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Biomedical subjects

Seema A Khan

Publications and source records attributed to Seema A Khan.

At least 19 recordsLinked to original sources
PubMed2006

Selecting patients for breast-conserving therapy: the importance of lobular histology.

BACKGROUND: Concerns exist regarding the ability to select patients with lobular carcinoma for breast-conserving therapy (BCT) using mammography. The purpose of this study was to compare the conversion rate from BCT to mastectomy among patients with lobular (ILC) and ductal carcinoma (IDC), and to compare the number of resections needed to obtain negative margins. METHODS: In all, 349 patients with pure or mixed ILC were identified from a database and 318 were successfully matched to 2 controls with IDC on the basis of year of diagnosis, menopausal status, and stage of disease. Conditional logistic regression was used to control for matching. RESULTS: Patients with ILC were older, had larger tumors (2.6 vs. 2.1 cm; P<.001), and were more likely to have contraindications to BCT (25% vs. 20%). In patients thought to be candidates for BCT, no difference in success rate was noted on the basis of histologic type after controlling for age and stage. In those undergoing BCT, no difference in the number of procedures was seen on the bases of histology after adjustment for age and stage. CONCLUSIONS: Patients with ILC are not more likely to fail BCT than those with IDC, nor do they require more operations to obtain negative margins. These results do not support the use of more extensive preoperative evaluation such as magnetic resonance imaging in patients with ILC.

Adult↗
PubMed2006

Quantitative multiplex methylation-specific PCR analysis doubles detection of tumor cells in breast ductal fluid.

PURPOSE: The challenges of cytology for accurate diagnosis of breast cancer are well recognized. We previously showed that normal and tumor tissue can be distinguished using a technique called quantitative multiplex methylation-specific PCR (QM-MSP). We hypothesized that quantitative analysis of methylated genes will provide enhanced detection of cancer cells present in cytologic specimens. EXPERIMENTAL DESIGN: QM-MSP was done on ductal lavage cells from a set of 37 ductal lavage samples from women undergoing mastectomy (27 with cancer and 3 without). Duct histology information was available for each lavaged duct. QM-MSP data was assessed by measuring cumulative methylation index and by receiver operating characteristic threshold analysis. To determine the baseline level of methylation for each gene in this population, cells from 60 ducts of women at high risk of developing breast cancer were analyzed. RESULTS: QM-MSP findings on a panel of nine genes were correlated to duct histology and ductal lavage cytology. Cytology detected cancer in 33% (7 of 21 ducts) with a specificity of 99% (92 of 93). QM-MSP detected cancer as calculated by cumulative methylation index with a sensitivity of 62% (13 of 21) and specificity of 82% (62 of 76) and by receiver operating characteristic threshold analysis with a sensitivity of 71% (15 of 21) and specificity of 83% (63 of 76). CONCLUSIONS: Compared with cytology, QM-MSP doubled the sensitivity of detection of cancer. This study provides proof of principle by showing the advantages of using methylation analyses to query cytologic specimens and indicates its potential use in diagnosis and in stratifying risk.

Body Fluids↗
PubMed2005

Identification of biomarkers for breast cancer in nipple aspiration and ductal lavage fluid.

