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PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) offer a promising path for cancer therapy, leveraging the specificity of monoclonal antibodies and the cytotoxicity of linked drugs. The success of ADCs hinges on precise targeting of cancer cells based on protein expression levels. This review explores the relationship between target protein expression and ADC efficacy in solid tumours, focusing on results of clinical trials conducted between January 2019 and May 2023. RECENT FINDINGS: We hereby highlight approved ADCs, revealing their effectiveness even in low-expressing target populations. Assessing target expression poses challenges, owing to variations in scoring systems and biopsy types. Emerging methods, like digital image analysis, aim to standardize assessment. The complexity of ADC pharmacokinetics, tumour dynamics, and off-target effects emphasises the need for a balanced approach. This review underscores the importance of understanding target protein dynamics and promoting standardized evaluation methods in shaping the future of ADC-based cancer therapies.
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BACKGROUND: Metastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line. METHODS: A cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first. RESULTS: Of the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0-66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8-32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002). CONCLUSION: Our analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.
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Acetato de Abiraterona , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Acetato de Abiraterona/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Prospectivos , Resultado do Tratamento , Nitrilas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases. METHODS: We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index. RESULTS: The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status. CONCLUSIONS: The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Sarcoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Brain metastases (BM) from adult soft tissue or bone sarcomas are rare, and sparse data exist on their prognostic factors and management. SUBJECTS, MATERIALS AND METHODS: A retrospective study was conducted in 15 centers of the French Sarcoma Group, plus one Canadian and one Swiss center, to report on clinical, histological, and treatment characteristics and to identify predictive factors of outcome. RESULTS: Between 1992 and 2012, 246 patients with a median age of 50 years (range: 16-86) were managed for BM. BM included 221 cerebral and cerebellar metastases and 40 cases of meningeal sarcomatosis. The most frequent histopathological subtype was leiomyosarcoma (18.7%). Histological grade was high in 118 (48%) cases. Surgery of BM was carried out for 38 (15.5%) patients. Radiotherapy and chemotherapy were administered in 168 (68.3%) and 91 (37.0%) patients, respectively. Irrespective of treatment modality, BM were controlled in 113 patients (45.9%), including 31 partial responses (12.6%) and 18 complete responses (7.3%). The median overall survival from diagnosis of brain metastasis was 2.7 months (range: 0-133). In the multivariate analysis, the following parameters influenced overall survival: chemotherapy (hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.26-0.48), surgery (HR = 0.40; 95% CI: 0.22-0.72), stereotactic radiotherapy (HR = 0.41; 95% CI: 0.19-0.90), whole-brain radiotherapy (HR = 0.51; 95% CI: 0.35-0.76), and grade (HR = 0.65; 95% CI: 0.43-0.98). CONCLUSION: BM of sarcomas are rare and associated with a dismal outcome. Multidisciplinary management with chemotherapy, radiation therapy, and surgery is associated with a better survival. IMPLICATIONS FOR PRACTICE: The incidence of brain and meningeal metastasis in bone and soft tissue sarcomas is estimated between 1% and 8%. Published data are derived from small retrospective case series, often in the pediatric population. A prognostic index is important to guide both clinical decision-making and outcomes research, but one such is lacking for adult sarcoma patients with brain metastases. The current study describes brain metastasis in a large cohort of sarcoma patients. This study, conducted within the French Sarcoma Group, describes the natural history of sarcoma brain metastasis and enables the proposal of strategic recommendations for subsequent clinical trials and for the management of such patients.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Sarcoma/patologia , Sarcoma/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/epidemiologia , Canadá/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sarcoma/epidemiologia , Suíça/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
The BRF14 trial is a prominent study that investigated the effect of prolonged imatinib treatment in advanced gastrointestinal stromal tumor patients. The key messages deduced from this study are as follows: imatinib drastically improved progression-free and overall survival in advanced gastrointestinal stromal tumor patients. Treatment ought to be maintained indefinitely in nonprogressing patients, as interruption entails a high risk of progression, even in patients in complete response. Imatinib rechallenge is effective, achieving new disease control in patients progressing after imatinib interruption. Rechallenge response profiles reflect the initial responses, albeit of poorer quality. Imatinib interruption does not affect the incidence of secondary resistance; however, the imatinib-free interval influences the time to secondary resistance. Specific clinical, biological and molecular characteristics seem to identify the patients who are long responders to imatinib. Surgery of residual disease after maximal imatinib response improves progression-free and overall survival.
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Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma/tratamento farmacológico , Antineoplásicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Progressão da Doença , França , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib/farmacologia , Estimativa de Kaplan-Meier , Estudos Multicêntricos como Assunto , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/diagnóstico , Sarcoma/mortalidade , Resultado do TratamentoRESUMO
There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999-2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines.
