Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy : A report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA)

Background: The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter >4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. Patients and methods: From 2007 to 2010, 897 patients were included in a prospective, population-based, riskadapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (n=469) or surveillance (n=422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. Results: At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, P = 0.011] and tumor diameter >4 cm (HR 2.7, P <0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin 4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin

One Course of Adjuvant BEP in Clinical Stage I Nonseminoma Mature and Expanded Results from the SWENOTECA group.

SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results

An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer

The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients