Two Germline Pathogenic Variants in Cancer Susceptibility Genes and Their Null Implication in Breast Cancer Pathogenesis: The Importance of Tumoral Homologous Recombination Deficiency Testing.

Homologous recombination proficiency in patients with breast cancer despite germline PALB2/RAD51C pathogenic variants.

Germline TP53 pathogenic variants and breast cancer: A narrative review.

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.

Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders.

BACKGROUND/OBJECTIVES: Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls). METHODS: This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method. RESULTS: The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1 and RAD51C. Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001). CONCLUSION: SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history.

Association between missense variants of uncertain significance in the CHEK2 gene and hereditary breast cancer: a cosegregation and bioinformatics analysis.

Inherited mutations in the CHEK2 gene have been associated with an increased lifetime risk of developing breast cancer (BC). We aim to identify in the study population the prevalence of mutations in the CHEK2 gene in diagnosed BC patients, evaluate the phenotypic characteristics of the tumor and family history, and predict the deleteriousness of the variants of uncertain significance (VUS). A genetic study was performed, from May 2016 to April 2020, in 396 patients diagnosed with BC at the University Hospital Lozano Blesa of Zaragoza, Spain. Patients with a genetic variant in the CHEK2 gene were selected for the study. We performed a descriptive analysis of the clinical variables, a bibliographic review of the variants, and a cosegregation study when possible. Moreover, an in-depth bioinformatics analysis of CHEK2 VUS was carried out. We identified nine genetic variants in the CHEK2 gene in 10 patients (two pathogenic variants and seven VUS). This supposes a prevalence of 0.75% and 1.77%, respectively. In all cases, there was a family history of BC in first- and/or second-degree relatives. We carried out a cosegregation study in two families, being positive in one of them. The bioinformatics analyses predicted the pathogenicity of six of the VUS. In conclusion, CHEK2 mutations have been associated with an increased risk for BC. This risk is well-established for foundation variants. However, the risk assessment for other variants is unclear. The incorporation of bioinformatics analysis provided supporting evidence of the pathogenicity of VUS.

Genetic and functional homologous repair deficiency as biomarkers for platinum sensitivity in TNBC: A case report.

Triple-negative breast cancer is the most aggressive subtype of mammary carcinoma. In the early stage, neoadjuvant chemotherapy (NAC) is the standard of care for prognostic stratification and the best adjuvant treatment strategy. A 30-year-old female presented in the emergency room because of a gigantic right breast associated with an ulcerated lump at the upper quadrants. The right axillary nodes were palpable. An ultrasound was performed, showing the ulcerated neoformation with enlarged right axillary lymph nodes observed to level III. A core biopsy of the breast lesion was performed, and the pathological examination revealed a nonspecial type, grade 3, invasive, triple-negative breast cancer. No distant disease was found in the PET-CT scan. A germline genetic panel by next-generation sequencing identified a likely pathogenic variant in RAD51D (c.898C>T). Assessment of the functionality of the DNA homologous recombination repair pathway by RAD51 foci in the tumor revealed a profile of homologous recombination deficiency. NAC consisting of weekly carboplatin and paclitaxel followed by dose-dense doxorubicin/cyclophosphamide was performed with a complete metabolic response achieved in the PET-CT scan. The patient underwent a modified radical mastectomy plus axillary lymphadenectomy with a pathological complete response in the breast and axilla and remains disease-free after 2 years of follow-up. We report a young female with a triple-negative breast cancer stage cT4bN3M0 and a hereditary pathogenic mutation in RAD51D. The tumor was highly proliferative and homologous recombination-deficient by RAD51. The patient received platinum-based NAC, achieving a pathologic complete response. More effort should be made to identify predictive functional biomarkers of treatment response, such as RAD51 foci, for platinum sensitivity.

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects.

Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.

Estudio retrospectivo del uso de antimicrobianos en pacientes que fallecen en un servicio de oncología / A retrospective study of the use of antimicrobials in patients dying in an oncology department

