Recently reported cell migration inhibitors: Opportunities and challenges for antimetastatic agents.

Antimetastatic agents are highly desirable for cancer treatment because of the severe medical challenges and high mortality resulting from tumor metastasis. Having demonstrated antimetastatic effects in numerous in vitro and in vivo studies, migration inhibitors present significant opportunities for developing a new class of anticancer drugs. To provide a useful overview on the latest research in migration inhibitors, this article first discusses their therapeutic significance, targetable proteins, and developmental avenues. Subsequently it reviews over 20 representative migration inhibitors reported in recent journals in terms of their inhibitory mechanism, potency, and potential clinical utility. The relevance of the target proteins to cellular migratory function is focused on as it is crucial for assessing the overall efficacy of the inhibitors.

El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales: una revisión narrativa / The role of minimally invasive spine surgery in the treatment of vertebral metastasis: A narrative review

Introducción: Las metástasis vertebrales son un problema muy frecuente y asocian un deterioro importante de la calidad de vida en los pacientes oncológicos. El objetivo de esta revisión es determinar el encaje de las técnicas quirúrgicas mínimamente invasivas dentro del manejo de esta entidad. Métodos: Se realizó una revisión bibliográfica en las bases de datos Google Scholar, PubMed, Scopus y Cochrane. Se revisaron los artículos publicados en los últimos 10 años que fueran de una relevancia y calidad adecuadas. Resultados: Tras el cribado de los 2.184 trabajos identificados inicialmente en las distintas bases de datos, se incluyeron un total de 24 artículos en esta revisión. Conclusión: La cirugía mínimamente invasiva de columna es especialmente útil en pacientes oncológicos frágiles con metástasis vertebrales por la reducida comorbilidad que presentan las técnicas que se engloban en ella en comparación con la de la cirugía abierta convencional. Los avances en tecnología aplicada a la cirugía, como la navegación y la robótica, mejoran la precisión y reducen las complicaciones de esta técnica.(AU)

Background: Spinal metastases are a very common problem which dramatically affects the quality of life of cancer patients. The objective of this review is to address the issue of how minimally invasive surgery can play an important role in treating this pathology. Methods: A literature review was performed, searching in the Google Scholar, PubMed, Scopus and Cochrane databases. Relevant and quality papers published within the last 10 years were included in the review. Results: After screening the 2184 initially identified registers, a total of 24 articles were included for review. Conclusion: Minimally invasive spine surgery is specially convenient for fragile cancer patients with spinal metastases, because of its reduced comorbidity compared to conventional open surgery. Technological advances in surgery, such as navigation and robotics, improve accuracy and safety in this technique.(AU)

[Translated article] The role of minimally invasive spine surgery in the treatment of vertebral metastasis: A narrative review / El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales: una revisión narrativa

Introducción: Las metástasis vertebrales son un problema muy frecuente y asocian un deterioro importante de la calidad de vida en los pacientes oncológicos. El objetivo de esta revisión es determinar el encaje de las técnicas quirúrgicas mínimamente invasivas dentro del manejo de esta entidad. Métodos: Se realizó una revisión bibliográfica en las bases de datos Google Scholar, PubMed, Scopus y Cochrane. Se revisaron los artículos publicados en los últimos 10 años que fueran de una relevancia y calidad adecuadas. Resultados: Tras el cribado de los 2.184 trabajos identificados inicialmente en las distintas bases de datos, se incluyeron un total de 24 artículos en esta revisión. Conclusión: La cirugía mínimamente invasiva de columna es especialmente útil en pacientes oncológicos frágiles con metástasis vertebrales por la reducida comorbilidad que presentan las técnicas que se engloban en ella en comparación con la de la cirugía abierta convencional. Los avances en tecnología aplicada a la cirugía, como la navegación y la robótica, mejoran la precisión y reducen las complicaciones de esta técnica.(AU)

