Marguerite Ennis

Risk of menopause during the first year after breast cancer diagnosis.

PURPOSE Premenopausal women with breast cancer often enter a premature menopause during initial treatment of their malignancy, with resulting loss of childbearing capacity, onset of menopausal symptoms, and subsequent prolonged exposure to long-term risks of menopause. Adjuvant therapy is believed to contribute to this early menopause. PATIENTS AND METHODS One hundred eighty-three premenopausal women with locoregional breast cancer (tumor-node-metastasis staging system classification, T1-3 N0-1 M0) who had undergone surgical treatment and provided information on menopausal status at diagnosis and 1 year later were enrolled. Systemic adjuvant therapy was recorded. Univariate and multivariate predictors of menopause were examined. RESULTS Age, weight gain, tumor stage, nodal stage, and systemic adjuvant therapy (chemotherapy, tamoxifen) were all significant univariate correlates of menopause. In multivariate analysis, age, chemotherapy, and hormone therapy (tamoxifen) made significant independent contributions to the onset of menopause. CONCLUSION Age and systemic chemotherapy are the strongest predictors of menopause in women with locoregional breast cancer. They independently contribute to menopause. A graphic representation of our multivariate model allows an estimation of risk of menopause according to patient age and planned adjuvant treatment, and it may facilitate clinical decision-making.

Prognostic Effects of 25-Hydroxyvitamin D Levels in Early Breast Cancer

PURPOSE Vitamin D has been linked to breast cancer risk, but prognostic effects are unknown. Such effects are biologically plausible given the presence of vitamin D receptors in breast cancer cells, which act as nuclear transcription factors to regulate gene activity. PATIENTS AND METHODS The study was conducted in a prospective inception cohort of 512 women with early breast cancer diagnosed 1989 to 1996. Vitamin D levels were measured in stored blood. Clinical, pathologic, and dietary data were accessed to examine prognostic effects of vitamin D. RESULTS Mean age was 50.4 years, mean vitamin D was 58.1 +/- 23.4 nmol/L. Vitamin D levels were deficient (< 50 nmol/L) in 37.5% of patients, insufficient (50 to 72 nmol/L) in 38.5% of patients, and sufficient (> 72 nmol/L) in 24.0% of patients. There was little variation in mean vitamin D levels between summer and winter months. Mean follow-up was 11.6 years; 116 women had distant recurrences, and 106 women died. Women with deficient vitamin D levels had an increased risk of distant recurrence (hazard ratio [HR] = 1.94; 95% CI, 1.16 to 3.25) and death (HR = 1.73; 95% CI, 1.05 to 2.86) compared with those with sufficient levels. The association remained after individual adjustment for key tumor and treatment related factors but was attenuated in multivariate analyses (HR = 1.71; 95% CI, 1.02 to 2.86 for distant recurrence; HR = 1.60; 95% CI, 0.96 to 2.64 for death). CONCLUSION Vitamin D deficiency may be associated with poor outcomes in breast cancer.

Adjuvant Treatment and Onset of Menopause Predict Weight Gain After Breast Cancer Diagnosis

PURPOSE Weight gain is common during the first year after breast cancer diagnosis. In this study, we examined clinical factors associated with body size at diagnosis and weight gain during the subsequent year. PATIENTS AND METHODS An inception cohort of 535 women with newly diagnosed locoregional breast cancer underwent anthropometric measurements at baseline and 1 year. Information was collected on tumor- and treatment-related variables, as well as diet and physical activity. RESULTS Mean age was 50.3 years; 57% of women were premenopausal. Mean baseline body mass index (weight [kg] divided by height [m] squared) was 25.5 kg/m2. Overall, 84.1% of the patients gained weight. Mean weight gain was 1.6 kg (95% confidence interval, 1.2 to 1.9 kg), 2.5 kg (95% confidence interval, 1.8 to 3.2 kg) in those receiving chemotherapy, 1.3 kg (95% confidence interval, 0.7 to 1.8 kg) in those receiving tamoxifen only, and 0.6 kg (95% confidence interval, 0.01 to 1.3 kg) in those receiving no adjuvant treatment. Menopausal status at diagnosis (P = .02), change in menopausal status over the subsequent year (P = .002), axillary nodal status (P = .009), and adjuvant treatment (P = .0002) predicted weight gain in univariate analysis. In multivariate analysis, onset of menopause and administration of chemotherapy were independent predictors of weight gain (all P < or = .05). Caloric intake decreased (P < .01) and physical activity increased (P < .05) during the year after diagnosis; these factors did not explain the observed weight gain. CONCLUSION Weight gain is common after breast cancer diagnosis; use of adjuvant chemotherapy and onset of menopause are the strongest clinical predictors of this weight gain.

