Tumor-intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer.

Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.

Mutations Associated With High-Grade irAEs in NSCLC Patients Receiving Immunotherapies.

OBJECTIVES: Compared to low-grade irAEs, high-grade irAEs are more often dose-limiting and can alter the long-term treatment options for a patient. Predicting the incidence of high-grade irAEs would help with treatment selection and therapeutic drug monitoring. MATERIALS AND METHODS: We performed a retrospective study of 430 stage III and IV patients with non-small cell lung cancer (NSCLC) who received an immune checkpoint inhibitor (ICI), either with or without chemotherapy, at a single comprehensive cancer center from 2015 to 2022. The study team retrieved sequencing data and complete clinical information, including detailed irAEs medical records. Fisher's exact test was used to determine the association between mutations and the presence or absence of high-grade irAEs. Patients were analyzed separately based on tumor subtypes and sequencing platforms. RESULTS: High-grade and low-grade irAEs occurred in 15.2% and 46.2% of patients, respectively. Respiratory and gastrointestinal irAEs were the 2 most common irAEs. The distribution of patients with or without irAEs was similar between ICI and ICI+chemotherapy-treated patients. By analyzing the mutation data, we identified 5 genes (MYC, TEK, FANCA, FAM123B, and MET) with mutations that were correlated with an increased risk of high-grade irAEs. For the adenocarcinoma subtype, mutations in TEK, MYC, FGF19, RET, and MET were associated with high-grade irAEs; while for the squamous subtype, ERBB2 mutations were associated with high-grade irAEs. CONCLUSION: This study is the first to demonstrate that specific tumor mutations correlate with the incidence of high-grade irAEs in patients with NSCLC treated with an ICI, providing molecular guidance for treatment selection and drug monitoring.

Treatment Options for Brain Metastases.

OPINION STATEMENT: Therapies for brain metastasis continue to evolve as the life expectancies for patients have continued to prolong. Novel advances include the use of improved technology for radiation delivery, surgical guidance, and response assessment, along with systemic therapies that can pass through the blood brain barrier. With increasing complexity of treatments and the increased need for salvage treatments, multi-disciplinary management has become significantly more important.

Brain metastases from renal cell carcinoma: Effects of novel systemic agents on brain metastasis outcomes.

OBJECTIVE: The objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone. METHODS: The Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included. RESULTS: Overall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001). CONCLUSION: Prior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies.

Fertilización asistida con óvulos propios en mujeres mayores de 40 años: indicaciones y resultados

Las mujeres posponen su maternidad por el deseo de superación personal y profesional. Se conoce que la cantidad y calidad de los óvulos por ciclo dependen de la edad de la paciente. Las tasas de éxito en tratamientos de reproducción asistida disminuyen con la edad, especialmente después de los 40 años. Se observan tasas más altas de nacidos vivos en mujeres más jóvenes y las tasas disminuyen significativamente en mujeres mayores debido a la disminución de la fertilidad y el aumento de abortos espontáneos. Por ello, la edad es crucial al evaluar la posibilidad de un embarazo exitoso mediante tratamientos de reproducción asistida (TRA). Las indicaciones para realizar fertilización in vitro (FIV) con óvulos propios en mujeres mayores de 40 años incluyen iniciar lo más pronto procedimientos de alta complejidad, buena evaluación de la reserva ovárica con análisis de la hormona antimülleriana y conteo de folículos antrales para realizar asesoramiento genético, proponer FIV-inyección intracitoplasmática de espermatozoides (ICSI) antes de los 44 años, generar expectativas realistas y realizar consentimiento informado, con estadisticas propias. En la REDLARA, de todos los procedimientos de FIV-ICSI, el 34% de las pacientes tienen más de 40 años; se prefiere transferir blastocistos con prueba genética preimplantacional de aneuploidías (PGT-A) para seleccionar embriones euploides. Las tasas de éxito son bajas, inclusive cuando son tasas de embarazo por transferencia de un embrión en el grupo de mujeres ≥ 40 años (18,2% sin PGT, 42,7% con PGT en el IMRCRP). Se recomienda acumular óvulos o embriones realizando múltiples estimulaciones ováricas. Se debe optar por transferir un solo embrión para evitar complicaciones obstétricas con embarazos múltiples en pacientes ≥ 40 años, por el alto riesgo debido a la edad.

Women postpone motherhood because of their desire for personal and professional improvement. It is known that the quantity and quality of oocytes per cycle depends on the patient's age. Success rates in assisted reproduction treatments decrease with age, especially after 40 years of age. Higher live birth rates are observed in younger women, and rates decrease significantly in older women due to decreased fertility and increased miscarriages. Therefore, age is crucial when assessing the possibility of a successful pregnancy through assisted reproductive treatments (ART). The indications to perform in vitro fertilization (IVF) with own ovules in women older than 40 years include starting as soon as possible highly complex procedures, good evaluation of ovarian reserve with antimüllerian hormone analysis (AMH) and antral follicle count (AFC) for genetic counseling, proposing IVF-intracytoplasmatic sperm injection (ICSI) before the age of 44 years, generating realistic expectations and informed consent, with own statistics. At REDLARA, of all IVF-ICSI procedures, 34% of patients are over 40 years old; preference is given to transfer blastocysts with preimplantation genetic testing for aneuploidy (PGT-A) to select euploid embryos. Success rates are low, even when they are pregnancy rates per embryo transfer in the group of women ≥ 40 years (18.2% without PGT, 42.7% with PGT in IMRCRP). It is recommended to bank ovules or embryos by performing multiple ovarian stimulations. A single embryo transfer should be chosen to avoid obstetric complications with multiple pregnancies in patients ≤ 40 years, because of the high risk due to age.