Progesterone Receptor-positive Cancer Research Articles

Abstract PO3-15-09: LobSig4 is a superior and readily implementable ILC-focussed prognostic biomarker set

Abstract Invasive Lobular Carcinoma (ILC) is the most common special histological subtype of breast cancer. ILC typically present as Oestrogen and Progesterone Receptor positive cancers, without over-expression of HER2 and are defined by their invasive pattern of growth. Despite clinical and biological differences, including diverse sites of metastasis, ILC are managed in the same way as the more commonly diagnosed, Invasive Carcinomas of no special type. Previously, we derived the LobSig lobular specific gene signature in an attempt to prognosticate within an otherwise homogeneous tumour category. We showed that this set of genes could stratify Grade 2 and Nottingham Prognostic Index moderate tumours into high and low risk groups. Herein, we use a nanoString nCounter custom codeset and immunohistochemistry to validate the LobSig signature. Using a CoxBoost analysis we further refined the geneset to 14 genes of interest which we examined using Immunohistochemistry on a large panel of ILC with clinical follow up data. Four targets showed a significant association with breast cancer specific survival, with high levels correlating with the poorest outcomes. Considering the expression data for these 4 candidates together, we performed a Cox Proportional Hazard Regression resulting in a combined prognostic power of (P=0.00034, HR=8.07 (CI 2.58-25.30)), which has superior prognostic power over variables including tumor size and patient age. ‘LobSig4’ represents a readily implementable and informative biomarker set for prognostication in Invasive Lobular Carcinoma. Citation Format: Lauren Kalinowski, Jamie Kutasovic, Sriganesh Srihari, Yufan Feng, Samir Lal, Kaltin Ferguson, Haarika Chittoory, Anna Sokolova, Malcolm Lim, Priyakshi Kalita De Croft, Sunil Lakhani, Peter Simpson, Amy McCart Reed. LobSig4 is a superior and readily implementable ILC-focussed prognostic biomarker set [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-09.

TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2, and an important regulator of cancer growth and metastasis. Here, we evaluated the relationship between TIMP-2 gene rs4789936 polymorphism and breast cancer risk and prognosis in Southern Chinese women. Analysis of 480 breast cancer cases and 530 healthy controls revealed that compared to the CC genotype, the TT/CT genotypes increased the risk of breast cancer (CT: odds ratio (OR)=1.46, 95%CI: 1.11-1.92; TT: OR=2.57, 95%CI: 1.76-3.77). Stratified and cross-over analyses indicated that the increased risk of the rs4789936 polymorphism was associated with age, smoking, drinking, and the body mass index. The TT and CT genotypes were more common than the CC genotype in patients with lymph node metastases (TT: OR=2.54, 95%CI: 1.54-4.18; CT: OR=2.10, 95%CI: 1.40-3.15), advanced stage (TT: OR=1.91, 95%CI: 1.17-3.14; CT: OR=1.80, 95%CI: 1.20-2.70), or progesterone receptor positive cancer (TT: OR=2.02, 95%CI: 1.23-3.32). Multivariate cox regression indicated the CT and TT genotypes (HR=4.65, 95%CI: 1.26-17.18, P=0.021; HR=6.62, 95%CI: 1.51-29.11, P=0.012) were associated with poor prognosis in breast cancer patients. Thus, the TIMP-2 gene rs4789936 polymorphism is associated with elevated breast cancer risk and may be an independent prognosis factor in breast cancer patients.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

IntroductionAntiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure.ObjectiveWe explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer.ResultsAmong the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist.ConclusionsThese results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Impact of oestrogen and progesterone receptor expression in the cancer cells and myometrium on survival of patients with endometrial cancer

