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The efficacy and added benefit of platinum-based chemotherapy (PtCT) for metastatic breast cancer (MBC) remain unclear in patients with and without germline BRCA1 or BRCA2 mutations (gBRCA1/2m and gBRCA1/2wt, respectively).We selected from the French national real-world multicentre ESME cohort (2008-2016) all patients with HER2-negative MBC with known gBRCA1/2 status at first-line chemotherapy initiation. Using multivariable Cox models, we compared the outcome (progression-free (PFS) and overall survival (OS)) of first-line PtCT and non-PtCT regimens based on the patients' gBRCA1/2 status and tumour subtype.Patients who received PtCT had more aggressive tumour features. In the multivariable analysis, first-line PtCT was associated with better adjusted PFS and OS in gBRCA1/2m carriers (N = 300), compared with non-PtCT (HR 0.54, 95% CI 0.4-0.73, P 0.001, and HR 0.70, 95% CI 0.49-0.99, P = 0.047, respectively). Conversely, outcomes were similar in gBRCA1/2wt patients (N = 922) treated with PtCT and non-PtCT, whatever the tumour subtype. Landmark analyses at months 3 and 6 post treatment initiation supported these results.In this pre-PARP inhibitor real-world cohort, PFS and OS were better after PtCT than non-PtCT in patients with gBRCA1/2m, but not in those with gBRCA1/2wt. These results emphasise the need of early gBRCA1/2 testing in patients with MBC.NCT03275311.

Simple Summary The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the ``matched therapy group'' than in the ``non-matched therapy group''. Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio >= 1.3 versus 5% in the ``non-matched therapy group'' (n = 25). The objective response and disease control rates were higher in the ``matched therapy group'' (33% and 58%, respectively) than in the ``non-matched therapy group'' (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to ``matched therapy'' in 19%, and provided clinical benefit in 8%.

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

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Overall, 2021 was marked by the confirmation of the major interest of cell cycle inhibitors for hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative advanced breast cancers with very high overall survival data exceeding five years for hormone-sensitive disease. Studies have also confirmed the efficacy and safety of this therapeutic class in the elderly population. New cell cycle inhibitors are under development (SHR6390). New combinations are also being evaluated, notably palbociclib with SAR439859 (a new selective estrogen receptor degrader: SERD). Targeting of the Phosphoinositide 3-kinases (PI3K) pathway by taselisib, in hormone-resistant disease with a Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutation, modestly improves progression-free survival but with a non-negligible toxicity of the treatment.

Background Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. Patients and Methods Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. Results A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. Conclusion Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.

Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.

The association of a germline mutation in the BRCA1/2 genes in breast cancer leads to a higher genomic instability and, thus, a potential higher sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this review, we will summarize the different DNA-repair pathways including PARP-dependent mechanisms that support the use of PARP inhibitors. We will present clinical trials evaluating PARP inhibitors alone or in combination in early or advanced stage breast cancer. We will then discuss the different mechanisms involved in the resistance to PARP inhibitors. We will also introduce the concept of BRCAness by which the use of PARP inhibitors could be extended to BRCA1/2-wild type patients. Finally, we will describe the new channels implemented for the theranostic genetic screening.

One of the standard management options for high-risk localized prostate cancer is radiotherapy combined with long-term androgen deprivation therapy. Trials involving chemotherapy or next-generation hormone therapies in combination with a local treatment are ongoing for this specific subgroup.

Background High-dose chemotherapy (HDCT) with autologous stem-cell transplantation (aSCT) has been a standard therapy for relapsed metastatic germ-cell tumors (GCTs) over the last 2 decades, but there have been many changes in practice over time with respect to stem-cell source, mobilization, and conditioning regimens. Mobilization is impaired with greater cisplatin exposure. Patients and Methods Patients with relapsed GCT who received HDCT/aSCT at Dana-Farber Cancer Institute between 1997 and 2017 were identified. Diagnosis, first-line chemotherapy, stem-cell mobilization, HDCT, toxicity, and survival outcomes were annotated and descriptively summarized. Univariable associations of clinicopathologic features and relapse and survival were assessed. Time-to-event analyses were performed by HDCT type and duration. Results Thirty-five eligible patients were identified. The most common regimen before HDCT was paclitaxel, ifosfamide, and cisplatin, and it resulted in a high rate of successful initial mobilization (95%). Ten patients (29%) were mobilized with filgrastim and plerixafor (CXCR4 antagonist). All plerixafor-treated patients were mobilized with sufficient cells for 2 transplants. Oxazaphosphorine (cyclophosphamide or ifosfamide)-containing (O-C) HDCT was provided between 1997 and 2008, and subsequent patients were treated with high-dose carboplatin plus etoposide (CE). O-C HDCT was associated with excessive cardiac (33%), severe liver (93%), and renal dysfunction compared to CE. Two O-C–treated patients died of drug-related lung toxicity. Fifty-one percent of the cohort experienced relapse, and 46% died. Conclusion Plerixafor has a role in stem-cell mobilization and aSCT for relapsed GCT when cisplatin in bridging before HDCT may be problematic. O-C and CE HDCT regimens have different toxicity patterns that are clinically meaningful.

