Progesterone Receptor Negative Breast Cancer Research Articles

Physical activity and risk of breast cancer: a meta-analysis of prospective studies

We conducted a meta-analysis to summarize the evidence from prospective studies regarding the association between physical activity and breast cancer risk. A comprehensive search was conducted to identify eligible studies. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. Overall, 31 studies with 63,786 cases were included, and the combined relative risk (RR) with 95% CI of breast cancer was 0.88 (0.85-0.91). In subgroup analysis by activity type, data from 27 studies including 37,568 cases for non-occupational activity (including recreational activity and household activity) and seven studies including 28,268 cases for occupational activity were used, and the RR (95% CI) of breast cancer was 0.87 (0.83-0.91) and 0.90 (0.83-0.97), respectively. The inverse association was consistent among all subgroups analyses. Stronger association was found for subjects with BMI <25kg/m(2) [0.72 (0.65-0.81)], premenopausal women [0.77 (0.72-0.84)], and estrogen and progesterone receptor-negative breast cancer [0.80 (0.73-0.87)]. Dose-response analysis suggested that the risk of breast cancer decreased by 2% (P<0.00) for every 25 metabolic equivalent (MET)-h/week increment in non-occupational physical activity, 3% (P<0.00) for every 10 MET-h/week (roughly equivalent to 4h/week of walking in 2 miles/h or 1h/week of running in 6 miles/h) increment in recreational activity, and 5% (P<0.00) for every 2h/week increment in moderate plus vigorous recreational activity, respectively. Physical activity could significantly reduce the risk of breast cancer.

Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium

Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

Abstract 2879: Mechanisms of integration for androgen receptor and phosphatidylinositol 3-kinase signaling in estrogen receptor negative class A breast cancer

Abstract Effective targeted therapies for estrogen receptor-negative, progesterone receptor-negative breast cancer remains elusive. Previously, we identified a new subclass of ER- / PR- / AR+ breast cancers as Class A [1]. Class A breast cancer derived cell lines are growth inhibited by anti-androgens (bicalutamide) and stimulated by testosterone [1]. Interestingly, these cell lines harbor mutations in the PIK3CA gene leading to persistent activation of the PI3Kinase pathway [2,3]. In this report we examined the incidence of PIK3CA mutations in ER-/PR-/AR+ breast cancers. We also investigated the role of PI3K/AKT signaling on AR activity and growth of Class A cancer derived cell lines. We examined 100 primary ER-/PR- breast tumors and determined that 28% express AR by IHC. By Sequenom analysis we determined that 12% contain mutations in the PIK3CA gene within the canonical hot spots (exon 9,20). The expression of AR in ER- / PR- breast cancers positively correlated with PIK3CA mutations (p=0.0039), pAkt levels (p=0.01), and HER2 (p=0.05) expression. In addition, we observed a strong association between HER2 expression and pAkt levels in ER-/PR-/AR+ breast cancers. A number of in vitro studies were performed in order to examine the potential functional consequences of PI3K signaling in Class A breast cancer cell lines (MDA-MB-453 and HCC202). We first determined that the cell lines harboring PIK3CA mutations were more responsive to PI3K inhibitors for growth inhibition compared to class B cell lines (ER-,PR-,AR- breast cancer subclass [1]) lacking PIK3CA mutations. Induction of proliferation by synthetic androgen in class A breast cancer cell lines is decreased by androgen antagonist as well as PI3K inhibitors and the combination of both inhibitors had an additive effect. We also examined serine phosphorylated AR levels (a modification leading to enhanced AR transcriptional activity), AR transcriptional activity and the expression of AR target genes GGT1 and CYP4F8 in class A breast cancer cell lines. When cells were incubated with androgen agonists, the levels of all three elements were increased compared to vehicle control. Treatment with a PI3K inhibitor decreased the levels of all three elements compared to vehicle control. When cells were treated with the combination of the androgen agonist and a PI3K inhibitor, the levels of all three elements were higher than the inhibitor but lower than the agonist alone. These findings suggest that components of PI3K/AKT pathway can modulate AR activity suggesting a putative cross-talk between AR and PI3K pathways. This potential cooperative effect represents a new paradigm in targeted therapeutic strategies directed at the biological signal integration contributing to AR+ / ER- / PR- cancers. 1. Doane, A.S. Oncogene, 2006. 25(28): p. 3994 2. Kataoka, Y. Ann Oncol, 2010. 21(2): p. 255 3. Oda, K. Cancer Res, 2008. 68(19): p. 8127 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2011-2879