Loss of oestrogen receptor (ER) and progesterone receptor (PR) expression in endometrial cancer cells indicates poor prognosis. The aim of this study was to determine the correlation of ER and PR expression in cancer cells and the surrounding myometrium with the disease progression. Immunohistochemical expression of ER and PR was detected in cancer and myometrial cells of patients with EC. ER was detected in 65.2% of cancer cells and in 88.4% of myometrial cells. PR was detected in 59.4% of cancer cells and in 84.1% of myometrial cells. The 5-year overall survival (OS) was 76.8%. Patients with ER and PR negative EC had a shorter period until recurrence (p = .013 and .043) and shorter OS (p = .011 and .066) than those with ER and PR positive cancer. Negative ER and PR status in EC has an impact on recurrence and poor OS. The status of hormone receptors in myometrium may be useful in disease prognosis.Impact StatementThe status of hormone receptors in endometrial cancer has been the subject of numerous studies and loss of hormone receptors indicates higher tumor grade and higher clinical stage, lympho-vascular space invasion and deeper myometrial invasion. Although, the communication between the endometrium and myometrium is crucial under physiological conditions, the status of hormone receptors in the myometrium and its significance in cancer progression is poorly studied.Our results showed that loss of ER in the myometrium indicate poor prognosis. The assessment of hormone receptor status in myometrium might be useful in predicting the course of the disease. Results of our research support the theory that stromal and myometrial cells may contribute to tumorigenesis in endometrial cancer.Better understanding of ER/PR expression in myometrial cells is needed, and our research opens new possibilities for identification of key pathways and new potential target molecules in EC prognosis and treatment. It is probable that future classification of endometrial cancer will rely on molecular sub-typing, where the status of hormone receptors in the myometrium might play an important role.

Abstract 5325A: Fruit and vegetable intake and risk of breast cancer: Pooled analysis of the Nurses’ Health Study and the Nurses’ Health Study II

Abstract Fruit and vegetable intake has been hypothesized to protect against breast cancer, but the overall evidence has not been supportive. Using pooled data from the Nurses’ Health Study and the Nurses’ Health Study II cohorts, we evaluated fruit and vegetable intake in relation to breast cancer risk. Diet was assessed every 4 years using semi-quantitative food frequency questionnaires. Cox proportional hazards regression, adjusting for multiple breast cancer risk factors, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs)for each category, using the lowest quintile of intake as the reference category. Among 182,204 women aged 27 to 66 years, we prospectively identified 10,973 invasive breast cancer cases during follow-up from 1980 through 2012 for the Nurses’ Health Study and from 1991 through 2013 for the Nurses’ Health Study II. Fruit and vegetable intake was significantly associated with a lower risk of breast cancer. The pooled multivariate HR (95% CIs) for highest (3.2 servings/day) versus lowest (0.4 serving/day) quintile intake of total fruit intake was 0.93 (0.86-0.99; Ptrend=0.03) and for highest (4.9 servings/day) versus lowest (1.5 servings/day) quintile intake of total vegetable was 0.92 (0.86-0.99; Ptrend=0.02). We also observed that a higher intake of yellow/orange vegetables, cruciferous vegetable, fruits and vegetables rich in vitamin C, fruits and vegetables rich in α-carotene, fruits and vegetables rich in β-carotene, and fruits and vegetables rich in lutein was each associated with a lower breast cancer risk. In addition, the association with vegetable intake was stronger for both estrogen and progesterone receptor negative (HR=0.91; 95%CIs=0.87-0.95) than both estrogen and progesterone receptor positive cancers (HR=0.98; 95%CIs=0.96-1.00; Pheterogeneity=0.003). Our findings support an association of a higher fruit and vegetable intake with a lower breast cancer risk. Citation Format: Maryam S. Farvid, Walter C. Willett, A. Heather Eliassen. Fruit and vegetable intake and risk of breast cancer: Pooled analysis of the Nurses’ Health Study and the Nurses’ Health Study II [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5325A. doi:10.1158/1538-7445.AM2017-5325A