Background: Spinal metastases are a very common problem which dramatically affects the quality of life of cancer patients. The objective of this review is to address the issue of how minimally invasive surgery can play an important role in treating this pathology. Methods: A literature review was performed, searching in the Google Scholar, PubMed, Scopus and Cochrane databases. Relevant and quality papers published within the last 10 years were included in the review. Results: After screening the 2184 initially identified registers, a total of 24 articles were included for review. Conclusion: Minimally invasive spine surgery is specially convenient for fragile cancer patients with spinal metastases, because of its reduced comorbidity compared to conventional open surgery. Technological advances in surgery, such as navigation and robotics, improve accuracy and safety in this technique.(AU)

El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales (parte 1): una revisión clínica / The role of minimally invasive spine surgery in the treatment of vertebral metastasis (part 1): A clinical review

Las metástasis espinales representan una importante carga sobre la calidad de vida en los pacientes afectados por una enfermedad oncológica activa, debido a la alta incidencia de síndromes dolorosos, deformidad espinal y deterioro neurológico. La cirugía juega un papel determinante a la hora de mejorar la calidad de vida mediante el control del dolor, el restablecimiento de la función neurológica y el mantenimiento de la estabilidad espinal, además de contribuir a la respuesta de la terapia médica. La cirugía mínimamente invasiva (MIS) es una opción de tratamiento en determinados pacientes con alto riesgo quirúrgico, ya que tiene una baja tasa de complicaciones, de sangrado intraoperatorio, de estancia hospitalaria y ofrece resultados similares a la cirugía abierta. Presentamos en esta revisión el papel de la MIS en esta enfermedad, y algunos casos tratados en nuestro centro hospitalario.(AU)

Spinal metastases represent a significant burden on the quality of life in patients affected by active oncological disease due to the high incidence of pain syndromes, spinal deformity, and neurological impairment. Surgery plays a decisive role in improving quality of life by controlling pain, restoring neurological function and maintaining spinal stability, as well as contributing to the response to medical therapy. Minimally invasive surgery (MIS) is a treatment option in certain patients with high surgical risk since it has a low rate of complications, intraoperative bleeding, hospital stay, and offers similar results to open surgery. In this review, we present the role of MIS in this pathology and some cases treated in our hospital.(AU)

[Translated article] The role of minimally invasive spine surgery in the treatment of vertebral metastasis (Part 1): A clinical review / El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales (parte 1): una revisión clínica

Las metástasis espinales representan una importante carga sobre la calidad de vida en los pacientes afectados por una enfermedad oncológica activa, debido a la alta incidencia de síndromes dolorosos, deformidad espinal y deterioro neurológico. La cirugía juega un papel determinante a la hora de mejorar la calidad de vida mediante el control del dolor, el restablecimiento de la función neurológica y el mantenimiento de la estabilidad espinal, además de contribuir a la respuesta de la terapia médica. La cirugía mínimamente invasiva (MIS) es una opción de tratamiento en determinados pacientes con alto riesgo quirúrgico, ya que tiene una baja tasa de complicaciones, de sangrado intraoperatorio, de estancia hospitalaria y ofrece resultados similares a la cirugía abierta. Presentamos en esta revisión el papel de la MIS en esta enfermedad, y algunos casos tratados en nuestro centro hospitalario.(AU)

Spinal metastases represent a significant burden on the quality of life in patients affected by active oncological disease due to the high incidence of pain syndromes, spinal deformity, and neurological impairment. Surgery plays a decisive role in improving quality of life by controlling pain, restoring neurological function and maintaining spinal stability, as well as contributing to the response to medical therapy. Minimally invasive surgery (MIS) is a treatment option in certain patients with high surgical risk since it has a low rate of complications, intraoperative bleeding, hospital stay, and offers similar results to open surgery. In this review, we present the role of MIS in this pathology and some cases treated in our hospital.(AU)