Epidemiology of triple negative breast cancers

Triple negative (TN) breast cancers fail to express the three most common breast cancer receptors; i.e., estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Accumulating data demonstrate that epidemiological risk factor profiles also vary between TN (ER-PR-HER2-) and other breast cancers, especially the so-called Luminal A breast cancers (ER+PR ± HER2-) [1]. A more comprehensive understanding of the epidemiology of TN breast cancers has important public health implications for risk assessment [2], prevention and treatment. The epidemiology of TN breast cancers can be first understood in the age-related reproductive risk factor patterns for ER, PR, and HER2. For example, there is a clear and strong association between older age at diagnosis (and therefore postmenopausal status) and the development of ER positive, PR positive, and HER2 negative breast cancers. On the other hand, younger age at diagnosis (and premenopausal status) is related to the development of ER negative, PR negative, and HER2 positive breast cancers. This gives rise to the somewhat counterintuitive suggestion that menopause has a greater relative impact upon hormone receptor negative than positive breast cancers [3,4]. Throughout this review, we will primarily contrast ER-PR-HER2- (TN) with ER+PR ± HER2- (Luminal A) breast cancers. We will first summarize the population-based age-specific incidence rate patterns and clinical outcomes, and then will review the available analytical studies. Information sources for this review included the National Cancer Institute's Surveillance, Epidemiology, and End Results 13 Registries Public-Use Database [5], CANCERLIT, Index Medicus, and PubMed.

Abstract PD01-02: Integration of Capecitabine into Anthracycline-and Taxane-Based Adjuvant Therapy for Triple-Negative Early Breast Cancer: Final Subgroup Analysis of the FinXX Study

Abstract Background: Standard adjuvant chemotherapy regimens for patients with moderate-to-high risk early breast cancer typically contain a taxane, an anthracycline and cyclophosphamide. The randomised, phase III FinXX study aimed to investigate whether the integration of capecitabine into such a regimen enhances outcome. Here we present final 5-year exploratory analyses from the subgroup of patients with triple-negative early breast cancer (TNBC). Methods: Patients aged 18-65 years, with histologically confirmed invasive node positive breast cancer or node negative progesterone receptor negative breast cancer &amp;gt; 20 mm, and with a WHO performance status of 0 or 1, with no previous neoadjuvant chemotherapy were randomised. Patients received 3 x XT (capecitabine 900mg/m2 bid d1-15 + docetaxel 60mg/m2 d1)≥3 x CEX (cyclophosphamide 600mg/m2 d1, + epirubicin 75mg/m2 d1 + X 900mg/m2 bid d1-15, q3w) or 3 x T (80mg/m2 d1)≥3 x CEF (C 600mg/m2 d1, E 75mg/m2 d1, 5-FU 600mg/m2 d1, q3w). The primary endpoint was RFS, defined as the time from randomisation to the first time the patient is recorded as having disease recurrence or the date of death if the patient dies due to causes other than disease recurrence. Secondary endpoints included overall survival and safety. Results: Between January 2004 and May 2007, 1,500 women from Finland and Sweden were randomised (XT→CEX n=753, T→CEF n=747). Of these, 202 patients (13.5%) had TNBC (XT→CEX n=93, T→CEF n=109). After a median follow-up of 59 months, RFS was significantly improved in the TNBC XT→CEX arm versus control (HR 0.48, 95% CI 0.26-0.88; p=0.018). The following endpoints were also significant: 5-year RFS in patients with TNBC versus those without TNBC (HR 0.50, 95% CI 0.36-0.69; P&amp;lt;0.001); 5-year distant disease-free survival in TNBC patients receiving XT→CEX versus control (HR 0.51, p=0.035); overall survival in TNBC patients receiving XT→CEX versus control (HR 0.42, p=0.019). Conclusions: The FinXX trial is the first to report the efficacy of capecitabine in combination with anthracycline-/taxane-containing therapy in the adjuvant treatment of early breast cancer. The exploratory subgroup analysis shows that XT→CEX is more effective than T→CEF in triple-negative BC, a population with a high unmet need; XT→CEX versus control resulted in a significant improvement in RFS and OS after 5 years. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-02.

