Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Identifying and preventing burnout in young oncologists, an overwhelming challenge in the COVID-19 era: a study of the Spanish Society of Medical Oncology (SEOM).

BACKGROUND: Young oncologists are at particular risk of professional burnout, and this could have a significant impact on their health and care of their patients. The coronavirus disease 2019 (COVID-19) pandemic has forced rapid changes in professionals' jobs and training, with the consequent physical and psychological effects. We aimed to characterize burnout levels and determinants in young oncologists, and the effects of the pandemic on their training and health. METHODS: Two online surveys were conducted among oncology residents and young oncology specialists in Spain. The first addressed professional burnout and its determinants before the COVID-19 pandemic, while the second analyzed the impact of the pandemic on health care organization, training, and physical and psychological health in the same population. RESULTS: In total, 243 respondents completed the first survey, and 263 the second; 25.1% reported significant levels of professional burnout. Burnout was more common among medical oncology residents (28.2%), mainly in their second year of training. It was significantly associated with a poor work-life balance, inadequate vacation time, and the burnout score. Nearly three-quarters of respondents (72%) were reassigned to COVID-19 care and 84.3% of residents missed part of their training rotations. Overall, 17.2% of this population reported that they had contracted COVID-19, 37.3% had scores indicating anxiety, and 30.4% moderate to severe depression. Almost a quarter of young oncologists (23.3%) had doubts about their medical vocation. CONCLUSIONS: Burnout affects a considerable number of young oncologists. The COVID-19 pandemic has had a profound impact on causes of burnout, making it even more necessary to periodically monitor it to define appropriate detection and prevention strategies.

Metaplasia sinovial capsular mamaria: a propósito de un caso / Mammary capsular synovial metaplasia: a case report

La metaplasia sinovial capsular mamaria es una patología poco frecuente, de origen desconocido, que se presenta generalmente con aumento de volumen mamario (colección líquida) en un período breve y frecuentemente unilateral el posoperatorio (3 meses o más). Su diagnóstico se realiza por punción con aguja fina guiada por ecografía y estudios histomorfológico y de inmunohistoquímica. Debe diferenciarse del linfoma anaplásico de células grandes asociado a implantes mamarios. El tratamiento consiste en extracción por punción de la colección líquida, reposo del brazo del lado afectado y en caso de recidivas cambio de implante e instilación de corticoides en bolsillo capsular. Presentación a propósito de un caso.

Breast capsular Synovial Metaplasia is a rare pathology of unknown origin, which usually occurs with increased breast volume (liquid collection) in a short and often unilateral postoperatively (3 months or more). Diagnosis is made with fine needle puncture guided by ultrasound and histomorphological and immunohistochemistry studies. It should differ from anaplastic large cell lymphoma associated with breast implants. Treatment consists of puncture extraction of the liquid collection, rest of the arm of the affected side and in case of relapses implant change and installation of Corticoids in capsular pocket. Filing on a case

Introducing FDG PET/CT-guided chemoradiotherapy for stage III NSCLC in low- and middle-income countries: preliminary results from the IAEA PERTAIN trial.

PURPOSE: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC. METHODS: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts. RESULTS: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012). CONCLUSION: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

Two decades of SPECT/CT - the coming of age of a technology: An updated review of literature evidence.

PURPOSE: Single-photon emission computed tomography (SPECT) combined with computed tomography (CT) was introduced as a hybrid SPECT/CT imaging modality two decades ago. The main advantage of SPECT/CT is the increased specificity achieved through a more precise localization and characterization of functional findings. The improved diagnostic accuracy is also associated with greater diagnostic confidence and better inter-specialty communication. METHODS: This review presents a critical assessment of the relevant literature published so far on the role of SPECT/CT in a variety of clinical conditions. It also includes an update on the established evidence demonstrating both the advantages and limitations of this modality. CONCLUSIONS: For the majority of applications, SPECT/CT should be a routine imaging technique, fully integrated into the clinical decision-making process, including oncology, endocrinology, orthopaedics, paediatrics, and cardiology. Large-scale prospective studies are lacking, however, on the use of SPECT/CT in certain clinical domains such as neurology and lung disorders. The review also presents data on the complementary role of SPECT/CT with other imaging modalities and a comparative analysis, where available.

Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.

BACKGROUND: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. PATIENTS AND METHODS: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. RESULTS: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. CONCLUSIONS: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations. CLINICALTRIALS.GOV NUMBER: NCT01704703. EUDRACT NUMBER: 2012-001955-38.