PURPOSE: To establish a comprehensive proteomic approach for biomarker discovery and validation in breast fluid. EXPERIMENTAL DESIGN: A total of 95 specimens from three institutions were used including 10 nipple aspiration fluid (5 stage I/II cancerous breasts and 5 age-matched healthy controls), 42 ductal lavage fluid from 14 patients with unilateral stage I/II cancer (25 from 9 cancerous breasts and 17 from 7 contralateral breasts), and 42 ductal lavage fluid from 14 high-risk women (multiple ducts repeated lavage). Differentially expressed protein/peptides were discovered by proteomic analysis of training sample, using ProteinChip arrays and surface-enhanced laser desorption ionization (SELDI) time-of-flight mass spectrometry, and validated on independently collected testing samples. After protein identification, ELISA was done to confirm the SELDI findings. RESULTS: We were able to obtain reproducible protein profiles using minimal amount of protein (1 mug) by applying an optimized chip protocol and SELDI. We were able to select cancer-associated biomarkers despite large individual variability by applying both unsupervised and supervised cluster analysis. Furthermore, we were able to train and test candidate biomarkers on independently collected samples and identified one component of a multimarker panel as human neutrophil peptides 1 to 3. CONCLUSIONS: Breast fluid is a rich source of breast cancer biomarkers. In combination with high-throughput novel proteomic profiling technology and multicenter study design, markers that are highly specific to breast cancer can be discovered and validated. Our observations also suggest that persistent elevation of human neutrophil peptide in high-risk women may imply early onset of cancer not yet detectable by current detection method. Proof of this hypothesis requires follow-up on a larger study population.

Adenocarcinoma↗
PubMed2005

Tamoxifen use in patients with ductal carcinoma in situ and T1a/b N0 invasive carcinoma.

BACKGROUND: The purpose of this study was to determine how often patients with ductal carcinoma in situ and T1a/b N0 cancer are offered and accept tamoxifen for secondary chemoprevention. STUDY DESIGN: A retrospective review of 284 patients with T1a/b N0 invasive cancer treated between February 1995 and December 2001 and 129 patients with DCIS treated after September 1998 was carried out. Patient and tumor characteristics associated with being offered and accepting tamoxifen were compared. RESULTS: Tamoxifen was offered to 67% of the invasive cancer patients and accepted by 76% (51% of the entire group). Hormone receptor status was the only significant predictor of being offered tamoxifen (p = 0.004). Older age (p = 0.04), Caucasian race (p = 0.01), and parity (p = 0.04) in premenopausal women were significant predictors of tamoxifen acceptance on univariate analysis. After the publication of the National Surgical Adjuvant Breast and Bowel Project P-1 trial, significantly more patients were offered tamoxifen (p = 0.02), but acceptance rates did not change. Tamoxifen was offered to 91% of the ductal carcinoma in situ patients and accepted by 73% (67% overall). Lumpectomy was associated with significantly higher rates of being offered (p = 0.02) and accepting tamoxifen (p = 0.002) on univariate analysis. CONCLUSIONS: Factors associated with tamoxifen risks and benefits correlate poorly with the use of the drug.

Antineoplastic Agents, Hormonal↗
PubMed2005

Ductal lavage findings in women with mammographic microcalcifications undergoing biopsy.

BACKGROUND: We designed a prospective study to assess the likelihood that early lesions presenting as mammographic calcifications could be accessed for cytological diagnosis by ductal lavage (DL). METHODS: Consenting women with calcifications (Breast Imaging Reporting and Data System 4 or 5) underwent DL of fluid-yielding ducts (FYDs) before stereotactic core or excisional biopsy. The DL catheter was used to inject .2 to 1 mL of Isovue 300 into the duct to determine whether the FYD corresponded to the duct containing calcifications (designated overlap). Additional FYDs were injected, if possible, until overlap was identified. DL cytology was compared with histology. RESULTS: Twenty women were enrolled (mean age, 54.2 years); the mean size of the calcification-bearing area was 190 mm(2). The histological findings were as follows: 1 invasive cancer, 9 ductal carcinomas-in-situ (DCIS), 5 atypical hyperplasias, and 5 usual hyperplasias or fibrocystic changes. Four women had no FYD. In 15 women who underwent DL and ductography, overlap of dye and calcifications was seen in 4 (27%): 1 fibrocystic change, 1 hyperplasia, 1 atypical hyperplasia (cytological diagnosis mildly atypical), and 1 DCIS (cytological diagnosis benign). Of the remaining 8 DCIS lesions, 4 had no nipple aspiration fluid, 1 showed extravasation, and 3 were lavaged but the duct did not overlap. CONCLUSIONS: These results are consistent with data from women undergoing mastectomy for larger invasive cancer and DCIS and show that cancer-containing ducts do not yield nipple fluid in most cases.

