Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

P38 MAPK and Radiotherapy: Foes or Friends?

Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.

Impact of the COVID-19 Lockdown on Physical Activity Levels and Health Parameters in Young Adults with Cancer.

The lockdown of the COVID-19 pandemic impacted physical activity (PA) levels around the world, affecting health parameters in young adults with cancer (YAC). To our knowledge, there is no evidence of the impact of the lockdown on the Spanish YAC. To analyse the changes in PA levels before, during, and after the lockdown of the YAC and its impact on health metrics in Spain, in this study, we utilized a self-reported web survey. PA levels decreased during the lockdown, and a significant increase in PA was observed after the lockdown. Moderate PA had the largest reduction (49%). Significant increases in moderate PA were noted after the lockdown (85.2%). Participants self-reported more than 9 h of sitting per day. HQoL and fatigue levels were significantly worse during the lockdown. The impact of the COVID-19 pandemic in this cohort of Spanish YAC showed a decrease in PA levels during the lockdown, affecting sedentarism, fatigue and HQoL. After lockdown, PA levels partially recovered, while HQoL and fatigue levels remained altered. This may have long-term physical effects such as cardiovascular comorbidities associated with sedentarism and psychosocial effects. It is necessary to implement strategies such as cardio-oncology rehabilitation (CORE), an intervention that can be delivered online, potentially improving participants' health behaviours and outcomes.

Practical prognostic index for patients with metastatic recurrent breast cancer: retrospective analysis of 2,322 patients from the GEICAM Spanish El Alamo Register.

Women with recurrent metastatic breast cancer from a Spanish hospital registry (El Alamo, GEICAM) were analyzed in order to identify the most helpful prognostic factors to predict survival and to ultimately construct a practical prognostic index. The inclusion criteria covered women patients diagnosed with operable invasive breast cancer who had metastatic recurrence between 1990 and 1997 in GEICAM hospitals. Patients with stage IV breast cancer at initial diagnosis or with isolated loco-regional recurrence were excluded from this analysis. Data from 2,322 patients with recurrent breast cancer after primary treatment (surgery, radiation and systemic adjuvant treatment) were used to construct the prognostic index. The prognostic index score for each individual patient was calculated by totalling up the scores of each independent variable. The maximum score obtainable was 26.1. Nine-hundred and sixty-two patients who had complete data for all the variables were used in the computation of the prognostic index score. We were able to stratify them into three prognostic groups based on the prognostic index score: 322 patients in the good risk group (score < or =13.5), 308 patients in the intermediate risk group (score 13.51-15.60) and 332 patients in the poor risk group (score > or =15.61). The median survivals for these groups were 3.69, 2.27 and 1.02 years, respectively (P < 0.0001). In conclusion, risk scores are extraordinarily valuable tools, highly recommendable in the clinical practice.

Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study.

PURPOSE: This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A-->T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m(2) every 21 days followed by three cycles of docetaxel 100 mg/m(2), every 21 days (A-->T) or six cycles of the combination doxorubicin 50 mg/m(2) and docetaxel 75 mg/m(2) (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A-->T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m(2) every 21 days. RESULTS: Febrile neutropenia was less common in the A-->T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P =.02 and P =.0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A-->T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A-->T) and 7.6 months (AT); the median time to progression was 10.5 months (A-->T) and 9.2 months (AT); the median overall survival was 22.3 months (A-->T) and 21.8 months (AT); and no significant differences were found. CONCLUSION: A-->T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A-->T represents a valid option for the treatment of MBC.

Factors Associated with the Selection of First-line Bevacizumab plus Chemotherapy and Clinical Response in HER2-negative Metastatic Breast Cancer: ONCOSUR AVALOX Study.

