Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

Exosomes and prostate cancer management.

Exosomes (and other extracellular vesicles) are now part of the cancer research landscape, involved both as players in pathophysiological mechanisms, as biomarkers of the cancer process and as therapeutic tools. One step they have yet to take is to move into routine clinical practice and management of prostate cancer is an example of this necessary maturation. More than for many other cancers and because a possible alternative is active surveillance (neither removal nor destruction), the diagnosis of prostate cancer does not only involve the detection of cancerous cells but also the determination of its true aggressiveness. By measuring TRMPRSS2:ERG fusion and PCA3 transcripts in urine exosomes, the EPI assay seems able to help prostate biopsy decision. Results from clinical studies showed that it can reduce the proportion of unnecessary biopsies while missing only a minimal proportion of clinically significant cancers. In metastatic prostate cancer, after failure of a first step androgen deprivation therapy, when a choice has to be made between a second-generation androgen receptor (AR) signaling inhibitor and taxane-based chemotherapy, detection of the AR splicing variant AR-V7 in circulating tumor cells (CTCs) has appeared promising. Whether exosomes could be a better material (simpler to isolate from the bloodstream than CTCs?) to detect AR-V7 has been suggested by some studies and remains to be confirmed. At last, a couple of exploratory studies either targeted or used exosomes to treat prostate cancer, by respectively inhibiting their secretion (to prevent exosome-mediated transfer of biologically active oncogenic actors), or loading them with immunogenic cancer-specific proteins (to generate anticancer vaccine) or with pharmacologic agents. Overall efforts are however still needed to confirm these results and generalize exosome-based diagnostic, prognostic or therapeutic strategies in prostate cancer management.

Treatment patterns for metastatic colorectal cancer in Spain.

PURPOSE: The primary aim of this retrospective study was to describe the treatment patterns according to the type of treatment received by patients with metastatic colorectal cancer (mCRC) in Spain. METHODS: This was a retrospective, observational, multicenter study performed by 33 sites throughout Spain that included consecutive patients aged 18 years or older who had received or were receiving treatment for mCRC. RESULTS: At the time of inclusion, of the 873 evaluable patients, 507 (58%) had received two lines, 235 (27%) had received three lines, 106 (12%) had received four lines, and the remaining patients had received up to ten lines. The most frequent chemotherapy schemes were the FOLFOX or CAPOX regimens (66%) for first-line treatment, FOLFOX, CAPOX or FOLFIRI (70%) for second-line treatment, and FOLFOX, FOLFIRI or other fluoropyrimidine-based regimens for third- and fourth-line (over 60%) treatment. Sixty percent of patients received targeted therapy as part of their first-line treatment, and this proportion increased up to approximately 70% of patients as part of the second-line of treatment. A relevant proportion of patients were treated with unknown KRAS, and especially the BRAF, mutation statuses. CONCLUSIONS: This study reveals inconsistencies regarding adherence to the recommendations of the ESMO guidelines for the management of mCRC in Spain. Improved adherence to the standard practice described in such guidelines for the determination of RAS and BRAF mutation statuses and the use of targeted therapies in first-line treatment should be considered to guarantee that patients can benefit from the best therapeutic approaches available.

European edition of the NCCN clinical practice guidelines: relevance of the translation and adaptation into Spanish.

The NCCN-evidence-based oncology guidelines are consensus-based management documents, to ensure that all patients receive the most appropriate diagnosis, treatment and support services to achieve the best results. However, the use of these guidelines for decision-making by physicians in Spain is sometimes controversial, as treatments or diagnostic procedures are recommended which might not be authorised in our country, or other management options may exist. In March 2015, the ECO Foundation reached an agreement to translate and adapt the NCCN's clinical practice guidelines in oncology for the Spanish sector. Consequently, ECO is the first European organization to reach an agreement of this type with the NCCN. This agreement will allow all agents involved in managing the cancer patients to have available guidelines that are adapted to the specific needs of Spain.

Urinary PCA3 to predict prostate cancer in a cohort of 1015 patients.