Long-term survival among 298 Hodgkin lymphoma (HL) patients who develop breast cancer (BC): A population-based study.

1502 Background: The markedly increased risk of BC among women receiving chest radiotherapy for HL is well established. However, no large, population-based studies exist that describe overall survival (OS) and cause-specific survival (CSS) compared to women with a first primary BC. Methods: For 298 HL survivors who developed BC (HL-BC patients) and 405,223 women with a first or only BC (BC-1 patients), actuarial OS and CSS were compared, accounting for age, BC stage, hormone receptor status, sociodemographic status, radiation for HL and other variables. All patients were derived from the population-based Surveillance, Epidemiology, and End Results program. Results: Compared with BC-1 patients, the HL-BC group was significantly younger at BC diagnosis (p < 0.0001), had a greater likelihood of high grade BC (p > 0.02), and greater likelihood of estrogen negative BC (p < 0.004) and progesterone receptor negative BC (p > 0.005 for localized BC and p > 0.06 for regional BC). HL-BC patients were > 1.5 times (p < 0.0001) more likely to undergo mastectomy (rather than breast conserving surgery) compared with BC-1 pts, and were > 2 times (p < 0.0001) less likely to have received radiation than BC-1 patients. Fifteen-year OS among HL-BC patients was significantly inferior to BC-1 patients: 48% versus 69% respectively (p<0.0001) for localized BC, and 33% versus 43% (p < 0.0001) for regional/distant BC. HL-BC patients had a significantly increased 7-fold risk (p < 0.0001) of death from other cancers (i.e., not HL or BC) compared to BC-1 patients. Mortality due to heart disease among HL-BC patients with either localized or regional/distant disease was also significantly increased (hazard ratio 2.22, p > 0.04; and hazard ratio 4.28, p > 0.02 respectively) compared to BC-1 patients. While 10-year BC CSS was similar for HL-BC and BC-1 patients with regional/distant disease, it was inferior for patients with localized BC (82% versus 88% respectively (p > 0.002). Conclusions: Women with HL may survive a subsequent diagnosis of BC only to experience significant excesses of death from other primary cancers and cardiac disease. Greater awareness of screening for cardiac disease and subsequent primary cancers in HL-BC patients is warranted. No significant financial relationships to disclose.

Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation

Androgens exert growth inhibitory effects on estrogen receptor and progesterone receptor-negative breast cancer cell lines that show androgen receptor expression. These laboratory findings may be translated into inexpensive alternative therapies for hormone receptor-negative invasive breast cancers. Our aim was to systematically evaluate androgen receptor expression by immunohistochemistry in invasive breast cancers. Androgen receptor (clone AR441, Dako) expression was analyzed on 189 well-characterized consecutive invasive breast carcinomas represented with threefold redundancy on tissue microarrays. Androgen receptor expression was semi-quantitated using a histochemical score-like method and a score >10 was considered positive. Of the 189 consecutive invasive breast cancers, 151 (80%) were positive and 38 (20%) were negative for androgen receptor. The majority (95%) of estrogen receptor-positive tumors were also androgen receptor positive. Of the estrogen receptor-negative tumors, androgen receptor reactivity was seen in 3 of 30 (10%) triple-negative cases and in 5/8 (63%) estrogen receptor-negative/progesterone receptor-negative/HER2+ cases. Six of eight estrogen receptor-negative/androgen receptor-positive cases showed apocrine differentiation. Androgen receptor expression in estrogen receptor-positive cases was associated with smaller tumor size (P=0.0001), lower Nottingham grade (P=0.002) and less frequent tumor cell necrosis (P=0.0001). Androgen receptor expression in estrogen receptor-negative tumors was associated with lower Nottingham grade (P=0.005) and apocrine differentiation (P=0.039). In conclusion, most estrogen receptor-positive breast tumors also express androgen receptor. Androgen receptor expression in estrogen receptor-negative/progesterone receptor-negative/HER2+ tumors (which commonly show apocrine differentiation) and a subset of triple - negative apocrine tumors suggest that these tumors together comprises the ‘molecular apocrine’ group described previously. However, these findings should be further confirmed on larger series of triple-negative and estrogen negative/progesterone negative/HER2+ tumors. Androgen receptor-targeted therapy in estrogen/progesterone receptor-negative tumors may provide an inexpensive alternative to usual high-dose chemotherapy with or without trastuzumab.