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Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/mortalidade , Adulto , Fatores Etários , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Língua/patologia , Adulto JovemRESUMO
BACKGROUND: Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival (OS) and in progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients. No standard of care currently exists for second-line treatment. The association of Gemcitabine-Oxaliplatine (GEMOX) has shown efficacy in the first-line setting. The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic (AA) therapy. PATIENT AND METHODS: We performed a multicenter retrospective analysis of advanced HCC patients that received GEMOX chemotherapy after progression on at least one line of AA therapy. RESULTS: We analyzed a total of 40 patients that received a median of 7 cycles of GEMOX over a 6-year period. Grade 3/4 toxicity was observed in 25 % of patients, mainly neurotoxicity, thrombocytopenia and neutropenia in 12.5 %, 5 % and 5 % of patients respectively. Grade <3 toxicity was mainly hematological and neurotoxicity. In the sub-cohort of 35 patients evaluable for response, partial response was observed in 20 % of patients, while 46 % had stable disease. Median OS was 8.3 months, with a 6-month OS rate of 59 %. Median PFS was 3.1 months. Prognostic factors for OS in univariable analysis were the performance status and AFP levels at GEMOX start, and the BCLC score at diagnosis. None of these factors were prognostic for PFS or tumor response. CONCLUSION: The GEMOX schedule seems to show clinical activity and an acceptable toxicity profile in advanced HCC patients who progressed after anti-angiogenic treatment. The observed median OS of over 8 months is encouraging in this population of heavily pretreated patients. These results would merit confirmation in a prospective randomized study.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/diagnóstico por imagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Treatment de-escalation strategies in patients with seminoma with retroperitoneal metastases are being investigated in ongoing clinical trials. Primary retroperitoneal lymph node dissection conducted by expert surgeons may avoid any cytotoxic treatment and related long-term side effects in ≥70% of patients with clinical stage IIA/B seminoma.
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Excisão de Linfonodo , Estadiamento de Neoplasias , Seminoma , Neoplasias Testiculares , Humanos , Excisão de Linfonodo/métodos , Masculino , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Seminoma/cirurgia , Seminoma/patologia , Espaço Retroperitoneal , Neoplasias Retroperitoneais/cirurgia , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/secundário , Metástase Linfática , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/secundárioRESUMO
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.
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BACKGROUND: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs. METHODS: Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114). RESULTS: The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS (p < 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort. CONCLUSIONS: The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.
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BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.
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BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Modelos Animais de DoençasRESUMO
BACKGROUND: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear. METHODS: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI). RESULTS: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts. CONCLUSIONS: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC.
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CONTEXT: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). OBJECTIVE: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. EVIDENCE ACQUISITION: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. EVIDENCE SYNTHESIS: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. CONCLUSIONS: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. PATIENT SUMMARY: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Urologia , Masculino , Humanos , Neoplasias Testiculares/terapia , Neoplasias Testiculares/diagnóstico , Qualidade de Vida , Neoplasias Embrionárias de Células Germinativas/terapiaRESUMO
Few prognostic factors have been identified in patients with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs). The Lung Immune Prognostic Index (LIPI) was associated with clinical outcomes for ICIs in several tumor types. We aim to assess the value of the LIPI in patients with mUC treated with ICIs. A retrospective ICI cohort and a validation cohort (SAUL cohort) included, respectively, patients with mUC treated with ICI in 8 European centers (any line) and patients treated with atezolizumab in a second or further line. A chemotherapy-only cohort was also analyzed. The LIPI score was based on 2 factors, derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) > 3 and lactate dehydrogenase > upper limit of normal, and defined 3 prognostic groups. The association of LIPI with progression-free survival (PFS) and overall survival (OS) was assessed. In the ICI and SAUL cohorts, 137 and 541 patients were respectively analyzed. In the ICI cohort, mPFS and mOS were 3.6 mo (95% CI; 2.6-6.0) and 13.8 mo (95% CI; 11.5-23.2) whereas in the SAUL cohort the mPFS and mOS were 2.2 mo (95% CI; 2.1-2.3) and 8.7 mo (95% CI; 7.8-9.9) respectively. The LIPI classified the population of these cohorts in good (56%; 52%), intermediate (35%; 36%) and poor (9%; 12%) prognostic groups (values for the ICI and SAUL cohorts respectively). Poor LIPI was associated with a poorer OS in both cohorts: hazard ratio (HR) for the ICI cohort = 2.69 (95% CI; 1.24-5.84, p = 0.035); HR = 2. 89 for the SAUL cohort (CI 95%: 1.93-4.32, p < 0.0001). Similar results were found in the chemo cohort. The LIPI score allows to identify different subgroups in patients with good prognostis according to the Bellmunt score criteria, with a subset of patients with poorer outcomes having an mOS of 3.7 mo compared to the good and intermediate LIPI subgroups with mOS of 17.9 and 7.4 mo, respectively. The LIPI score was associated with survival in mUC patients treated by ICIs. Future prospective studies will be required to test the combination of Bellmunt score and the LIPI score as a more accurate prognosis tool.