AIM: To evaluate the performance of urinary PCA3 test to predict prostate biopsy outcome in a large French cohort. PATIENTS AND METHODS: A urine sample was prospectively obtained in 1015 patients undergoing prostate biopsies to determine the PCA3 score. The predictive value of PCA3 was explored using receiver operating characteristic curve analysis (ROC), multivariable logistic regression analysis and decision curve analysis. RESULTS: The median PCA3 score was significantly higher in patients with positive biopsies. The PCA3 score AUC was 0.76 (0.73-0.79), significantly higher than that of PSA (0.55; 0.51-0.58). At the cut-off of 35, sensitivity was 68 %, specificity 71 %, positive and negative predictive values 67 % and 71 %, and accuracy 69 %. Using multivariate analysis, PCA3 score appeared as an independent predictor of biopsy outcome and its addition to a base model including usual clinico-biological parameters resulted in a significant increase in predictive accuracy. At the cut-off of 20, about 1/2 of the eventual useless biopsies would have been avoided while ignoring 7 % of cancers with Gleason score ≥ 7. PCA3 score did not correlate to Gleason score but correlated to tumor volume (proportion of invaded cores). CONCLUSION: Urinary PCA3 is a useful test with high diagnostic performance for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score.

Spanish Mediterranean diet and other dietary patterns and breast cancer risk: case-control EpiGEICAM study.

BACKGROUND: Although there are solid findings regarding the detrimental effect of alcohol consumption, the existing evidence on the effect of other dietary factors on breast cancer (BC) risk is inconclusive. This study aimed to evaluate the association between dietary patterns and risk of BC in Spanish women, stratifying by menopausal status and tumour subtype, and to compare the results with those of Alternate Healthy Index (AHEI) and Alternate Mediterranean Diet Score (aMED). METHODS: We recruited 1017 incident BC cases and 1017 matched healthy controls of similar age (±5 years) without a history of BC. The association between 'a priori' and 'a posteriori' developed dietary patterns and BC in general and according to menopausal status and intrinsic tumour subtypes (ER+/PR+ and HER2-; HER2+; and ER-/PR- and HER2-) was evaluated using logistic and multinomial regression models. RESULTS: Adherence to the Western dietary pattern was related to higher risk of BC (OR for the top vs the bottom quartile 1.46 (95% CI 1.06-2.01)), especially in premenopausal women (OR=1.75; 95% CI 1.14-2.67). In contrast, the Mediterranean pattern was related to a lower risk (OR for the top quartile vs the bottom quartile 0.56 (95% CI 0.40-0.79)). Although the deleterious effect of the Western pattern was similarly observed in all tumour subtypes, the protective effect of our Mediterranean pattern was stronger for triple-negative tumours (OR=0.32; 95% CI 0.15-0.66 and Pheterogeneity=0.04). No association was found between adherence to the Prudent pattern and BC risk. The associations between 'a priori' indices and BC risk were less marked (OR for the top vs the bottom quartile of AHEI=0.69; 95% CI 0.51-0.94 and aMED=0.74; 95% CI 0.46-1.18)). CONCLUSIONS: Our results confirm the harmful effect of a Western diet on BC risk, and add new evidence on the benefits of a diet rich in fruits, vegetables, legumes, oily fish and vegetable oils for preventing all BC subtypes, and particularly triple-negative tumours.

Additional value of PCA3 density to predict initial prostate biopsy outcome.