Pembrolizumabe (em monoterapia ou associado à quimioterapia) para pacientes com câncer de pulmão de células não pequenas avançado ou metastático (PD-L1 positivo) em primeira linha de tratamento / Pembrolizumab (in monotherapy or in association with chemotherapy) for patients with advanced or metastatic small cell lung cancer (PD-L1 positive) in the first line of treatment

INTRODUÇÃO: No Brasil, estima-se que ocorreram 30 mil novos casos de câncer de pulmão em cada ano entre 2020 e 2022. As terapias antineoplásicas preconizadas na DDT de Câncer de Pulmão (DDTCP) incluem medicamentos à base de platina e etoposídeo. Em Diretrizes internacionais se recomenda, como primeira linha de tratamento, o pembrolizumabe isolado ou associado à quimioterapia para adultos com CPCNP avançado ou metastático e que expressam PDL-1. Discute-se que o preço de medicamentos como o pembrolizumabe pode tornar seu uso proibitivo, o que reforça a importância de ofertar pembrolizumabe à população de pacientes que mais se beneficiaria deste tratamento. Uma das possibilidades seria por meio da avaliação quantitativa da expressão da proteína PD-L1. PERGUNTA: Para adultos com diagnóstico de câncer de pulmão de células não pequenas avançado (estádio III) ou metastático (estádio IV) cujos tumores expressam a mutação de PD-L1, o tratamento com pembrolizumabe (em monoterapia ou associado à quimioterapia) em primeira linha é mais eficaz, seguro, custo-efetivo e viável economicamente quando comparado à quimioterapia à base de platina? EVIDÊNCIAS CIENTÍFICAS: Em tempo mediano d

Alectinibe para o tratamento do câncer de pulmão de células não pequenas localmente avançado ou metastático cujos tumores expressam rearranjo no gene ALK em pacientes não tratados previamente ou após falha com crizotinibe / Alectinib for the treatment of locally advanced or metastatic non-small cell lung cancer whose tumors express regrowth of the ALK gene in patients not previously treated or after failure with crizotinib

INTRODUÇÃO: O câncer de pulmão pode ser divido em dois grandes grupos, carcinoma de células não pequenas (CPCNP) e o carcinoma de pequenas células. O primeiro compreende aproximadamente 85% dos cânceres de pulmão e pode ser dividido em quatro subtipos histológicos principais: adenocarcinoma, carcinoma de células escamosas, carcinoma adenoescamoso e carcinoma de células grandes. Normalmente, o CPCNP é diagnosticado em estágio avançado para o qual a sobrevida em cinco anos estimada está entre 3% e 6%. A quinase do linfoma anaplásico (ALK) é uma tirosina quinase cuja expressão pode ocorrer de forma aberrante em vários tipos de câncer. No CPCNP os rearranjos cromossômicos nos loci do gene ALK são encontrados em 3 a 5% dos casos. Nesse caso o rearranjo cromossômico mais comum resulta no gene de fusão ELM-ALK, cuja atividade está relacionada a tumores com caraterísticas clinicopatológicas distintas e tem importância na correta programação do tratamento. Tumores positivos para os genes de fusão ALK estão associados a características clínicas específicas, tais como ausência de histórico de tabagismo e incidência em indivíduos mais jovens. Os tumores ALK positivos são altamente sensíveis ao tratamento com medicamentos inibidores da ALK (terapia-alvo). No SUS est

Pharmacological targeting of netrin-1 inhibits EMT in cancer.

Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1-7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFß1 administration8,9-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.

Rapid Reduction of CEA and Stable Metastasis in an NRAS-mutant Rectal-Cancer Patient Treated With FOLFIRI and Bevacizumab Combined With Oral Recombinant Methioninase and a Low-Methionine Diet Upon Metastatic Recurrence After FOLFIRI and Bevacizumab Treatment Alone.

