Impact of NR5A2 and RYR2 3'UTR polymorphisms on the risk of breast cancer in a Chinese Han population.

OBJECTIVES: The NR5A2 and RYR2 genes are important players in steroid metabolism and play an important role in cancer research. In this research, we want to evaluate the effect of NR5A2 and RYR2 polymorphisms on breast cancer (BC). METHODS: Four single nucleotide polymorphisms on NR5A2 and RYR2 were selected to genotype by Agena MassARRAY in 379 BC patients and 407 healthy controls. Using the PLINK software to calculate the Odds ratio (OR) and 95% confidence intervals (CIs) via the logistic regression analysis to evaluate the risk for BC. RESULTS: We found that NR5A2 rs2246209 significantly decreased the risk of BC with the AA genotype (OR 0.58, 95%CI 0.34-0.99, p = 0.049), and recessive model (OR 0.59, 95%CI 0.35-0.99, p = 0.046); rs12594 in the RYR2 gene significantly decreased the risk of BC in the GG genotype (OR 0.44, 95%CI 0.22-0.88, p = 0.020), and recessive model (OR 0.43, 95%CI 0.21-0.85, p = 0.016). Further stratification analysis showed that NR5A2 rs2246209 was related to a lower incidence of BC affected by age, lymph nodes metastasis, and tumor stage; RYR2 rs12594 was related to a decreased BC risk restricted by age, estrogen receptor (ER), progesterone receptor (PR), menopausal status, tumor size, and tumor stage. Rs12594 in the RyR2 gene remained significant on the genetic susceptibility of PR-positive BC after Bonferroni correction (p < 0.0125). CONCLUSIONS: This study provides an evidence that NR5A2 rs2246209 and RYR2 rs12594 decreased the risk of breast cancer.

Changes in the pattern of breast cancer burden among African American women: evidence based on 29 states and District of Columbia during 1998 to 2010.

PURPOSE: Assessment of breast cancer (BC) pattern in individual states with respect to ethnicity. METHODS: Population-based cancer registries from the Cancer Incidence in Five Continents databases (1998-2007) supplemented with Surveillance, Epidemiology, and End Results data from 2008 to 2010 were used. RESULTS: The age-specific burden showed a clear convergence of BC burden among African American (AA) and Caucasian American (CA) in most states. This was primarily because of a decrease in the BC rate among CA aged 50 years or older and an increase among AA of the same age group. The 2003-2007/1998-2002 rate ratio for CA was 0.91 (95% confidence interval [CI], 0.90-0.91) in the South, whereas it was 1.06 (95% CI, 1.04-1.08) for AA. This convergence was confirmed in states with available data for the period 2008 to 2010. The AA/CA rate ratio among women aged younger than 40 years was 0.99 (95% CI, 0.99-1.04) in the Northeast, 1.29 (95% CI, 1.25-1.33) in the South, and 1.10 (95% CI, 1.04-1.17) in the West. This pattern correlates with the estrogen receptor positive and progesterone receptor positive pattern. The strongest disparity in estrogen receptor negative was observed in Louisiana which with Detroit, have had the highest rates of estrogen receptor negative. CONCLUSIONS: The changes in postmenopausal hormone use and mammography screening might have played a role in the observed convergence.

Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women.

Changes in the activity of drug metabolizing enzymes (DMEs) are potentially associated with cancer risk. This relationship is attributed to their involvement in the bioactivation of multiple procarcinogens or the metabolism of multiple substrates including an array of xenobiotics and environmental carcinogens. 326 Lebanese women of whom 99 were cancer free (controls) and 227 were diagnosed with breast cancer (cases) were included. Blood for DNA was collected and medical charts were reviewed. Three genotyping methods were employed including: (1) restriction fragment length polymorphism (RFLP) for CYP2E1*5B, CYP2E1*6, NAT2*5 and NAT2*6; (2) gel electrophoresis for GSTM1 and GSTT1; and (3) real-time PCR for GSTP1 Ile/Val polymorphism. We analyzed the relationship between genetic susceptibilities in selected xenobiotic metabolizing genes and breast cancer risk. Allele frequencies were fairly similar to previously reported values from neighboring populations with relevant migration routes. There were no statistically significant differences in the distribution of variant carcinogen metabolizing genes between cases and controls even after adjusting for age at diagnosis, menopausal status, smoking, and alcohol intake. Despite its limitations, this is the first study that assesses the role of genetic polymorphisms in DMEs with breast cancer in a sample of Lebanese women. Further studies are needed to determine the genetic predisposition and gene-environment interactions of breast cancer in this population.

Biology of breast cancer in Nigerian women: a pilot study.

BACKGROUND: Compared to the developed world, there are relatively few studies that describe the tumor biology of breast cancer in African women. While little is known about the tumor biology, clinical and epidemiologic studies suggest that breast cancer in African women are characterized by presentation at late stage and poor clinical outcomes. Analysis of the biological features of breast cancers in Nigerian women was designed to bring additional insight to better understand the spectrum of disease, the phenotypes that present, and the types of interventions that might improve outcomes. MATERIALS AND METHODS: We performed histological analyses for hormone receptors (estrogen and progesterone receptors), HER2, and tumor infiltrating macrophages (TAM) on 17 breast cancers, obtained from Abia State University Teaching Hospital (Aba, Nigeria), between November 2008 and October 2009. On a subset of these cases, we investigated the potential role of a virus in the etiology of these aggressive cancers. RESULTS: The majority of cases in this cohort were characterized as high grade (100% were grade III), triple-negative (65%), and occur in young women (mean age 47 years). We observed high infiltration of TAMs in these tumors, but no evidence of a viral etiology. CONCLUSION: Our findings indicate that breast cancers in Nigerian women have a highly aggressive phenotype (high grade, hormone receptor negative), which is similar to other studies from Africa and other developing nations, as well as from African American women, but is significantly different from Caucasian women in the developed world. The presence of high numbers of TAMs in these tumors raises the possibility of targeting the immune microenvironment for therapeutic interventions.

[Constitutional risk factors in prostate cancer]. / Factores de riesgo constitucionales en el cáncer de próstata.

INTRODUCTION: The aim of this review is to update and divulge the main constitutional risk factors involved in the etiopathology of prostate cancer. MATERIALS AND METHODS: Bibliographic review of the scientific literature on the constitutional risk factors associated with prostate cancer between 1985 and 2010, obtained from MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk Factors, Genetic Factors, Genetic Polymorphisms, Genomics, Etiology, Epidemiology, Hormonal Factors, Endocrinology, Primary Prevention and Prostate Cancer. RESULTS: The principal constitutional risk factors are: age (before the age of 50 years at least 0.7% of these neoplasms are diagnosed and between 75-85% are diagnosed after the age of 65 years), ethnic-racial and geographic (African Americans present the highest incidence rates, and the lowest are found in South East Asia), genetic, family and hereditary (family syndromes cover 13-26% of all prostate cancers, of which 5% are of autosomal dominant inheritance), hormonal (it is a hormone-dependent tumour), anthropometric (obesity increases the risk), perinatal, arterial hypertension and type 2 diabetes. CONCLUSIONS: Constitutional risk factors play a very important role in the etiopathology of prostate cancer, especially age, ethnic-racial-geographic factors and genetic-family factors. We cannot know what percentage of these neoplasms are a result of constitutional factors, because our knowledge of these factors is currently lacking.

African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study.

