EORTC 2238 "De-Escalate": a pragmatic trial to revisit intermittent androgen deprivation therapy in the era of new androgen receptor pathway inhibitors.

The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT), significantly improving survival rates. However, prolonged use of these therapies introduces notable side effects, prompting a need to revisit intermittent treatment duration. The EORTC 2238 De-Escalate trial is a pragmatic trial seeking to reassess the role of intermittent therapy in patients undergoing maximal androgen blockade (MAB) for metastatic hormone naïve prostate cancer (mHNPC), i.e., the combination of ADT with an ARPI, with the aims of reducing side effects, enhancing Quality of Life (QoL) and optimizing resource usage, while maintaining oncological benefits.

Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer.

PURPOSE OF REVIEW: This review aims to explore the evolving landscape of treatments available for metastatic castration-sensitive prostate cancer (mCSPC) patients. RECENT FINDINGS: In less than a decade, evidence was chronologically provided that (1) systemic treatment intensification with docetaxel improves outcomes, including survival, in men with mCSPC, (2) then that these outcomes are also improved when a second-generation androgen receptor pathway inhibitor (ARPI) is combined with androgen deprivation therapy (ADT), and (3) using a "triplet systemic therapy," which consists in the combination of ADT, an ARPI and docetaxel, further improves outcomes, including survival. Radiotherapy to the prostate combined with ADT alone is now recommended in men with low-volume mCSPC. Combining prostate radiotherapy and intensified systemic treatment including abiraterone may be synergistic as suggested in the PEACE-1 trial. Also, the role of metastases-directed local therapies (mostly stereotactic radiotherapy) is currently being assessed in phase 3 trials. Finally, the integration of biomarkers (e.g. BRCA2 gene alterations, PTEN loss, PSMA expression) for decision making is not currently established, though trials are also currently underway. Importantly, most evidence currently available was obtained in men with de novo metastases, while for those with metastatic relapse after definitive local treatment, the role of treatment intensification is less well established. Treatment intensification is nowadays the standard of care for patients with de novo mCSPC as it leads to outcomes improvement, including survival, and the standard of care is evolving almost on a yearly basis.

Integrative Pan-Cancer Genomic and Transcriptomic Analyses of Refractory Metastatic Cancer.

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared with primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers-9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer. SIGNIFICANCE: This study highlights the paucity of standard-of-care markers that explain treatment resistance and the promise of investigational and hypothetical markers awaiting further validation. It also demonstrates the utility of molecular profiling in advanced-stage cancers, particularly breast cancer, to improve the survival prediction and assess eligibility to phase I clinical trials. This article is highlighted in the In This Issue feature, p. 1027.

The Impact of Primary Versus Secondary Muscle-invasive Bladder Cancer at Diagnosis on the Response to Neoadjuvant Chemotherapy.

Background: There might be differential sensitivity to neoadjuvant chemotherapy (NAC) in patients with primary muscle-invasive bladder cancer (MIBC) in comparison to patients with secondary MIBC after a history of non-muscle-invasive disease. Objective: To investigate pathologic response rates and survival associated with primary versus secondary MIBC among patients treated with cisplatin-based NAC for cT2-4N0M0 MIBC. Design setting and participants: Oncologic outcomes were compared for 350 patients with primary MIBC and 64 with secondary MIBC treated with NAC and radical cystectomy between 1992 and 2021 at 11 academic centers. Genomic analyses were performed for 476 patients from the Memorial Sloan Kettering/The Cancer Genome Atlas cohort. Outcome measurements and statistical analysis: The outcome measures were pathologic objective response (pOR; ≤ypT1 N0), pathologic complete response (pCR; ypT0 N0), overall mortality, and cancer-specific mortality. Results and limitations: The primary MIBC group had higher pOR (51% vs 34%; p = 0.02) and pCR (33% vs 17%; p = 0.01) rates in comparison to the secondary MIBC group. On multivariable logistic regression analysis, primary MIBC was independently associated with both pOR (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.26-0.87; p = 0.02) and pCR (OR 0.41, 95% CI 0.19-0.82; p = 0.02). However, on multivariable Cox regression analysis, primary MIBC was not associated with overall mortality (hazard ratio 1.70, 95% CI 0.84-3.44; p = 0.14) or cancer-specific mortality (hazard ratio 1.50, 95% CI 0.66-3.40; p = 0.3). Genomic analyses revealed a significantly higher ERCC2 mutation rate in primary MIBC than in secondary MIBC (12.4% vs 1.3%; p < 0.001). Conclusions: Patients with primary MIBC have better pathologic response rates to NAC in comparison to patients with secondary MIBC. Chemoresistance might be related to the different genomic profile of primary versus secondary MIBC. Patient summary: We investigated the treatment response to neoadjuvant chemotherapy (NAC; chemotherapy received before the primary course of treatment) and survival for patients with a primary diagnosis of muscle-invasive bladder cancer (MIBC) in comparison to patients with a history of non-muscle-invasive bladder cancer that progressed to MIBC. Patients with primary MIBC had a better response to NAC but this did not translate to better survival after accounting for other tumor characteristics.