Biopsy↗
PubMed2005

A comparison of ductoscopy-guided and conventional surgical excision in women with spontaneous nipple discharge.

INTRODUCTION: Radiologic imaging is routinely used to evaluate women with spontaneous nipple discharge (SND), but definitive diagnosis is usually only achieved by surgical terminal duct excision (TDE). Ductoscopy has been reported to result in improved localization of intraductal lesions and may avoid surgery in women with endoscopically normal ducts. MATERIALS AND METHODS: We conducted a retrospective review of the records of 117 consecutive women who underwent ductoscopy to guide ductal excision (scope-DE) or received conventional TDE without ductoscopy. Two women had atypical ductal lavage cytology and the remainder presented with SND from 1 or more duct. Preoperative evaluation included radiologic imaging as clinically indicated. RESULTS: Fifty-nine women underwent scope-DE, and 58 underwent conventional TDE. There were no significant differences in age, race, discharge characteristics, or radiologic findings. The proportion of women with intraductal neoplasia was slightly greater in the group undergoing scope-DE (88% vs. 81%, P = 0.2). In the conventional TDE group, 8.5% were found to have atypical hyperplasia or duct carcinoma in situ compared with 18.6% in the scope-DE group. In the ductoscopy group, 22 of 59 (37.3%) had lesions >5 cm from the nipple, compared with 1 of 17 women for whom distance of the lesion from the nipple was known in the conventional group (P = 0.02). Of the ductoscopy-detected cancers, 5 of 6 had no symptoms other than SND, whereas 1 of the 4 malignancies in the conventional group presented as SND alone. DISCUSSIONS: Ductoscopy identifies intraductal lesions in a high proportion of women with SND, and it may contribute to more accurate resection of these. A prospective study is required to obtain an unbiased assessment of these possible advantages.

Adult↗
PubMed2005

Endocrine biomarkers in ductal lavage samples from women at high risk for breast cancer.

BACKGROUND: Ductal lavage is a method of minimal epithelial sampling of the breast, with potential utility for repeat sampling and biomarker analysis in chemoprevention studies. We report here the baseline findings from a study designed to assess the utility of ductal lavage in this setting. METHODS: Tamoxifen-eligible, high-risk women underwent ductal lavage; epithelial cell number (ECN) and morphology were assessed on Papanicolaou-stained slides. Additional slides were immunostained for estrogen receptor (ER) alpha, Ki-67, and cyclooxygenase-2, and the labeling index (LI) was established by counting negative and positive cells. The ductal lavage supernatant (DLS) was assayed for estradiol, several of its precursors, progesterone, cathepsin D, interleukin-6, and epidermal growth factor (EGF). RESULTS: One hundred sixty-eight women have entered the study (mean age, 51 years; mean 5-year Gail score, 2.8). Ductal lavage was accomplished in 145 (86.3%) women. Data were analyzed by duct and by woman (averaging data across all ducts). Mild atypia was seen in 43 of 145 (29.6%), whereas severe atypia was seen in 2 (1.4%) of women. We observed significant positive correlations between ECN and cytologic atypia, ER LI, cyclooxygenase-2 LI, and Ki-67 LI. EGF levels in supernatant were significantly associated with estrogenic precursors, ER LI and ECN. A factor representing the DLS hormone and protein variables explained 36% of the variance; total ECN was highest when factor score and ER LI were high and was lowest when both were low (P for interaction = 0.001). CONCLUSIONS: Biomarker analyses in epithelial cells and DLS are feasible. The significant associations of EGF with other markers suggest a possible role in increasing epithelial cell mass.

Biomarkers, Tumor↗
PubMed2004

Ductal lavage findings in women with known breast cancer undergoing mastectomy.

