Adetunji T. Toriola

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial

BACKGROUND In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). METHODS We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. RESULTS Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. INTERPRETATION CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. FUNDING Washington University-Pfizer Biomedical Collaborative.

The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione

Knowledge of the stability of serum samples stored in large biobanks is pivotal for reliable assessment of hormone-dependent disease risks. We studied the effects of sample storage time and season of serum sampling on the stability of 25-hydroxy vitamin D (25-OHD) and androstenedione in a stratified random sample of 402 women, using paired sera from the Finnish Maternity Cohort. Serum samples selected were donated between 6 and 24 yr ago. The storage time did not affect serum 25-OHD and androstenedione levels. However, there was a significant mean difference in the 25-OHD levels of sera withdrawn during winter (first sample) vs. during summer (second sample; –18.4 nmol/l, P ≤ 0.001). Also at the individual level, there were significant differences in average 25-OHD levels between individuals with the paired sera taken at winter–winter compared with other alternatives (summer–winter, winter–summer, and summer–summer). The androstenedione levels showed no such differences. Long-term storage does not affect serum 25-OHD and androstenedione levels, but sampling season is an important determinant of 25-OHD levels. Stored serum samples can be used to study disease associations with both hormones. However, sampling season needs to be taken into account for 25-OHD by considering matching and stratification and, if possible, serial sampling.

Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels

Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose‐derived adiponectin and leptin levels. We investigated the effects of 12‐month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations.

Cardiorespiratory fitness, lifestyle factors and cancer risk and mortality in Finnish men.

BACKGROUND Physical fitness along with lifestyle factors may have important roles in the prevention of cancer. We examined the relationship between common lifestyle factors such as energy expenditure, physical activity and maximal oxygen uptake (VO(2max)), nutrition and smoking habits and the risk of cancer. METHODS A population-based cohort study was carried out in 2268 men from Eastern Finland with no history of cancer. They were followed up for an average of 16.7 years. The outcome measures were cancer incidence (n=387) and cancer mortality (n=159). RESULTS Men with VO(2max) of more than 33.2 mL/kg/min (highest tertile) had 27% (95% confidence interval (CI) 0.56-0.97) decreased cancer incidence and 37% (95% CI 0.40-0.97) reduced cancer mortality than men with VO(2max) of less than 26.9 mL/kg/min (lowest tertile) after adjustment for age, examination year, alcohol, smoking, socioeconomic status, waist-to-hip ratio and energy, fibre and fat intake. The risk reduction was mainly due to decreased risk of lung cancer in fit men. The adjusted risk of cancer was 0.73 (95% CI 0.55-0.98) among fit (VO(2max)> or =26.9 mL/kg/min) men with the total energy expenditure of physical activity over 2500 kcal/week. A total of 290 active (energy expenditure >2500 kcal and at least 2h of physical activity per week) men with a favourable lifestyle (good fitness, balanced diet and non-smoking) had an adjusted relative risk of 0.63 (95% CI 0.46-0.87) for cancer. CONCLUSION Favourable lifestyle including good cardiorespiratory fitness and healthy dietary habits with active and non-smoking lifestyle considerably reduces the risk of cancer.

Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers.

Initial studies have investigated the association between inflammation and colorectal cancer (CRC) using C‐reactive protein (CRP) as a proinflammatory biomarker and have noted inconsistent results among women. We here report the findings from a large prospective study with repeat measurements of CRP, as well as serum amyloid A (SAA), an additional biomarker of inflammation, and risk of CRC. In the Womens Health Initiative Observational Study, we examined associations of CRP and SAA with CRC using repeat assessments (baseline and 3‐year follow‐up) among 953 matched case–control pairs for CRP and 966 pairs for SAA. Multivariate‐adjusted conditional‐logistic regression models were used with two‐sided tests of significance. Receiver operating characteristic (ROC) curve analysis assessed their utility as early detection markers. Colon cancer risk (odds ratio [OR] and 95% confidence intervals) among women in the highest quintiles of CRP or SAA compared to those in the lowest quintiles was ORcolon/CRP = 1.37 (0.95–1.97, p‐trend = 0.04) and ORcolon/SAA = 1.26 (0.88–1.80, p‐trend = 0.10), respectively. Women with elevated concentrations of both CRP and SAA had an increased risk of ORcolon = 1.50 (1.12–2.00, p‐value = 0.006) compared to those with low concentrations. No positive associations were observed with rectal cancer and weaker associations for CRC overall. Temporal changes in biomarkers more than 3 years did not predict risk. The area under the 6‐month ROC curve for CRP+SAA was 0.62 (95% confidence interval = 0.55–0.68). Elevated inflammatory biomarkers are associated with an increased risk of CRC, mainly colon cancer. Nevertheless, changes in the biomarkers over time do not suggest that they merit consideration as early detection markers for CRC.

Determinants of maternal sex steroids during the first half of pregnancy.

OBJECTIVE: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). METHODS: We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. RESULTS: Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. CONCLUSION: Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation. LEVEL OF EVIDENCE: II

Independent and joint effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: a prospective nested case-control study.

