Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study.

Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs. Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study. Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.

Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies.

BACKGROUND: The aim of this study was to assess the diagnostic performance of an autoantibody battery in patients receiving immune checkpoint inhibitors who experienced immune-related adverse events (irAEs). METHODS: We retrospectively analyzed several variables potentially related to irAEs, namely, demographic, clinical, and laboratory characteristics, including an autoantibody battery (antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor). RESULTS: Sixty-nine patients (48 men; 61.8 ± 10.9 years at baseline) diagnosed with stage-4 solid-organ cancer and treated with nivolumab were followed up for 12 ± 10.3 months. Thirty-two irAEs were detected in 26 patients (37.5%). Adverse events occurred more commonly in women (62% vs. 27%, p = .006), and younger patients (irAEs: 58.1 ± 9.8, no irAEs: 64.1 ± 10.9 years, p = .024). Autoantibody battery results were available for 26 patients and were more frequently positive in patients with irAEs (87% vs. 30%, p = .009). The positive predictive value, negative predictive value, and diagnostic accuracy of the battery were 82.3%, 77.8%, and 80.8%, respectively. Among the 64 patients with an evaluable response, 23 (38.5%) experienced tumour progression, this being less frequent in patients with irAEs (19% vs. 48.5%, p = .03). Overall survival was higher in patients developing irAEs (HR = 1.88, p = .05). CONCLUSION: Positivity in a readily available autoantibody battery may be associated with the occurrence of irAEs.KEY MESSAGESPositivity in an accessible and inexpensive autoantibody battery including antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor may be associated with the occurrence of immune-related adverse events.Patients with cancer on immune checkpoint inhibitors experiencing immune-related adverse events showed a lower risk of progression and better overall survival than patients not experiencing this type of adverse effect.

Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer.

The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients.

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body ß-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.

The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin.

Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC). Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction. Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29-82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (OR A/C,C/C = 7.94, 95%CI: 1.60-39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (OR A/C,C/C = 0.77, 95%CI: 0.20-2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm. Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients. Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study.

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 µmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

The cost of colorectal cancer according to the TNM stage. / Valoración del coste económico del cáncer colorrectal según estadio tumoral.

INTRODUCTION: The aim of this study was to measure the cost of treatment of colorectal cancer in the Basque public health system according to the clinical stage. METHODS: We retrospectively collected demographic data, clinical data and resource use of a sample of 529 patients. For stagesi toiii the initial and follow-up costs were measured. The calculation of cost for stageiv combined generalized linear models to relate the cost to the duration of follow-up based on parametric survival analysis. Unit costs were obtained from the analytical accounting system of the Basque Health Service. RESULTS: The sample included 110 patients with stagei, 171 with stageii, 158 with stageiii and 90 with stageiv colorectal cancer. The initial total cost per patient was 8,644€ for stagei, 12,675€ for stageii and 13,034€ for stageiii. The main component was hospitalization cost. Calculated by extrapolation for stageiv mean survival was 1.27years. Its average annual cost was 22,403€, and 24,509€ to death. The total annual cost for colorectal cancer extrapolated to the whole Spanish health system was 623.9million€. CONCLUSIONS: The economic burden of colorectal cancer is important and should be taken into account in decision-making. The combination of generalized linear models and survival analysis allows estimation of the cost of metastatic stage.

Valoración del coste económico del cancer colorrectal según estadio tumoral / The cost of colorectal cancer according to the TNM stage