BACKGROUND: Ductal lavage has the potential to detect cancer by sampling breast epithelium in asymptomatic high-risk women. To assess the utility of ductal lavage as a cancer diagnostic test, we investigated the association between ductal lavage cytologic findings and histologic findings in women with known breast cancer undergoing mastectomy. METHODS: Ductal lavage was performed in the operating room before mastectomy on 44 breasts from 32 women with known cancer and on eight breasts from seven women undergoing prophylactic mastectomy, two with occult malignancy. If the ductal lavage sample from one or more ducts contained enough epithelial cells for a cytologic diagnosis, lavaged ducts were injected with a mixture of colored dye, gelatin, and a radiographic contrast compound after mastectomy, and breast tissue was radiographed and sectioned. Histologic findings in ducts with and without dye were recorded. Associations between cytologic results and histologic results were examined by univariate and multivariable analyses. RESULTS: At least one duct was lavaged in 36 breasts (mean = 1.4 ducts per breast); all histologic and cytologic procedures were completed in 28 breasts and in 39 ducts. Markedly atypical or malignant cytology was found in five cancer-containing breasts. In 39 ducts with complete cytologic and histologic data and when marked atypia or malignant cells defined a positive cytologic test, sensitivity was 43% (95% confidence interval [CI] = 23% to 72%), specificity was 96% (95% CI = 86% to 100%), and accuracy was 77% (95% CI = 63% to 89%). When mild or marked atypia or malignant cells defined a positive cytologic test, sensitivity was 79% (95% CI = 57% to 96%), specificity was 64% (95% CI = 46% to 83%), and accuracy was 69% (95% CI = 55% to 83%). When all 31 cytologically evaluable breasts were analyzed, sensitivity was 17% (95% CI = 7% to 35%), specificity was 100% (95% CI = 5% to 100%), and accuracy was 19% (95% CI = 9% to 38%). CONCLUSION: In breasts with cancer, ductal lavage appears to have low sensitivity and high specificity for cancer detection, possibly because cancer-containing ducts fail to yield fluid or have benign or mildly atypical cytology.

Adult↗
PubMed2004

The role of ductal lavage in the management of women at high risk for breast carcinoma.

Ductal lavage (DL) is a recently introduced technique for nonsurgical breast epithelial sampling of asymptomatic high-risk women. It is based on exfoliative cytology of duct epithelial cells, obtained by cannulation and lavage of ducts that produce nipple fluid after breast massage and nipple aspiration. DL provides information similar to that obtained by cytologic examination of nipple aspiration fluid and random periareolar fine needle aspiration. Women who demonstrate cytologic atypia on these tests can be assumed to be at higher risk for breast cancer and may benefit from prophylactic medication. DL promises to provide more reproducible sampling of the same area of the breast, as opposed to methods of random sampling, such as random fine needle aspiration, but the degree of reproducibility remains to be demonstrated. If reproducibility is greater than with random periareolar fine needle aspiration, DL may represent an important advance in the design of phase II chemoprevention trials, particularly because it also provides another source of material for judging response to prevention agents (ie, the protein component of nipple aspiration fluid), which can be analyzed for levels of hormones, specific proteins, and protein profiles obtained with proteomics. Early data do not suggest that DL is an effective screening tool for breast cancer on the basis of cytologic interpretation of DL samples, although this may change if effective molecular markers are validated for cancer detection in women at high risk.

Biomarkers, Tumor↗
PubMed2004

Normal breast lobular architecture in breast biopsy samples from breast cancer cases and benign disease controls.

