Measurement of perceived pressures in psychiatry: paper-and-pencil and computerized adaptive version of the P-PSY35 scale.

PURPOSE: Formal coercion in psychiatry is widely studied yet much less is known about pressures patients may experience, partly because of the very few measures available. The goal of this study was to validate the P-PSY35 (Pressures in Psychiatry Scale) and provide a paper-and-pencil and a computerised adaptive test (CAT) to measure pressures experienced by patients in psychiatry. METHODS: The P-PSY35 items were developed with users. Patients were evaluated during psychiatric hospitalisation or through an online survey. Mokken scale analysis and Item response theory (IRT) were used to select and estimate the items parameters. A Monte-Carlo simulation was performed to evaluate the number of items needed to transform the paper-and-pencil test into a reliable psychometric CAT. RESULTS: A total of 274 patients were assessed. The P-PSY35 demonstrated good internal validity, internal consistency, convergent and divergent validity. The P-PSY35 could be substantially shortened while maintaining excellent reliability using the CAT procedure. CONCLUSION: The P-PSY35 was developed in collaboration with users. It is a psychometrically rigorous tool designed to measure experienced pressures in French-language. The development and successful validation of the P-PSY35 represent a welcome step towards implementing and evaluating programs aimed at reducing negative consequences of coercion.

How do decision making and fairness mediate the relationship between involuntary hospitalisation and perceived coercion among psychiatric inpatients?

BACKGROUND: Coercion perceived by psychiatric inpatients is not exclusively determined by formal measures such as involuntary admissions, seclusion or restraint, but is also associated with patients' characteristics and professionals' attitude. AIMS: This study examined how inpatients' involvement in the decision making process, the respect of their decision making preference, and their feeling of having been treated fairly mediate the relationship between involuntary hospitalisation and perceived coercion both at admission and during hospital stay. METHODS: Mediation analysis were performed in order to study the relationship between involuntary hospitalisation and perceived coercion among 230 patients, voluntarily and involuntarily admitted in six psychiatric hospitals. RESULTS: 32.2% of the participants were involuntarily hospitalised. Taken individually, stronger participants' involvement in decision making process, better respect for their decision making preference and higher level of perceived fairness partially mediated the relationship between involuntary hospitalisation and perceived coercion by reducing the level of the latter both at admission and during the hospitalisation. In multiple mediator models, only involvement and respect played an important role at admission. During the hospitalisation, perceived fairness was the most relevant mediator, followed by involvement in decision making. CONCLUSIONS: During psychiatric hospitalisation patients' involvement in decision making, respect of their decision making preference and perceived fairness determined the relationship between involuntary hospitalisation and perceived coercion, but not in the same way at admission and during the stay. Involving patients in decision making and treating them fairly may be more relevant than taking account of their decision making preference in order to reduce perceived coercion.

[Burden and perceived stress among informal caregivers of people suffering from mental disorders]. / Fardeau et stress perçu chez les proches aidants de personnes souffrant de troubles psychiques.

Informal caregivers of people with severe mental illness are particularly at risk of experiencing high levels of burden and perceived stress, which can worsen their global health. In addition, the semi-confinement in 2020 represented a period of additional difficulties for informal caregivers in French-speaking of Switzerland. The burden represents all the negative consequences linked to the informal caregiver role. Perceived stress is the way in which the informal caregiver will perceive a potentially threatening situation, according to their coping strategies and personal resources. Burden and perceived stress can be rapidly assessed in primary care, to suggest useful and effective support interventions to the informal caregivers.

Les proches aidants de personnes atteintes d'un trouble psychique sont particulièrement à risque de vivre des niveaux élevés de fardeau et de stress perçu, ce qui peut détériorer leur état de santé globale. En outre, le semi-confinement de 2020 a représenté une période de difficultés supplémentaires pour les proches en Suisse romande. Le fardeau représente l'ensemble des conséquences défavorables relatives au rôle d'aidant. Le stress perçu est la façon dont le proche aidant va percevoir une situation potentiellement menaçante, selon ses stratégies de coping et ses ressources personnelles. Fardeau et stress perçu peuvent être évalués de façon rapide déjà en soins de première ligne afin de proposer aux proches aidants une orientation vers des interventions de soutien utiles et efficaces.