SEOM clinical guidelines for diagnosis and treatment of metastatic colorectal cancer (2018).

Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases.

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. RESULTS: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. CONCLUSIONS: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.

KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer.

PURPOSE: Several angiogenic prognostic markers are under investigation because of their potential clinical utility, aiming to improve patient outcomes. We hypothesized that genetic variant in the VEGF pathway could be used as prognostic markers of survival in non-small cell lung cancer (NSCLC) patients undergoing pulmonary resection. METHODS: We evaluated the relationship between genetic variants in the VEGF pathway and relapse-free survival (RFS, main endpoint) and overall survival (OS, secondary endpoint) among 131 patients with stage I-III NSCLC treated with surgical resection from 2009 to 2013. Clinical, pathological and surgical data were prospectively collected. Twenty-five variants in sixteen relevant genes were selected and genotyped in tumor samples by real time PCR. The Kaplan-Meier method with the log-rank test and Cox's regression models were used for RFS and OS analyses. RESULTS: With a median follow-up of 36 (min = 2.8; max = 67.4) months, there were 31 (24%) relapses and 31 (24%) deaths. Overall, median RFS was not reached and median OS was 65 [95% confidence interval (CI) 56-75] months. The KRAS rs1137282 and PIK3C2A rs4356203 variants were significantly associated with RFS. For KRAS rs1137282, the 3-year RFS was 76% [95% CI 64-84%] in patients harboring an A/A genotype compared to 53% [95% CI 37-69%] in patients harboring an A/G or G/G genotype (p = 0.02). For PIK3C2A rs4356203, patients with an A/A or an A/G genotype had a 3-year RFS of 72% [95% CI 58-76%], whereas in patients with a G/G genotype was 49% [95% CI 28-70%] (p = 0.02). These associations remained statistically significant after adjusting for all the relevant clinical parameters in the multivariable analysis. CONCLUSION: Genetic variants in VEGF pathway may be associated with recurrence in stage I-III NSCLC. Specifically, the KRAS rs1137282 could be considered as a prognostic factor for recurrence in resectable NSCLC patients. Although PIK3C2A rs4356203 was associated with RFS, further analyses are necessary to confirm these data.

Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy.

Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer.

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer.

Epidermal growth factor receptor (EGFR) activation by radiation leads to increased cell proliferation and acts as a radioresistance mechanism. Neoadjuvant chemoradiation is the standard of care for locally advanced rectal cancer, and to date, no biomarkers of response have been found. We analyzed polymorphisms in the EGFR and its ligands, DNA repair genes and the thymidylate synthase in 84 stages II and III rectal cancer patients treated with neoadjuvant capecitabine plus radiotherapy. The rs11942466 polymorphism in the amphiregulin (AREG) gene region was associated with a pathological complete response (ypCR) (odds ratio: 0.26; 95% confidence interval: 0.06-0.79; P=0.014). The rs11615 C>T polymorphism in the ERCC1 gene also correlated with the ypCR as no patients with a C/C genotype achieved ypCR; P=0.023. This is the first work to propose variants within the AREG and the ERCC1 genes as promising predictive biomarkers of ypCR in rectal cancer.

The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis.

To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

Intergenic polymorphisms in the amphiregulin gene region as biomarkers in metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan.

In the epidermal growth factor receptor (EGFR) pathway, polymorphisms in EGFR and its ligand EGF have been studied as biomarkers for anti-EGFR treatment. However, the potential pharmacogenetic role of other EGFR ligands such as amphiregulin (AREG) and epiregulin (EREG) has not been elucidated. We studied 74 KRAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan. Twenty-two genetic variants in EGFR, EGF, AREG and EREG genes were selected using HapMap database and literature resources. Three tagging single-nucleotide polymorphisms in the AREG gene region (rs11942466 C>A, rs13104811 A>G, and rs9996584 C>T) predicted disease control in the multivariate analyses. AREG rs11942466 C>A and rs9996584 C>T were also associated with overall survival (OS). The functional polymorphism, EGFR rs712829 G>T, was associated with progression-free and OS. Our findings support that intergenic polymorphisms in the AREG gene region might help to identify colorectal cancer patients that will benefit from irinotecan plus anti-EGFR therapy.

Association of common gene variants in the WNT/ß-catenin pathway with colon cancer recurrence.

Wnt/ß-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/ß-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/ß-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.

Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy.

This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.