Insulin-Lowering Effects of Metformin in Women with Early Breast Cancer

BACKGROUND Obesity has been associated with poor breast cancer outcomes. Insulin may mediate this effect, interacting with insulin receptors on breast cancer cells. Metformin, a biguanide derivative used in the treatment of diabetes, reduces insulin levels in subjects with type 2 diabetes and other insulin-resistant states. If metformin lowers insulin levels in women with breast cancer, it may also improve breast cancer outcomes. PATIENTS AND METHODS We administered metformin (1500 mg per day) to 32 women with early breast cancer whose baseline insulin levels were at least 45 pmol/L to determine its effect on insulin levels. RESULTS Twenty-two (69%) women completed the 6-month intervention. Four women (12.5%) dropped out because of gastrointestinal side effects; the others withdrew for reasons not related to toxicity. Completers were similar to noncompleters for all baseline characteristics apart from global health, overall physical condition, overall quality of life, physical function, and social function (HRQOL), which was decreased in noncompleters. Metformin significantly lowered fasting insulin levels by 15.8 pmol/L (22.4%; P=.024) and improved insulin sensitivity by 25.6% (P=.018), total cholesterol by 5.3%, and low-density lipoprotein (LDL) cholesterol by 9.1%. Metformin reduced weight by 1.9 kg (2.5%; P=.01), and it had no significant effects on HRQOL or specific gastrointestinal symptoms (appetite, nausea/vomiting, diarrhea, constipation). CONCLUSION Metformin significantly lowers insulin levels, and it improves insulin resistance in nondiabetic women with breast cancer. A phase III randomized trial to evaluate its effects on breast cancer outcomes is recommended.

Insulin- and Obesity-Related Variables in Early-Stage Breast Cancer: Correlations and Time Course of Prognostic Associations

PURPOSE To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time. PATIENTS AND METHODS Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model. RESULTS There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses. CONCLUSION Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.

Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes

The IGF family of growth factors is believed to play a role in the development and progression of breast cancer. We recently identified an adverse prognostic effect of insulin in breast cancer; we now report prognostic effects of circulating IGFBPs 1 and 3. 512 women with T1-3, N0-1, M0 breast cancer provided fasting blood which was analysed for IGFBPs 1 and 3. Information on body size, diet and traditional prognostic factors and treatment was obtained; women were followed for recurrence and death. IGFBP-1 levels correlated inversely with insulin levels (Spearman r = −0.60, p < 0.0001), reflecting known inhibition of IGFBP-1 gene expression by insulin. Insulin explained 36% of the variance in IGFBP-1 levels. IGFBP-1 levels were also correlated with obesity and diet. Levels of IGFBP-1 significantly predicted distant recurrence and death, hazard ratio (95% CI) for lower versus upper quartile 2.08 (1.20–3.61) and 3.0 (1.45–6.21), respectively. These effects persisted after adjustment for tumor-related variables and treatment but were not independent of insulin levels. High levels of IGFBP-3 predicted distant recurrence (hazard ratio upper v.s. lower quartile 1.8, 95% CI 1.1–3.0) but not death (hazard ratio 1.0, 95% CI 0.5–1.9). The effect on distant recurrence was restricted to postmenopausal women (hazard ratio 3.8, 95% CI 1.6–9.0) and to those with estrogen receptor positive tumors (p = 0.002). Prognostic effects of IGFBP-1 appear related to the known effect of insulin on IGFBP-1 gene expression. The adverse effect of IGFBP-3 on distant recurrence in postmenopausal women with estrogen receptor positive breast cancer should be further investigated.

