Randall E. Harris

Nonsteroidal antiinflammatory drugs and breast cancer

We examined the association of nonsteroidal antiinflammatory drugs and breast cancer risk in a case-control study of 511 breast cancer patients and 1,534 population control subjects. The relative risk of breast cancer was reduced in women using these compounds at least 3 times per week for > or = 1 year [odds ratio (OR) = 0.66; 95% confidence interval (CI) = 0.52-0.83]. Odds ratios were similar for use of ibuprofen (0.57) or aspirin per se (0.69). Breast cancer risk declined with increasing exposure, and the greatest risk reduction (40%; odds ratio = 0.60; 95% CI = 0.40-0.91) occurred at the highest level of use (daily intake for > or = 5 years). These results indicate that nonsteroidal antiinflammatory drugs may have chemopreventive potential against the development of breast cancer.

Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens

Aromatase, the enzyme system catalyzing estrogen biosynthesis, is found in stromal tissue in the breast. The increased expression of the aromatase CYP19 gene in breast cancer tissues was recently associated with a promoter region regulated through cAMP-mediated pathways. PGE2, derived from cyclooxygenase, increases intracellular cAMP levels and stimulates estrogen biosynthesis. This association suggest that local production of PGE2 via cyclooxgenase isozymes may influence estrogen biosynthesis. The present study represents the first to examine the levels of mRNA expression of CYP19, COX-1, and COX-2 genes in human breast cancer specimens and normal breast tissue samples using semi-quantitative RT-PCR methods. Positive correlations were observed between CYP19 and COX-2 and the greater extent of breast cancer cellularity. Linear regression analysis using a bivariate model shows a strong linear association between CYP19 expression and the sum of COX-1 and COX-2 expression. This significant relationship between the aromatase and cyclooxygenase enzyme systems suggests that autocrine and paracrine mechanisms may be involved in hormone-dependent breast cancer development via growth stimulation from local estrogen biosynthesis.

Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung

Abstract.The existing epidemiologic literature was comprehensively reviewed to retrieve all epidemiologic studies (case control and cohort studies) that examined exposure to traditional over the counter nonsteroidal anti-inflammatory drugs (OTC NSAIDs) and the risk of cancers of the colon, breast, prostate and lung from 1980 forward. These malignancies account for more that half of all cancer deaths in the United States and the United Kingdom. Estimates of effects (relative risks or odds ratios) and 95% confidence intervals were abstracted from these reports for meta-analysis. Regular intake of OTC NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase- 2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system. Nevertheless, meta-analysis of independent estimates from 72 studies provides no evidence that the selective COX-2 inhibitor, celecoxib, influences the relative risk of cardiovascular disease (composite relative risk = 0.98, 95% CI = 0.88–1.10). Molecular studies reveal that over-expression of COX-2 is a prominent feature of premalignant and malignant neoplasms. Evidence is accumulating that carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the “inflammogenesis of cancer”.

Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors

BackgroundEpidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade.MethodsWe conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals.ResultsResults showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14–0.59), regular aspirin (OR = 0.49, 95% CI = 0.26–0.94), and ibuprofen or naproxen (0.36, 95% CI = 0.18–0.72). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of breast cancer.ConclusionSelective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.

Comparative epidemiology of cancer between the united states and japan. A second look

Vital statistics were examined for the years 1955 through 1985 for Japanese natives and United States whites to elucidate changes in cancer mortality and related antecedent patterns of life‐style in these two populations. Results show that lung cancer rates are rapidly accelerating among Japanese males as a consequence of their prior history of heavy cigarette smoking. Oropharyngeal cancer rates are also rising in Japan paralleling increases in alcohol and tobacco utilization. As the Japanese life‐style and diet continue to become more “westernized,” the rates of malignancies of the breast, ovary, corpus uteri, prostate, pancreas, and colon also continue to rise. Nevertheless, the mortality patterns of certain malignancies, viz., laryngeal, esophageal, and urinary bladder cancer, are discrepant with their established risk factor associations, suggesting the existence of other differences in risk factor exposure between the two countries. Epidemiologists and health educators need to develop innovative international programs of investigation and health promotion with preventive impact on common malignancies associated with risk factors of life‐style.