BACKGROUND: The study of breast cancer in women with African ancestry offers the promise of identifying markers for risk assessment and treatment of triple-negative disease. METHODS: African American and white American women with invasive cancer diagnosed at the Henry Ford Health System comprised the primary study population, and Ghanaian patients diagnosed and/or treated at the Komfo Anokye Teaching Hospital in Kumasi, Ghana constituted the comparison group. Formalin-fixed, paraffin-embedded specimens were transported to the University of Michigan for histopathology confirmation, and assessment of estrogen and progesterone receptors and HER-2/neu expression. RESULTS: The study population included 1008 white Americans, 581 African Americans, and 75 Ghanaians. Mean age at diagnosis was 48.0 years for Ghanaian, 60.8 years for African American, and 62.4 for white American cases (P=.002). Proportions of Ghanaian, African American, and white American cases with estrogen receptor-negative tumors were 76%, 36%, and 22%, respectively (P<.001), and proportions with triple-negative disease were 82%, 26%, and 16%, respectively (P<.001). All Ghanaian cases were palpable, locally advanced cancers; 57 (76%) were grade 3. A total of 147 American women were diagnosed as stage III or IV; of these, 67.5% (n=46) of African Americans and 44.6% (n=29) of white Americans were grade 3. Among palpable, grade 3 cancers, Ghanaians had the highest prevalence of triple-negative tumors (82.2%), followed by African Americans (32.8%) and white Americans (10.2%). CONCLUSIONS: Our study demonstrates progressively increasing frequency of estrogen receptor-negative and triple-negative tumors among breast cancer patients with white American, African American, and Ghanaian/African backgrounds. This pattern indicates a need for additional investigations correlating the extent of African ancestry and high-risk breast cancer subtypes.

Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer.

BACKGROUND: The combination of increased parity and shorter breastfeeding duration might increase the odds of the least differentiated triple-negative breast cancer (BC) phenotype, theoretically because an expanded progenitor cell population from each pregnancy would incompletely differentiate postpartum. METHODS: Subjects consisted of a consecutive case series of 2473 women treated for invasive breast cancer between 2001 and 2006. Breast cancer phenotype (triple-negative BC, vs non-triple-negative BC) was compared with reproductive and demographic information. Odds ratios (OR) with 95% confidence intervals (CIs) for the association of breastfeeding duration (months per child) and parity with triple-negative BC were calculated after adjusting for ethnicity, age at menarche, family history, and age at diagnosis. RESULTS: Compared with non-triple-negative BC, triple-negative BC was associated with shorter duration of breastfeeding per child (OR, 0.93; 95% CI, 0.90-0.97) and with higher parity (OR, 1.12; 95% CI, 1.06-1.20). By using multivariate logistic regression, triple-negative BC was independently associated with higher parity (OR, 2.76 [95% CI, 1.86-4.08] if ≥3 live births; OR, 1.89 [95% CI, 1.30-2.74] if ≤2 live births vs nulliparae), breastfeeding duration (OR, 0.55 [95% CI, 0.41-0.74] if >2 mo/child and OR, 0.58 [95% CI, 0.42-0.82] if ≤2 mo/child vs none), African American ethnicity (OR, 2.10; 95% CI, 1.52-2.92), and younger age at diagnosis (OR, 3.02 [95% CI, 2.03-4.47] if ≤40 years vs >60 years). CONCLUSIONS: Among women with invasive breast cancer, higher parity and the absence or short duration of breastfeeding were independently associated with triple-negative BC. Any duration of breastfeeding was found to be associated with lower probability of triple-negative BC, and the odds of this phenotype decreased with increasing duration of breastfeeding.

Analysis of demographic and tumor characteristics of an inner city breast cancer patient population compared with patients treated in National Surgical Adjuvant Breast and Bowel Project trials.

In June of 2008 we initiated a breast clinic designed to serve patients regardless of funding status. We analyzed age, race,tumor size, nodal status, estrogen, progesterone, and her-2-neu status. We compared our results to NSABP B-06 (nodal status), B-15 (estrogen, progesterone, and Her-2-neu receptor status), B-18, and B-27 (age, race, and tumor size) to determine whether our patient population was similar to patients included in these trials. Forty-nine patients with newly diagnosed breast cancer were treated during our first year (53 total cancers). Eight patients had noninvasive cancer; 45 had invasive disease. The mean age was 52.2 +/- 12.2 years compared to a mean age of 48.4 +/- 9.8 years in the B-06 trial (P = 0.005). Thirty six patients were African American (74%) compared to 10% and 12% in the NSABP B-18 and B-27 trials (P < 0.00001). A total of 23 of our patients with invasive cancer had involved axillary lymph nodes which was statistically more common than the 35.3% of node positive patients in the B-06 trial (P = 0.03). Tumor size (3.6 +/- 3.3 cm), estrogen (54.4%), and progesterone (52.8%) receptor status were similar to NSABP trials. Only 6 (13.3%) of our patients were considered Her-2-neu positive compared to 29.4% in the B-15 trial which was significantly less prevalent (P = 0.02). Significantly different demographic and tumor characteristics were identified in our inner city breast cancer patient population compared to NSABP patients. These results question the validity of using recommendations from large cooperative group trials in the development of treatment plans for our inner city patient population.