BACKGROUND/AIM: The choice of chemotherapy agents for RAS-mutant colorectal cancer is limited, and prognosis is poor compared to RAS-wild-type colorectal cancer. The purpose of the present study was to evaluate the effectiveness of methionine restriction combined with chemotherapy in a patient with NRAS-mutant rectal cancer. PATIENTS AND METHODS: A 59-year-old female was diagnosed with lung-metastatic recurrence of NRAS-mutant rectal cancer two and a half years after resection of the primary tumor. She started chemotherapy, which consisted of fluorouracil, irinotecan (FOLFIRI), and bevacizumab, in October 2020. Eight months later, stereotactic body radiation therapy (SBRT) was performed to treat the lung metastases. She stopped chemotherapy at this point and had blood tests and computed tomography (CT) scans regularly. Her CEA level increased to 139.91 ng/ml and her lung metastasis became larger by September 2022. Therefore, she was reintroduced to FOLFIRI and bevacizumab in October 2022, and also started a low-methionine diet and oral recombinant methioninase (o-rMETase) as a supplement. RESULTS: After starting the combination therapy with o-rMETase, a low-methionine diet, FOLFIRI, and bevacizumab, blood CEA levels very rapidly decreased and were almost within the normal limits five months later. CT findings showed the lung metastasis did not grow. CONCLUSION: Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Histone deacetylase inhibitors inhibit lung adenocarcinoma metastasis via HDAC2/YY1 mediated downregulation of Cdh1.

Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.

Local Therapeutics for the Treatment of Oligo Metastatic Prostate Cancer.

PURPOSE OF REVIEW: Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies are increasingly utilized in the early treatment of the disease, particularly in patients with oligometastatic prostate cancer (OMPC). OMPC represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC. RECENT FINDINGS: To date, there are three utilized forms of local therapy for OMPC: cryoablation, radiation therapy, and cytoreductive prostatectomy. Cryoablation can be utilized for the total ablation of the prostate and has shown promising results in patients with OMPC either in combination with ADT or with ADT and systemic chemotherapy. Radiation therapy along with ADT has demonstrated improvement in progression-free survival. The STAMPEDE Arm G, PEACE-1, and the HORRAD clinical trials have investigated radiation therapy for mPCa compared to standard of care versus systemic therapy with varying results. Cytoreductive radical prostatectomy (CRP) in conjunction with ADT has also been proposed in the management of OPMC with promising results from case-control and retrospective studies. Currently there are larger controlled trials investigating CRP for OPMC including the SIMCAP, LoMP, TRoMbone, SWOG 1802, IP2-ATLANTA, g-RAMPP, and FUSCC-OMPCa trials. Given the novel nature of local treatments for OPMC, treatment selection is still controversial and requires long-term follow-up and randomized clinical trials to aid patient and clinician decision making.