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast

Columnar cell lesions (CCLs) of the breast with low-grade/monomorphic-type cytologic atypia are being identified increasingly in biopsies performed owing to mammographic microcalcifications. The WHO Working Group on the Pathology and Genetics of Tumours of the Breast recently introduced the term ‘flat epithelial atypia’ (FEA) for these lesions. However, the ability of pathologists to reproducibly diagnose FEA and to distinguish it from CCLs without atypia has not been previously evaluated. Eight pathologists with an interest in breast pathology participated in a study to address this issue. The study reference pathologist provided the other seven study pathologists with a Powerpoint tutorial that included written criteria for, and representative images of, FEA and CCLs without atypia (ie, columnar cell change and columnar cell hyperplasia). Following review of the tutorial, the study pathologists examined images in Powerpoint format from 30 CCLs and were instructed to categorize each as either ‘FEA’ or ‘not atypical’. Overall agreement among the eight pathologists was 91.8% (95% CI, 84.0–96.9%), and the multi-rater kappa value was 0.83 (95% CI, 0.67–0.94), which is within the ‘excellent agreement’ range. Agreement was slightly better for determining absence of FEA (92.8%: 95% CI, 84.1–97.4%), than for determining its presence (90.4%: 95% CI, 79.9–96.7%). We conclude that the diagnosis of FEA and its distinction from CCLs without atypia is highly reproducible with the use of available diagnostic criteria.

Health-Related Quality of Life and Psychosocial Status in Breast Cancer Prognosis: Analysis of Multiple Variables

PURPOSE Evidence that psychosocial status and health-related quality of life (HRQOL) are associated with breast cancer (BC) outcomes is weak and inconsistent. We examined prognostic effects of these factors in a prospective cohort study. PATIENTS AND METHODS Three hundred ninety-seven women with surgically resected T1 to T3, N0/N1, M0 BC completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30 items), Profile of Mood States, Psychosocial Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer Scale, and the Courtauld Emotional Control Scale 2 months after diagnosis and 1 year later. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records, and Cox survival analyses were performed. RESULTS Mean age was 52.0 +/- 9.9 years. Two hundred twenty-five women had T1, 136 women had T2, 16 women had T3, and 20 women had TX tumors; 127 were N1. One hundred thirteen women received adjuvant chemotherapy, 130 received hormone therapy, 45 received both, and 109 received neither. We investigated 140 prognostic associations; four were found to be statistically significant at a P value of </= .05 (three fewer than expected by chance). Two were in the hypothesized direction of effect, and two were in the opposite direction. All arose from measurements 1 year after diagnosis, which were most susceptible to confounding by treatment. There was no evidence of consistency of associations across outcomes or questionnaires. These results are in keeping with chance as the explanation for our statistically significant findings. CONCLUSION HRQOL and psychosocial status at diagnosis and 1 year later are not associated with medical outcome in women with early-stage BC.

Breast Cancer Prognosis in BRCA1 and BRCA2 Mutation Carriers: An International Prospective Breast Cancer Family Registry Population-Based Cohort Study

PURPOSE To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease. PATIENTS AND METHODS An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed. RESULTS Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64). CONCLUSION Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study

The United States National Cancer Institute Breast/Ovarian Cancer Family Registry is the largest international Registry of this type; over 37 724 individuals have been enrolled to date. One activity of this Registry is the semicentralized pathologic review of tumors from all probands. Given the semicentralized nature of the review, this study was undertaken to determine the reproducibility, source(s) of classification discrepancies and stratagems to circumvent discrepancies for histologic subtyping and grading of invasive breast cancer among the reviewing pathologists. A total of 13 pathologists reviewed 35 invasive breast cancers and classified them by primary and secondary histologic type, Nottingham grade and score. Lymph–vascular space invasion, circumscribed margins, syncytial growth and lymphocytic infiltrate were also evaluated. A training session using a separate set of slides was conducted prior to the study. General agreement, in terms of category-specific κs and percent agreement, and accuracy of classification relative to a reference standard were determined. Classification of histologic subtype was most consistent (and accurate) for mucinous carcinoma (κ=1.0), followed by tubular (κ=0.8) and lobular subtypes (κ=0.8). Classification of medullary subtype was moderate (κ=0.4), but additional evaluation of degree of lymphocytic infiltrate, syncytial growth and circumscribed margins identified most cases. Category-specific κs were moderate to good for Nottingham grade (κ=0.5–0.7), with the greatest agreement obtained in categorizing grade I (κ=0.7), and grade III tumors (κ=0.7). A flexible classification strategy that employs individual and combined criteria provides good interobserver agreement for invasive breast cancers with uniform, unambiguous histology and compensates for classification discrepancies in the more histologically ambiguous or heterogeneous cancers.