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ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.

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BACKGROUND: Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib. PATIENTS AND METHODS: Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities. CONCLUSIONS: The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting.

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Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

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BACKGROUND: PI3K pathway hyperactivation due to PIK3CA mutations contributes to endocrine resistance, and PIK3CA is one of the most frequently mutated genes in breast cancer (BC), occurring approximately 40 % of HR+, HER2- advanced BC (ABC). Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the treatment landscape of HR+, HER2- ABC. Putative mechanisms of resistance to CDK4/6i have been identified, but limited data are available on PI3K deregulation. The present study evaluates the impact of PIK3CA mutations on CDK4/6i plus hormone therapy and evaluates potential characteristics that may suggest for a PI3K screening in patients with ABC. METHODS: ABC patients were enrolled, and 12 mL of blood were collected in EDTA tubes at baseline prior to CDK4/6i plus hormone therapy. Plasma was separated and circulating free DNA (cfDNA) was extracted. PIK3CA mutation analysis was performed on a ddPCR. Selected and analyzed mutations included: p.C420R, p.E542 K, p.E545A, p.E545D, p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y. Statistical analysis were performed to investigate the predictive power of such mutations and any association with clinical factors. RESULTS: Thirty patients were enrolled. PIK3CA mutation status at baseline was independently associated with shorter median PFS (7.44 vs 12.9 months, p = 0.01) in subject receiving CDK4/6i plus hormone therapy. PIK3CA mutations were found to be associated to Ki67 expression in primary lesions (p = 0.006). Moreover, the probability to find a PI3K mutation improved considering also the therapeutic management in previous lines of treatment (McFadden's R2 = 0.415, p = 0.004; AUC of the ROC curve = 0.914). CONCLUSION: The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.

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El presente trabajo de investigación pretende identificar representaciones sociales de los profesionales que intervienen en internaciones breves de pacientes con intento de suicidio, busca conocer sus opiniones sobre los recursos eficaces en la remoción de esa crisis que motivó su ingreso en el Hospital General San Martín de Paraná. Dicha institución se involucra directamente con esto que deseo investigar. Por su complejidad, es el hospital de referencia de la provincia de Entre Ríos, y en concordancia con la Ley Nacional de Salud Mental 26.657/11, viene realizando internaciones de diversas problemáticas del campo de la Salud Mental, específicamente situaciones de crisis subjetivas con intentos de suicidio. En mi trabajo cotidiano como psicóloga en la mencionada organización hospitalaria, he advertido en los días de internación de ese tipo de pacientes, cambios cualitativamente favorables. Es notable cómo al ingreso estas personas expresan sentimientos de desesperanza, se muestran poco colaboradores, parecieran estar "enojados" con todo aquel que intenta asistirlo, expresando desgano y resistencia a recibir la ayuda profesional, muchas veces evitan mirar a quien les habla, con lágrimas en los ojos, o un llanto que desborda. En ocasiones, incluso, evitan cualquier tipo de acercamiento con cualquiera de las personas que lo atienden en el transcurso de ese tiempo breve de internación. Durante esos pocos días de hospitalización, los pacientes suelen cambiar favorablemente su condición emocional, mostrando otro aspecto y actitud. Comienzan a hablar de lo que les pasa, dirigen la mirada hacia el profesional, respondiendo a las preguntas que este les hace, y dan apertura para que comience un vínculo con posibilidades de aceptar ayuda. Me interesa conocer cuáles son las opiniones de otros profesionales que intervienen en estos procesos, qué piensan ellos sobre lo que es eficaz en ese tiempo breve de internación en favor de ese cambio significativo en la actitud emocional de estos pacientes. Esta investigación es un estudio cualitativo de tipo exploratorio. Para ello, se llevaron a cabo entrevistas semiestructuradas a profesionales que intervienen en las internaciones de pacientes con intentos de suicidio, y los datos obtenidos fueron analizados a través del método que propone la Dra. María Teresa Sirvent como adaptación del método comparativo constante de Glasser y Strauss. En el análisis del discurso de los profesionales entrevistados, se encontraron representaciones que permitieron elaborar dos categorías generales: "La internación y técnicas profesionales" y "La disposición a un trato humano". La primera categoría; "La internación y técnicas profesionales" hace referencia a la confianza que parecen adjudicar los profesionales a la situación de la internación hospitalaria en sí misma y a la asistencia que prestan las diferentes especialidades profesionales a los pacientes durante el breve período de tiempo que permanecen internados en las salas del Hospital San Martín. Los entrevistados resaltaron que la prescripción de fármacos y la contención psicológica serían las principales intervenciones que favorecen al cambio en la condición emocional de las personas que permanecen en una internación breve por un intento de suicidio, y son propias de la especialidad del médico y del psicólogo, respectivamente. Por esta razón, dentro de la primera categoría general, se incluyen otras dos sub-categorías específicas: "El poder del fármaco" y "El poder de la contención", que agrupan las representaciones sociales que aluden a estas acciones. La segunda categoría general; "La disposición a un trato humano" hace referencia a la confianza que los profesionales del Hospital San Martín parecieran adjudicar a las posibilidades de entablar un "contacto humano" de características empáticas con el paciente que permanece internado por un intento de suicidio. Este contacto parece ser independiente de cualquier técnica o especialidad

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