Zhuidu Formula suppresses the migratory and invasive properties of triple-negative breast cancer cells via dual signaling pathways of RhoA/ROCK and CDC42/MRCK.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuidu Formula (ZDF) is composed of triptolide, cinobufagin and paclitaxel, which are the active ingredients of Tripterygium wilfordii Hook. F, dried toad skin and Taxus wallichiana var. chinensis (Pilg) Florin, respectively. Modern pharmacological studies show that triptolide, cinobufagin, and paclitaxel are well-known natural compounds that exert anti-tumor effects by interfering with DNA synthesis, inducing tumor cell apoptosis, and inhibiting the dynamic balance of the tubulin. However, the mechanism by which the three compounds inhibit triple-negative breast cancer (TNBC) metastasis is unknown. OBJECTIVE: The objective of this investigation was to examine the inhibitory essences of ZDF on the metastasis of TNBC and elucidate its potential mechanism. MATERIALS AND METHODS: Cell viability of triptolide (TPL), cinobufagin (CBF), and paclitaxel (PTX) on MDA-MB-231 cells was assessed employing a CCK-8 assay. The drug interactions of the three drugs on MDA-MB-231 cells were determined in vitro utilizing the Chou-Talalay method. MDA-MB-231 cells were identified for migration, invasion and adhesion in vitro through the implementation of the scratch assay, transwell assay and adhesion assay, respectively. The formation of cytoskeleton protein F-actin was detected by immunofluorescence assay. The expressions of MMP-2 and MMP-9 in the supernatant of the cells were determined by ELISA analysis. The Western blot and RT-qPCR were employed to explore the protein expressions associated with the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. The anti-tumor efficacy of ZDF in vivo and its preliminary mechanism were investigated in the mouse 4T1 TNBC model. RESULTS: The results demonstrated that ZDF could significantly reduce the viability of the MDA-MB-231 cell, and the combination index (CI) values of actual compatibility experimental points were all less than 1, demonstrating a favorable synergistic compatibility relationship. It was found that ZDF reduces RhoA/ROCK and CDC42/MRCK dual signaling pathways, which are responsible for MDA-MB-231cell migration, invasion, and adhesion. Additionally, there has been a significant reduction in the manifestation of cytoskeleton-related proteins. Furthermore, the expression levels of RhoA, CDC42, ROCK2, and MRCKß mRNA and protein were down-regulated. ZDF significantly decreased the protein expressions of vimentin, cytokeratin-8, Arp2 and N-WASP, and inhibited actin polymerization and actomyosin contraction. Furthermore, MMP-2 and MMP-9 levels in the high-dose ZDF group were decreased by 30% and 26%, respectively. ZDF significantly reduced the tumor volume and protein expressions of ROCK2 and MRCKß in tumor tissues without eliciting any perceptible alterations in the physical mass of the mice, and the reduction was more pronounced than that of the BDP5290 treated group. CONCLUSION: The current investigation demonstrates that ZDF exhibits a proficient inhibitory impact on TNBC metastasis by regulating cytoskeletal proteins through the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. Furthermore, the findings indicate that ZDF has significant anti-tumorigenic and anti-metastatic characteristics in breast cancer animal models.

Eficacia y seguridad de enzalutamida en pacientes adultos con cáncer de próstata resistente a la castración metastásico, con progresión a quimioterapia basada en docetaxel, y tienen contraindicaciones al uso, o desarrollan reacciones adversas que lleven a la interrupción de acetato de abiraterona / Efficacy and safety of enzalutamide in adult patients with metastatic castration-resistant prostate cancer, with progression to docetaxel-based chemotherapy, and have contraindications to use, or develop adverse reactions leading to discontinuation of abiraterone acetate