A randomized controlled trial of a targeted support program for informal caregivers in adult psychiatry.

Background: The importance of informal caregivers for persons with severe mental illness has been demonstrated. However, this role may cause a high care burden that considerably affects caregiver health. The Ensemble program is a five-session brief individual intervention designed to support informal caregivers. This trial aimed to assess the efficacy of the program versus SAU (support as usual) for participants with a high care burden. Methods: A single-center randomized controlled trial including 149 participants was conducted. Caregivers in the intervention arm participated in the Ensemble program. The effects of the intervention were assessed using mixed models for repeated measures analysis of variance on improvements in informal caregivers' psychological health status, optimism levels, burden scores, and quality of life at three time points (T0 = pretest; T1 = posttest at 2 months, and T2 = follow-up at 4 months). Results: Analysis of the Global Psychological Index showed no significant effect at the two endpoints in favor of the Ensemble group. However, the Brief Symptom Inventory-Positive Symptom Distress Index was significantly lower at the two-month follow-up. A significant reduction in burden on the Zarit Burden Interview was observed post-intervention, along with an increase in optimism levels on the Life Orientation Test-Revised at follow-up in the Ensemble group. No significant differences were observed in quality of life. Clinical improvements in both psychological health status and burden levels were also identified. Conclusion: The Ensemble program offers an inclusive approach based on a recovery perspective that significantly reduces symptom distress and burden and increases optimism among informal caregivers.Clinical trial registration: https://clinicaltrials.gov/, NCT04020497.

[The Ensemble Program: Making sense of your actions through ACT]. / Programme Ensemble : redonner du sens à ses actions grâce à l'ACT.

The Ensemble program supports informal caregivers of people with mental health problems. Tailor-made support is offered in order to target the tools that will be most useful to them in their personal situation. Acceptance and commitment therapy can be used to help them give meaning to their actions.

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer.

Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.

Feeling coerced during voluntary and involuntary psychiatric hospitalisation: A review and meta-aggregation of qualitative studies.

Objective: This review aimed to provide an aggregative synthesis of the qualitative evidence on patients' experienced coercion during voluntary and involuntary psychiatric hospitalisation. Design: A qualitative review. Data sources: The search was conducted, in five bibliographic databases: Embase.com, Ovid MEDLINE(R) ALL, APA PsycINFO Ovid, Web of Science Core Collection and the Cochrane Database of Systematic Reviews. Review methods: Following the Joanna Briggs Institute approach, a systematized procedure was applied throughout the review process, from data search to synthesis of results. The reporting of this review was guided by the standards of the PRISMA 2020 statement. The quality of the included studies was critically appraised by two independent reviewers using the JBI Critical Appraisal Checklist. Included findings were synthesized using meta-aggregation. Confidence in the review findings was assessed following the Confidence in the Output of Qualitative research synthesis (ConQual) approach. Results: A total of 423 studies were identified through the literature search and 26 were included in the meta-aggregation. Totally, 151 findings were extracted and aggregated into 27 categories and 7 synthesized findings. The synthesized findings focused on: the patients' experience of the hospitalisation and the associated feeling of coercion; the factors affecting this feeling, such as the involvement in the decision-making process, the relationships with the staff and the perception of the hospital treatment as effective and safe; the coping strategies adopted to deal with it and the patients' suggestions for alternatives. All synthesized findings reached an overall confidence score of "moderate". The seven findings were downgraded one level due to dependability limitations of the included studies. Conclusion: Based on these findings, seven recommendations for clinical practice where developed, such as fostering care ethics, promoting patients' voice and shared decision-making, and enhancing patients' perceived closeness, respect and fairness. Five recommendations for future research were also prompted, for instance improving the methodological quality and cultural variation of future qualitative studies, and exploring the psychosocial impact of experienced coercion on patients. For these recommendations to be effectively implemented, a profound change in the structure and culture of the mental health system should be promoted. The involvement of patients in the design, development and scientific evaluation of this change is strongly recommended.