Abstract B12: Racial disparities in breast cancer treatment delay and type in three North Carolina counties

Abstract Objective: The purpose of this study was to explore racial disparities in delays in treatment and type of treatment received among breast cancer patients in three North Carolina counties represented in the Carolina Community Network to Reduce Cancer Health Disparities (CCN). The CCN is a regional community-based cancer network that aims to reduce prostate, breast and colorectal cancer disparities among adult African Americans in North Carolina. Methods: North Carolina Central Cancer Registry data on black and white women diagnosed with breast cancer in Orange, Edgecombe, and Nash counties between 2000 and 2005 (n=1205) were used to obtained information on treatment and tumor status. Using standard guidelines for breast cancer care, delay in first course of treatment, type of treatment received, and tumor receptor status were assessed. Results: Although within the recommended guidelines, treatment delay was longer for black breast cancer patients in comparison to white patients, regardless of stage at diagnosis. Treatment delay was highest for black patients in Edgecombe, a county with the highest proportion of blacks overall. Majority of stage I and II breast cancer patients received surgery and tended to elect for breast conservation surgery over mastectomy. Estrogen and Progesterone receptor negative breast cancers were more common in blacks than whites across the three counties, especially in Edgecombe County. Conclusions: Our findings suggest treatment standards are not equivalently met among black and white women. Findings warrant further research into the identified treatment delays and tumor type differences to improve survival for black women, especially those in Edgecombe County. These preliminary results suggest that patients in Edgecombe County may have a higher prevalence of the hormone receptor negative phenotype of breast cancer. This more aggressive type of breast cancer may be attributing to the higher mortality rates in comparison to the other two counties. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B12.

Exercise and breast cancer prevention

Epidemiologic research continues to confirm a strong inverse association between physical activity and breast cancer risk. New studies suggest that activity during adolescence is most important for premenopausal breast cancer. Long-term activity patterns are clearly important for postmenopausal breast cancer, although recent activity often highly correlates with long-term activity, accounting for its influence on risk. Whether physical activity has greater influence on estrogen receptor- or progesterone receptor-negative breast cancers or affects receptor-negative and receptor-positive tumors equally remains a question. Studies have established that lower sex hormone levels likely explain lower breast cancer risk in physically active women. Overall, the evidence regarding physical activity and breast cancer risk highlights the importance for young women to adopt a physically active lifestyle that is maintained throughout life and for medical practitioners to counsel patients and prescribe exercise for its critically important health benefits, which include reducing a woman's breast cancer risk.

Statins May Reduce Breast Cancer Risk, Particularly Hormone Receptor-Negative Disease.

Estrogen and progesterone receptor-negative breast cancer disproportionately affects young women and African Americans, has a poor prognosis, and lacks an effective chemoprevention agent. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as "statins," are appealing candidate agents for breast cancer chemoprevention because of their demonstrated safety after decades of widespread use. In preclinical studies, statins inhibit multiple cancer-associated pathways in both hormone receptor (HR)-negative and HR-positive cell lines. Epidemiologic studies of statins and breast cancer show inconsistent results, with some suggesting a reduction in HR-negative breast cancer incidence in lipophilic statin users. However, large meta-analyses show no association between statin use and overall risk of breast cancer, although most did not evaluate tumor HR status. Multiple phase 1 and 2 prevention studies of statins for breast cancer risk reduction are ongoing. If results are promising, they may justify a randomized trial of statins for breast cancer chemoprevention, with a focus on HR-negative disease.