ANTECEDENTES En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de enzalutamida en pacientes adultos con cáncer de próstata resistente a la castración metastásico, con progresión a quimioterapia basada en docetaxel e intolerantes a acetato de abiraterona. Así, el Dr. Nelson Cuevas Muñoz, médico especialista en oncología del Hospital Nacional Edgardo Rebagliati Martins (HNERM), siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envió a través del comité farmacoterapéutico del Hospital HNERM al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico enzalutamida no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: El cáncer de próstata (CP) es el segundo cáncer más frecuente en hombres a nivel mundial y el más frecuente en Perú; registrándose 30.7 y 44.3 casos nuevos por cada 100 000 hombres en el 2020, respectivamente (GLOBOCAN [Internet] 2022). Asimismo, en el mismo año, se registró más de 375 000 muertes por CP en el mundo y 2433 muertes por CP en el Perú, representando así la segunda causa de muerte por cáncer en la población peruana (GLOBOCAN [Internet] 2022). El tratamiento sistémico de primera línea para el CP en estadios avanzados es la terapia de deprivación de andrógenos (Dawson y Leger 2022). Entre el 10 % y 27 % progresa a esta terapia, y el estado de la enfermedad se conoce como CP resistente a la castración (CPRC) (Bretoni, Ferrario, y Foglia 2019; Colloca et al. 2016). Aproximadamente, más del 70 % de pacientes con CPRC tienen CPRC metastásico (CPRCm) (Bretoni, Ferrario, y Foglia 2019). METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de enzalutamida en pacientes adultos con CPRCm, con progresión a quimioterapia basada en docetaxel e intolerantes a AA. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library, Web of Science y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), el Scottish Intercollegiate Guidelines Network (SIGN). el Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), la International Database of GRADE Guideline, el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Guidelines International Network (GIN), el National Health and Medical Research Council (NHMRC), la Cancer Guidelines Database, el New Zealand Guidelines Group (NZGG), el Instituto de Evaluación Tecnológica en Salud (IETS), el Instituto de Efectividad Clínica y Sanitaria (IECS), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en oncología o urología, tales como: National Comprehensive Cancer Network (NCCN), la Cancer Council Australia (CCA), la European Society for Medical Oncology (ESMO), la American Society of Clinical Oncology (ASCO), la Sociedad Española de Oncología Médica (SEOM), la European Association of Urology (EAU) y la American Urological Association (AUA). Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica hasta mayo de 2023, se identificaron cinco GPC elaboradas por la NCCN (NCCN 2022), la ESMO (Parker et al. 2020), la EAU (EAU 2022a), la SEOM (González del Alba et al. 2021) y la ASCO (Basch et al. 2014), y un ECA denominados AFFIRM (Scher et al. 2012). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de enzalutamida para pacientes adultos con CPRCm, con progresión a quimioterapia basada en docetaxel, con contraindicaciones al uso, o desarrollo de reacciones adversas que lleven a la interrupción, de AA, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Adagrasib (Krasati®) en cáncer colorectal metastásico / Adagrasib (Krasati®) in metastatic colorectal cancer