INTRODUCTION Ovarian cancer has very few known modifiable risk factors but dietary studies suggest a role for vitamin D and calcium in the prevention of ovarian cancer. Thus, we investigated the association between pre-diagnostic serum calcium and 25-hydroxyvitamin D (25-OHD) on the risk of later development of ovarian cancer. METHODS We conducted a population-based nested case-control study within the Finnish Maternity Cohort (FMC). The cohort subset comprised 172 ovarian cancer cases with 172 matched controls (age ± 1 year, parity and season of blood donation ± 2 weeks). RESULTS We observed a significant inverse association between calcium and ovarian cancer risk. Relative risk (estimated as odds ratio, OR) comparing the highest quartile to the lowest quartile was significantly decreased; 0.41 [95% confidence interval (CI) 0.19-0.85, P-trend 0.004]. Even though a comparable association between 25-OHD and ovarian cancer did not reach statistical significance (OR 0.57, 95% CI 0.26-1.24, P-trend 0.07), having sufficient (> 75 nmol/L) serum 25-OHD levels compared to insufficient serum 25-OHD was associated with a significantly decreased risk of ovarian cancer (OR 0.32; 95% CI 0.12-0.91, p-value 0.03). No synergistic protective interaction between high levels of calcium and 25-OHD against ovarian cancer was observed, the joint effect being just multiplicative. CONCLUSION Calcium and vitamin D act independently to reduce the risk of ovarian cancer. The decreased risk of ovarian cancer associated with pre-diagnostic serum calcium and vitamin D needs to be evaluated further for possible new insights into ovarian cancer prevention.

Metabolic, hormonal and immunological associations with global DNA methylation among postmenopausal women

DNA methylation is an epigenetic modification essential for the regulation of gene expression that has been implicated in many diseases, including cancer. Few studies have investigated the wide range of potential predictors of global DNA methylation, including biomarkers. Here, we investigated associations between DNA methylation and dietary factors, sex-steroid hormones, metabolic, lipid, inflammation, immune and one-carbon biomarkers. Data and baseline biomarker measurements were obtained from 173 overweight/obese postmenopausal women. Global DNA methylation in lymphocyte DNA was measured using the pyrosequencing assay for LINE-1 repeats. We used correlations and linear regression analyses to investigate associations between continuous data and DNA methylation, while t-tests were used for categorical data. Secondary analyses stratified by serum folate levels and multivitamin use were also conducted. There was little variability in LINE-1 methylation (66.3–79.5%). Mean LINE-1 methylation was significantly higher among women with elevated glucose levels. Mean LINE-1 methylation was also higher among women with high CD4+/CD8+ ratio, and lower among women with elevated vitamin B6, but neither reached statistical significance. In analyses stratified by folate status, DNA methylation was negatively associated with sex hormone concentrations (estrone, estradiol, testosterone and sex hormone binding globulin) among women with low serum folate levels (n = 53). Conversely, among women with high serum folate levels (n = 53), DNA methylation was positively associated with several immune markers (CD4/CD8 ratio, NK1656/lymphocytes and IgA). Results from this screening suggest that global DNA methylation is generally stable, with differential associations for sex hormones and immune markers depending on one-carbon status.

Serum 25-hydroxyvitamin D and the risk of ovarian cancer

INTRODUCTION Ecological and experimental studies suggest that vitamin D may be associated with a reduced risk of ovarian cancer. In this study, we sought to determine the risk of developing ovarian cancer according to serum 25-hydroxyvitamin D (25-OHD) concentrations assessed on average 5 years before the diagnosis. METHODS We conducted a population-based longitudinal case-control study nested within the Finnish Maternity Cohort (FMC) which contains serum samples of virtually all pregnant women in Finland since 1983. Among them, 201 ovarian cancers diagnosed within 10 years of serum sampling were randomly selected as cases for this study. For each case, we selected two controls matched for age, parity and sampling season (+/-4 weeks) and one control matched for age and parity but for the opposite sampling season (6 months+/-4 weeks). RESULTS The relative risks (estimated as odds ratio, OR) for ovarian cancer comparing the lowest quintile to the highest quintile of serum 25-OHD concentration were 1.8 (95% CI 0.9-3.5) among controls matched for the same season, and 1.1 (95% CI 0.6-2.2) among controls matched for the opposite season. The OR among women with insufficient (<75 nmol/L) serum 25-OHD concentration was 2.7 (95% CI 1.0-7.9, lower limit, 0.95) compared to that among those with sufficient (75 nmol/L) serum 25-OHD concentration. No differences in the point estimates were observed between serous or mucinous histological subtypes of ovarian cancer. CONCLUSION Overall, we did not observe a significant association between serum 25-OHD concentrations and the risk of ovarian cancer. However, we found evidence suggestive of an increased risk among women with low to insufficient serum 25-OHD concentrations.

Circulating 25-hydroxyvitamin D Levels and Prognosis among Cancer Patients: A Systematic Review

Circulating 25-hydroxyvitamin D (25-OHD) is associated with a reduction in risk of some cancers, but its association with prognosis among patients with cancer is poorly understood. In view of the increasing number of cancer survivors in the United States and the high prevalence of vitamin D deficiency among patients with cancer, an evaluation of the role of circulating 25-OHD in prognosis among patients with cancer is essential. We conducted a systematic review of studies published in the following databases—PubMed, OvidSP, BioMed Central, EMBASE, and Scopus till September 2013 using the following search terms: “vitamin D,” “25-hydroxyvitamin D,” “calcidiol,” “cancer,” “survival,” “mortality,” and “prognosis.” Our search yielded 1,397 articles. From the 1,397 articles, we identified 26 studies that evaluated the associations of circulating 25-OHD with prognosis among patients with cancer. Evidence suggests that circulating 25-OHD levels may be associated with better prognosis in patients with breast and colorectal cancer, but there is a paucity of information on its association with prognosis in other cancers. This review highlights the need for further studies evaluating the role of vitamin D in prognosis among patients with cancer. Cancer Epidemiol Biomarkers Prev; 23(6); 917–33. ©2014 AACR.