Teemu Daniel Laajala

Objectives: Adjuvant pembrolizumab has improved overall survival after surgery for clear cell renal cell carcinoma (ccRCC) with an intermediate‐high and high risk of recurrence according to the inclusion criteria of Keynote‐564 study, but non‐RCC mortality is common during postoperative follow‐up. We aimed to evaluate the competing risk of death after surgery in patients with ccRCC stratified according to the risk of recurrence with Keynote‐564, Three‐feature and Leibovich models.Material and Methods: A total of 1108 patients with ccRCC operated with curative intent between 2005 and 2021 before the use of adjuvant immunotherapy were identified from two academic centres in Finland and Sweden. Patients with cytoreductive nephrectomy, multiple kidney tumours or non‐ccRCC were excluded. Baseline characteristics and survival outcomes were described, and the Kaplan–Meier method was used to estimate overall survival.Results: During the median postoperative follow‐up of 5.0 years, 134 (12%) patients had died from RCC with a median time to death of 3.7 years (IQR 1.6–6.6) while for 220 (20%) patients the cause of death was other than RCC, most commonly other cancers (n = 59, 5%) and cardiovascular diseases (n = 54, 5%). According to the Keynote‐564 criteria, 34 (3%) patients were classified as having high risk of recurrence, 336 (30%) patients intermediate‐high risk and 738 (67%) patients low risk of recurrence with 41% of RCC deaths observed in this subgroup. Limitations of this study include the lack of information on performance status, comorbidities and systemic treatments for recurrent RCC.Conclusions: In addition to deaths from RCC, deaths from other cancers and cardiovascular diseases were common after surgery for ccRCC. As 41% of RCC deaths were observed among patients currently excluded from adjuvant therapy, more research on patient selection for perioperative immunotherapy is needed as well as interventions improving the treatment of comorbidities and lifestyle after nephrectomy.

Importance: Magnetic Resonance Imaging (MRI) coupled with Prostate Imaging-Reporting and Data System (PI-RADS) provides a standardized scoring system for assessing the clinical significance of prostate cancer (PCa). The association between PI-RADS scores and key clinical end-points remains underexplored due to limited follow-up data. Objective: To evaluate the association of PI-RADS with prostate cancer-specific mortality (PCSM), overall survival (OS), metastasis-free survival (MFS), and biochemical recurrence (BCR) across three cohorts. Design, Setting, Participants: A retrospective registry cohort, Helsinki University Hospital (HUS) for men with clinical suspicion of PCa, included 4,674 men who underwent diagnostic MRI during the PI-RADS version-2 era (2015-2019, median follow-up [mFU] 5.0 years). Validation cohorts were: Tampere University Hospital (n=1,474, 2016-2021, mFU 2.2 years) and Lille University Hospital (N=301, 2016-2024, mFU 6.2 years). Exposures: Diagnostic MRI imaging was scored using PI-RADS v2. Main outcomes and measures: Primary outcomes were PCSM, OS, MFS, and BCR. Secondary measures included clinical confounders, such as age, Grade Group (GG), and Charlson’s Comorbidity Index (CCI). Results: 84 of 4,674 HUS-cohort patients (1.7%) died of PCa, with 79 patients (94%) presenting with PI-RADS score 5. Multivariable Cox regression adjusted for clinical confounders found PI-RADS score 5 was significantly associated with PCSM (Hazard Ratio (HR) 18.4, 95% CI [6.62-51.1], p<0.001), along with biopsy GG 5 (HR 5.45 [1.82-16.3], p=0.002), CCI (HR 1.53 [1.42-1.7], p<0.001), and log2-PSA (HR 1.28 [1.11-1.5], p<0.001). Kaplan-Meier curves demonstrated negligible PCSM after negative MRI (nMRI; PI-RADS score 0-2) (log-rank p<0.001). PI-RADS score 5 was associated with OS in the Helsinki and Tampere cohorts (p<0.001) and MFS and BCR in the Lille cohort (p<0.001). Conclusion and relevance: PI-RADS score 5 is strongly associated with an increased risk of PCSM and other clinically relevant outcomes. A non-suspicious MRI associates with a negligible risk of adverse outcomes. These findings support the use of MRI for risk stratification in PCa.

Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

Supplementary Table from NPEPPS Is a Druggable Driver of Platinum Resistance

Supplementary Figures and Supplementary Table legends.

Supplementary Tables from NPEPPS Is a Druggable Driver of Platinum Resistance

Supplementary Tables from NPEPPS Is a Druggable Driver of Platinum Resistance

Supplementary Tables from NPEPPS Is a Druggable Driver of Platinum Resistance

Supplementary Table from NPEPPS Is a Druggable Driver of Platinum Resistance