INTRODUCCIÓN: El cáncer colorrectal (CCR) representa la segunda causa de mortalidad por tumores en la Argentina. Según la Agencia Internacional de Investigación sobre el Cáncer la incidencia en nuestro país durante el año 2020 se calculó en aproximadamente 15.600 casos, registrándose en el mismo período de tiempo unas 8.600 muertes. que otros pacientes diagnosticados en estadios iniciales progresarán en el transcurso de la enfermedad requiriendo quimioterapia sistémica. Sin tratamiento, el promedio de sobrevida de estos pacientes es de unos 6 meses. Los esquemas de quimioterapia utilizados frecuentemente están basados en la combinación de fluoropirimidinas con oxaliplatino o irinotecan asociados con anticuerpos monoclonales contra el factor de crecimiento endotelial vascular (bevacizumab) o el receptor del factor de crecimiento epidérmico (cetuximab, panitunumab) en tumores sin mutaciones en la vía RAS (wildtipe o "salvajes"). En aquellos tumores con deficiencia del sistema de reparación de apareamientos erróneos o alta inestabilidad de microsatélites (por sus siglas en inglés, dMMR o MSI-H, respectivamente) se listan dentro de las opciones terapéuticas el uso de inmunoterapia. En aquellos pacientes en los cuales la enfermedad progresa a pesar de los esquemas mencionados se pueden utilizar regorafenib o trifluridina/tipiracilo y en ciertos subtipos moleculares encorafenib (mutación V600E en el gen BRAF); trastuzumab +/-pertuzumab/lapatinib/tucatinib (HER2 amplificado y sin mutaciones en los genes RAS y BRAF), entre otras. Se debe tener en cuenta que alguna de estas opciones no cuentan con aprobación o no se encuentran disponibles aún en nuestro país. En este documento se plantea evaluar la eficacia y seguridad del uso de adagrasib en pacientes con carcinoma colorectal metastásico portadores de la mutación G12C en el gen KRAS. TECNOLOGÍA: Adagrasib (Krasati®) es un inhibidor irreversible y selectivo de la proteína mutante KRAS G12C (homólogo del oncogén vírico de sarcoma de rata Kirsten). La proteína pertenece a la subfamilia de proteínas RAS (KRAS, HRAS y NRAS) que actúan como GTPasas y se desempeñan como reguladores moleculares, controlando un amplio espectro de actividades celulares, como la proliferación y la sobrevida celular. Su inactivación por parte de adagrasib bloquea la transmisión de señales inhibiendo el crecimiento celular y favoreciendo la apoptosis de manera selectiva en tumores portadores de la mutación KRAS G12C. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de adagrasib en pacientes con diagnóstico de carcinoma colorectal metastásico. MÉTODOS Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. La fecha de búsqueda de información fue hasta el 19 de mayo de 2023. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (adagrasib [Supplementary Concept] OR adagrasib [tiab] OR MRTX849 [tiab]) AND ("Colonic Neoplasms"[Mesh] OR ¨Colorectal Cancer¨ [tiab]). CONCLUSIONES: La evidencia sobre el uso de adagrasib para el tratamiento de pacientes con diagnóstico de carcinoma colorectal metastásico progresados a múltiples líneas de tratamiento se basa en un único ensayo clínico no aleatorizado de fase I-II. Este estudio mostró que aquellos pacientes, progresados generalmente a tres líneas de tratamiento y con tumores que presentan mutaciones G12C en el gen KRAS, que utilizaron adagrasib con cetuximab reportaron una mediana de sobrevida global de 13,4 meses y libre de progresión de 6,9 meses, y una tasa de respuesta del 46%. Los eventos adversos severos fueron reportados en el 16% de los pacientes. Actualmente se encuentra en curso un ensayo clínico aleatorizado de fase III que cuenta con centros en Argentina y tratará de establecer la seguridad y eficacia de la adición de adagrasib a un esquema de poliquimioterapia como segunda línea de tratamiento La Administración de Alimentos y Medicamentos de Estados Unidos y la Agencia Europea de Medicamentos aún no ha autorizado la comercialización del medicamento en la indicación antes mencionada. En referencias a las recomendaciones relevadas, no se hallaron guías que mencionen los esquemas de adagrasib combinado con cetuximab o en monoterapia como una opción para el tratamiento del carcinoma colorectal avanzado. Utilizando precios de referencia internacionales, el costo de adquisición para un ciclo de tratamiento fue estimado en aproximadamente 4,8 millones de pesos argentinos.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

Pegylated liposomal doxorubicin (Duomeisu®) monotherapy in patients with HER2-negative metastatic breast cancer heavily pretreated with anthracycline and taxanes: a single-arm, phase II study.

PURPOSE: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. METHODS: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. RESULTS: Of 44 enrolled patients (median age, 53.5 years; range, 34-69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3-4.1) and median OS was 15.0 months (95% CI 12.1-17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. CONCLUSION: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.

Molecular predictors of metastasis in patients with prostate cancer.

INTRODUCTION: Prostate cancer is a serious threat to the health of older adults worldwide. The quality of life and survival time of patients sharply decline once metastasis occurs. Thus, early screening for prostate cancer is very advanced in developed countries. The detection methods used include Prostate-specific antigen (PSA) detection and digital rectal examination. However, the lack of universal access to early screening in some developing countries has resulted in an increased number of patients presenting with metastatic prostate cancer. In addition, the treatment methods for metastatic and localized prostate cancer are considerably different. In many patients, early-stage prostate cancer cells often metastasize due to delayed observation, negative PSA results, and delay in treatment time. Therefore, the identification of patients who are prone to metastasis is important for future clinical studies. AREAS COVERED: this review introduced a large number of predictive molecules related to prostate cancer metastasis. These molecules involve the mutation and regulation of tumor cell genes, changes in the tumor microenvironment, and the liquid biopsy. EXPERT OPINION: In next decade, PSMA PET/CT and liquid biopsy will be the excellent predicting tools, while 177 Lu- PSMA-RLT will be showed excellent anti-tumor efficacy in mPCa patients.

STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFß. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.