Disparities in medical care among commercially insured patients with newly diagnosed breast cancer: opportunities for intervention.

BACKGROUND: African-American women have increased breast cancer mortality compared with white women. Diagnostic and treatment gaps may contribute to this disparity. METHODS: In this retrospective, longitudinal cohort study, Southern US health plan claims data and linked medical charts were used to identify racial disparities in the diagnoses, treatment, and mortality of commercially insured women with newly diagnosed breast cancer. White women (n = 476) and African-American women (n = 99) with newly diagnosed breast cancer were identified by breast cancer claims codes (International Classification of Diseases, Ninth Revision, Clinical Modification codes 174, 233.0, 238.3, and 239.3) between January 2000 and December 2004. Race, diagnoses (breast cancer stage, estrogen/progesterone receptor [ER/PR]-positive status), treatment (breast-conserving surgery, antiestrogen therapy, and chemotherapy interruption or reduction), and all-cause mortality were assessed from medical charts. Multivariate regression analyses were adjusted for age, geography, and socioeconomic status to test the association of race with diagnoses/treatment. RESULTS: White women were older (P < .001) and had higher rates of diagnosis at stage 0/I (55.2% vs 38.4%; P < .05) than African-American women. More white women had positive ER/PR status (75% vs 56% African-American; P = .001) and received antiestrogen therapy if they were positive (37.2% vs 27.3% African-American; P < .001). White women received slightly more breast-conserving surgery and chemotherapy dose modification than African-American women (P value nonsignificant). African-American women had a higher mortality rate (8.1%) than white women (3.6%; P = .06). In adjusted analyses, African-American women were diagnosed at later stages (odds ratio, 1.71; P = .02), and white women received more antiestrogen therapy (odds ratio, 2.1; P = .03). CONCLUSIONS: Disparities in medical care among patients with newly diagnosed breast cancer were evident between African-American women and white women despite health plan insurance coverage. Interventions that address the gaps identified are needed.

Second primary breast cancer occurrence according to hormone receptor status.

BACKGROUND: Contralateral second primary breast cancers occur in 4% of female breast cancer survivors. Little is known about differences in risk for second primary breast cancers related to the estrogen and progesterone receptor (hormone receptor [HR]) status of the first tumor. METHODS: We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for contralateral primary breast cancers among 4927 women diagnosed with a first breast cancer between January 1, 1992, and December 31, 2004, using the National Cancer Institute's Surveillance, Epidemiology, and End Results database. RESULTS: For women whose first breast tumors were HR positive, risk of contralateral primary breast cancer was elevated, compared with the general population, adjusted for age, race, and calendar year (SIR = 2.22, 95% CI = 2.15 to 2.29, absolute risk [AR] = 13 cases per 10 000 person-years [PY]), and was not related to the HR status of the second tumor. For women whose first breast tumors were HR negative, the risk of a contralateral primary tumor was statistically significantly higher than that for women whose first tumors were HR positive (SIR = 3.57, 95% CI = 3.38 to 3.78, AR = 18 per 10 000 PY), and it was associated with a much greater likelihood of an HR-negative second tumor (SIR for HR-positive second tumors = 1.94, 95% CI = 1.77 to 2.13, AR = 20 per 10 000 PY; SIR for HR-negative second tumors = 9.81, 95% CI = 9.00 to 10.7, AR = 24 per 10 000 PY). Women who were initially diagnosed with HR-negative tumors when younger than 30 years had greatly elevated risk of HR-negative contralateral tumors, compared with the general population (SIR = 169, 95% CI = 106 to 256, AR = 77 per 10 000 PY). Incidence rates for any contralateral primary cancer following an HR-negative or HR-positive tumor were higher in non-Hispanic blacks, Hispanics, and Asians or Pacific Islanders than in non-Hispanic whites. CONCLUSIONS: Risk for contralateral second primary breast cancers varies substantially by HR status of the first tumor, age, and race and/or ethnicity. Women with HR-negative first tumors have nearly a 10-fold elevated risk of developing HR-negative second tumors, compared with the general population. These findings warrant intensive surveillance for second breast cancers in women with HR-negative tumors.