Women involvement in the informal caregiving field: A perspective review.

The patient recovery process of individual with mental health disorder is reinforced if they are connected with their community and supported by relatives. The literature has shown that caregivers are important, although their roles can lead to alterations in their own health; and women are the most involved in this role. The present review investigated women's involvement in the informal caregiver scientific field. A literature review indicated gender differences; researchers who are women are more interested in this field than men. Even with a good representation of women in this scientific field, the results showed a statistically significant gender difference for the first and second authors, whereas there was no significant gender difference among the last authors. More efforts must be made to recognize the importance of women's involvement in research because they raise a specific important field. Family caregivers are key players in the healthcare system, but to date, there has been little recognition of their enormous contribution. Our results also indicated the informal caregiver role is filled more by women than by men, which creates social inequalities in many domains, especially in opportunities at the professional level. Tailored interventions are required to address the specific needs and issues of family caregivers. A better redistribution of unpaid work, such as informal caregiving, compared to paid work must be made to respect gender in social existence.

Satisfaction and Perceived Coercion in Voluntary Hospitalisations: Impact of Past Coercive Experiences.

Coercion in psychiatry is associated with several detrimental effects, including in the long term. The effect of past experience of coercion on the perception of subsequent hospitalisations remains less studied. The present study aimed to assess the impact of past experience of coercion on the perception of coercion and satisfaction with subsequent voluntary hospitalisations. A total of 140 patients who were hospitalised on a voluntary basis were included. Fifty-three patients experienced coercion before this hospitalisation and 87 did not. Patients were assessed for treatment satisfaction and perceived coercion. Health status was also evaluated by both patients and carers. Past experience of coercion was the independent variable. Perceived coercion and satisfaction scores were used as different dependent variables in a series of regression models. Results suggested a long-term detrimental impact of past experience of coercion on some aspects of satisfaction and perceived coercion in subsequent voluntary hospitalisations even when controlling for self and carers-rated health status. Overall, this study suggests that special attention should be paid to patients who are voluntarily admitted to hospital but have a history of coercion, as they may still be impacted by their past coercive experiences. Ways to increase satisfaction and reduce perceived coercion of these patients are discussed.

Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer.

Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.

SARS-CoV-2 vs. COVID-19 de adquisición nosocomial: estudio en un hospital pediátrico de tercer nivel de atención / Acquired nosocomial SARS-CoV-2 vs. COVID-19: Study in a pediatric hospital of tertiary level hospital care

Resumen Introducción: La infección nosocomial por coronavirus, del síndrome respiratorio agudo grave (SARS-CoV-2) se ha reportado sobre todo en unidades de adultos. Objetivo: Dar a conocer un reporte de casos pediátricos con infección nosocomial por SARS-CoV-2. Materiales y métodos: Se analizaron pacientes con infección nosocomial por SARS-Cov-2 vs. COVID-19, confirmados mediante reacción en cadena de la polimerasa transcriptasa inversa (RT-PCR) en tiempo real, ingresados al Hospital Infantil de México. Resultados: De un total de 163 pacientes analizados, solo 9 (5.5%) adquirieron SARS-CoV-2 durante su estancia hospitalaria. Cinco fueron del sexo masculino (55.5%) y 4 (44.4%) femenino, predominando los adolescentes (4 [44.4%]), todos mayores de 17 años. Solo uno desarrolló síndrome inflamatorio multisistémico. Analizamos 18 datos clínicos, de los cuales el síntoma más frecuente fue la fiebre, seguida de hiporexia y dolor abdominal. Discusión: La infección nosocomial por SARS-CoV-2 en pediatría se estará reportando más seguido. Conclusiones: Es necesario tener una definición más homogénea en cuanto a SARS-CoV-2 vs. COVID-19 nosocomial.