Serum High-Density Lipoprotein Cholesterol and Breast Cancer Risk by Menopausal Status, Body Mass Index, and Hormonal Receptor in Korea

High-density lipoprotein cholesterol (HDL-C) has been suggested to be associated with breast cancer. However, the roles of HDL-C and hypertriglyceridemia on breast cancer still have been controversial. The goal of this study was to investigate the association between HDL-C with breast cancer risk, stratifying by menopausal status, and body mass index. The hormonal receptor status of breast has been proposed to modify the effect of HDL-C on breast cancer. Multicenter hospital-based case-control study was conducted from November 2004 to December 2005 in Korea. After one to two individual matchings by age (+/-5 years) and menopausal status, 690 cases and 1,380 controls were included in the analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by conditional, unconditional, and multinomial logistic regressions. Protective effect of HDL-C on breast cancer was only observed among premenopausal women with an OR (95% CI) of 0.49 (0.33-0.72) for HDL-C > or = 60 versus <50 mg/dL (P(trend) < 0.01). Only nonobese premenopausal women had a significant decreased risk (OR, 0.34; 95% CI, 0.22-0.53). OR (95% CI) of low HDL-C (<50 mg/dL) and high triglyceride (TG; > or = 150 mg/dL) category was 2.20 (1.32-3.67) on estrogen receptor-negative and progesterone receptor-negative breast cancer compared with high HDL-C (> or = 50 mg/dL) and low TG (<150 mg/dL) category. This study suggests that higher level of HDL-C may reduce breast cancer risk among premenopausal women. Estrogen receptor-negative and progesterone receptor-negative breast cancer was associated with dyslipidemia, which implicates that association among HDL-C, TG, and breast cancer may be modified by receptor status.

Caffeine Consumption and the Risk of Breast Cancer in a Large Prospective Cohort of Women

Prospective data relating caffeine consumption to breast cancer risk are limited. We evaluated the association between caffeine consumption and breast cancer risk in women enrolled in a completed cancer prevention trial. Detailed dietary information was obtained at baseline (1992-1995) from 38 432 women 45 years or older and free of cancer. During a mean follow-up of 10 years, we identified 1188 invasive breast cancer cases. Consumption of caffeine and caffeinated beverages and foods was not statistically significantly associated with overall risk of breast cancer. The multivariate relative risks (RRs) of breast cancer were 1.02 (95% confidence interval [CI], 0.84-1.22) for caffeine (top vs bottom quintile), 1.08 (0.89-1.30) for coffee (> or =4 cups daily vs almost never), and 1.03 (0.85-1.25) for tea (> or =2 cups daily vs almost never). However, in women with benign breast disease, a borderline significant positive association with breast cancer risk was observed for the highest quintile of caffeine consumption (RR, 1.32; 95% CI, 0.99-1.76) and for the highest category of coffee consumption (> or =4 cups daily) (1.35; 1.01-1.80); tests for interaction were marginally significant. Caffeine consumption was also significantly positively associated with risk of estrogen receptor-negative and progesterone receptor-negative breast cancer (RR, 1.68; 95% CI, 1.01-2.81) and breast tumors larger than 2 cm (1.79; 1.18-2.72). These data show no overall association between caffeine consumption and breast cancer risk. The possibility of increased risk in women with benign breast disease or for tumors that are estrogen and progesterone receptor negative or larger than 2 cm warrants further study.