Global management of brain metastasis from renal cell carcinoma.

During the last decade, major improvements have been made in the treatment of renal cell carcinoma (RCC) with the development and use of multiple tyrosine kinase inhibitors and immune checkpoint inhibitors. Brain metastases in RCC patients (BM-RCC) is associated with poor outcome and their management represents a challenge for clinicians. In most of case, brain metastases in this context require local intervention such as radiotherapy, stereotactic radiotherapy/stereotactic radiosurgery and whole brain radiation therapy. Despite efficacy in extracranial metastases, systemic therapies have modest antitumoral effect on cerebral lesions. In this review, we highlight the benefits and pitfalls of the available therapies in BM-RCC.

Future Strategies Involving Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma.

OPINION STATEMENT: Immune checkpoint inhibitors have importantly improved the outcome of patients with urothelial carcinoma. Different immune checkpoint inhibitors are currently approved and used in first- and second-line setting. The multiple agents currently approved in these setting make the choice sometimes difficult for clinicians. Furthermore, only a minority of patients present drastic response and long-term benefit with current immunotherapy. In this review, we describe the current use of immunotherapy in urothelial carcinoma but we also highlight the new strategies of treatment involving immune checkpoint inhibitors; we describe the place of immunotherapy with chemotherapy, targeted agents, and anti-angiogenic agents, incorporating the recent results presented at ASCO 2020. This review explores also the different action mechanisms of immune checkpoint inhibitors and the molecular rational to evaluate these agents in other strategies, such as maintenance and salvage strategies. The new advances in biomarker development are also presented.

c-MET as a Potential Resistance Mechanism to Everolimus in Breast Cancer: From a Case Report to Patient Cohort Analysis.

BACKGROUND: We describe in a patient with breast cancer the change in c-MET expression during everolimus treatment, opening a better understanding of the resistance to everolimus and a role for cabozantinib. OBJECTIVE: The objective of this study was to evaluate c-MET as a potential predictive biomarker for everolimus efficacy in breast cancer. METHODS: We first selected a patient with breast cancer with a long-lasting response to everolimus and retrospectively profiled biopsies that were taken before everolimus initiation (Biopsy 1) and at progression on everolimus (Biopsy 2) using amplicon sequencing and immunohistochemistry. We then retrospectively evaluated c-MET expression in a cohort of patients with breast cancer treated with everolimus. RESULTS: While not expressed in Biopsy 1, c-MET was highly expressed in Biopsy 2, suggesting a role for c-MET in breast cancer progression. Cabozantinib resulted in a rapid radiological response in this patient. Twenty-nine patients were included (12 c-MET-positive and 17 c-MET-negative patients) in the second part of the study. Baseline c-MET expression was associated with higher tumor grade, higher frequency of visceral metastases, and lower endocrine sensitivity. The c-MET-positive patients presented with a shorter progression-free survival (6.1 vs 10.5 months, respectively; p = 0.002) and a lower response rate (0% vs 12%) to everolimus, compared with c-MET-negative patients. CONCLUSIONS: c-MET could play a role in the resistance to everolimus and its inhibition should be evaluated in breast cancer.

Critical size bone defect reconstruction by an autologous 3D osteogenic-like tissue derived from differentiated adipose MSCs.

For critical size bone defects and bone non-unions, bone tissue engineering using osteoblastic differentiated adipose mesenchymal stem cells (AMSCs) is limited by the need for a biomaterial to support cell transplantation. An osteoblastic three-dimensional autologous graft made of AMSCs (3D AMSC) was developed to solve this issue. This autograft was obtained by supplementing the osteoblastic differentiation medium with demineralized bone matrix. Two surgical models were developed to assess the potential of this 3D osteogenic AMSC autograft. A four-level spinal fusion using polyetheretherketone cages was designed in six pigs to assess the early phase of ossification (8-12 weeks postimplantation). In each pig, four groups were compared: cancellous bone autograft, freeze-dried irradiated cancellous pig bone, 3D AMSC, and an empty cage. A critical size femoral defect (n = 4, bone non-union confirmed 6 months postoperatively) was used to assess the 3D AMSCs' ability to achieve bone fusion. Pigs were followed by CT scan and explanted specimens were analyzed for bone tissue remodeling by micro-CT scan, micro-radiography, and histology/histomorphometry. In the spine fusion model, bone formation with the 3D AMSC was demonstrated by a significant increase in bone content. In the critical-size femoral defect model, the 3D AMSC achieved new bone formation and fusion in a poorly vascularized fibrotic environment. This custom-made 3D osteogenic AMSC autograft is a therapeutic solution for bone non-unions and for critical-size defects.