Monoclonal antibodies targeting immune checkpoint molecules CTLA-4, PD-1 or PD-L1 are emerging as promising anticancer therapeutics in multiple cancer subtypes resulting in remarkable and long-lasting clinical responses. These immune checkpoint blockers (ICBs) have already obtained approval for the treatment of patients with metastatic melanoma, advanced/refractory non-small cell lung cancer and renal cell cancer. ICBs enhance immune responses against cancer cells but can also lead to inflammatory side effects called immune-related adverse events (irAEs). Such toxicities are distinct from those associated with traditional chemotherapeutic agents or molecularly targeted therapies. Although severe irAEs remain rare (~10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. As malignancies are frequently diagnosed in older patients, ICB treatment of elderly presents a unique challenge. However, the knowledge about efficacy and toxicity of these molecules in this specific population is limited, as most of the studies have involved a low number of older patients. In this review, we will discuss about the different ICB efficacy data available for older patients. We will then highlight the specific spectrum of immunotherapy toxicities and talk about their management in the context of older adults.

Introduction : le cancer du sein représente le cancer le plus fréquent et la première cause de décès par cancer chez la femme dans le monde. Le cancer du sein, au stade métastatique (CSM), est une maladie incurable. La médiane de survie globale (OS) est d’environ 40 mois avec une grande différence selon le sous type: 42 mois pour les cancers hormono dépendants et 14 mois pour les cancers triple négatifs. Les cancers du sein sont héréditaires dans 5-10% des cas dont 20%lié à une mutation des gènes BRCA, gènes impliqués dans la réparation de l’ADN par recombinaison homologue (RH). Certaines tumeurs sporadiques présentent un défaut de RH sans mutation germinale de BRCA (appelé « BRCAness »). Ces défauts de réparation permettent d’envisager de sélectionner ces tumeurs pour certains traitements spécifiques : les sels de platine (cisplatine et carboplatine). Les recommandations actuelles dans le CSM suggèrent l’utilisation des sels de platine pour le sous-type triple négatif(TN)et BRCA muté. Elles reposent sur des études menées sur de faibles effectifs de patientes, non contrôlées avec un faible niveau de preuves.Objectifs : l’objectif de cette étude était d’étudier la survie globale des patients présentant un cancer du sein métastatique HER2 négatif traité par sels de platine, selon la ligne de chimiothérapie. Les objectifs secondaires étaient l’étude de la survie sans progression et l’étude des sous-groupes triple négatifs et BRCA muté. Patients et méthode : notre étude était une étude de cohorte, rétrospective, multicentrique, réalisée sur la base de données nationale ESME. Les critères d’inclusions étaient: un CSM inclus dans la base ESME entre 2008 et 2016, statut HER2-négatif, ayant reçu au moins une ligne de chimiothérapie cytotoxique. Deux groupes de traitement ont été formés pour chaque ligne de chimiothérapie: groupe A « platine » et groupe B « non platine ». Les données cliniques, histologiques et thérapeutiques ont été recueillies. Le critère de jugement principal était la médiane de survie globale (OS). Nous avons réalisé des analyses descriptives avec un test du χ2, pour comparer les groupes. La méthode de Kaplan-Meier a été utilisée pour analyser les données de survie. Une analyse multivariée a été effectuée à l'aide du modèle de Cox pour les facteurs pronostiques. Résultats : Nous avons inclus, 13 396 patients HER2-négatif ayant reçu au moins une première ligne de chimiothérapie. Dans le groupe A, le principal sel de platine utilisé était le Carboplatine, majoritairement associé à d’autres chimiothérapies. Dans le groupe B: les principales molécules utilisées étaient en L1 les taxanes, en L2 la capécitabine et en L3 la capécitabine et l’eribuline. La médiane de survie globale dans le groupe HER2-négatif « platine » était de 12,6mois en L1, et de 8,1 mois en L2-L3. L’OS était plus élevée dans le groupe B pour les trois lignes de traitement. La survie globale n’était pas différente entre les deux groupes pour les trois lignes dans les sous-groupes TN et BRCAmuté. Les principaux facteurs de mauvais pronostiques, significatifs étaient : une récidive métastatique, une maladie viscérale, la plurifocalité des sites, un grade histologique élevé et le phénotype triple négatif. Le facteur pronostique « traitement par platine » a montré que ce traitement était délétère en L1 et L2dans la population HER2-négatif. En L3, il était bénéfique en terme de PFS mais n’impactait pas l’OS. Dans le sous-groupe triple négatif, ce traitement n’impactait ni l’OS, ni la PFS pour les deux premières lignes de traitement. Cependant il était bénéfique en L3. Dans le sous-groupe BRCA muté, il apportait un bénéfice significatif en terme d’OS et de PFS.Conclusion : notre étude nous a permis d’accéder à des données de vie réelle sur un nombre conséquent de patients, reflétant les pratiques en France dans le CSMHER2-négatif. Les sels de platine trouvent une place non équivoque dans le traitement des CSM HER2-négatifprésentant une mutation de BRCA. Dans la population globale HER2-négatif, les sels de platines sont délétères pour les deux premières lignes de traitement, mais peuvent être utilisés en L3 au même titre que les autres chimiothérapies cytotoxiques. Pour les CSM triple négatifs, les sels de platines restent une option thérapeutique majeure puisqu’elle est aussi efficace que les autres drogues en L1 et L2; et bénéfique en troisième ligne.