[show abstract][hide abstract] ABSTRACT: Effective methods of serial epithelial sampling to measure breast-specific biomarkers will aid the rapid evaluation of new preventive interventions. We report here a proof-of-principle phase 2 study to assess the utility of ductal lavage (DL) to measure biomarkers of tamoxifen action. We enrolled women with a 5-year breast cancer risk estimate >1.6% or the unaffected breast of women with T1a or T1b breast cancer. After entry DL, participants chose tamoxifen or observation and underwent repeat DL 6 months later. Samples were processed for cytology and immunohistochemistry for estrogen receptor alpha, Ki-67, and cyclooxygenase-2. Of 182 women recruited, 115 (63%) underwent entry and repeat DL; 85 (47%) had sufficient cells for analysis from > or =1 duct at both time points; in 78 (43%), cells were sufficient from > or =1 matched ducts. Forty-six women chose observation and 39 chose tamoxifen. We observed greater reductions in the tamoxifen group than in the observation group for Ki-67 (adjusted P = 0.03) and estrogen receptor alpha (adjusted P = 0.07), but not in cyclooxygenase-2 (adjusted P = 0.4) labeling. Cytologic findings showed a trend toward improvement in the tamoxifen group compared with the observation group. Interobserver variability for cytologic diagnosis between two observers showed good agreement (kappa = 0.44). Using DL, we observed the expected changes in tamoxifen-related biomarkers; however, poor reproducibility of biomarkers in the observation group, the 53% attrition rate of subjects from recruitment to biomarker analyses, and the expense of DL are significant barriers to the use of this procedure for biomarker assessment over time.
Cancer Prevention Research 02/2009; 2(3):265-73. · 4.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4-6 cycles of CTAP/VMAC induction, patients aged < or =65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients < or =55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P = 0.001; OS P = 0.0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.
British Journal of Haematology 02/2008; 140(4):385-93. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ductal lavage (DL) allows repeat sampling of breast epithelium for serial observation in a chemoprevention setting; however, the reproducibility of duct cannulation, cell yield and cytology has not been addressed.
We conducted a Phase 2 trial, wherein high risk women chose tamoxifen treatment or observation following an entry DL procedure. We present data from the non-intervention arm of our study to assess the reproducibility of cannulation, cell yield, and cytologic diagnosis from DL of the same duct at two time-points. Inter-observer variability was assessed by a blinded review of Papanicoloau-stained slides by two cytopathologists.
Sixty-five women had a successful lavage of 187 ducts at baseline and chose observation; 63/65 (97%) had a successful lavage 6 months later. Successful recannulation of the same duct was accomplished in 63 women (97%) and162 ducts (87%). Total epithelial cell yields >or=100 were obtained from 57/65 women (88%) and 129/187 ducts (69%) at baseline, and 46/63 women (73%) and 80/162 ducts (49%) at both time-points. Cytologic diagnosis was reproducible in 27/63 (43%) women and 77/162 (48%) ducts. Inter-observer variability for cytologic diagnosis between two observers showed good agreement (kappa = 0.62).
Recannulation and lavage of the same duct after a 6 month interval can be achieved with high frequency; however, reproducibility of cell yield and cytologic findings from the same duct is sub-optimal, leading to significant attrition of evaluable subjects. The utility of DL for the serial monitoring of breast epithelium is therefore limited.