Rodent studies suggest a relationship between lobular maturation and breast cancer risk. Human data are sparse, and were developed using whole mounts of mastectomy or mammoplasty samples, without consideration of menstrual phase in premenopausal women. We studied normal breast lobules in relation to cancer risk in 284 women, using surgical biopsy material (mean two sections and 43.2 lobular structures per subject): 167 were premenopausal; 89 with breast cancer (cases) and 78 undergoing benign breast biopsy (controls). Of 117 postmenopausal women, 67 were cases and 50 were controls. Normal lobular type was classified based on size, and was designated predominant if it constituted 60% or more of the total lobules classified. The control group showed 66% type I, 34% type II and 1% type III lobules while cases showed 69% type I, 31% type II and 7% type III structures. Predominant lobule type showed no association with cancer (p = 0.9). Postmenopausal women had a substantially higher proportion of type I lobules compared to premenopausal women, irrespective of the parity or cancer status (p < 0.001). Lobule type was not associated with menstrual phase classified by dates; however, when menstrual phase was classified using breast morphological characteristics, type I lobules were more abundant in follicular phase and type II in the luteal phase (p < 0.001). In conclusion, we did not observe a relationship between lobular architecture and breast cancer susceptibility when using smaller breast samples usually available in epidemiological studies, but these data highlight the need for menstrual phase stratification in future investigations.

Adult↗
PubMed2004

Variation in estradiol, estradiol precursors, and estrogen-related products in nipple aspirate fluid from normal premenopausal women.

The purpose of the study was to measure the concentrations of estradiol, its primary precursors, and factors with which it interacts in the breast, and determine their sources of variation. Nipple aspirate fluid (NAF) was collected from premenopausal women during the mid-luteal phase of the menstrual cycle. The fluid was diluted and unconjugated steroids were extracted. Estradiol was further purified by a solvent partition into aqueous NaOH. Androgens were measured in the non-phenolic fraction. Water-soluble, conjugated steroids and proteins were measured in the aqueous residue. All analytes were measured by immunoassays. Permutation methods were used to determine the correlations over multiple periods of time. The average concentration of estradiol in NAF was 435 pmol/L after purification but was many times higher when assayed without purification. Estrone and dehydroepiandrosterone (DHEA) sulfates were present in 3.7 and 75 micromol/L concentrations, respectively, while unconjugated androstenedione and DHEA were present in nanomole per liter concentrations. Lack of the steroid sulfates in NAF in 19% of subjects had no effect on NAF estradiol levels but was associated with a 77% lower concentration of unconjugated DHEA. Progesterone was present in concentrations that were 3- to 4-fold higher than normal serum concentrations (mean: 291 nmol/L). Cathepsin D, epidermal growth factor, and interleukin 6 had average values of 3.4 microg/mL, 424 ng/mL, and 1.7 ng/mL, respectively. Correlations between breasts were between 0.57 and 0.84 for the several analytes; correlations over time ranged from 0.64 and 0.93 with estrone sulfate highest in both categories. The lower correlation between breasts than within breasts indicates that local factors play an important role in determining the levels of many of these analytes in the breast. The high stability of the concentrations of several analytes over time indicates that fluctuations in environmental factors have little immediate effect on levels in the breast, and portends their utility as surrogate breast cancer risk markers.

Adult↗
PubMed2003

Formation of estrone and estradiol from estrone sulfate by normal breast parenchymal tissue.

The study was designed to determine the process and limitations by which estrone sulfate may be a precursor of estradiol in the parenchymal cells of the normal breast. The concentration of estrone sulfate in breast nipple aspirate fluid was 1000-fold greater than that of estradiol. Concentrations of 3H-estrone sulfate in parenchymal cells were only 0.20-0.33 times that of the 1.0 nM concentration in the medium, while 3H-estrone achieved concentrations up to 24 times that in the medium at 37 degrees C. Nevertheless, estrone sulfate added to the medium was linearly converted within a 1000-fold concentration range to estrone in intact cells with a mean half-time of conversion of 628 min per 10(6) cells. Homogenized cells had a half-time of 246 min per 10(6) cells. Thus, the time for entry of estrone sulfate into cells reduced the rate by approximately 55%. In split samples, the Vmax values (+/- S.D.) for intact and homogenized cells were 12.6 +/- 1.4 and 18.3 nmol/h mg DNA, respectively (P<0.03). The corresponding Km values for intact and homogenized cells were 6.0 +/- 1.1 and 4.7 +/- 1.0 microM. Conversion of estrone sulfate to estradiol was more efficient in intact cells than in homogenates with mean half-times of 2173 and 7485 min per 10(6) cells, respectively. Conversion of estrone to estrone sulfate did not occur in these cells despite sulfonation of estrone by MCF-7 breast cancer cells under identical conditions. It is concluded that estrone sulfate can serve as a precursor for estradiol in normal breast tissue. Conversion of estrone to estradiol is a limiting step in the process.

