Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal transduction of the mitochondrial unfolded protein response (UPRmt) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPRmt, and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS–induced UPRmt. Activation of the UPRmt, but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS–induced UPRmt, suggesting that surveillance-activated defenses specifically inhibit the UPRmt but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism.

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Background: The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo-and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. Methods: In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL).

Introduction: Diagnostic testing of germline mutations in breast cancer susceptibility genes 1 or 2 (gBRCA1/2) in patients with human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC; locally advanced or metastatic breast cancer) is necessary to assess eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). We investigated awareness, clinical practice, and the availability of gBRCA1/2 mutation testing in the German outpatient oncology setting. Methods: Office-based oncologists completed a 23-item online survey. Responses were evaluated collectively and by center type. Results: Of 50 oncologists, 33 and 17 were medical and gynecological oncologists, respectively. Oncologists treated a median of 65 (range 14–350) patients with ABC per year. The strongest decision factors to initiate gBRCA1/2 mutation testing were: patient’s known family history of gBRCA1/2 mutation-related cancer(s), guideline recommendations, and triple-negative breast cancer (TNBC). In routine practice, 86% of oncologists tested for gBRCA1/2 mutations. Most oncologists (76–98%) reported testing patients with a known family history of gBRCA1/2 mutation-related cancer(s) irrespective of receptor status. For unknown family history, 92% of oncologists reported testing patients with advanced TNBC versus 30% for HR+/HER2– ABC. Oncologists (66%) rated the awareness of therapeutic relevance of gBRCA1/2 mutation testing for targeted treatment selection as good to satisfactory; 22% rated awareness as poor to in­sufficient. Conclusion: Diagnostic gBRCA1/2 mutation testing in patients with HER2– ABC is available and routinely performed in Germany’s outpatient oncology setting. However, specific patient subgroups were not routinely tested despite therapeutic indications. Given PARPi availability, opportunities exist to improve testing rates especially for patients with HR+/HER2– ABC without a known family history of gBRCA1/2 mutation-related cancer(s).