression. Consistent with the opposing effects of AKT1 and AKT2 activation on E-cadherin expression, a pro-migratory effect of AKT1 activation was not observed in breast cancer cells with PTEN loss or expression of an activating PIK3CA mutation, alterations which induce the activation of both AKT isoforms. The results suggest that the use of AKT inhibitors in patients with breast cancer could paradoxically accelerate metastatic progression in some genetic contexts and may explain the frequent coselection for CDH1 mutations in AKT1-mutated breast tumors. Implications: AKT1 E17K mutation in breast cancer impairs migration/invasiveness via sequestration of β-catenin to the cell membrane leading to decreased ZEB1 transcription, resulting in increased E-cadherin expression and a reversal of epithelial–mesenchymal transition.
