Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer.

BACKGROUND: Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. OBJECTIVE: To evaluate neoadjuvant bevacizumab in a randomized phase II trial. METHODS: Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. RESULTS: Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. CONCLUSIONS: Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.

Physical activity and breast cancer risk by pathological subtype.

OBJECTIVE: To examine the influence of physical activity on breast cancer risk and evaluate whether adherence to international recommendations is associated with a decreased risk. METHODS: This is a multicenter matched case-control study where 698 pairs completed a physical activity questionnaire. Recreational physical activity during the last year was quantified in metabolic equivalent hours per week (MET-h/week) and categorized in activities of moderate (3.0-5.9 MET) and vigorous (>6 MET) intensity. The adherence to World Cancer Research Fund and the American Institute for Cancer Research recommendation was also assessed. The association with breast cancer risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. RESULTS: Mean MET-h/week was 16.6 among cases and 20.4 among controls. Premenopausal breast cancer risk decreased by 5% (P=0.007) for every 6 MET-h/week increase in energy expenditure. By contrast, postmenopausal women needed to do more intense exercise to observe benefits. The protection was more pronounced for nulliparous women, as well as for hormone receptor positive and HER2+ tumors. Physically inactive women displayed a 71% increased risk when compared with those who met the international recommendation (P=0.001). Finally, women who were inactive during the previous year, regardless of the overall physical activity reported in previous periods, showed an increased risk when compared to always active women. CONCLUSIONS: Women who report adherence to international physical activity recommendations entail a significant decrease in risk for all pathologic breast cancer subtypes. This is of particular interest in Spain, where a significant increase in overweight and obesity in recent decades is observed.

Analysis of Tumor Microenvironment Changes after Neoadjuvant Chemotherapy with or without Bevacizumab in Advanced Ovarian Cancer (GEICO-89T/MINOVA Study).

PURPOSE: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients. EXPERIMENTAL DESIGN: IHC and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 patients with ovarian cancer enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery. RESULTS: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells, and an upregulation in effector/regulatory cell ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophage-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significantly associated with progression-free survival (PFS). CONCLUSIONS: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at the cellular level, changes in CD4+, CD8+ lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. On the basis of our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T-effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first-line treatment of advanced epithelial ovarian cancer. See related commentary by Soberanis Pina and Oza, p. 12.

Prognostic impact of tumor location and gene expression profile in sporadic desmoid tumor.

PURPOSE: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed. METHOD: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation. RESULTS: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations. CONCLUSION: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/ß-catenin, TGFß, IFN, and TNF pathways.

High-intensity exercise prescription guided by heart rate variability in breast cancer patients: a study protocol for a randomized controlled trial.

BACKGROUND: Breast cancer is a chronic disease with a large growth in its treatments, prognosis, improvements, side effects and rehabilitation therapies research. These advances have also highlighted the need to use physical exercise as a countermeasure to reduce the cardiotoxicity of pharmacological treatments, increase patients' strength and quality of life and improve body composition, physical condition and mental health. However, new investigations show the need for a closed exercise individualisation to produce higher physiological, physical and psychological benefits in remote exercise programs. To this end, the present study will use, in a novel way in this population, heart rate variability (HRV) as a measure for prescribing high-intensity training. Thus, the primary objective of this randomised clinical trial is to analyse the effects of a high-intensity exercise program daily guided by HRV, a preplanned moderate to high-intensity exercise intervention and a usual care group, in breast cancer patients after chemotherapy and radiotherapy treatments. METHODS: For this purpose, a 16-week intervention will be carried out with 90 breast cancer patients distributed in 3 groups (a control group, a moderate to high-intensity preplanned exercise group and a high-intensity exercise group guided by HRV). Both physical exercise interventions will be developed remotely and supervised including strength and cardiovascular exercises. Physiological variables, such as cardiotoxicity, biomarkers, lipid profile, glucose, heart rate and blood pressure; physical measures like cardiorespiratory capacity, strength, flexibility, agility, balance and body composition; and psychosocial variables, as health-related quality of life, fatigue, functionality, self-esteem, movement fear, physical exercise level, anxiety and depression will be measure before, after the intervention and 3 and 6 months follow up. DISCUSSION: Personalized high-intensity exercise could be a promising exercise intervention in contrast to moderate-intensity or usual care in breast cancer patients to reach higher clinical, physical and mental effects. In addition, the novelty of controlling HRV measures daily may reflect exercise effects and patients' adaptation in the preplanned exercise group and a new opportunity to adjust intensity. Moreover, findings may support the effectiveness and security of physical exercise remotely supervised, although with high-intensity exercise, to reach cardiotoxicity improvements and increase physical and psychosocial variables after breast cancer treatments. Trial registration ClinicalTrials.gov nº NCT05040867 ( https://clinicaltrials.gov/ct2/show/record/NCT05040867 ).