Breast cancer screening and diagnosis: Clinical practice guidelines in oncology™

The intent of these guidelines is to give health care providers a practical, consistent framework for screening and evaluating a spectrum of breast lesions. Clinical judgment should always be an important component of optimal management. If the physical breast examination, radiologic imaging, and pathologic findings are not concordant, the clinician should carefully reconsider the assessment of the patients problem. Incorporating the patient into the health care teams decision-making empowers the patient to determine the level of breast cancer risk that is personally acceptable in the screening or follow-up recommendations.

Familial association of breast/ovarian carcinoma

Twelve pedigrees which show clustering of breast/ovarian cancer among female relatives are analyzed from a medical‐genetic standpoint. The significant linear decline in estimates of cumulative breast/ovarian cancer risk to females with diminishing genetic relationship to probands and index cases, plus the lack of excessive site‐specific cancer risk to male relatives, supports a sex‐limited genetic etiology. Breast/ovarian cancer typically occurred at an early age (x̄ = 50.6 years) in these kindreds compared to the general population, which is another characteristic of hereditary cancer. Examples of apparent mother to daughter and father to daughter genetic transmission of proclivity for breast/ovarian carcinoma were prevalent in the 12 pedigrees. Excluding probands and index cases, the estimated cumulative risk of breast/ovarian cancer to female progeny of affected mothers was 46% for the age interval 20–80 years, suggesting that affected mothers in the pedigrees are transmitting a deleterious cancer‐predisposing gene to one‐half of their daughters. Eight sibships involving putative carrier males contain a total of 15 female progeny over age 20. Of these, six have manifested breast cancer and five have had ovarian cancer. These results underscore the need for physicians to be cognizant of both males and females as potential transmitters of cancer in this familial tumor association.

Genetic and pathologic findings in a kindred with hereditary sarcoma breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma

A familial cancer aggregation comprising sarcomas, brain tumors, leukemias, and carcinomas of breast, larynx, lung, adrenal cortex, and other sites has been studied from a pathologic—genetic standpoint. Based upon sibships segregating for cancer, the genetic segregation parameter is estimated to be 45.6 ± 11% which is compatible with that expected for a rare deleterious autosomal gene showing complete dominance. Pathologic review of 16 tumors by bright field microscopy revealed variable occurrences of intranuclear cytoplasmic invaginations, intranucleolar bodies, and acidophilic intracytoplasmic inclusions in eight lesions. Two tumors showed both intranuclear cytoplasmic invaginations and intranucleolar inclusions. Morphological findings coupled with the observed pattern and distribution of cancer in the subject kindred suggest that the cancer‐prone genotype interacts with one or more exogenous factors in causing this familial tumor association.

Role of heredity in multiple primary cancer

The occurrence of multiple primary malignant neoplasms characterizes virtually all varieties of hereditary cancer. This report focuses on this phenomenon in 11 families with the Cancer Family Syndrome (heritable adenocarcinomas of the colon and endometrium) and a single extended kindred with sitespecific colon cancer. Of the 316 relatives with cancer in the 12 families, 68 (21.5%) had two or more primary malignancies and 59 (86.8%) of these multiple primaries involved the colon and/or endometrium. A pooled analysis of this resource revealed a consistent 3% risk for a second primary cancer in each year of survival following first onset. If a second primary occurs, the risk for a third is extremely high (6.9% per year), but shows a nonlinear trend with increasing survival following second onset. The high risk for development of extraprimary malignancies in patients from these kindreds indicates that careful consideration should be given to total removal of their principal target organs following the initial manifestation of cancer.

Cigarette smoking and plasma cholesterol

Plasma cholesterol levels were determined for 51,723 participants of community-based cholesterol screenings in 10 United States cities during 1988. Among white adult men and women under the age of 60 without other cardiovascular disease risk factors, a dose-response relationship was found between the number of cigarettes smoked per day and increasing levels of plasma cholesterol. In men aged 18 to 60 years, average plasma cholesterol increased by 0.33 mg/dl for each cigarette smoked (p less than 0.001); in women aged 31 to 50 years, average plasma cholesterol increased by 0.48 mg/dl for each cigarette smoked (p less than 0.001). Plasma cholesterol levels among ex-smokers were found to be similar to those of nonsmokers. No association between cigarette smoking and levels of plasma cholesterol was observed in men and women over age 60. Possible mechanisms for this observed relationship include an antiestrogenic effect of cigarette smoking that makes the observation more noticeable in younger female cohorts, enhanced lipolysis that increases levels of plasma free fatty acids, or differences in dietary intake between smokers and nonsmokers.