Hormone Receptor, Grade, Human Epidermal Growth Factor Receptor 2, and Topoisomerase II As Predictors of Response to Chemotherapy

TO THE EDITOR: Pritchard et al report an interaction among human epidermal growth factor receptor 2 (HER-2) status and anthracycline and taxane chemosensitivity in their review, but they do not mention tumor grade. Multivariate analysis has revealed that Scarff-Bloom-Richardson grade 3 tumors respond better to neoadjuvant treatment than Scarff-Bloom-Richardson grade 1 tumors (P .0001). A recent study suggests that an interaction between HER-2 and estrogen-receptor pathways may lead to a higher proliferation rate and thus a higher tumor grade. Therefore, inclusion of tumor grade in all the reviewed trials would have provided the relative predictive value of HER-2 status and grade in predicting anthracycline and taxane chemosensitivity. Moreover, among patients who have HER2–negative, estrogen receptor–positive and or progesterone receptor– positive breast cancer, those with higher tumor grades may benefit from anthracycline and taxanes. Furthermore, patients who have HER-2–negative, estrogen receptor–negative, and progesterone receptor–negative breast cancer, there is a high rate of pathologic complete response, specifically with anthracyclines administered biweekly compared with every 3 weeks, and paclitaxel administered weekly compared with every 3 weeks, and thus improved survival. Of the prospectively maintained database of 14 patients with stage II-III or local relapse HER-2–negative, estrogen receptor–negative, and progesterone receptor–negative infiltrating ductal carcinoma of breast who received dose-dense doxorubicin and cyclophosphamide followed by either dose-dense paclitaxel (n 2) or once-a-week paclitaxel (cremophoror albumin-bound) with carboplatin (both 3 weeks on, 1 week off; n 12) plus or minus six doses of bevacizumab every 2 weeks (n 4), 10 (71%; 95% CI, 42% to 92%) of 14 patients achieved pathologic complete response. The progression-free survival of 86% of 14 patients at a median follow-up of 33 months is promising. Therefore, the high pathologic complete response reported by us parallels the benefit of biweekly anthracyclines, and biweekly or weekly paclitaxel scheduling in phase III trials. In an otherwise comprehensive review by Pritchard et al, it needs to be emphasized that within patients with HER-2–negative tumors, patients with estrogen receptor–negative and progesterone receptor–negative subtype (triple-negative), or patients with higher tumor grade, optimally scheduled doxorubicin and cyclophosphamide and paclitaxel should be standard. The potential additional benefit of carboplatin and bevacizumab over optimum scheduling of standard chemotherapy needs to be tested in randomized trials.

A polymorphism in the 3′UTR region of E-cadherin associates with recurrence of breast cancer

22101 Background: Maintenance of epithelial integrity plays a major role in tumor suppression but may also be important in metastasis and recurrence of cancer. Loss of E-cadherin (CDH1) is implicated in invasive lobular carcinomas of the breast. Furthermore, a polymorphic variant in the CDH1 promoter has been reported in association studies. We investigated the association of polymorphic variants in CDH1 with recurrence of breast cancer. Methods: TaqMan allelic discrimination assays were performed on genomic DNA prepared from whole blood of breast cancer patients. Genotyping was determined for several loci in CDH1 and were linked to clinical information. Results: CDH1 genotypes for the 3’UTR Ex16+246C>T polymorphism are in Hardy-Weinberg equilibrium with frequencies of: CC 69%, CT 27%, and TT 4%. Population-specific genotype frequencies were observed. There were no frequency differences between invasive ductal and invasive lobular carcinomas, but a trend toward a 4-year earlier age of onset of the latter associated with the low frequency allele. Seventeen percent of women in this cohort recurred, nearly half representing progesterone receptor-negative (PgR−) and half progesterone receptor-positive (PgR+) breast cancers. The recurrence rate for each genotype was 14.3%, 26%, and 7.1% for CC, CT, and TT genotypes, respectively. In women without recurrence, the genotype distribution was the same for PgR+ and PgR− disease. However, in those that recur, women with the CC genotype were more likely to be PgR− OR 2.32 CI [1.13–4.77] with a p value=0.023. The converse could not be evaluated due to small numbers. Conclusions: A polymorphic variant in the 3’UTR region of CDH1 is associated with recurrence of breast cancer. This association is strongest in recurrence of progesterone receptor-negative breast cancers. Recurrence in this SNP association study may reflect the effect of progesterone on proteins in adherence junctions or desmosomes or the role of CDH1 in the beta-catenin pathway. Support was from the New Jersey Commission on Cancer Research. No significant financial relationships to disclose.

