PERFORM: a non-interventional study assessing the patients' treatment starting with 1L palbociclib in HR+/HER2- ABC.

The prospective, non-interventional PERFORM study describes and analyzes the effectiveness of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) as first-line treatment for patients with locally advanced or metastatic HR+/HER2- breast cancer in the real-world setting in Germany and Austria. PERFORM will reflect current patient characteristics and routine treatment patterns including treatment sequences and time to subsequent (chemo)therapy. Besides, second-line treatment effectiveness and patient-relevant end points such as longitudinal patient-reported outcome measurements beyond disease progression will be analyzed. Accounting for the heterogenous real-world patient population, data on clinicopathologic subgroups underrepresented in clinical trials such as elderly or male will be analyzed. Taken together, PERFORM will close knowledge gaps from clinical trials in real world.

Palbociclib in combination with endocrine therapy is the standard first-line treatment for patients with advanced HR+/HER2- breast cancer. Data from clinical trials have shown high response rates and good tolerability. To support these data and close potential knowledge gaps, we conduct the multicenter, observational PERFORM study to evaluate the effectiveness and patient-reported outcomes in patients with advanced HR+/HER2- breast cancer treated with endocrine-based palbociclib therapy in routine clinical practice in Germany. Clinical Trial Registration: NCT04767594 (ClinicalTrials.gov) Sponsor: Pfizer Pharma GmbH, Linkstraße 10, D-10785 Berlin, Germany.

Awareness and Availability of Routine Germline BRCA1/2 Mutation Testing in Patients with Advanced Breast Cancer in Germany.

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 in-sufficient. 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).

Doxycyclin ameliorates a starvation-induced germline tumor in C. elegans daf-18/PTEN mutant background.

Managing available resources is a key necessity of each organism to cope with the environment. The nematode C. elegans responds to nutritional deprivation or harsh environmental conditions with a multitude of developmental adaptations, among them a starvation-induced quiescence at early larval development (L1). daf-18, the C. elegans homolog of the human tumor suppressor gene PTEN, is essential for the maintenance of survival and germline stem cell arrest during the L1 diapause. We show here that daf-18 mutants, independently to their failure to maintain G2 arrest of the primordial germ cells, develop a gonad phenotype after refeeding. This highly penetrant gonadal phenotype is further enhanced by a mutation in shc-1, encoding a protein homologous to the human adaptor ShcA. Features of this phenotype are a tumor-like phenotype encompassing hyper-proliferation of germ cell nuclei and disruption/invasion of the basement membrane surrounding the gonad. The penetrance of this phenotype is reduced by decreasing starvation temperature. In addition, it is also ameliorated in a dose-dependent way by exposure to the antibiotic doxycyclin either during starvation or during subsequent refeeding. Since, in eukaryotic cells, doxycyclin specifically blocks mitochondrial translation, our results suggest that daf-18 and shc-1;daf-18 mutants fail to adapt mitochondrial activity to reduced nutritional availability during early larval developing.

Mitochondrial stress: balancing friend and foe.

Mitochondria are vital organelles of the aerobic eukaryotic cell. Their dysfunction associates with aging and widespread age-related diseases. To sustain mitochondrial integrity, the cell executes a distinct set of stress-induced protective responses. The mitochondrial unfolded protein response (UPR(mt)) is a response of the cell to mitochondrial damage. The transcription factor ATFS-1 triggers UPR(mt) effector gene expression in the nucleus. The selective exclusion of ATFS-1 from mitochondrial import by stress-induced alterations of the mitochondrial membrane potential is currently discussed as key activation mechanism. Surprisingly, UPR(mt) activation often coincides with a lifespan extension in Caenorhabditis elegans and the same has recently been reported for mammalian cells. This review summarizes the current model of the UPR(mt), its inducers, and its crosstalk with other cellular stress responses. It focuses on the role of mitochondrial function as a regulator of aging and longevity.