Lisa Madlensky

Greater Survival After Breast Cancer in Physically Active Women With High Vegetable-Fruit Intake Regardless of Obesity

PURPOSE Single-variable analyses have associated physical activity, diet, and obesity with survival after breast cancer. This report investigates interactions among these variables. PATIENTS AND METHODS A prospective study was performed of 1,490 women diagnosed and treated for early-stage breast cancer between 1991 and 2000. Enrollment was an average of 2 years postdiagnosis. Only seven women were lost to follow-up through December 2005. RESULTS In univariate analysis, reduced mortality was weakly associated with higher vegetable-fruit consumption, increased physical activity, and a body mass index that was neither low weight nor obese. In a multivariate Cox model, only the combination of consuming five or more daily servings of vegetables-fruits, and accumulating 540+ metabolic equivalent tasks-min/wk (equivalent to walking 30 minutes 6 d/wk), was associated with a significant survival advantage (hazard ratio, 0.56; 95% CI, 0.31 to 0.98). The approximate 50% reduction in risk associated with these healthy lifestyle behaviors was observed in both obese and nonobese women, although fewer obese women were physically active with a healthy dietary pattern (16% v 30%). Among those who adhered to this healthy lifestyle, there was no apparent effect of obesity on survival. The effect was stronger in women who had hormone receptor-positive cancers. CONCLUSION A minority of breast cancer survivors follow a healthy lifestyle that includes both recommended intakes of vegetables-fruits and moderate levels of physical activity. The strong protective effect observed suggests a need for additional investigation of the effect of the combined influence of diet and physical activity on breast cancer survival.

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.

Tamoxifen Metabolite Concentrations, CYP2D6 Genotype, and Breast Cancer Outcomes

We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4‐hydroxytamoxifen (4OH‐tamoxifen), and N‐desmethyltamoxifen (ND‐tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)‐positive breast cancer who were participating in the Womens Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4‐hydroxytamoxifen, and ND‐tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55–1.00)). The predictors of this higher‐risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.

Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer.

Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.

Relatives of colorectal cancer patients: Factors associated with screening behavior

BACKGROUND The purpose of this study was to identify whether decisions regarding colorectal cancer (CRC) screening by relatives of CRC patients are influenced by social interactions with family members, friends, and physicians or by public awareness campaigns. METHODS Screened (n=236) and nonscreened (n=132) relatives of CRC patients were interviewed in 2001. A socioecologic model was used as the framework for the interview variables, which included interactions with relatives, medical professionals, and social groups, as well as perceived benefits and barriers to screening and perceived susceptibility. RESULTS Physician encouragement, fewer barriers to screening, strong CRC family history, encouragement from relatives, advice from a surgeon, and discussion of CRC screening with social groups were all associated with ever having been screened. Having been encouraged by a physician was the strongest correlate of screening behavior. Perceived susceptibility to CRC, advice from family members, and exposure to public awareness information were not associated with screening. CONCLUSIONS The socioecologic framework is a good explanatory model of CRC screening in increased-risk relatives, as variables from each level were associated with screening. These findings can guide interventions aimed at increasing screening uptake, particularly those involving physicians.

Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study

Abstract. Background and aims: The Korean Hereditary Tumor Registry has proposed criteria for suspected hereditary nonpolyposis colorectal cancer (S-HNPCC criteria I and II) and confirmed their validity in an international collaborative study. The S-HNPCC criteria included families that did not fulfill the Amsterdam criteria, but in whom HNPCC was nevertheless strongly suspected. The S-HNPCC criteria was also revised accordingly since some S-HNPCC families now fullfil the revised Amsterdam criteria. The original Amsterdam criteria have recently been revised, including some extracolonic cancers. This study compared the mutation detection rates between the revised and previous Amsterdam and S-HNPCC criteria. Patients and methods: Data on the mutational status of 393 HNPCC suspected families were collected from ten different institutes. Two hundred families were categorized into old S-HNPCC criteria (142 into criteria I and 58 into criteria II) and 193 families into Amsterdam criteria I. Results: Of the 142 old S-HNPCC criteria I families 24 fulfilled the Amsterdam criteria II as the data were reclassified according to the revised criteria, increasing the proportion of the families fulfilling the Amsterdam criteria by 12.4%. The mutation detection rate of the revised criteria was very little changed compared to the old criteria; 26% and 27% in the S-HNPCC criteria, and 50% and 52% in the Amsterdam criteria. Conclusion: The mutation detection rate is hardly affected by the revision of the Amsterdam criteria although the population of patients fulfilling the criteria is increased. The value of revised S-HNPCC criteria is equivalent to that of as the old S-HNPCC criteria in selecting of candidate patients for genetic testing.

Hereditary and familial ovarian cancer in southern ontario

Background. Hereditary ovarian cancer may be site specific or may appear in combination with breast cancer or other cancers in a family. The most common hereditary form is the breast‐ovarian cancer syndrome. It is estimated that in 100% of these families, there is linkage to a cancer susceptibility gene on chromosome 17q, BRCAl.

Chemotherapy for desmoid tumors in association with familial adenomatous polyposis

PURPOSE: This study was designed to assess the effect of chemotherapy on complex desmoid tumors associated with familial adenomatous polyposis. METHODS: Five patients (3 males, 2 females; age range, 29–45 years) had symptomatic, unresectable intra-abdominal desmoid tumors in association with familial adenomatous polyposis that were unresponsive to conventional medical therapy. Each patient was treated with a cytotoxic chemotherapeutic regimen consisting of doxorubicin and dacarbazine followed by carboplatin and dacarbazine. Response to treatment was assessed by measurement of tumor size using computerized tomography. Follow-up has been for a mean of 22 (range, 10–30) months. RESULTS: One patient has had a complete response, and three patients have had a partial response, with a reduction in tumor volume of at least 50 percent. One patient had a minimum response to treatment and developed a rapid increase in tumor size on cessation of therapy. Complications of treatment included febrile neutropenia, severe epistaxis, and subclavian vein thrombosis. CONCLUSIONS: The cytotoxic chemotherapeutic regimen described is effective in the treatment of selected unresectable desmoid tumors associated with familial adenomatous polyposis and should be considered in symptomatic patients who do not respond to conventional medical therapy.

Colorectal cancer survivors undergoing genetic testing for hereditary non-polyposis colorectal cancer: motivational factors and psychosocial functioning.

Hereditary non‐polyposis colorectal cancer (HNPCC) represents about 1–3% of all cases of colorectal cancer (CRC). The objectives of the study were to examine motivational factors, expectations and psychosocial functioning in a sample of CRC survivors undergoing genetic testing for HNPCC. A cross‐sectional survey of 314 colorectal cancer patients recruited through a population‐based colon cancer family registry was conducted. Motivations for genetic testing for hereditary cancer were similar to those of clinic‐based samples of CRC patients and included learning of the increased risk to offspring and finding out if additional screening was needed. While age at diagnosis and sex were associated with psychological functioning, significant predictors of post‐counseling distress were perceived lower satisfaction with social support, an escape‐avoidant coping style and the anticipation of becoming depressed if a mutation was present. Most cancer survivors anticipated disclosing test results to relatives and physicians. Cancer survivors reported several motivations for genetic testing for HNPCC that varied by sex. A subgroup of survivors with lower satisfaction with social support and an escape‐avoidant coping style were worried about the potential impact of genetic test results and demonstrated more distress following counseling. Findings have implications for future research and potential support needs during the genetic counseling and testing process.

Dietary Pattern Influences Breast Cancer Prognosis in Women Without Hot Flashes: The Women's Healthy Eating and Living Trial

PURPOSE To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment. PATIENTS AND METHODS A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines. RESULTS Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002). CONCLUSION A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.