Estrogen and progesterone receptor levels in nonneoplastic breast epithelium of breast cancer cases versus benign breast biopsy controls

BackgroundPrevious studies and biological mechanisms of carcinogenesis suggest that the steroid receptor content of benign breast epithelium may be related to breast cancer risk. The objective in this study was to compare the levels of estrogen receptor-α (ER) and progesterone receptor (PR) in nonneoplastic breast epithelium between breast cancer cases and biopsy controls.MethodsBetween 1995 and 1997 at two sites (Women's College Hospital in Toronto and Kingston General Hospital), 667 women who were scheduled for diagnostic excisional breast biopsies completed a questionnaire providing personal information and agreed to allow analysis of routinely resected tissue. Histological slides with nonneoplastic epithelium were available for 101 cancer cases and 200 biopsy controls in Toronto and for 105 cancer cases and 119 controls in Kingston. Nonneoplastic epithelium was examined with immunohistochemical assays to determine the percent of epithelial cells staining for ER and PR. Unconditional logistic regression was used to calculate odds ratios (OR) stratified by study site.ResultsThe ER content of nonneoplastic tissue was higher in cases than biopsy controls in unadjusted analyses; after adjustment for age, however, a weak association remained in only one of the study sites. After adjustment for age, the PR content of nonneoplastic tissue was slightly lower in breast cancer cases than controls in one study site. Furthermore, this inverse association was confined to women with PR negative breast cancer in comparison to the controls. No interaction between ER and PR content of nonneoplastic tissue was observed in relation to the odds of having breast cancer.ConclusionThe results of this study are consistent with only a slight indication of increased ER levels in nonneoplastic tissue in breast cancer cases relative to controls. This study contributes to the understanding of breast cancer by examining both ER and PR in nonneoplastic tissue. Limitations remain, however, such as the necessity of using as controls women with benign breast changes, difficulties in selecting the appropriate tissue for analysis, and tissue sampling concurrent to diagnosis.

A Prospective Study of Multivitamin Supplement Use and Risk of Breast Cancer

The authors evaluated the association between multivitamin supplement use and breast cancer risk in a completed trial. At baseline (1992-1995), 37,920 US women aged > or =45 years and free of cancer provided detailed information on multivitamin supplement use. During an average of 10 years of follow-up, 1,171 cases of invasive breast cancer were documented. Multivitamin use was not significantly associated with overall risk of breast cancer. Compared with the risk for never users, the multivariable relative risks were 0.97 (95% confidence interval: 0.81, 1.16) for past users and 0.99 (95% confidence interval: 0.82, 1.19) for current users. Current multivitamin use for > or =20 years or > or =6 times/week was also not significantly associated with risk. Multivitamin use was nonsignificantly inversely associated with risk of breast cancer among women consuming > or =10 g/day of alcohol and with risk of estrogen receptor negative-progesterone receptor negative breast cancer. Multivitamin use was nonsignificantly associated with a reduced risk of developing < or =2-cm breast tumors but an increased risk of >2-cm tumors. The authors' data indicate no overall association between multivitamin use and breast cancer risk but suggest that multivitamin use might reduce risk for women consuming alcohol or decrease risk of estrogen receptor negative-progesterone receptor negative breast cancer.