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Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients. Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC. Design and methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints. Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1-62.2 months] versus AA (51.6 months; 95% CI, 42.6-60.6 months; p = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0-55.7 months) than those having AA (22.0 months; 95% CI, 18.1-26.0 months; p = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza (p = 0.51 and p = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA. Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC.
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BACKGROUND: Genomic stratification may help improve the management of patients with metastatic urothelial cancer (mUC), given the recent identification of targetable alterations. However, the collection of tissue samples remains challenging. Here, we assessed the clinical utility of plasma circulating tumour DNA (ctDNA) sequencing in these patients. METHODS: Patients with mUC were prospectively enroled in the STING trial (NCT04932525), in which ctDNA was profiled using the Foundation One Liquid CDx Assay (324 genes, blood tumour mutational burden [bTMB], microsatellite instability status). Each genomic report was reviewed by a multidisciplinary tumor board (MTB). RESULTS: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. The median time to obtain the assay results was 20 days ((confidence interval) CI95%: [20,21]). The ctDNA analysis reproduced the somatic genomic landscape of previous tissue-based cohorts. Concordance for serial ctDNA samples was strong (r = 0.843 CI95%: [0.631-0.938], p < 0.001). At least one actionable target was detected in 63 patients (45%) with a total of 35 actionable alterations, including bTMB high (≥10 mutations/Mb) (N = 39, 21.1%), FGFR3 (N = 20, 10.8%), and Homologous recombination deï¬ciency (HRD) alterations (N = 14, 7.6%). MTB recommended matched therapy in 63 patients (45.0%). Eight patients (5.7%) were treated, with an overall response rate of 50% (CI95%: 15.70-84.30) and a median progression-free survival (PFS) of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with a shorter PFS in patients treated with immunotherapy. CONCLUSION: Overall, we demonstrated that genomic profiling with ctDNAs in mUC is a reliable and feasible approach for the timely initiation of genotype-matched therapies.
Assuntos
DNA Tumoral Circulante , Neoplasias , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , DNA Tumoral Circulante/genética , Biomarcadores Tumorais/genética , Genômica/métodos , MutaçãoRESUMO
PURPOSE: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. EXPERIMENTAL DESIGN: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. RESULTS: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. CONCLUSIONS: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Proteínas Hedgehog , Estudos Prospectivos , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Genômica , NitrilasRESUMO
BACKGROUND: Upregulation of nuclear factor kappa B (NFκB) activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer (PC) progression to castration resistance. We have observed that major components of these pathways, including NFκB, proteasome, neutral endopeptidase (NEP) and endothelin 1 (ET-1), exhibit an inverse and mirror image pattern in androgen-dependent (AD) and -independent (AI) states in vitro. METHODS: We have now investigated for evidence of a direct mechanistic connection between these pathways with the use of immunocytochemistry (ICC), western blot analysis, electrophoretic mobility shift assay (EMSA) and proteasome activity assessment. RESULTS: Neuropeptide (NP) stimulation induced nuclear translocation of NFκB in a dose-dependent manner in AI cells, also evident as reduced total inhibitor κB (IκB) levels and increased DNA binding in EMSA. These effects were preceded by increased 20 S proteasome activity at lower doses and at earlier times and were at least partially reversed under conditions of NP deprivation induced by specific NP receptor inhibitors, as well as NFκB, IκB kinase (IKK) and proteasome inhibitors. AD cells showed no appreciable nuclear translocation upon NP stimulation, with less intense DNA binding signal on EMSA. CONCLUSIONS: Our results support evidence for a direct mechanistic connection between the NPs and NFκB/proteasome signaling pathways, with a distinct NP-induced profile in the more aggressive AI cancer state.
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Interleukin (IL)-8 promotes cellular proliferation and angiogenesis in patients with non-small-cell lung cancer (NSCLC) and may be related to cachexia. Our aim was to investigate the relationship of IL-8 levels with nutritional status, and clinical outcome of patients with NSCLC. Patients with metastatic NSCLC referred for first-line therapy were eligible. Baseline IL-8 levels were measured in plasma. The Mini Nutritional Assessment (MNA) was used for the evaluation of the nutritional status, and patients were classified into 3 groups: A (score 24-30) "well nourished," B (score 17-23.5) "risk of malnutrition," and C (0-16.5) "malnourishment." Response to first-line chemotherapy, time-to-tumor progression (TTP), and overall survival (OS) were also recorded. In total, 114 patients (101 males, 88.5%; mean age = 67.5 yr) were evaluated. Performance status was 0-1 in 62% of the patients. According to the MNA, the majority of patients (71%) was either at nutritional risk or malnourished. IL-8 levels were significantly different between MNA groups (P = 0.023) and correlated with TTP (P = 0.013) and OS (P = 0.001) in univariate analysis. Baseline IL-8 levels correlate with the nutritional status of patients with metastatic NSCLC, suggesting that this cytokine may be related with cachexia.