Trends in Reoperation After Initial Lumpectomy for Breast Cancer

Surgery after initial lumpectomy to obtain more widely clear margins is common and may lead to mastectomy. To describe surgeons' approach to surgical margins for invasive breast cancer, and changes in postlumpectomy surgery rates, and final surgical treatment following a 2014 consensus statement endorsing a margin of "no ink on tumor." This was a population-based cohort survey study of 7303 eligible women ages 20 to 79 years with stage I and II breast cancer diagnosed in 2013 to 2015 and identified from the Georgia and Los Angeles County, California, Surveillance, Epidemiology, and End Results registries. A total of 5080 (70%) returned a survey. Those with bilateral disease, missing stage or treatment data, and with ductal carcinoma in situ were excluded, leaving 3729 patients in the analytic sample; 98% of these identified their attending surgeon. Between April 2015 and May 2016, 488 surgeons were surveyed regarding lumpectomy margins; 342 (70%) responded completely. Pathology reports of all patients having a second surgery and a 30% sample of those with 1 surgery were reviewed. Time trends were analyzed with multinomial regression models. Rates of final surgical procedure (lumpectomy, unilateral mastectomy, bilateral mastectomy) and rates of additional surgery after initial lumpectomy over time, and surgeon attitudes toward an adequate lumpectomy margin. The 67% rate of initial lumpectomy in the 3729 patient analytic sample was unchanged during the study. The rate of final lumpectomy increased by 13% from 2013 to 2015, accompanied by a decrease in unilateral and bilateral mastectomy (P = .002). Surgery after initial lumpectomy declined by 16% (P < .001). Pathology review documented no significant association between date of treatment and positive margins. Of 342 responding surgeons, 69% endorsed a margin of no ink on tumor to avoid reexcision in estrogen receptor-positive progesterone receptor-positive cancer and 63% for estrogen receptor-negative progesterone- receptor-negative cancer. Surgeons treating more than 50 breast cancers annually were significantly more likely to report this margin as adequate (85%; n = 105) compared with those treating 20 cases or fewer (55%; n = 131) (P < .001). Additional surgery after initial lumpectomy decreased markedly from 2013 to 2015 concomitant with dissemination of clinical guidelines endorsing a minimal negative margin. These findings suggest that surgeon-led initiatives to address potential overtreatment can reduce the burden of surgical management in patients with cancer.

Evaluation of the Quality of Adjuvant Endocrine Therapy Delivery for Breast Cancer Care in the United States

Randomized trials in breast cancer have demonstrated the clinical benefits of adjuvant endocrine therapy (AET) in preventing recurrence and death. The examination of concordance with AET guidelines at a national level as a measure of quality of care is important. To investigate temporal trends and factors related to receipt of AET for breast cancer. This retrospective cohort study included 981 729 women with breast cancer in the National Cancer Database from January 1, 2004, to December 31, 2013. Women with stages I to III breast cancer who received all or part of their treatment at the reporting institution were included in the analysis. Temporal changes in AET receipt (estimating the annual percentage change) and AET practice patterns (using logistic regression) and the effect of AET guideline concordance on survival of women with hormone receptor-positive (HR+) breast cancer (using the multivariable Cox proportional hazards model). Of the 981 729 eligible patients (mean [SD] age, 60.8 [13.3] years), 818 435 had HR+ and 163 294 had HR-negative (HR-) cancer. Among the patients with HR+ cancer, receipt of AET increased over time, from 69.8% in 2004 to 82.4% in 2013. Among patients with HR- cancer, receipt decreased from 5.2% in 2004 to 3.4% in 2013. Hospital-level adherence (≥80% of patients with HR+ cancer received AET) increased from 40.2% in 2004 to 69.2% in 2013. Receipt of AET varied significantly by age (lower in patients ≥80 years), race (lower in African American and Hispanic participants), geographic location (lower in West South Central, Mountain, and Pacific census regions), and receptor status (lower in patients with estrogen receptor-negative and progesterone receptor-positive cancer). Surgery and radiotherapy were the factors most significantly associated with appropriate AET receipt (only 45.0% in patients who received lumpectomy without radiotherapy). Receipt of AET was associated with a 29% relative risk reduction in mortality. Based on this effectiveness estimate, if all patients with HR+ cancer received AET, approximately 14 630 lives would have been saved over 10 years. From 2004 to 2013, underuse and misuse of AET have decreased for patients with breast cancer, but optimal use has not been achieved, and significant variation in care remains. The involvement of surgery and radiotherapy were among the most significant factors associated with optimal use, which underscores the benefits of team-based care to support guideline-concordant therapy.