Survival outcomes in men receiving androgen-deprivation therapy as primary or salvage treatment for localized or advanced prostate cancer: 20-year single-centre experience.

OBJECTIVES: To evaluate the overall survival (OS) and disease-specific survival (DSS) in men receiving primary androgen-deprivation therapy (PADT) or salvage medical ADT (SADT) for prostate cancer. PATIENTS AND METHODS: After Institutional Review Board approval, we retrospectively reviewed patients receiving ADT for prostate cancer between July 1987 and June 2007. Variables included age at diagnosis and ADT induction, race, PSA level before ADT, ADT schedule (continuous/intermittent), clinical/pathological stage, hormone-refractory prostate cancer (HRCP) status, PADT or SADT, and deaths. RESULTS: In all, 548 men were analysed. The mean age at diagnosis and ADT induction were 70.1 and 72.3 years, respectively, and 321 (58.6%) were African-American. The median PSA level before ADT was 16.3 ng/mL. ADT was administered continuously in 497 (90.7%) patients; 342 (62.4%) received PADT while 206 (37.6%) received SADT. At mean (range) follow-up of 81.8 (2.1-445) months, 98 (17.9%) deaths occurred; 31 (31.6%) were cancer-specific. The OS and DSS in the PADT and SADT groups were not significantly different (P = 0.36 and P = 0.81, respectively). Mortality rates/distributions were similar between groups (P = 0.68). Multivariate predictors of OS and DSS included age at diagnosis (P = 0.03) and ADT induction (P = 0.009), tumour stage (P < 0.001), and PSA level at ADT induction (P = 0.01). Progression to HRPC worsened OS and DSS (both P < 0.001). CONCLUSION: PADT and SADT prolong survival in men with prostate cancer. HRPC portends a poor DSS. Age at diagnosis and ADT induction, PSA level before ADT, and disease stage predict both OS and DSS in this population. However, most men died from causes unrelated to prostate cancer, thus questioning the true value of ADT in prolonging patient survival.

Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women.

FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

Recent breast cancer trends among Asian/Pacific Islander, Hispanic, and African-American women in the US: changes by tumor subtype.

BACKGROUND: Recently, unprecedented drops in breast cancer incidence have been reported for populations of mostly White European descent. Incidence patterns in non-White racial/ethnic groups are less described. Therefore, we examined population-based breast cancer incidence trends separately for US Asian/Pacific Islander, Hispanic, African-American, and non-Hispanic White women by etiologically relevant tumor subtype characteristics, including hormone receptor status, histology, size, and in situ behavior. METHODS: We obtained breast cancer data from 13 Surveillance, Epidemiology, and End Results (SEER) cancer registries to calculate age-adjusted incidence rates and trends, stratified by race/ethnicity and tumor subtype for the period 1992-2004. Detailed analyses were limited to women 50 years old or older. Joinpoint regression was used to assess incidence trends by annual quarter of diagnosis. RESULTS: Between 2001 and 2004, incidence rates of invasive breast cancer in women 50 years old or older declined appreciably among Asians/Pacific Islanders (-8.5%) and Hispanics (-2.9%) and were stable in African-Americans (+0.5%), reductions substantially lower than those observed among non-Hispanic Whites (-14.3%). In Asian/Pacific Islander women, perceptible but statistically nonsignificant decreases were observed for hormone receptor-positive, lobular, and small tumors only. Rates of hormone receptor-negative tumors increased among African-Americans (26.1%) and Hispanics (26.9%) during 2001-2004. Incidence trends in most groups, except African-American women, peaked between 1999 and mid-2002. Rates of in situ cancer remained stable in all groups. CONCLUSION: Recently reported reductions in breast cancer incidence varied considerably by race/ethnicity. These patterns are consistent with documented racial/ethnic differences in the prevalence and discontinuation of hormone therapy (HT) after July 2002 but do not correspond as well to patterns of mammography use in these groups. The data presented in this analysis provide further evidence that population-level HT use is a major influence on population-level rates of particular breast cancer subtypes, especially receptor-positive tumors.

Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome.

INTRODUCTION: Breast cancer is currently viewed as a heterogeneous disease made up of various subtypes, with distinct differences in prognosis. Our goal was to study the distribution and to characterize the clinical and biological factors that influence the behavior and clinical management of the different molecular breast cancer subtypes in premenopausal African-American women. METHODS: A retrospective analysis of Howard University Hospital tumor registry, for all premenopausal African-American women aged less than 50 years, diagnosed with breast cancer from 1998-2005, was performed. RESULTS: The luminal A subtype was the most prevalent (50.0%), vs basal-cell-like (23.2%), luminal B (14.1%), and HER-2/neu (12.7%). However when stratified by age groups, results showed that in the age group <35 years the basal-cell-like subtype was the most prevalent (55.6%), vs 25.9%, 14.8%, and 5.6% for luminal A, luminal B, and HER-2/neu subtypes, respectively (P < .000). P53 mutation was more prevalent in the basal-cell-like subtype compared to luminal A (48.0% vs 18.6%, P < .01). The expression of the Bcl-2 gene differed by subtype, with the luminal A and luminal B subtypes more likely to overexpress the Bcl-2 gene (89.1% luminal A, 80.0% luminal B vs 47.6% basal-cell-like and 40.0% HER-2/neu, P < .000). Though not statistically significant, HER-2/neu and basal-cell-like subtypes had the shortest survival time (P < .31). CONCLUSION: The high prevalence of the basal-cell-like subtype in young premenopausal African-American women aged <35 years may contribute to the poorer prognosis observed in this cohort of African-American women.

Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16.

BACKGROUND: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. METHODS: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. RESULTS: Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. CONCLUSIONS: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

The polymorphic CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is considered a hormonal-dependent tumor; estrogen induces endometrial cellular proliferation, whereas progestins display an antiproliferative effect on endometrial tissue. The role that androgen and its receptor (androgen receptor [AR]) play in the pathogenesis of endometrial carcinoma is less clear. Although androgen has an in vitro inhibitory effect on endometrial cell proliferation, up to 75% of endometrial carcinoma express AR somatically. A polymorphic CAG repeat within exon 1 of the AR encodes for a polyglutamine tract, with length range of 8 to 33 repeats, which is inversely correlated with the transcriptional activity of the AR. METHODS: To gain insight into the role of AR in endometrial carcinoma, the authors analyzed the polymorphic CAG repeat in 79 Jewish Israeli patients with endometrial carcinoma as compared with 44 healthy Jewish women serving as controls. Analysis was conducted using germline DNA as template and using polymerase chain reaction primers flanking the CAG repeat with subsequent fluorescent determination of allele sizes. RESULTS: Allele size range of the longer of the two alleles in the patients was 11-33 (mean, 19.8 +/- 2.7) and in the controls 10-22 (mean, 17.9 +/- 1.9), a statistically significant difference (P < 0.01). Allele size variation within the patient group did not correlate with disease stage, grade, reproductive history, or age at diagnosis. CONCLUSIONS: The authors conclude that AR-CAG repeat length differs in Jewish patients with endometrial carcinoma as compared with healthy individuals in Israel, and this finding increases the possibility that the AR is involved in the predisposition to this neoplasm.

Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2).

Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk.

Aromatase and breast cancer susceptibility.

Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-Latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA)n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.