Kimberly A. Lowe

Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer

BACKGROUND Prior studies suggest that combining the Symptom Index (SI) with a serum HE4 test or a CA125 test may improve prediction of ovarian cancer. However, these three tests have not been evaluated in combination. METHODS A prospective case-control study design including 74 women with ovarian cancer and 137 healthy women was used with logistic regression analysis to evaluate the independent contributions of HE4 and CA125, and the SI to predict ovarian cancer status in a multivariate model. The diagnostic performance of various decision rules for combinations of these tests was assessed to evaluate potential use in predicting ovarian cancer. RESULTS The SI, HE4, and CA125 all made significant independent contributions to ovarian cancer prediction. A decision rule based on any one of the three tests being positive had a sensitivity of 95% with specificity of 80%. A rule based on any two of the three tests being positive had a sensitivity of 84% with a specificity of 98.5%. The SI alone had sensitivity of 64% with specificity of 88%. If the SI index is used to select women for CA125 and HE4 testing, specificity is 98.5% and sensitivity is 58% using the 2-of-3-positive decision rule. CONCLUSIONS A 2-of-3-positive decision rule yields acceptable specificity, and higher sensitivity when all 3 tests are performed than when the SI is used to select women for screening by CA125 and HE4. If positive predictive value is a high priority, testing by CA125 and HE4 prior to imaging may be warranted for women with ovarian cancer symptoms.

An international assessment of ovarian cancer incidence and mortality

OBJECTIVE To assess and characterize the temporal variation in ovarian cancer incidence and mortality by age within countries in the Americas, Europe, Asia, and Oceania. METHODS/MATERIALS Data from the National Cancer Institutes Surveillance, Epidemiology, and End Results Program in the United States (U.S.) were used to assess ovarian cancer incidence rates (1998-2008) and mortality rates, (1988-2007 for 12-month survival, 1988-2006 for 24-month survival, and 1988-2003 for 60-month survival), stratified by age at diagnosis. Data from GLOBOCAN were used to calculate country-specific incidence rates for 2010 and 2020 and case-fatality rates for 2010. RESULTS A statistically significant decrease in Annual Percent Change (APC) of ovarian cancer incidence was observed in the U.S. for all women (-1.03%), among women who were diagnosed at <65 years of age (-1.09%) and among women who were diagnosed at ≥65 years of age (-0.95%). There was a statistically significant increase in the observed APC for survival at 12-months (0.19%), 24-months (0.58%), and 60-months (0.72%) for all women; however, 5-year survival for advanced stage (III or IV) disease was low at less than 50% for women <65 years and less than 30% for women ≥65 years. Global results showed a wide range in ovarian cancer incidence rates, with China exhibiting the lowest rates and the Russian Federation and the United Kingdom exhibiting the highest rates. CONCLUSIONS Ovarian cancer survival has shown modest improvement from a statistical perspective in the U.S. However, it is difficult to ascertain how clinically relevant these improvements are at the population or patient level.

META-ANALYSIS OF PROSPECTIVE STUDIES OF RED MEAT CONSUMPTION AND COLORECTAL CANCER

The relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. To estimate the summary association between red meat intake and CRC and to examine sources of heterogeneity, a meta-analysis of prospective studies was conducted. Thirty-four prospective studies of red meat and CRC were identified, of which 25 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose–response relationships were calculated. In the high versus low intake meta-analysis, the SRRE was 1.12 (95% CI: 1.04–1.21) with significant heterogeneity (P=0.014). Summary associations were modified by tumor site and sex. The SRREs for colon cancer and rectal cancer were 1.11 (95% CI: 1.03–1.19) and 1.19 (95% CI: 0.97–1.46), respectively. The SRREs among men and women were 1.21 (95% CI: 1.04–1.42) and 1.01 (95% CI: 0.87–1.17), respectively. The available epidemiologic data are not sufficient to support an independent and unequivocal positive association between red meat intake and CRC. This conclusion is based on summary associations that are weak in magnitude, heterogeneity across studies, inconsistent patterns of associations across the subgroup analyses, and the likely influence of confounding by other dietary and lifestyle factors.

