Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2- advanced breast cancer: a real-world evidence cohort.

PURPOSE: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(-) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4-6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. METHODS: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan-Meier method were used for survival estimates. RESULTS: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1-56 months). The median age at diagnosis was 49 years (range: 35-90 years). The estimated mPFS was 6.0 months (95%CI 5.3-7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6-11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8-10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9-8.4 months). CONCLUSION: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs.

Vacunación con SOBERANA®02 y SOBERANA®Plus en trabajadores: éxito en el enfrentamiento a la pandemia de COVID-19

La vacunación es una forma de contribuir a la protección de la población al reducir el riesgo de efectos graves de la enfermedad COVID-19. Para marzo de 2021, en tiempo récord, la industria biotecnológica cubana contaba con cinco candidatos vacunales. Se realizó una intervención sanitaria con un esquema heterólogo: dos dosis de SOBERANA®02 más una dosis de SOBERANA®Plus, en trabajadores durante el período de marzo a junio de 2021, en el Instituto Finlay de Vacunas, en La Habana, Cuba. Se evaluaron los efectos directos e indirectos de la vacunación con SOBERANA®02 y SOBERANA®Plus en una cohorte de riesgo de infección, enfermedad y diseminación de la COVID-19. La cohorte se estableció en marzo de 2021 en trabajadores con alta exposición al coronavirus de tipo 2 causante del síndrome respiratorio agudo severo, en el área de consulta médica de Instituto Finlay de Vacunas, establecida como sitio clínico. Entre el 22 de marzo de 2021 y el 11 de junio de 2021, se inscribieron un total de 1.776 participantes; de ellos, 1.719 cumplieron los criterios de inclusión con un porcentaje de 96,79 % para la primera dosis, 1.675 recibieron la segunda dosis y 1.653 se vacunaron SOBERANA®Plus como tercera dosis para un 97,87. Mil cuatrocientos cincuenta y siete tenían entre 19 y 59 años, con predominio del sexo femenino. De los participantes, 175 tuvieron acontecimientos adversos y se observaron, predominantemente, una hora después de la administración de cada dosis. La reacción local más referida fue el dolor en el lugar de la inyección. Se registraron pocos acontecimientos adversos no solicitados. No se notificó ningún evento adverso grave o severo asociado a la vacuna. La distribución de casos de COVID-19 fue de 30, 16 y 6 posterior a cada dosis recibida. No se notificaron muertes asociadas a COVID-19. Las vacunas SOBERANA®02 y SOBERANA®Plus tuvieron un buen perfil de seguridad y fueron capaces de reducir la enfermedad grave por COVID-19 y la muerte, ayudando a revertir la situación epidemiológica causada por el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo en Cuba.

Vaccination is a way to help protect people by reducing the risk of serious effects from COVID-19 illness. By March of 2021, in record time, Cuba's biotech industry had five vaccine candidates. A sanitary intervention with a heterologous scheme, two doses of SOBERANA®02 and one dose of SOBERANA®Plus, was carried out in workers during the period of March to June 2021 at Finlay Vaccine Institute, in Havana, Cuba. We evaluated the direct and indirect effects of vaccination with SOBERANA®02 and SOBERANA®Plus, in a cohort at risk of infection, disease and spread of the epidemic COVID-19. The cohort was established in March 2021, among workers with high exposure to SARS-CoV-2, at the area of medical consultation at Finlay Vaccine Institute, established as clinical site. Between March 22, 2021 and June 11, 2021, were enrolled a total of 1,776 participants and, of them, 1,719 met the inclusion criteria with a percentage of 96.79% for first dose, of which 1,675 received the second dose and 1,653 received SOBERANA®Plus as third dose for 97.87%. The majority of participants were aged 19-59 years (1,457), being female, the predominant sex. Among the participants, 175 had adverse events, predominantly observed one hour after the administration of each dose. The most common local reaction was injection site pain. Few unsolicited adverse events were recorded. No vaccine-associated severe or serious adverse events were reported. The distribution of COVID-19 case was 30 post first dose, 16 post second dose and 6 post last dose. No deaths associated with COVID-19 were reported. SOBERANA®02 and SOBERANA®Plus vaccines had a good safety profile and were capable of a reduction of severe COVID-19 illness and death helping to reverse the epidemiological situation caused by the SARS-COV-2 in Cuba.

Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors.

Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity. We interrogated a longitudinal collection of 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors and were subsequently treated with endocrine therapy (ET) by means of highly sensitive and affordable digital PCR and SafeSEQ sequencing. Baseline PIK3CA and TP53 mutations were prognostic of a shorter progression-free survival in our population. Mutant PIK3CA was prognostic in the subset of patients receiving fulvestrant monotherapy after progression to a CDK4/6 inhibitor (CDK4/6i)-containing regimen, and its suppression was predictive in a case of long-term benefit with alpelisib. Mutant ESR1 was prognostic in patients who did not receive concurrent CDK4/6i, an impact influenced by the variant allele frequency, and its early suppression was strongly predictive of efficacy and associated with long-term benefit in the whole cohort. Mutations in ESR1, TP53, and KRAS emerged as putative drivers of acquired resistance. These findings collectively contribute to the characterization of longitudinal ctDNA in real-world cases of HR+/HER2- mBC previously exposed to aromatase inhibitors and support ongoing studies either targeting actionable alterations or leveraging the ultra-sensitive tracking of ctDNA.

Case report: Clinical success targeting BRAF-mutated, hormone receptor positive, HER2- negative advanced breast cancer patient with BRAF-inhibitor plus MEK- inhibitor.

BACKGROUND: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients have had a wide range of therapeutical options since the incorporation of targeted therapies alongside classic chemotherapy. However, because of their disease, virtually all patients will eventually experience disease progression that might compromise their lives. Thriving investigation regarding molecular therapies has provided clinicians with new options for the treatment of many cancer patients. Dabrafenib and trametinib combination has proven useful in treating malignant melanoma patients harboring a BRAF V600E mutation, improving progression-free survival and overall survival, and it has been tested in other tumors. Here we report the case of a metastatic breast cancer patient harboring a BRAF V600E mutation that achieved complete response with dabrafenib and trametinib combination.

Caracterización de las aguas residuales generadas en la producción de conjugados monovalentes en el Instituto Finlay de Vacunas / Characterization of the wasteswater generated in the production of conjugated monovalent at the Finlay Vaccine Institute

En la actualidad la contaminación de las aguas terrestres es un grave problema ambiental. La industria farmacéutica es una de las que produce un mayor impacto por la gran variedad de químicos que aporta al agua; sus efluentes generalmente tienen asociadas elevadas cargas orgánicas no biodegradables. La preservación de la calidad de las aguas terrestres es un tema regulado por la legislación nacional, donde se exige la caracterización de las aguas residuales antes de su vertimiento con vistas a evaluar el impacto ambiental que producen y diseñar el sistema adecuado para su tratamiento. El Instituto Finlay de Vacunas, pertenece al grupo de BioCubaFarma, es una empresa de ciclo completo, cuenta con nueve instalaciones, cinco de ellas son generadoras de grandes volúmenes de aguas residuales industriales. El presente trabajo tiene el objetivo de presentar los resultados obtenidos en la evaluación de los parámetros físico-químico de los residuales líquidos del proceso productivo de conjugados monovalentes, para esto se muestrearon los residuales líquidos generados al final de cada etapa del proceso. Se determinaron los indicadores de contaminación: pH, temperatura, conductividad eléctrica, demanda química y bioquímica de oxígeno, fósforo total, nitrógeno total y sólidos sedimentables; los ensayos fueron realizados en el laboratorio de la Empresa Nacional de Servicios Técnicos de la Habana, acreditado para la realización de las caracterizaciones de aguas residuales. Los resultados fueron comparados con los límites máximos permisibles establecidos en la Norma Cubana NC-27:2012 de vertimiento de aguas residuales al alcantarillado, además se calculó el índice de biodegradabilidad. Se demostró que el pH, la conductividad eléctrica, demanda química de oxígeno y demanda bioquímica de oxígeno no cumplen con el vertido para la descarga al alcantarillado pudiendo impactar de manera negativa en los recursos hídricos(AU)