Introducción: Las infecciones al final de la vida constituyen una importante causa de morbimor- talidad y las indicaciones de antibioterapia en este contexto no están claras. Objetivos: El objetivo del estudio es describir el uso de antibióticos en la etapa final de la vida en pacientes hospitalizados por cáncer y analizar su relación con las características de la en- fermedad oncológica, el estado funcional y la probabilidad de alta al ingreso. Metodología: Se trata de un estudio retrospectivo de todos los pacientes fallecidos en planta de oncología médica acotado a un periodo de 7 meses comprendidos entre el 1 de mayo y el 31 de diciembre de 2019. El número total de pacientes incluidos fue 101. Se evaluó el porcentaje de pacientes que recibieron tratamiento antibiótico durante su ingreso y el tiempo transcurrido entre la última dosis y el exitus letalis. Resultados: La edad media fue de 65,3 años y el 54,5 % eran hombres. El 23,7 % de los pacientes presentaban ECOG < 2, el 63,3 % ECOG ≥ 2. La localización más frecuente de tumor primario fue el pulmón (38,6 %). El 53 % de los pacientes recibían tratamiento oncológico con quimioterapia paliativa en el momento del ingreso, encontrándose el 66,3 % en situación de progresión de la enfermedad. En el 72,3 % de los pacientes la probabilidad de alta al ingreso era baja. El foco infeccioso de sospecha principal fue el respiratorio (27,7 %) seguido del abdominal (18,8 %). El 58,4 % recibió tratamiento antibiótico durante el ingreso en el que fallecieron. El antimicrobiano usado con mayor frecuencia fue la amoxicilina-clavulánico (36,2 %). Respecto a la búsqueda del microorganismo responsable del probable cuadro infeccioso del paciente, se extrajo he- mocultivo en 23 pacientes (23 %), urocultivo en 12 (12 %), coprocultivo en 7 (7 %) y cultivo de esputo, en 10 pacientes (10 %). Se aislaron microorganismos en 9 hemocultivos, 4 urocultivos, un coprocultivo y 2 cultivos de esputo respectivamente. [...]. (AU)

Objectives: To describe the use of antibiotics at the end of life and analyze its relationship with the characteristics of the oncological disease, functional status and probability of discharge upon admission. Methodology: A retrospective study of deceased patients in the oncology ward limited to a period of 7 months between May 1 and December 31, 2019. The number of patients included was 101. The percentage of patients who received antibiotic treatment during their admission and the time elapsed between the last dose and exitus lethalis were evaluated. Results: Mean age was 65.3 years and 54.5 % were men; 23.7 % had an ECOG < 2, 63.3 % ≥ 2. The most frequent location of the primary tumor was the lung (38.6 %); 53 % of the patients received palliative chemotherapy at the time of admission, and 66.3 % were in disease progression. In 72.3 % the probability of discharge upon admission was low. The main suspected infectious focus was respiratory (27.7 %) followed by the abdomen (18.8 %); 58.4 % received antibiotic treatment. The most frequently used antimicrobial was amoxicillin-clavulanate (36.2 %). Regarding the search for the microorganism responsible for the patient’s probable infectious condition, a blood culture was obtained in 23 patients (23 %), a urine culture in 12 (12 %), a stool culture in 7 (7 %) and a sputum culture in 10 patients (10 %). Microorganisms were isolated in 9 blood cultures, 4 urine cultures, one stool culture, and 2 sputum cultures, respectively. The most frequently isolated microorganisms in the positive cultures were: Escherichia coli (4), Pseudomonas aeruginosa (2) and Clostridium perfringens (2). [...] (AU)

How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review.

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.

Microbiota and Lung Cancer. Opportunities and Challenges for Improving Immunotherapy Efficacy.

The advances in molecular biology and the emergence of Next Generation Sequencing (NGS) have revealed that microbiome composition is closely related with health and disease, including cancer. This relationship affects different levels of cancer such as development, progression, and response to treatment including immunotherapy. The efficacy of immune checkpoint inhibitors (ICIs) may be influenced by the concomitant use of antibiotics before, during or shortly after treatment with ICIs. Nevertheless, the linking mechanism between microbiote, host immunity and cancer is not clear and the role of microbiota manipulation and analyses in cancer management has not been clinically validated yet. Regarding the use of microbiome as biomarker to predict ICI efficacy it has been recently shown that the use of biochemical serum markers to monitor intestinal permeability and loss of barrier integrity, like citrulline, could be useful to monitor microbiota changes and predict ICI efficacy. There are still many unknowns about the role of these components, their relationship with the microbiota, with the use of antibiotics and the response to immunotherapy. The next challenge in microbiome research will be to identify individual microbial species that causally affect lung cancer phenotypes and response to ICI and disentangle the underlying mechanisms. Thus, further analyses in patients with lung cancer receiving treatment with ICIs and its correlation with the composition of the microbiota in different organs including the respiratory tract, peripheral blood and intestinal tract could be useful to predict the efficacy of ICIs and its modulation with antibiotic use.

From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy.

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRß (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

Intratumoral Versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.