Adult↗
PubMed2003

Novel agents for chemoprevention, screening methods, and sampling issues.

An aggressive approach to breast cancer control based on preventing the disease must complement efforts at effective treatment. To date clinical trials testing new chemopreventative agents have not generally met with the kind of success expected. A wide range of new breast cancer chemopreventative agents are poised to be tested in clinical trials. We review these novel agents and approaches, including those for which clinical trials have been initiated and those that are promising in the preclinical arena. Further progress in this area requires not only new agents, but novel methods for screening for risk assessment, sampling and development of intermediate biomarkers. We review these novel potential surrogate endpoints, including new imaging-techniques, breast sampling approaches, and methods to assess biomarkers in breast epithelium. Factors that could contribute to a meaningful choice of the chemopreventive agents and the design of clinical trials are discussed.

Anticarcinogenic Agents↗
PubMed2002

Estrogen receptor alpha expression in normal human breast epithelium is consistent over time.

If increased expression of estrogen receptor alpha (ER) in benign breast epithelium increases susceptibility to breast cancer, such overexpression should be stable over time. There are no published data regarding this important aspect of ER expression in breast epithelium. We examined the temporal consistency of ER expression in the normal breast tissue of 28 women who had 2 separate breast surgical procedures, at least 6 months apart (mean interval, 2.8 years). Paraffin embedded breast tissue blocks containing an adequate sample of normal breast epithelium and no cancer, were sectioned and processed using the 6F11 antibody and standard immunohistochemical techniques. The ER labelling index (ER LI) was calculated by counting a mean of 2,000 epithelial cells. The median ER LI at first sampling was 13.6 and at second sample 15.5, with R(2) = 0.34 and p = 0.001. The ER LI was categorized into high and low values, using a threshold of 10. Twenty-four women (85.7%) showed concordance of high and low expression between the 2 samples (p = 0.002). There were 11 women who were premenopausal at both time points. Among them, much of the variation in ER LI was explained by differences in the menstrual cycle day at the time of sampling and adding the day of cycle to the regression model substantially improved the correlation between first and second labeling indices. These data suggest that ER expression of normal breast tissue is fairly consistent over time and support the notion that overexpression of ER in normal epithelium is a constant feature of the high risk breast.

Adult↗
PubMed2002

Mastalgia and breast cancer: a protective association?

Breast pain (mastalgia) is a common complaint, with a potentially important relationship to breast cancer risk. We have examined the association between mastalgia and breast cancer in the patient population of the Breast Care Center of University Hospital, Syracuse, New York. Of 5463 women with complete breast cancer risk factor information, 1532 (28%) reported breast pain as an incidental complaint at their initial visit, and 861 were diagnosed with breast cancer. Forward stepwise logistic regression was used to analyze the association between breast pain and a diagnosis of breast cancer. The age-adjusted OR for breast cancer was 0.60 (95% CI 0.50-0.74). Adjustment for additional risk factors (early menarche, late first birth, late menopause, exogenous hormone use, positive family history) yielded an OR of 0.63, 95% CI 0.49-0.79. Thus, women who experienced breast pain in our patient population were less likely to be diagnosed with breast cancer than women who did not complain of breast pain, regardless of age, and of other breast cancer risk factors. Further investigation of this possible protective association is warranted.

Adult↗