Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression.

BACKGROUND: Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation. METHODS: In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment. RESULTS: We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor-associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation. CONCLUSIONS: This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response. TRIAL REGISTRATION NUMBER: EudraCT: 2015-004252-22 NCT02978755.

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

Adjuvant trastuzumab in HER2-positive breast cancer.

BACKGROUND: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).

Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.

PURPOSE: Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. METHODS: A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. RESULTS: Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. CONCLUSION: In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought.

Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study.

BACKGROUND: Childhood-cancer survival is dismal in most low-income countries, but initiatives for treating paediatric cancer have substantially improved care in some of these countries. The My Child Matters programme was launched to fund projects aimed at controlling paediatric cancer in low-income and mid-income countries. We aimed to assess baseline status of paediatric cancer care in ten countries that were receiving support (Bangladesh, Egypt, Honduras, Morocco, the Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam). METHODS: Between Sept 5, 2005, and May 26, 2006, qualitative face-to-face interviews with clinicians, hospital managers, health officials, and other health-care professionals were done by a multidisciplinary public-health research company as a field survey. Estimates of expected numbers of patients with paediatric cancer from population-based data were used to project the number of current and future patients for comparison with survey-based data. 5-year survival was postulated on the basis of the findings of the interviews. Data from the field survey were statistically compared with demographic, health, and socioeconomic data from global health organisations. The main outcomes were to assess baseline status of paediatric cancer care in the countries and postulated 5-year survival. FINDINGS: The baseline status of paediatric oncology care varied substantially between the surveyed countries. The number of patients reportedly receiving medical care (obtained from survey data) differed markedly from that predicted by population-based incidence data. Management of paediatric cancer and access to care were poor or deficient (ie, nonexistent, unavailable, or inconsistent access for most children with cancer) in seven of the ten countries surveyed, and accurate baseline data on incidence and outcome were very sparse. Postulated 5-year survival were: 5-10% in Bangladesh, the Philippines, Senegal, Tanzania, and Vietnam; 30% in Morocco; and 40-60% in Egypt, Honduras, Ukraine, and Venezuela. Postulated 5-year survival was directly proportional to several health indicators (per capita annual total health-care expenditure [Pearson's r(2)=0.760, p=0.001], per capita gross domestic product [r(2)=0.603, p=0.008], per capita gross national income [r(2)=0.572, p=0.011], number of physicians [r(2)=0.560, p=0.013] and nurses [r(2)=0.506, p=0.032] per 1000 population, and most significantly, annual government health-care expenditure per capita [r(2)=0.882, p<0.0001]). INTERPRETATION: Detailed surveys can provide useful data for baseline assessment of the status of paediatric oncology, but cannot substitute for national cancer registration. Alliances between public, private, and international agencies might rapidly improve the outcome of children with cancer in these countries.

Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer.

PURPOSE: In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups. PATIENTS AND METHODS: A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group. RESULTS: Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced. CONCLUSION: Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.

Could uric acid have a role in acute renal failure?

Acute renal failure (ARF), induced by either toxins or ischemia, is associated with significant morbidity. The pathogenesis of ARF is complex and is characterized by renal vasoconstriction and oxidative stress in association with tubular and microvascular injury and interstitial inflammation. In many situations, ARF is associated with a rise in serum uric acid as a result of both increased generation and decreased excretion. Although it is widely recognized that markedly elevated levels of uric acid can cause ARF via supersaturation within the tubules with crystallization and intrarenal obstruction ("acute urate nephropathy"), the possibility that uric acid may affect renal outcomes at concentrations that do not lead to tubular obstruction have not been considered. This article reviews both the salutary and the adverse effects of uric acid on biologic processes and presents the hypothesis that hyperuricemia, particularly if chronic and marked, likely represents a true risk factor for ARF. Hyperuricemia also may account for the paradoxic lack of benefit of diuretics in the management of ARF. It is suggested that studies are needed to investigate the role of chronic hyperuricemia on renal outcomes after acute tubular injury.

Effect of elevated serum uric acid on cisplatin-induced acute renal failure.

Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer.

PURPOSE: Oxaliplatin, fluorouracil, and leucovorin are commonly used to treat advanced and resected colorectal cancer. This analysis compares the safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) in patients age younger than and at least 70 years. PATIENTS AND METHODS: This retrospective analysis included 3,742 colorectal cancer patients (614 age > or = 70) from four clinical trials testing FOLFOX4 in the adjuvant, first-, and second-line settings. End points included grade > or = 3 adverse events, response rate (in advanced disease), progression or relapse-free survival, dose-intensity, and overall survival in the studies with mature survival data. RESULTS: Grade > or = 3 hematologic toxicity (neutropenia [43% v 49%; P = .04] and thrombocytopenia [2% v 5%; P = .04]) were significantly higher in older patients. Older age was not associated with increased rates of severe neurologic adverse events, diarrhea, nausea/vomiting, infection, overall incidence of grade > or = 3 toxicity (63% v 67%; P = .15), or 60-day mortality (1.1% v 2.3%; P = .20). The relative benefit of FOLFOX4 versus control did not differ by age for response rate, progression or recurrence free-survival (hazard ratio, 0.70 for FOLFOX4 v control for age < 70, 0.65 for age > or = 70; P = .42), or overall survival (hazard ratio, 0.77 age < 70, 0.82 age > or = 70; P = .79). Dose-intensity did not differ by age at cycles 1, 3, 6, or 12. CONCLUSION: FOLFOX4 maintains its efficacy and safety ratio in selected elderly patients with colorectal cancer. Its judicious use should be considered without regard to patient age, although scant data are available among patients older than 80 years.

OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study.

PURPOSE: In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. PATIENTS AND METHODS: Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS: Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. CONCLUSION: Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

BACKGROUND: The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. METHODS: We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. RESULTS: A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). CONCLUSIONS: Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.