Relationship between traditional Chinese medicine constitutional types with chemotherapy-induced nausea and vomiting in patients with breast cancer: an observational study.

BackgroundThe theory of traditional Chinese medicine (TCM) constitution involves genetic characteristics, psychological factors, organ functions, and many other aspects. Studies have shown that TCM constitution is associated with HLA polymorphisms and has a genetic basis. A large number of Chinese studies have suggested that the clinical evolution of breast cancer may differ among patients with different TCM constitutions. In addition, patients with breast cancer and different TCM constitutions may have different degrees of myelosuppression after chemotherapy. Some studies have revealed that some constitutions may become predictive factors for death and morbidity of some diseases. The study was to investigate the risk factors among TCM constitutions for chemotherapy-induced nausea and vomiting (CINV) in patients with primary breast cancer undergoing chemotherapy.MethodsFrom September 2008 to January 2014, 612 patients who underwent surgery and chemotherapy for breast cancer in three hospitals in Xi’an, Shanxi province, underwent TCM constitution assessment using the Nine Basic Constitutions in Chinese Medicine Questionnaire before chemotherapy. CINV was monitored during treatments. Patients were asked to complete the Functional Living Index-Emesis (FLIE) questionnaire. The most severe CINV grade during chemotherapy was recorded according to the WHO standard. The relationships between TCM constitutions, CINV, and clinical and pathological characteristics of the cancers were assessed.ResultsThere were no differences in the incidence of CINV among breast cancer patients receiving different chemotherapy regimens, and among patients with different TCM constitutions. The wetness-heat score was an independent risk factor for severe CINV (grade III-IV) (OR = 1.012, 95 % CI: 1.007–1.021, P < 0.001). In-depth analyses of the wetness-heat constitution showed that bitter taste/smelly mouth was an independent risk factor for severe CINV (OR = 1.209, 95 % CI: 1.035–1.412, P = 0.017), as well as progesterone receptor-positive cancer (OR = 1.429, 95 % CI: 1.030–1.981, P = 0.032). Vomiting history was a protective factor against CINV (OR = 0.548, 95 % CI: 0.353–0.849, P = 0.007).ConclusionRisk of grade III-IV nausea and vomiting was higher in breast cancer patients with TCM constitution of wetness-heat, especially bitter taste or smelly mouth.

High fruit intake, lower alcohol consumption associated with lower breast cancer risk