PURPOSE: Similar to prostate-specific antigen (PSA) density, PCA3 density (PCA3D: ratio of urinary PCA3 score/prostate volume) can be calculated, but whether it can be an aid to decide biopsy in patients at risk of prostate cancer (PCa) is uncertain. The objective was to demonstrate that PCA3D provides better specificity than PCA3 in predicting initial prostate biopsy outcome. METHODS: Serum and urine samples were obtained from 595 consecutive patients scheduled for initial prostate biopsy. The urinary PCA3 test was performed before biopsy. Additional measures were prostate volume, PSA density (PSAD) and PCA3D. Multivariate logistic regression models including baseline characteristics and the markers were evaluated. The presumed net benefit was assessed through decision curve analyses. RESULTS: PSAD and PCA3D performed better than PSA and PCA3 score, respectively. PCA3D provided the best specificity (76 %). The best calculated cutoff for PCA3D was 1. The risk of positive biopsy significantly increased to 70 % if PCA3D ≥ 1 versus 29 % if PCA3D was <1. Using a cutoff at 0.5 for PCA3D, biopsies could have been avoided in up to 52 % of the patients without PCa while missing 15 % of any PCa and 10 % of PCa with Gleason score ≥7. Decision curve analyses showed that PSAD was the best predictor of Gleason score at biopsy while PCA3D best predicted the proportion of invaded cores. CONCLUSIONS: PCA3D showed a significant increase in specificity when compared with PSA, PSAD and PCA3. PCA3D can be considered an easy-to-use mini-nomogram with a 70 % risk of positive initial biopsy when PCA3D > 1, i.e., PCA3 score > prostate volume.

Oncological translational research in the Spanish national health system: the INTRO study.

OBJECTIVES: Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. METHODS: A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. RESULTS: The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. CONCLUSIONS: A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.

[Does PCA3 score and prostatic MRI help selection of patients scheduled for initial prostatic biopsy?]. / Le score PCA3 et l'IRM prostatique permettent-ils de sélectionner les patients candidats a une première série de biopsies prostatiques ?

INTRODUCTION: Determinate if the adjunction of PCA3 score and/or prostatic MRI can improve the selection of the patients who have an indication of first prostate biopsy. PATIENTS AND METHODS: Multiparametric prostatic MRI and PCA3 score were made before biopsy to men scheduled for initial prostate biopsy for abnormal digital rectal examination and/or PSA superior to 4 ng/mL. T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging looked for suspect target classified on a scale of four. It was a prospective, single centre study. The diagnostic accuracy of PCA3 score and MRI was to evaluate in comparison with biopsy results. RESULTS: Sixty-eight patients were included, median PSA was 5.2 ng/mL (3.2-28). Negative predictive value (NPV) of MRI score 0, 1 and 2 were respectively 80%, 43% and 69%. Positive predictive value (PPV) of MRI score 3 and 4 were 50% and 81%. The PCA3 cutoff with best accuracy was 21 (Se: 0.91; Sp: 0.50). Only one patient with positive biopsy (0.5mm of Gleason score 3+3) had negative MRI and PCA3 inferior to 21. CONCLUSION: MRI and PCA3 score in association allowed, in this study, to consider reduction of unnecessary initial biopsy without ignoring potential aggressive tumor.

Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane.

BACKGROUND: Aromatase inhibitors (AIs) may promote ovarian function recovery (OFR). True incidence, predictors and impact on the outcome of OFR are unknown. PATIENTS AND METHODS: We carried out a prospective study to assess ovarian function in estrogen receptor (ER)-positive BC patients on tamoxifen who had at least 2 years of chemotherapy-induced amenorrhea (CIA) and postmenopausal E2 levels. Patients switched to exemestane and underwent a series of investigations including vaginal ultrasound, antimullerian hormone, follicle stimulating hormone (FSH), and E2. E2 measurements were made using a clinical assay (direct) and a highly sensitive (indirect) immunoassay for comparison. RESULTS: Both E2 assays (indirect versus direct) showed a similar incidence of OFR 32% (95% CI 19.5-44.5) versus 30% (95% CI 17.7-42.3) and median time to OFR 5.4 months (95% CI 1.2-9.6) versus 6.0 months (95% CI 4.8-7.1).On multivariate analysis, the mean age at the start of exemestane treatment was the only marker associated with probability of OFR (OR: 0.44, 0.24-0.78; P = 0.006). According to a receiver operating characteristic (ROC) analysis, age <48 years predicted for OFR (sensitivity: 59%; 1-specificity: 17%; AUC: 0.796; P = 0.001). Patients with OFR had higher mean E2 levels (43.6 versus 5.76 pmol/l; P = 0.001) and a reduced disease-free survival [DFS; HR 9.3 (95% CI 3.3-48.0; P = 0.04)] than those without it. CONCLUSION: Even with a clinical and biochemical profile compatible with menopause, switching from tamoxifen to an AI should be avoided in patients <48 with CIA.

Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.

[Value of urinary PCA3 test for prostate cancer diagnosis]. / Place du test urinaire PCA3 pour le diagnostic du cancer de la prostate.

PCA3 gene has been discovered in 1999 because of its differential expression between prostate cancer and nonneoplastic tissue. Several studies evaluated its value for prostate cancer diagnosis. These papers are consistent with significant statistical accuracy of measure of the urinary number of PCA3 copies (PCA3 test). While sensitivity is slightly weaker than that of seric PSA, specificity as well as positive and negative predictive values are quite better. PCA3 test seems therefore to be a good indicator of prostate biopsy results. As a commercial kit is available, large studies will be conducted to confirm these results, precise when to perform the test and evaluate the benefit/cost ratio. One of the aims is better selection of those patients who will really benefit from prostate biopsies.

Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies.

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a matched control group (n=64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P=0.016) and cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.

Germ cell tumours of the ovary.

Germinal cell tumours represent only 2-5% of all cancers of the ovary. However, the characteristics of the tumour and the patients have some special qualities as high rates of healing goes together with a strong desire to keep fertility intact because this condition occurs in female children and adolescent girls. Neither the prognosis nor the treatment of these tumours is homogeneous; the low incidence is the reason it is hard to develop prospective studies for establishing prognostic factors and specific treatments. The introduction of adjuvant chemotherapy into initial surgery has improved the prognosis of these patients. The BEP scheme has proved to be equally efficient and less toxic than PVB, and for this reason it has become the standard scheme despite the fact that no randomised studies have been carried out. The surgical treatment demands the application of the same principles seen in cytoreduction surgery of epithelial cancers of the ovary (maximum possible cytoreduction), though in many cases hysterectomy and double adnexectomy may be obviated. In view of the rarity of these tumours, it is advisable to work within cooperative groups that may have subgroups for the treatment of rare tumours. This will probably be the only way to move forward in the prospective knowledge of prognostic factors for these tumours.

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.

Seguimiento clínico al año de angioplastias coronarias exitosas en pacientes no seleccionados / One year follow up of successful coronary angioplasty in non selected patients

Background:Re-stenosis after percutaneous Coronary Angioplasty (PTCA) is related to clinical and angiographic features. Aim: To describe the clinical and angiographic characteristic of our patients with coronary cardiopathy subjected to PTCA and the predictor factors for re-stenosis. Material and methods: We gathered the clinical and angiographic characteristics of all patients who underwent a successful PTCA of a native coronary artery. All patients had a clinical assessment one year after the procedure. Patients were classified in Group 1, if they did not have angina or coronary events after the angioplasty or Group 2, if they had angina or a coronary event after the procedure. Only Group 2 patients were subjected to a coronary angiogram. Results: We collected 383 PTCA procedures. Follow up information was obtained in 92.2 percent. Three hundred forty two patients (89.3 percent) were assessed one year the procedure. Nine patients (2.3 percent) died of a cardiovascular cause. Ninety patients (26.3 percent) were classified in Group 2. In 65 patients, angiographic re-stenosis was demonstrated (19 percent). Re-stenosis occurred in 36 and 13 percent of patients with an without Diabetes Mellitus, respectively (p <0.01). The other clinical predictor variables were a history of myocardial infarction (p =0.007), obesity (p =0.041) and hypercholesterolemia (p =0.050). None of the angiographic characteristics predicted restenosis. Stents were protective factors against restenosis (15.6 percent in stented lesions vs 25.4 percent in nonstented; p =0.01). Conclusions: Re-stenosis after angioplasty occured in 19 percent of our patients with angina or coronary events. The clinical variables associated with a higher risk of re-stenosis were diabetes (the main risk factor), previous myocardial infarction, obesity and hypercholesterolemia. Angiographic variables were not associated with re-stenosis. The use of stents decreases the incidence of re-stenosis in all groups).