At present, the pollution of terrestrial waters is a serious environmental problem. The drug industry is one of those that produces a greater impact, due to the great variety of chemicals that can contribute to the water; its effluents generally have associated high non-biodegradable organic loads. The preservation of the quality of terrestrial waters is a subject regulated by legislation, where the characterization of wastewater is required before its discharge, since it allows evaluating the environmental impact it produces and designing the appropriate system for its treatment. The Finlay Vaccine Institute, belongs to the BioCubaFarma group, is a full cycle company, has nine facilities, five of them are generators of large volumes of industrial wastewater. The current work presents the results obtained in the evaluation of the physical-chemical parameters of the liquid waste from the production process of monovalent conjugates, for this the liquid waste generated at the end of each stage of the process was sampled. Pollution indicators were determined: pH, temperature, electrical conductivity, chemical and biochemical oxygen demand, total phosphorus, total nitrogen and sedimentable solids. The results were compared with the maximum permissible limits established in NC-27: 2012 for the discharge of wastewater. The biodegradability index was also calculated. It was shown that some of the determined parameters do not comply with the discharge to release to the sewer system, which could have a negative impact on water resources(AU)

A snapshot of COVID-19 infection in patients with solid tumors.

Coronavirus disease 2019 (COVID-19) pandemic is affecting a high percentage of the population at an unprecedented rate. Cancer patients comprise a subgroup especially vulnerable to this infection. Herein, we present a prospective analysis of epidemiological, clinical, radiological and laboratory data of consecutive adult cancer patients seen in the Clínico San Carlos University Hospital (Madrid, Spain), and admitted to hospital and tested for COVID-19 between 21 February 2020 and 8 May 2020 due to clinical suspicion of infection. Data from 73 patients with confirmed COVID-19 and active solid tumors or diagnosed within the previous 5 years were analyzed. The most frequent malignancy was lung cancer (19%) and 54 patients (74%) were on active cancer treatment. Most common findings on presentation included cough (55%), fever (52%) and dyspnea (45%), and 32 (44%) patients showed oxygen saturation levels below 95%. Radiologically, 54 (73%) patients presented an abnormal pattern, the most frequent being infiltrates (64%). 18 (24.7%) patients died in hospital and 55 (75.3%) were discharged with clinical resolution of the event. Multivariable logistic regression adjusted for age and tumor stage showed higher odds of in-hospital death associated with a history of cardiovascular disease, hospitalization in the previous 30 days, and several features on admission including dyspnea, higher qSOFA score, higher C-reactive protein levels and an abnormal neutrophil count. We present prospective, real-world evidence that can help articulate cancer care protocols for patients infected with SARS-CoV-2, with special focus on features on admission that can stratify patients with a higher risk of death from COVID-19.

Safety and efficacy of cyclin-dependent kinase inhibitor rechallenge following ribociclib-induced limiting hypertransaminasemia.

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Real-world effectiveness of dual HER2 blockade with pertuzumab and trastuzumab for neoadjuvant treatment of HER2-positive early breast cancer (The NEOPETRA Study).

PURPOSE: Neoadjuvant clinical trials with dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy demonstrated high rates of pathological complete response (pCR) in HER2-positive early breast cancer (BC). We investigated whether the benefit on pCR seen in clinical trials is confirmed in a real-world setting. METHODS: Multicenter, retrospective study in patients with HER2-positive early BC receiving neoadjuvant treatment with pertuzumab and trastuzumab in routine clinical practice (n = 243). The primary endpoint was total pCR (tpCR) (ypT0/is ypN0). RESULTS: A total of 243 evaluable patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes in 74.1% of patients, with single-agent taxane in 11.1% of patients and with platinum-based chemotherapy (CT) in 14.4% of patients. The tpCR rate was 66.4%:71% with anthracyclines and taxanes, 59.3% with single-agent taxane, and 48.6% with platinum-based combinations. The tpCR rate was higher among patients with hormone receptor (HR)-negative tumors (80.9%) vs HR-positive tumors (55.4%) (p < 0.001). A pCR in the breast (ypT0/is) was achieved in 67.6% of patients. Of 143 patients who showed radiological complete response (rCR) (62%), 112 (78.3%) patients also achieved tpCR. Assessment of rCR by magnetic resonance imaging (MRI) showed the highest negative predictive value (NPV) for predicting tpCR (83.5%). Breast-conserving surgery was performed in 58.7% of patients. Grade 3 and grade 4 toxicities were reported in 33 (18.2%) and 12 (6.6%) patients, respectively. No toxicity leading to death was reported. CONCLUSIONS: This real-world analysis shows that neoadjuvant pertuzumab, trastuzumab, and chemotherapy achieve comparable or even higher rates of tpCR than those seen in clinical trials. The pCR benefit is higher in HR-negative tumors. The assessment of rCR by MRI showed the highest ability for predicting pCR. In addition, this neoadjuvant strategy confers an acceptable safety profile.