Researchers in 2 linked studies recently published in BMJ have revealed new data on the relation of alcohol and diet with breast cancer and heart disease.1, 2 The first study found that high fruit consumption during adolescence is associated with lower breast cancer risk, whereas the second reports that increased alcohol intake in later life is associated with an increase in breast cancer. Evidence about whether fruit and vegetable intake protects against breast cancer is conflicting. Most studies in this area have assessed intake during midlife and later, which may be after the period when breast tissue is most vulnerable to carcinogenic influences. As a result, researchers examined whether fruit and vegetable consumption would affect subsequent breast cancer risk. In the first study, participants included more than 90,000 premenopausal women aged 27 to 44 years from the Nurses' Health Study II who completed a questionnaire in 1991 on diet as well as more than 44,000 who completed a questionnaire in 1998 that focused on their diet during adolescence. The investigators concluded that high fruit consumption during adolescence (2.9 vs 0.5 servings per day) was associated with an approximately 25% lower risk of premenopausal breast cancer diagnosed in middle age. The association with adolescent fruit intake was stronger for both estrogen and progesterone receptor-negative cancers than estrogen and progesterone receptor-positive cancers. Specifically, apple, banana, and grape consumption during adolescence and orange and kale consumption during early adulthood were significantly associated with a reduced breast cancer risk; however, there was no link between the intake of fruit juice in either adolescence or early adulthood and risk. In an accompanying editorial, University of Oxford researchers note that although much more evidence is needed before conclusions can be drawn about the protective associations between adolescent fruit intake and breast cancer risk, fruit and vegetable intake should continue to be encouraged at all ages because of the known beneficial health effects.3 In the second study, Danish researchers analyzed the effect of a change in alcohol intake on the risk of breast cancer and heart disease. They followed the health of nearly 22,000 postmenopausal women in Denmark and found that women who increased their alcohol intake by 2 drinks per day over 5 years had an approximately 30% increased risk of breast cancer but an approximately 20% decreased risk of coronary heart disease in comparison with women who had stable alcohol intake. Decreased alcohol intake in women during the 5-year period, however, was not significantly associated with the risk of either breast cancer or coronary heart disease. The authors note that although their findings support the theory that alcohol is associated with breast cancer and coronary heart disease risk in opposite directions, the true effect of alcohol on ischemic heart disease is not certain. They add that although low to moderate alcohol consumption may provide some benefit to the heart, this is outweighed by an increased risk of breast cancer and other morbidities. Furthermore, heart disease risk can be substantially reduced by other lifestyle changes and drugs such as statins.

Fruit and vegetable consumption in adolescence and early adulthood and risk of breast cancer: population based cohort study

Objective To evaluate the association between fruit and vegetable intake during adolescence and early adulthood and risk of breast cancer.Design Prospective cohort study.Setting Health professionals in the United States.Participants 90...

Invasive Lobular Carcinoma: MRI Features and Clinicohistological Characteristics According to the ER, PR, and HER2 Statuses

Purpose: To investigate correlations of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2) statuses with magnetic resonance imaging (MRI) features and clinicohistological characteristics in patients with invasive lobular carcinoma (ILC). Materials and Methods: Data from 64 histologically confirmed ILCs were analyzed retrospectively. Preoperative breast MRI was reviewed for morphology and dynamic contrast-enhanced kinetics of the tumor. Pathologic reports were reviewed for ER, PR, and HER2 positivity, tumor size, lymph node metastasis, and the number of metastatic lymph nodes. Furthermore, there was an investigation of the MRI features and clinicohistologic characteristics, according to the ER, PR, and HER2 statuses. Results: A significant difference in MRI features and clinicohistological tumor characteristics were observed only in relation to PR status. Of the 64 ILCs, 10 (15.6%) were PR negative. PR negative cancers, compared with PR positive cancers, were more likely to present as non-mass enhancement (P = 0.027); have a significantly larger mean tumor size (5.00 ± 1.05 cm vs. 2.57 ± 0.21 cm, P = 0.021); and have significantly more metastatic lymph nodes (P = 0.010). Conclusion: PR negative ILC presented more frequently as non-mass enhancement on MRI, with larger tumors and increased numbers of metastatic lymph nodes. Therefore, the PR status plays an important role in determining MRI features and clinicohistological characteristics of ILC.

Abstract P1-13-13: Association between the serum concentrations of tamoxifen and its metabolites and age during steady state breast cancer treatment

