Breast Neoplasms: Visvanathan K

Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, Anonymous00092. · Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #19470930 No free full text.

Abstract: PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.

Visvanathan K, Sukumar S, Davidson NE. · No affiliation provided · Clin Cancer Res. · Pubmed #17121875 links to  free full text

This publication has no abstract.

Davidson NE, Visvanathan K, Emens L. · Johns Hopkins University, Schools of Medicine and Public Health, Baltimore, MD, USA · Breast. · Pubmed #14659107 No free full text.

Abstract: For over a decade, the selective estrogen receptor modulator, tamoxifen, has been the primary agent for adjuvant endocrine therapy for steroid receptor-positive breast cancer. New data over the last 2 years now suggest that its primacy may be challenged by strategies that lower circulating and/or intratumoral estrogens. Recent trials support the use of ovarian suppression approaches with or without tamoxifen in place of chemotherapy in premenopausal women. A large randomized trial has also established the short-term efficacy and safety of the aromatase inhibitor, anastrozole, in postmenopausal women. How and when to integrate these new approaches into standard practice are topics of debate. Ongoing research is focused on choice of endocrine approach, duration and sequencing of endocrine treatment, identification of better predictive markers for hormone response, and assessment of long-term risks and benefits.

Visvanathan K, Davidson NE. · Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · Oncology (Williston Park). · Pubmed #12661266 No free full text.

Abstract: The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen's benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.

Gallicchio L, Visvanathan K, Burke A, Hoffman SC, Helzlsouer KJ. · Prevention and Research Center, Weinberg Center for Women's Health and Medicine, Mercy Medical Center, Baltimore, MD 21202, USA. · Int J Cancer. · Pubmed #17330846 No free full text.

Abstract: The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors.

Berrington de Gonzalez A, Berg CD, Visvanathan K, Robson M. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. · J Natl Cancer Inst. · Pubmed #19176458 No free full text.

Abstract: BRCA mutation carriers are recommended to start mammographic screening for breast cancer as early as age 25-30 years. We used an excess relative risk model (based on a pooled analysis of three cohorts with 7600 subjects who received radiation exposure) to estimate the lifetime risk of radiation-induced breast cancer from five annual mammographic screenings in young (<40 years) BRCA mutation carriers. We then estimated the reduction in breast cancer mortality required to outweigh the radiation risk. Breast cancer rates for mutation carriers were based on a pooled analysis of 22 pedigree studies with 8139 subjects. For BRCA1 mutation carriers, the estimated lifetime risk of radiation-induced breast cancer mortality per 10,000 women resulting from annual mammography was 26 (95% confidence interval [CI] = 14 to 49) for screening at age 25-29 years, 20 (95% CI = 11 to 39) for screening at age 30-34 years, and 13 (95% CI = 7 to 23) for screening at age 35-39 years. To outweigh these risks, screening would have to reduce breast cancer mortality by 51% (95% CI = 27% to 96%) at age 25-29 years, by 12% (95% CI = 6% to 23%) at age 30-34 years, and by 4% (95% CI = 2% to 7%) at age 35-39 years; estimates were similar for BRCA2 mutation carriers. If we assume that the mortality reduction from mammography is 15%-25% or less for young women, these results suggest that there would be no net benefit from annual mammographic screening of BRCA mutation carriers at age 25-29 years; the net benefit would be zero or small at age 30-34 years, but there should be some net benefit at age 35 or older. These results depend on a number of assumptions due to the absence of empiric data. The impact of varying these assumptions was therefore examined.

Jorgensen TJ, Helzlsouer KJ, Clipp SC, Bolton JH, Crum RM, Visvanathan K. · Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #19124519 No free full text.

Abstract: Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Deficient DNA repair has been implicated in breast cancer etiology and may exert its effect before BBD, a known precursor. The association between allelic variants in DNA repair genes and BBD was examined in a cohort of women in Washington County, Maryland. BBD was defined by two criteria: (a) a physician diagnosis of BBD or fibrocystic disease and/or (b) a benign breast biopsy. 3,212 women without BBD at baseline were genotyped for 12 candidate single nucleotide polymorphisms in seven DNA repair genes. Of these women, 482 subsequently reported a diagnosis of BBD. The Cox model was used to calculate hazard ratios (HR). Variant alleles of XRCC1 Arg(194)Trp (rs1799782) and ERCC4 Arg(415)Gln (rs1800067) were significantly associated with BBD [HR, 1.36; 95% confidence interval (95% CI), 1.06-1.74 and HR, 1.39; 95% CI, 1.09-1.76, respectively]. Similar estimates were also observed for each of the BBD criterion used. The BBD association for ERCC4 was even stronger among women with a family history of breast cancer (HR, 2.68; 95% CI, 1.52-4.66; P(interaction) = 0.02). This study suggests that variant alleles in DNA repair genes may modify BBD risk, a potential intermediate marker of breast cancer risk, particularly among high-risk subgroups.