Abstract Background: Nosocomial infection by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been reported mainly in adult units. Objective: To present a report of pediatric cases with nosocomial infection by SARS-CoV-2. Materials and methods: Patients with nosocomial infection by SARS-Cov-2 vs. COVID-19, confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR), admitted to the Children´s Hospital of Mexico. Results: Of a total of 163 patients analyzed, only 9 (5.5%) acquired SARS-CoV-2 during their hospital stay. Five were male (55.5%) and 4 (44.4%) females, predominantly adolescents (4 [44.4%]), all older than 17 years. Only one developed multisystem inflammatory syndrome. We analyzed 18 clinical data, of which the most frequent symptom was fever, followed by hyporexia and abdominal pain. Discussion: Nosocomial SARS-CoV-2 infection in pediatrics will be reported more often. Conclusions: It is necessary to have a more homogeneous definition regarding SARS-CoV-2 vs. nosocomial COVID-19.

Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer.

BACKGROUND: Both clinical and genomic data independently predict survival and treatment response in early-stage HER2-positive breast cancer. Here we present the development and validation of a new HER2DX risk score, and a new HER2DX pathological complete response (pCR) score, both based on a 27-gene expression plus clinical feature-based classifier. METHODS: HER2DX is a supervised learning algorithm incorporating tumour size, nodal staging, and 4 gene expression signatures tracking immune infiltration, tumour cell proliferation, luminal differentiation, and the expression of the HER2 amplicon, into a single score. 434 HER2-positive tumours from the Short-HER trial were used to train a prognostic risk model; 268 cases from an independent cohort were used to verify the accuracy of the HER2DX risk score. In addition, 116 cases treated with neoadjuvant anti-HER2-based chemotherapy were used to train a predictive model of pathological complete response (pCR); two independent cohorts of 91 and 67 cases were used to verify the accuracy of the HER2DX pCR likelihood score. Five publicly available independent datasets with >1,000 patients with early-stage HER2-positive disease were also analysed. FINDINGS: In Short-HER, HER2DX variables were associated with good risk outcomes (i.e., immune, and luminal) and poor risk outcomes (i.e., proliferation, and tumour and nodal staging). In an independent cohort, continuous HER2DX risk score was significantly associated with disease-free survival (DFS) (p=0·002); the 5-year DFS in the low-risk group was 97·4% (94·4-100·0%). For the neoadjuvant pCR predictor training cohort, HER2DX variables were associated with pCR (i.e., immune, proliferation and HER2 amplicon) and non-pCR (i.e., luminal, and tumour and nodal staging). In both independent test set cohorts, continuous HER2DX pCR likelihood score was significantly associated with pCR (p<0·0001). A weak negative correlation was found between the HER2DX risk score versus the pCR score (correlation coefficient -0·19). INTERPRETATION: The two HER2DX tests provide accurate estimates of the risk of recurrence, and the likelihood to achieve a pCR, in early-stage HER2-positive breast cancer. FUNDING: This study received funding from Reveal Genomics, IDIBAPS and the University of Padova.

External quality assessment of serum indices: Spanish SEQC-ML program.

OBJECTIVES: Serum indices included in clinical chemistry instruments are widely used by laboratories to assess the quality of samples. Instruments that report quantitative results allow an evaluation of their diagnostic performance in a similar way to other biochemical tests. The Spanish Society of Laboratory Medicine (SEQC-ML) launched a monthly External Quality program of serum indices in 2018 using three lyophilized materials of simultaneous annual distribution. We present the results of the first three years of the program. METHODS: The use of four different quality control materials with different concentrations in three alternate months allows an annual evaluation of the participant's accuracy. Assigned values are established by consensus among homogeneous groups, considering necessary at least 10 participants for a comparison at instrument level. The average percentage difference results per instrument allow the assessment of bias among groups. RESULTS: The imprecision of the three indices ranges between 3 and 9%, with no major differences among instruments. Significant differences were observed in all indices among instruments with more than 10 participants (Roche Cobas, Abbott Architect, Abbott Alinity and Siemens Advia). The 90th percentile of the distribution of percentage differences was used as the analytical performance specification (APS). An improvement in performance was observed in the first three years of the program, probably due to the learning curve effect. In 2020, APS of 7.8, 12.2 and 9.7% were proposed for hemolytic, icteric and lipemic indices, respectively. CONCLUSIONS: Serum indices have a great impact on the quality and the reliability of laboratory test results. Participation in proficiency testing programs for serum indices is helpful to encourage harmonization among providers and laboratories.