Meta-analysis of animal fat or animal protein intake and colorectal cancer

BACKGROUND In the recent World Cancer Research Fund/American Institute for Cancer Research report of diet and cancer, it was concluded that there is limited but suggestive evidence that animal fat intake increases the risk of colorectal cancer. OBJECTIVE To clarify this potential relation, we conducted meta-analyses across a variety of subgroups, incorporating data from additional studies. DESIGN Analyses of high compared with low animal fat intakes and categorical dose-response evaluations were conducted. Subgroup analyses, consisting of evaluations by study design, sex, and tumor site were also performed. RESULTS Six prospective cohort studies with comprehensive dietary assessments, contributing 1070 cases of colorectal cancer and approximately 1.5 million person-years of follow-up, were identified. The summary relative risk estimate (SRRE) for these studies was 1.04 (95% CI: 0.83, 1.31; P for heterogeneity = 0.221) on the basis of high compared with low intakes. When data from case-control studies were combined with the cohort data, the resulting SRRE was 1.15 (95% CI: 0.93, 1.42) with increased variability (P for heterogeneity = 0.015). In our dose-response analysis of the cohort studies, no association between a 20-g/d increment in animal fat intake and colorectal cancer was observed (SRRE: 1.02; 95% CI: 0.95, 1.09). In a separate analysis of 3 prospective cohort studies that reported data for animal protein or meat protein, no significant association with colorectal cancer was observed (SRRE: 0.90; 95% CI: 0.70, 1.15). CONCLUSION On the basis of the results of this quantitative assessment, the available epidemiologic evidence does not appear to support an independent association between animal fat intake or animal protein intake and colorectal cancer.

Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125.

Objective: To evaluate the effect of ovarian cancer risk on the performance of the serum biomarkers mesothelin, human epididymis protein 4 (HE4), and CA125. Methods: We measured mesothelin, HE4, and CA125 levels from women with invasive ovarian cancer (n = 143), benign gynecologic conditions (n = 124), and controls (n = 344). Demographic, epidemiologic, reproductive, medical, and family history data were collected using a standardized questionnaire. Pedigree and BRCA 1/2 test results were used to stratify women into average and high-risk groups. The diagnostic accuracy of each biomarker was characterized using receiver operating characteristic curve methods. Results: Baseline characteristics did not vary by risk or case status. The distribution of stage and histology was similar in average and high-risk women. All three markers discriminated ovarian cancer cases from risk-matched healthy and benign controls. Marker performance did not vary by risk status. The sensitivity at 95% specificity for discriminating cases from risk-matched healthy control women in the average and high-risk groups, respectively, was 53.9% and 39.0% for mesothelin, 80.4% and 87.8% for HE4, and 79.4% and 82.9% for CA125. The performance of the markers was not as robust when cases were compared with benign controls. Area under the curve values for cases versus healthy and benign controls did not vary by risk status. Conclusions: The ability of serum mesothelin, HE4, and CA 125 levels to discriminate ovarian cancer cases from healthy and benign controls is not influenced by risk status. Our findings support the pursuit of additional studies evaluating the early detection potential of these markers in high-risk populations. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1365–72)

Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer.

Objective: To evaluate if serum levels of candidate ovarian cancer biomarkers vary with individual characteristics of healthy women who are likely candidates for an ovarian cancer screening program. Methods: We analyzed serum CA125, mesothelin, and HE4 levels in a sample of 155 healthy postmenopausal women at increased risk for developing ovarian cancer based on personal and family cancer history. Information on reproductive, family and medical histories, lifestyle factors, and anthropometry was collected by self-report. Twenty-two factors were examined using univariate and multiple linear regression models for the three biomarker levels. Results: In the multivariate models, CA125 levels were significantly higher in women who had used talcum powder (P = 0.02) and were lower in women who were parous (P = 0.05). Mesothelin levels were significantly higher in older women (P = 0.01) and lower in heavier women (P = 0.03). HE4 levels were higher in older women (P = 0.001) and in women who began menstruating at an older age (P = 0.03). Conclusions: CA125, mesothelin, and HE4 levels in healthy, postmenopausal women at increased risk for ovarian cancer are significantly associated with a few ovarian cancer risk factors. Since the effects of these personal characteristics on these serum markers are not large, their incorporation in screening algorithms may be unnecessary. This is true especially if a longitudinal algorithm is used because the marker level at the previous screen reflects personal characteristics such as age, body mass index, and age of menarche. Understanding the influence of personal factors on levels of novel early detection markers in healthy, unaffected women may have clinical utility in interpreting biomarker levels. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2480–7)

Combining a symptoms index with CA 125 to improve detection of ovarian cancer

The current study sought to examine whether an index based on the specific pattern of symptoms commonly reported by women with ovarian cancer could be used in combination with CA 125 to improve the sensitivity or specificity of experimental methods of screening for ovarian cancer.