Visvanathan K, Santor D, Ali SZ, Brewster A, Arnold A, Armstrong DK, Davidson NE, Helzlsouer KJ. · Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17507621 links to  free full text

Abstract: PURPOSE: Ductal lavage, a technique used to sample epithelial cells from breast ducts, has potential use in risk assessment and biomarker evaluation among women at increased risk for breast cancer. However, little is known about the reliability of the procedure. METHODS: We evaluated the reliability of nipple aspirate (NAF) and ductal lavage at two time points 6 months apart in women at increased risk for breast cancer. Eligible women had a 5-year Gail risk >or=1.66% or lifetime risk of >20%, and/or a family history or personal history of breast cancer. All ducts that produced NAF were cannulated. The kappa statistic was used to evaluate reliability of NAF production, cellular yield, and cytologic diagnosis. RESULTS: Sixty-nine women (mean age, 47 years) were enrolled over 35 months. Forty-seven returned for a second visit. At baseline, 65% of premenopausal and 41% of postmenopausal women produced NAF (P = 0.05), of which 72% underwent successful lavage of at least one duct. Samples of inadequate cellular material for diagnosis were significantly more likely in postmenopausal women than in premenopausal women (P = 0.04). Of the women who returned for a second visit, 18 of 24 who produced NAF had at least one duct successfully cannulated. Twenty-four ducts in 14 women were lavaged twice. Among these ducts, cellular yield for the two time points was inconsistent (kappa = 0.33 +/- 0.13), and only fair cytologic agreement was observed (kappa = 0.32 +/- 0.15). Ductal lavage was associated with moderate discomfort. CONCLUSION: Currently, the use of ductal lavage is limited by technical challenges in duct cannulation, inconsistent NAF production, a high rate of inadequate cellular material for diagnosis, fair cytologic reproducibility, and low participant return rates.

Visvanathan K, Crum RM, Strickland PT, You X, Ruczinski I, Berndt SI, Alberg AJ, Hoffman SC, Comstock GW, Bell DA, Helzlsouer KJ. · Department of Epidemiology, The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. · Alcohol Clin Exp Res. · Pubmed #17295732 No free full text.

Abstract: BACKGROUND: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. METHODS: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. RESULTS: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C*1 or ADH1B*2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A>G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls. CONCLUSIONS: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A>G needs further evaluation.

Visvanathan K, Santor D, Ali SZ, Hong IS, Davidson NE, Helzlsouer KJ. · Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17164385 links to  free full text

Abstract: The reproducibility of a test result is a critical component of its clinical utility. Little information is available concerning the intrarater reproducibility of cytologic assessments. This study evaluated the reproducibility of cytologic interpretation of epithelial cells obtained from ductal lavage (DL), a minimally invasive method used to obtain sample cells from breast tissue. Two cytospin slides were made for each duct sampled. Slides with <10 cells were considered inadequate to make a diagnosis; the remaining slides were classified into mildly atypical, markedly atypical, and malignant cells. Each pair of slides were classified by the more serious diagnosis. DL samples from 100 ducts were independently blind-reviewed by two experienced cytopathologists. All abnormal slides and a random sample of normal slides and slides identified as inadequate for diagnosis (n = 43) were re-reviewed. The kappa for intrarater agreement was 0.59 +/- 0.10 for cytopathologist 1 and 0.33 +/- 0.08 for cytopathologist 2. The kappa for interrater agreement of slides from 100 ducts was 0.46 +/- 0.07. The interrater agreement of the slides that were re-reviewed was kappa = 0.27 +/- 0.09. Fair to moderate intrarater and interrater agreement of DL cytology was observed. Low intrarater and interrater cytologic consistency may compromise the interpretation of clinical studies of DL.

Jorgensen TJ, Visvanathan K, Ruczinski I, Thuita L, Hoffman S, Helzlsouer KJ. · Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, TRB Room E212, Washington, DC 20057, USA. · Breast Cancer Res Treat. · Pubmed #16823510 No free full text.

Abstract: BACKGROUND: The genes mutated in the cancer-prone syndrome, xeroderma pigmentosum (XP genes), have been well studied both biochemically and mechanistically. These genes are important components of the DNA nucleotide excision repair (NER) pathway, which protects against environmentally-induced cancers. XP genes are also downstream of the hereditary breast cancer syndrome gene, BRCA1, suggesting that XP genes may be important to hereditary forms of breast cancer as well. Although mutated XP genes are rare, polymorphic forms with potential functional deficiencies are common, and could pose a significant cancer risk in the general population. HYPOTHESIS: This study tested the hypothesis that common polymorphic variants of XP genes were associated with the risk of breast cancer among a population of women in Washington County, Maryland. METHODS: Five single nucleotide polymorphisms (SNPs) among four XP genes (XPC, XPD, XPF and XPG) were genotyped from DNA samples collected at baseline, and then analyzed by conditional logistic regression for association with the incidence of breast cancer. 321 cases were individually matched to 321 controls, by age and menopausal status. RESULTS: No significant associations were found between breast cancer risk and any of the XP genotypes. Odds ratios for all genotypes ranged from 0.61 to 1.14, and none were statistically significant. Adjustment and stratification for family history of breast cancer did not alter the findings. CONCLUSION: These results suggest that polymorphisms of XP genes are not likely to be significant risk factors for women within the general population. This study did not address, however, risks for subpopulations of women with high exposures to DNA damaging agents.

Emens LA, Armstrong D, Biedrzycki B, Davidson N, Davis-Sproul J, Fetting J, Jaffee E, Onners B, Piantadosi S, Reilly RT, Stearns V, Tartakovsky I, Visvanathan K, Wolff A. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231-2410, USA. · Hum Gene Ther. · Pubmed #15018740 No free full text.

This publication has no abstract.