INTRODUCCIÓN: El objetivo de este trabajo fue medir el coste del tratamiento del cáncer colorrectal en un hospital del sistema sanitario público vasco según el estadio clínico. MÉTODOS: Se recogieron de forma retrospectiva variables demográficas, clínicas y uso de recursos de una muestra de 529 pacientes. Para los estadios I a III se midieron los costes iniciales y de seguimiento. El coste del estadio IV combinó los modelos lineales generalizados para relacionar el coste con la duración del seguimiento con el análisis de supervivencia de tipo paramétrico. Los costes unitarios se obtuvieron del sistema de contabilidad analítica del Servicio Vasco de Salud. RESULTADOS: La muestra se distribuyó en 110 pacientes en estadio I, 171 en estadio II, 158 en el estadio III y 90 en el estadio IV. El coste total inicial por paciente fue de 8.644 euros (Euros) en el estadio I, 12.675 Euros en el estadio II y 13.034 Euros en el estadio III. El principal componente del coste fue la hospitalización. La supervivencia media calculada por extrapolación para el estadio IV fue de 1,27 años. Su coste anual medio fue de 22.403 Euros, y de 24.509 Euros hasta el fallecimiento. El coste anual total para el tratamiento del cáncer colorrectal extrapolado a toda España fue de 623.900.000 Euros. CONCLUSIONES: La carga económica del cáncer colorrectal es importante y debe ser tenida en cuenta en la toma de decisiones. La combinación de los modelos lineales generalizados y el análisis de supervivencia para relacionar el coste con el seguimiento permite estimar el coste del estadio metastásico

INTRODUCTION: The aim of this study was to measure the cost of treatment of colorectal cancer in the Basque public health system according to the clinical stage. METHODS: We retrospectively collected demographic data, clinical data and resource use of a sample of 529 patients. For stages I to III the initial and follow-up costs were measured. The calculation of cost for stage IV combined generalized linear models to relate the cost to the duration of follow-up based on parametric survival analysis. Unit costs were obtained from the analytical accounting system of the Basque Health Service. RESULTS: The sample included 110 patients with stage I, 171 with stage II, 158 with stage III and 90 with stage IV colorectal cancer. The initial total cost per patient was 8,644 Euros for stage I, 12,675 Euros for stage II and 13,034 Euros for stage III. The main component was hospitalization cost. Calculated by extrapolation for stage IV mean survival was 1.27 years. Its average annual cost was 22,403 Euros, and 24,509 Euros to death. The total annual cost for colorectal cancer extrapolated to the whole Spanish health system was 623.9 million Euros. CONCLUSIONS: The economic burden of colorectal cancer is important and should be taken into account in decision-making. The combination of generalized linear models and survival analysis allows estimation of the cost of metastatic stage

Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer.

UNLABELLED: Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to the combination of hormone receptor (HR) and HER2 status; #2: Intrinsic subtype classification (Triple Negative (TN), HER2, Luminal B and Luminal A). RESULTS: Both subtype classifications yielded prognostic and predictive information. HR +/HER2- patients (and Luminal A patients) had a significantly better outcome than the other subgroups of patients. The superiority of FEC-P over FEC was clearly more marked in HR-/HER2- patients (TN patients), particularly in the subset with basal phenotype (TN and either EGFR+ or cytokeratins 5/6+). The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel.

Predictive value of P53, BCL-2, and BAX in advanced head and neck carcinoma.

Because the apoptotic process appears to be involved in the response-to-treatment of chemotherapy and radiotherapy, we investigated the prognostic value of the expression of three apoptosis-associated genes (p53, Bax, and Bcl-2) in tumor biopsies from patients with locally advanced head and neck carcinoma. Using specific monoclonal antibodies, immunohistochemical staining for p53, Bax, and Bcl-2 was performed on tumor material from 43 patients before their scheduled adjuvant chemoradiotherapy. Results indicated that the response to treatment was 83.7% (36 of 43 patients). Bax staining was positive in 8 cases (19.5%), p53 in 19 (47.5%), and Bcl-2 in 4 patients (10.8%). There were no statistically significant correlations between any of the apoptosis genes assayed and the patients' response to treatment or to overall survival. In the univariate statistical analysis, response-to-treatment was the only significant variable (p = 0.013) predictive of survival rate. These results suggest that p53, Bax, and Bcl-2 expression are not significant predictive factors of response to induction treatment in locally advanced head and neck carcinoma and that their routine use as prognostic markers cannot be recommended.