Prevalence of Severe (500 to 2,000 mg/dl) Hypertriglyceridemia in United States Adults

A growing amount of evidence has supported an association between elevated triglyceride levels and cardiovascular disease. However, little information regarding co-morbidities, levels of other cholesterol types, or medication use among adults with severe hypertriglyceridemia (SHTG; (500 to 2,000 mg/dl) is available. We examined the data from 5,680 subjects, ≥ 20 years old, who had participated in the National Health and Nutrition Examination Survey from 2001 and 2006, to evaluate the epidemiology of adults with SHTG. Approximately 1.7% of the sample had SHTG, equating to roughly 3.4 million Americans. The participants with SHTG tended to be men (75.3%), non-Hispanic whites (70.1%), and aged 40 to 59 years (58.5%). More than 14% of those with SHTG reported having diabetes mellitus, and 31.3% reported having hypertension. Only 14% of the subjects with SHTG reported using statins, and 4.0% reported using fibrates. The factors significantly associated with having SHTG included high-density lipoprotein <40 mg/dl (odds ratio [OR) 11.45, 95% confidence interval [CI] 6.28 to 20.86), non-high-density lipoprotein 160 to 189 mg/dl (OR 9.74, 95% CI 1.68 to 56.40) or non-high-density lipoprotein ≥ 190 mg/dl (OR 24.99, 95% CI 3.90 to 160.31), diabetes mellitus (OR 3.04, 95% CI 1.45 to 6.37), and chronic renal disease (OR 7.32, 95% CI 1.45 to 36.94). In conclusion, SHTG is rare among adults in the United States and the use of pharmacologic intervention is low among those with SHTG.

Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies.

A tremendous amount of scientific interest has been generated regarding processed meat consumption and cancer risk. Therefore, to estimate the association between processed meat intake and colorectal cancer (CRC), a meta-analysis of prospective studies was conducted. Twenty-eight prospective studies of processed meat and CRC were identified, of which 20 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose–response relationships were calculated. The SRRE for high (vs. low) processed meat intake and CRC was 1.16 [95% confidence interval (CI): 1.10–1.23] for all studies. Summary associations were modified considerably by sex; the SRRE for men was 1.23 (95% CI: 1.07–1.42) and the SRRE for women was 1.05 (95% CI: 0.94–1.16), based on nine and 13 studies, respectively. Sensitivity analyses did not indicate appreciable statistical variation by tumor site, processed meat groups, or study location. The SRRE for each 30-gram increment of processed meat and CRC was 1.10 (95% CI: 1.05–1.15) based on nine studies, and the SRRE for each incremental serving of processed meat per week was 1.03 (95% CI: 1.01–1.05) based on six studies. Overall, summary associations were weak in magnitude (i.e. most less than 1.20), processed meat definitions and analytical comparisons were highly variable across studies, and isolating the independent effects of processed meat intake is difficult, given the likely influence of confounding by other dietary and lifestyle factors. Therefore, the currently available epidemiologic evidence is not sufficient to support a clear and unequivocal independent positive association between processed meat consumption and CRC.

Neoadjuvant chemotherapy of breast cancer: tumor markers as predictors of pathologic response, recurrence, and survival.

Abstract:  This study reports the value of the tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in predicting the response of breast cancer to neoadjuvant chemotherapy. A community cancer center prospectively maintained breast cancer database containing over 8,000 patient records was used. Since 1989, 464 patients were treated with neoadjuvant chemotherapy followed by surgical resection and were tested for ER and PR. Estrogen receptor and/or PR positive patients were considered hormone receptor (HR) positive. Human epidermal growth factor receptor 2 status was available on 368 patients. Total, breast, and nodal pathologic complete response (pCR) rates, recurrence, and overall survival were assessed. Total and breast pCR rates were higher in HR negative (HR−) patients (26% and 32%, respectively) than in HR positive (HR+) patients (4% and 7%, respectively; p < 0.001). Compared to HR+ patients, HR− patients had higher recurrence rates (38% versus 22%; p < 0.001), a shorter time to recurrence (1.28 versus 2.14 years; p < 0.001), and decreased overall survival (67% versus 81%; p < 0.001). Human epidermal growth factor receptor 2 positive patients treated with neoadjuvant trastuzumab (NAT) demonstrated higher total pCR (34% versus 13%; p = 0.008), breast pCR (37% versus 17%; p = 0.02), and nodal pCR rates (47% versus 23%; p = 0.05) compared to HER2+ patients not treated with NAT. Furthermore, HER2+ patients who received NAT had lower recurrence rates (5% versus 42%; p < 0.001) and increased overall survival (97% versus 68%; p < 0.001). In conclusion, breast cancer HR status is predictive of total and breast pCR rates after neoadjuvant chemotherapy. Although HR− patients derive greater benefit from neoadjuvant chemotherapy in terms of pathologic response, they have worse outcomes in terms of recurrence and survival. Hormone receptor positive patients demonstrate significantly less response to neoadjuvant chemotherapy, but significantly better overall outcome. For both HR− and HR+, addition of NAT for HER2+ tumors results in both a superior response and outcome.