Breast Cancer Research and Treatment 12/2007; 112(2):327-33. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dose-intensity of chemotherapy is important in the treatment of Hodgkin lymphoma (HL) and granulocyte-colony stimulating factor (G-CSF) is commonly used to maintain it. We reviewed all newly diagnosed HL patients who were treated at our institution between 1996 and 2005. Fifty-nine patients received adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy with no dose reductions, treatment delays, and without G-CSF, regardless of absolute neutrophil count (ANC). The median ANC on all ABVD treatment days (n = 658) was 0.925 x 10(9)/l, and was <0.5 x 10(9)/l on 26% of treatment days. Median normalised ABVD dose-intensity was 99.1% (range, 93-100%) and median cycle duration was 28.2 d. Incidence of bleomycin lung toxicity was 1.6%, 0.44% treatments were complicated by febrile neutropenia, and no secondary malignancies have occurred (median follow-up 48 months; range, 11-130 months). Five-year event-free (EFS) and overall survival (OS) were 92.9% and 97.4% respectively. Furthermore, the 5-year EFS and OS (87.4% and 94.1% respectively) for advanced stage patients compared favourably with a similar ABVD patient group who received routine prophylactic G-CSF (n = 23) with EFS 80.0% and OS 91.3% (P = 0.46 and 0.67 respectively). Our experience suggests that ABVD may be safely and effectively administered at >99% dose-intensity without G-CSF support, regardless of the ANC.
British Journal of Haematology 06/2007; 137(6):545-52. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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).
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).
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.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
Factors associated with tamoxifen risks and benefits correlate poorly with the use of the drug.
Journal of the American College of Surgeons 12/2005; 201(5):688-94. · 4.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objective of the study was to characterize salivary sex steroid levels in 56 women undergoing annual mammography who were participating in a breast density study at the Lynn Sage Breast Center of Northwestern Memorial Hospital, and to determine the predictability of the patterns within women. Saliva was collected daily by the women at home for one complete menstrual cycle and then again at approximately 6-month intervals. The occurrence of sporadic anovulatory cycles was identified in 12 subjects, and persistent oestradiol (OE2) elevation in all three cycles without significant progesterone levels occurred in another five subjects. In addition, both OE2 and progesterone were significantly lower in initial menstrual cycles than in subsequent cycles, suggestive of an effect of participation in the study on hormone levels. Initial salivary OE2 levels were not good predictors of corresponding levels in either follicular or luteal phases of the menstrual cycles at the 6-month intervals. However, after the initial cycle, progesterone levels were highly predictable within individuals over a period of 6 months (r=0.78, P<0.001). The study emphasizes the natural variation among and within women in the absence of any intervention, and indicates the need for properly controlled studies before attributing changes in hormonal levels to therapy. In addition, it emphasizes the importance of sampling at multiple time points when examining the relationship between hormones and risk.
Journal of Endocrinology 08/2005; 186(1):77-84. · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Effective therapies to reduce the risk of hormone-sensitive breast cancers (ER or PR positive) exist. Available models predict the risk of breast cancer without addressing hormone receptor status. The purpose of this study was to identify risk factors predictive of the development of hormone-sensitive cancers.
A total of 1285 invasive breast cancers in 1263 women were identified from a prospectively maintained database. Risk factors were compared for ER+ and ER- cancers by using Fisher's exact test.
Models were developed for premenopausal and postmenopausal women. In premenopausal women, white race, age at menarche < 12 years, and nulliparity or age at first birth > 20 years were used. The risk of ER+ cancer increased from 67.7% with 0 variables to 83.8% with all three (P = .013). In postmenopausal women, white race and a history of estrogen therapy were used. With none of the variables present, the incidence of ER+ cancer was 70.0%; it was 77.6% with one variable and 85.4% with both variables (P = .002). In postmenopausal women, variables predicted significant differences in hormone sensitivity only for those aged < or = 60 years. In the subset of women with information on alcohol use, adding this variable to the model improved the prediction of hormonal status.
Our findings, if prospectively validated, may help identify those who would obtain the greatest benefit from hormonal chemoprevention strategies for breast cancer risk reduction.
Annals of Surgical Oncology 01/2005; 12(1):48-56. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen was shown to reduce breast carcinoma risk by 49% in high-risk women. The purpose of the current study was to identify factors associated with being offered, and accepting, tamoxifen chemoprevention.
The records of 219 women who sought risk evaluation after the publication of the NSABP P-1 trial between September 1998 and October 2002 were reviewed. Risk was calculated using the model of either Gail et al. or Claus et al. The impact of individual risk factors on the offering and acceptance of tamoxifen was compared using the Fisher exact test and logistic regression analysis.