Gene expression profiles of breast cancer metastasis according to organ site.

In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry-based groups. Second, HER2-low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype-related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ-specific and subtype-independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.

Estudio del desempeño de dos métodos de detección de antígenos rápidos en hisopados combinados y en hisopados nasofaríngeos para la detección de SARS-CoV-2 / Performance study of two rapid antigen detection methods in combined swabs and nasopharyngeal swabs for detection of SARS-CoV-2

Resumen Se realizó una comparación del desempeño de los métodos rápidos de detección de antígenos para el diagnóstico de SARS-CoV-2 Veritor System de Becton Dickinson y Panbio de Abbott versus una reacción en cadena de la polimerasa con retrotranscripción en tiempo real (RT-PCR) de Roche en un triage de demanda espontánea de pacientes febriles de un hospital público, para la detección de COVID-19. Se procesaron 36 hisopados de pacientes sospechosos por los tres métodos. La concordancia entre ambos métodos con la RT-PCR fue del 97%. La sensibilidad de los métodos de detección de antígenos versus la RT-PCR fue del 83% y la especificidad fue del 100%. El valor predictivo positivo (VPP) fue del 100% y el valor predictivo negativo (VPN) fue del 97%. La muestra que resultó discordante presentó un ciclo umbral (Ct) de 29,8. El método para detección de antígenos tuvo un desempeño aceptable, incluso con resultados de sensibilidad mayores que los declarados por los fabricantes (84% para el Veritor System y 93,3% para el Panbio).

Abstract A comparison of the performance of the rapid antigen detection methods for the diagnosis of SARS-CoV-2 Veritor System from Becton Dickinson and Panbio from Abbott versus a real-time polymerase chain reaction with reverse transcription (RT-PCR) Roche in a spontaneous demand triage of febrile patients of a public hospital was made, for the detection of COVID-19. Thirty six swabs from suspected patients were processed by the three methods. The concordance between both methods with RT-PCR real time was 97%. The sensitivity of the antigen detection methods versus RT-PCR real time was 83% and specificity was 100%. The positive predictive value (PPV) was 100% and the negative predictive value (NPV) was 97%. The sample that was discordant presented a threshold point (Ct) of 29.8. The method for antigen detection resulted in an acceptable performance, even with S results higher than those declared by the manufacturers (84% for the Veritor System and 93.3% for the Panbio).

Resumo Uma comparação do desempenho dos métodos rápidos de detecção de antígenos para o diagnóstico deSARS-CoV-2 Veritor System de Becton Dickinson e Panbio de Abbott versus uma reação em cadeia da polimerasecom transcrição reversa em tempo real (RT-PCR) da Roche em uma triagem de demanda espontâneade pacientes febris de um hospital público, para a detecção de COVID-19. Foram processadas 36 amostrasde esfregaços de pacientes suspeitos pelos três métodos e a concordância entre os dois métodos com aRT-PCR foi de 97%. A sensibilidade dos métodos de detecção de antigenos versus a RT-PCR foi de 83% ea especificidade de 100%. O valor preditivo positivo (VPP) foi de 100% e o valor preditivo negativo (VPN)foi de 97%. A amostra que resultou discordante apresentou um ciclo limiar (Ct) de 29,8. O método paradetecção de antígenos teve um desempenho aceitável, mesmo com resultados de sensibilidade superioresaos declarados pelos fabricantes (84% para o Veritor System e 93,3% para o Panbio).

Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer.

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.

Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy.

BACKGROUND: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation. METHODS: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels. FINDINGS: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy. INTERPRETATION: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods. FUNDING: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).

Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies.

PURPOSE: The prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials. METHODS: A retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease. RESULTS: Overall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P < .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P < .0001), LumB (HR, 0.52; P < .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77). CONCLUSION: In this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like.

Circulating tumor DNA dynamics in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy.

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.