Exploring autonomic modulation: day-to-day recovery after exercise sessions in breast cancer survivors.

Purpose: The current study aimed to analyze the changes in heart rate variability (HRV) 24h, 48h and 72h after exercise sessions in breast cancer survivors. Methods: Sixteen survivors who had undergone chemotherapy and radiotherapy were included. Participants trained resistance and cardiovascular components 3 times per week. The intervention was supervised and delivered online for 4 weeks. In this period, patients measured their HRV daily obtaining the lnrMSSD and lnSDNN values of: day 0 (the morning of the training sessions), 24h, 48h and 72h after exercise. Results: Significant changes in lnrMSSD (p=0.015) and lnSDNN (p=0.031) during recovery times and lnSDNN during the weeks were found (p=0.015). The most prominent differences were identified between the baseline measurement taken on day 0 and 24h after exercise (p=0.007 and p=0.048, respectively) and between measurements obtained 24h and 48h after the training session (p=0.019 and p=0.026, respectively). Conclusion: Our study suggests that patients may decrease their lnrMSSD and lnSDNN values 24h after exercise and they were close to recover 48h after the sessions. In this regard, HRV may be an useful tool to monitor their recovery and exercise tolerance.

Haemoperitoneum as an indicator of GIST.

We report the case of a 62-year-old woman who presented to the emergency department with abdominal pain and distension. She was diagnosed with haemoperitoneum and a large tumour that occupied the entire left hypochondrium and attached to the posterior surface of the fundus of the stomach at the level of the greater curvature. Anatomical pathology examination identified the tumour as a gastrointestinal stromal tumour with highly malignant characteristics and the haemoperitoneum was considered to contribute to a worse prognosis because of its ability to produce a peritoneal seeding. Considering these adverse characteristics, imatinib was initiated as an adjuvant treatment, with no evidence of relapse in the follow-up.

Overeating, caloric restriction and breast cancer risk by pathologic subtype: the EPIGEICAM study.

This study analyzes the association of excessive energy intake and caloric restriction with breast cancer (BC) risk taking into account the individual energy needs of Spanish women. We conducted a multicenter matched case-control study where 973 pairs completed lifestyle and food frequency questionnaires. Expected caloric intake was predicted from a linear regression model in controls, including calories consumed as dependent variable, basal metabolic rate as an offset and physical activity as explanatory. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. The association with BC risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. While premenopausal women that consumed few calories (>20% below predicted) had lower BC risk (OR = 0.36; 95% CI = 0.21-0.63), postmenopausal women with an excessive intake (≥40% above predicted) showed an increased risk (OR = 2.81; 95% CI = 1.65-4.79). For every 20% increase in relative (observed/predicted) caloric intake the risk of hormone receptor positive (p-trend < 0.001) and HER2+ (p-trend = 0.015) tumours increased 13%, being this figure 7% for triple negative tumours. While high energy intake increases BC risk, caloric restriction could be protective. Moderate caloric restriction, in combination with regular physical activity, could be a good strategy for BC prevention.

Evaluating the Applicability of Data-Driven Dietary Patterns to Independent Samples with a Focus on Measurement Tools for Pattern Similarity.