AIM: To evaluate factors associated with the selection of first-line bevacizumab plus chemotherapy and clinical response in HER2-negative metastatic breast cancer (MBC) in clinical practice in Spain. PATIENTS AND METHODS: All consecutive adult female patients with HER2-negative MBC who had received first-line bevacizumab plus chemotherapy for at least 3 months were enrolled in the present study. RESULTS: A total of 292 evaluable patients were included; 25% had triple-negative breast cancer (TNBC) and 75% had hormone receptor-positive breast cancer (HRPBC). Nearly 40% of patients had ≥3 metastatic sites, mainly located in the bone (48%) and liver (40%). Bevacizumab was mostly combined with paclitaxel (67.1%). ER-positive tumors were only identified as an independent factor associated with the choice of treatment (odds ratio (OR): 0.538; p=0.02). The overall response rate (ORR) was 63.7% (TNBC: 57.5%; HRPBC: 65.9%). Patients aged 36-50 years (OR: 3.03; p=0.028) and those with metastases at sites other than the bone (OR: 0.38; p=0.001) and ≥3 metastatic sites (OR: 1.41; p=0.018) were more likely to achieve objective responses. CONCLUSION: First-line bevacizumab plus chemotherapy, mainly paclitaxel, is an effective and well-tolerated treatment option for HER2-negative MBC, particularly in more aggressive disease.

Vinorelbine as a 96-hour continuous infusion in heavily pretreated patients with metastatic breast cancer: a cooperative study by the GEICAM group.

The efficacy of vinorelbine given as a continuous infusion was evaluated in 47 patients with breast cancer who had received previous treatment with first-line, second-line, and third-line chemotherapy including taxanes and/or anthracyclines. For inclusion into the study, patients were required to have histology-proven bi-dimensionally measurable disease. The treatment schedule was a bolus injection of vinorelbine 8 mg/m(2) administered over 5-10 minutes on day 1 followed by vinorelbine 8 mg/m(2) continuous infusion on days 1-4, every 21 days for 6 cycles. On an intent-to-treat basis, a 2% complete response rate and a 17% partial response rate were observed. The median time to progression was 2.4 months (95% CI, 1.83-2.97). Median survival was 7.73 months (95% CI, 4.48-10.98; range, 0.33-55.0 months). Major toxicities included febrile neutropenia in 40 cycles (24%) affecting 24 patients (51%) and 1 toxic death. Other nonhematologic toxicities included stomatitis (13%) and asthenia (13%). We conclude that this treatment shows considerable therapeutic activity, albeit at considerable toxicity costs, even in patients who have had multiple lines of prior chemotherapy. However, the results do not indicate clear advantages compared to the conventional weekly scheme of administration.

Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC.

The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.

Influence of timing of initiation of adjuvant chemotherapy over survival in breast cancer: a negative outcome study by the Spanish Breast Cancer Research Group (GEICAM).

PURPOSE: This retrospective trial evaluates whether the timing of initiation of the adjuvant chemotherapy has any influence over survival in early-stage breast cancer. PATIENTS AND METHODS: A total of 2782 patients from El Alamo project (from 1990 to 1997; n = 15,400) were selected with stages I-III, surgery and adjuvant chemotherapy. Data were gathered about prognostic factors such as age, tumor size, vessel permeation (vascular or lymphatic), histological grade, and number of involved nodes, hormonal receptor status and administration of hormone therapy. The time interval between surgery and initiation of chemotherapy, and dates of relapse, second primary breast tumor and death were recorded. Patients were assigned in four groups according to the surgery-chemotherapy interval: <3 weeks (group A), 3-6 weeks (group B), 6-9 weeks (group C) and >9 weeks (group D). RESULTS: There were no differences in disease-free survival (DFS), nor in 5-year overall survival (OS), according to the timing of initiation of adjuvant chemotherapy. Cox proportional hazards model was used to adjust analysis for known prognostic factors but the effect of surgery-chemotherapy interval remained non-significant. The variable timing of initiation of adjuvant chemotherapy has also been assessed as a continuous variable and no differences have been detected. CONCLUSION: The optimum time of initiation of adjuvant chemotherapy in early stages of breast cancer is unknown. The delay in the initiation of adjuvant chemotherapy has no influence over survival in the analyzed time intervals. Retrospective analysis like this one with enough statistical power would be necessary to detect differences among groups.