Tamoxifen was offered to 137 women (63%) in the current study. The magnitude of Gail risk, age, menopausal status, hysterectomy, and history of lobular carcinoma in situ (LCIS) or atypical hyperplasia (AH) were all found to be significant predictors of a patient being offered tamoxifen. On multivariate analysis, only a history of AH or LCIS and hysterectomy were found to be significant, with odds ratios of 20.3 and 3.4, respectively. Fifty-seven of the women who were offered tamoxifen (42%) took the drug. Only a history of LCIS or AH and older age were found to be predictive of tamoxifen acceptance.
In the current study, risk due to AH or LCIS was found to be the main predictor of being offered and accepting tamoxifen chemoprevention.
Cancer 06/2004; 100(9):1800-6. · 5.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: TGFBR1*6A is a hypomorphic polymorphic allele of the type I transforming growth factor beta receptor (TGFBR1). TGFBR1*6A is a candidate tumor susceptibility allele that has been associated with an increased incidence of various types of cancer. This study was undertaken to analyze all published case-control studies on TGFBR1*6A and cancer and determine whether TGFBR1*6A is associated with cancer.
All published case-control studies assessing the germline frequency of TGFBR1*6A were included. Studies assessing TGFBR1*6A in tumors were excluded. The results of seven studies comprising 2,438 cases and 1,846 controls were pooled and analyzed.
Overall, TGFBR1*6A carriers have a 26% increased risk of cancer (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.07 to 1.49). Cancer risk for TGFBR1*6A homozygotes (OR, 2.53; 95% CI, 1.39 to 4.61) is twice that of TGFBR1*6A heterozygotes (OR, 1.26; 95% CI, 1.04 to 1.51). Analysis of various types of tumors shows that TGFBR1*6A carriers are at increased risk of developing breast cancer (OR, 1.48; 95% CI, 1.11 to 1.96), hematological malignancies (OR, 1.70; 95% CI, 1.13 to 2.54), and ovarian cancer (OR, 1.53; 95% CI, 1.07 to 2.17). Carriers of TGFBR1*6A who are from the United States are at increased risk of colorectal cancer (OR, 1.38; 95% CI, 1.02 to 1.86). However, Southern European TGFBR1*6A carriers have no increased colorectal cancer risk. There is no association between TGFBR1*6A and bladder cancer.
TGFBR1*6A is emerging as a highfrequency, low-penetrance tumor susceptibility allele that predisposes to the development of breast, ovarian, and colorectal cancer, as well as hematologic malignancies.
Journal of Clinical Oncology 10/2003; 21(17):3236-43. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mammographic breast density has been proposed as a surrogate endpoint in breast cancer prevention studies, but little is known
about its variability over time, particularly in relation to menstrual cycle phase. The purpose of this study was to assess
variation in breast density on digital mammograms using quantitative and qualitative density measures. Menstrual cycle phase
was determined by salivary estradiol and progesterone assays. 73 healthy subjects with regular menses had 1–3 mammograms with
paired saliva collection during a 12-month period. The mean difference in density as a percentage of the mean density was
calculated for follicular–luteal (n=50), luteal–luteal (n=26) and follicular–follicular (n=23) pairs in the same woman using the same breast. Two density measures (measurement of dense area and BIRADS) were used.
The mean luteal density exceeded the mean follicular density by 7.1–9.2%, but density differences between luteal pairs and
follicular pairs did not exceed 5%. The intraclass correlation for measurement of dense area was greater than 85% in all phases
of the menstrual cycle, but was below 50% for BIRADS for luteal–follicular and follicular–follicular pairs. Our study provides
estimates of the amount of variation in mammographic density during the menstrual cycle, and that inherent in repeated density
measurement in premenopausal women, and suggests that menstrual phase of mammographic evaluation should be controlled for
in intervention studies where density is being used as a surrogate measure.
KeywordsMenstrual cycle-Mammographic density-Breast density-Mammogram
Breast Cancer Research and Treatment 121(3):565-574. · 4.47 Impact Factor