BACKGROUND: Diet is a key modifiable risk for many chronic diseases, but it remains unclear whether dietary patterns from one study sample are generalizable to other independent populations. OBJECTIVE: The primary objective of this study was to assess whether data-driven dietary patterns from one study sample are applicable to other populations. The secondary objective was to assess the validity of two criteria of pattern similarity. METHODS: Six dietary patterns-Western (n=3), Mediterranean, Prudent, and Healthy- from three published studies on breast cancer were reconstructed in a case-control study of 973 breast cancer patients and 973 controls. Three more internal patterns (Western, Prudent, and Mediterranean) were derived from this case-control study's own data. STATISTICAL ANALYSIS: Applicability was assessed by comparing the six reconstructed patterns with the three internal dietary patterns, using the congruence coefficient (CC) between pattern loadings. In cases where any pair met either of two commonly used criteria for declaring patterns similar (CC ≥0.85 or a statistically significant [P<0.05] Pearson correlation), then the true similarity of those two dietary patterns was double-checked by comparing their associations to risk for breast cancer, to assess whether those two criteria of similarity are actually reliable. RESULTS: Five of the six reconstructed dietary patterns showed high congruence (CC >0.9) to their corresponding dietary pattern derived from the case-control study's data. Similar associations with risk for breast cancer were found in all pairs of dietary patterns that had high CC but not in all pairs of dietary patterns with statistically significant correlations. CONCLUSIONS: Similar dietary patterns can be found in independent samples. The P value of a correlation coefficient is less reliable than the CC as a criterion for declaring two dietary patterns similar. This study shows that diet scores based on a particular study are generalizable to other populations.

Lower Breast Cancer Risk among Women following the World Cancer Research Fund and American Institute for Cancer Research Lifestyle Recommendations: EpiGEICAM Case-Control Study.

BACKGROUND: According to the "World Cancer Research Fund" and the "American Institute of Cancer Research" (WCRF/AICR) one in four cancer cases could be prevented through a healthy diet, weight control and physical activity. OBJECTIVE: To explore the association between the WCRF/AICR recommendations and risk of breast cancer. METHODS: During the period 2006 to 2011 we recruited 973 incident cases of breast cancer and 973 controls from 17 Spanish Regions. We constructed a score based on 9 of the WCRF/AICR recommendations for cancer prevention:: 1)Maintain adequate body weight; 2)Be physically active; 3)Limit the intake of high density foods; 4)Eat mostly plant foods; 5)Limit the intake of animal foods; 6)Limit alcohol intake; 7)Limit salt and salt preserved food intake; 8)Meet nutritional needs through diet; S1)Breastfeed infants exclusively up to 6 months. We explored its association with BC by menopausal status and by intrinsic tumor subtypes (ER+/PR+ & HER2-; HER2+; ER&PR-&HER2-) using conditional and multinomial logistic models respectively. RESULTS: Our results point to a linear association between the degree of noncompliance and breast cancer risk. Taking women who met 6 or more recommendations as reference, those meeting less than 3 showed a three-fold excess risk (OR=2.98(CI95%:1.59-5.59)), especially for postmenopausal women (OR=3.60(CI95%:1.24;10.47)) and ER+/PR+&HER2- (OR=3.60(CI95%:1.84;7.05)) and HER2+ (OR=4.23(CI95%:1.66;10.78)) tumors. Noncompliance of recommendations regarding the consumption of foods and drinks that promote weight gain in premenopausal women (OR=2.24(CI95%:1.18;4.28); p for interaction=0.014) and triple negative tumors (OR=2.93(CI95%:1.12-7.63)); the intake of plant foods in postmenopausal women (OR=2.35(CI95%:1.24;4.44)) and triple negative tumors (OR=3.48(CI95%:1.46-8.31)); and the alcohol consumption in ER+/PR+&HER2- tumors (OR=1.52 (CI95%:1.06-2.19)) showed the strongest associations. CONCLUSION: Breast cancer prevention might be possible by following the "World Cancer Research Fund" and the "American Institute of Cancer Research" recommendations, even in settings like Spain, where a high percentage of women already comply with many of them.

Gastrointestinal stromal tumours at present: an approach to burning questions.

Because of their well known origin in gene mutations and a revolutionary therapy by means of molecular targets, gastrointestinal stromal tumours (GIST) constitute a plentiful and paradigmatic model of translational investigation, resulting in an avalanche of exponential growth data. In this article, we focus on what we consider to be hot spots in GIST at present. A wide spectrum of events is approached, extending from subtle pathogenic mechanisms at a molecular level (gene mutations and their implications for cell receptors with subsequent activation of signalling pathways) to more practical problems facing diagnosis (molecular markers, role of biopsy), prognosis (risk stratification systems) and different therapeutic aspects (laparoscopic surgery, role of surgery in advanced disease, response criteria, adjuvant and neoadjuvant therapy, treatment for progressing and recurrent disease, therapy directed on mutation analysis and new developments, among others). The review has been endorsed by level of evidence evaluation through a recognised pattern to assist in teaching, and a final summary of recommendations and a management algorithm are included.