Androgen Receptor As A Target For the Treatment of Hormone Receptor-Negative Breast Cancer: An Unchartered Territory

Estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) breast cancers represent approximately 30% of all breast cancers and, in general, have a more aggressive clinical course. They are unresponsive to antiestrogens, more likely to be poorly differentiated, of higher histological grade and are associated with a higher recurrence rate and decreased overall survival. Androgen receptor (AR) expression has been reported in over 70% of breast cancer and in 45-50% of patients with ER-negative breast cancer. There is emerging evidence that the androgen signaling pathway plays a critical role in breast carcinogenesis, independent of ER. Preclinical data have suggested the inhibitory role of adrenal steroids, such as dehydroepiandosterone (DHEA) and its sulfate on the growth of human ER-negative breast cancer cell lines, when these demonstrate a strong expression of AR. This potentially results in decreased AR gene expression. However, DHEA has been shown to stimulate growth in breast cancer cells when an ER is expressed in ER-positive breast cancer cells. Therefore, the effect of adrenal steroids may differ based on the tumor hormone receptor status and ER-/PR- breast tumors may not be truly hormone 'insensitive'. Exploration of new androgen-based hormonal therapy is warranted in this patient population. This article reviews the role of the AR in breast cancer and discusses potential avenues for the treatment of ER-/PR-/AR+ tumors with 'hormonal therapy'.

Randomized Trial of High-Dose Chemotherapy With Autologous Peripheral-Blood Stem-Cell Support Compared With Standard-Dose Chemotherapy in Women With Metastatic Breast Cancer: NCIC MA.16

We conducted a multicenter, randomized trial to compare progression-free survival (PFS), overall survival (OS), and quality of life in women with metastatic breast cancer (MBC) receiving high-dose chemotherapy plus autologous stem-cell transplantation (ASCT; HDCT) compared with standard-dose therapy. Between April 1997 and December 2000, 386 women with MBC and no prior chemotherapy for metastatic disease were registered. After initial response to anthracycline- or taxane-based induction chemotherapy, 224 patients were randomly assigned: 112 to high-dose cyclophosphamide, mitoxantrone, and carboplatin chemotherapy and ASCT (HDCT), and 112 to standard therapy (ST). Median age was 47 years (range, 25 to 67 years). Thirty two percent of women randomly assigned had estrogen and progesterone receptor-negative breast cancer, 42% had visceral metastases, and 58% had bone metastases. Complete remission rates before random assignment were 11% for those receiving HDCT and 12% for those receiving ST. After a median follow-up of 48 months, 79 deaths were observed in the HDCT arm and 77 deaths were observed in the ST arm; seven patients (6%) in the HDCT arm died as a result of toxicity. The median OS was 24 months for the HDCT arm (95% CI, 21 to 35 months) and 28 months for ST (95% CI, 22 to 33 months; hazard ratio [HR], 0.9; 95% CI, 0.6 to 1.2; P = .43). PFS was 11 months for HDCT and 9 months for ST (HR, 0.6 in favor of HDCT; 95% CI, 0.5 to 0.9; P = .006). HDCT did not improve OS in women with MBC when used as consolidation after response to induction chemotherapy.

A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20-2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74-8.70] and OR = 2.52 [1.26-5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82-1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.

A Significant Correlation between Nuclear CXCR4 Expression and Axillary Lymph Node Metastasis in Hormonal Receptor Negative Breast Cancer

In breast cancer, the expression pattern of CXCR4 may be correlated with the degree of axillary lymph node involvement. The aim of this study was to evaluate the contributing factors that contribute to the correlation between CXCR4 expression and axillary lymph node metastasis in breast cancer. Between August 1997 and August 2002, sections of paraffin-embedded tissue were obtained from 107 patients who received optimal treatment for breast cancer. The expression of CXCR4 was evaluated by immunohistochemical staining. A significant correlation was found in the expression of nuclear CXCR4 and lymph node metastasis (P = 0.03). We found a significant correlation between a high nuclear expression of CXCR4 and axillary lymphatic metastasis in estrogen and progesterone receptor negative breast cancer (P = 0.01 and P = 0.01). There was a significant correlation between the high expression of nuclear CXCR4 and axillary lymphatic metastasis in comparisons between positive estrogen and/or progesterone receptor expression and negative expression (P = 0.02). Our results showed that high expression of nuclear CXCR4 was significantly correlated with lymph node metastasis in breast cancer. The high expression of nuclear CXCR4 in hormone receptor negative breast cancer was associated with a high possibility of lymph node metastasis.