Abstract It has been suggested that the concentrations of tamoxifen and its demethylated metabolites increase with age. Here, we measured the serum concentrations of the active tamoxifen metabolites, 4OHtamoxifen (4OHtam), 4OHNdesmethyltamoxifen (4OHNDtam, Endoxifen), tamoxifen and its demethylated metabolites. Their relations to age were examined. 151 breast estrogen receptor and/or progesterone receptor positive cancer patients were included. Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Their serum concentrations were related to the age of the patients. The concentrations of 4OHNDtam, tamoxifen, NDtam (N-desmethyltamoxifen), and NDDtam (N-desdimethyltamoxifen) were positively correlated to age (n = 151, P = 0.017, 0.045, 0.011, and 0.001 respectively). Up to tenfold inter-patient variation in the serum concentrations was observed. The median (inter-patient range) of the concentrations 4OHNDtam in the age groups 30-49, 50-69 and &amp;gt;69 years were 44 (65) ng/ml, 51 (116) ng/ml, and 54 (159) ng/ml, respectively. We conclude that the serum concentrations of 4OHNDtam (endoxifen), tamoxifen and its demethylated metabolites increase with age during steady state tamoxifen treatment. The observed high inter-patient range in serum concentrations of tamoxifen and its metabolites, especially in the highest age group, suggest that use of therapeutic monitoring of tamoxifen and its metabolites is warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-13.

Breast Cancer Among Nurses: Is the Intensity of Night Work Related to Hormone Receptor Status?

The aim of this study was to investigate whether night work is related to breast cancer receptor status. The effect of night work on the risk of estrogen receptor- and progesterone receptor-defined breast cancers was evaluated in 513 nurses diagnosed with breast cancer between 1996 and 2007 and in 757 frequency-matched controls, all of whom were selected from a cohort of Norwegian nurses. Odds ratios for the exposure "duration of work with a minimum of 6 consecutive night shifts" were compared for tumor subgroups with respect to the common control group through the use of polytomous logistic regression. Statistically significant associations were observed between breast cancer and work durations of ≥ 5 years with ≥ 6 consecutive night shifts, with the highest risk observed for progesterone receptor-positive tumors (odds ratio = 2.4, 95% confidence interval: 1.3, 4.3; P-trend = 0.01). When the exposure variable was dichotomized (ever/never worked ≥ 6 consecutive night shifts), a borderline statistically significant heterogeneity (P = 0.05) was seen between progesterone receptor-positive and progesterone receptor-negative tumors in postmenopausal women. The association observed between consecutive night shifts and progesterone receptor-positive cancers suggests that progesterone could play an important role in the detrimental effects of night work.

A retrospective review of demographics and stage of triple-negative breast cancer

e11553 Background: Triple negative breast cancer (TNBC) is a recently recognized subtype of breast cancer, notable to metastasize early. It accounts for 15–20% of all breast cancers, and is more prevalent in African-American and Hispanic women, and women younger than 40 years of age. Continual decline in breast cancer deaths since 1990 has been attributed to earlier detection, better treatment including hormonal blockade in estrogen- and progesterone-receptor positive cancers, as well as the addition of Trastuzumab, a monoclonal antibody directed against the Her2/neu receptors. These hormone receptors are not found in TNBC, and therefore the traditional targets for endocrine manipulation cannot be therapeutically exploited. While lower socioeconomic status and racial predisposition to this disease have been observed, there exists a paucity of research into other demographic risk factors. We reviewed data between January 2000 to December 2005 from our tumor registry with particular attention to age, race, family history, tobacco use, and stage of presentation, comparing this subset of patients (n=39) to other records (n=303). We included only those patients in whom the status of all three receptors were recorded. Results: Comparisons were made for TNBC vs non-TNBC patients respectively as follows: mean age (59.87± yrs vs 60.09±yrs). Analysis using χ2 test (χ2=0.855) and CMH test for Linear Trend analysis (p=0.47) showed no difference in percentages in association with the 5 stages or TNBC status and no linear trend respectively. Conclusions: This data suggests that at our institution, TNBC is less prevalent (12.87%) than estimates of 15- 20% published in other studies. There was no difference in age at diagnosis (p=0.92), with black patients more likely to have TNBC (p=0.004, OR=2.75). There was no significant association between smoking status and TNBC (p=0.43). There was no significant association between a family history of cancer and TNBC (p=0.8384). When accounting for samples size, TNBC was as prevalent as non TNBC at all stages of diagnosis. These results differ from other published data and may reflect differences in statistical analysis. No significant financial relationships to disclose.

A retrospective review of demographics and stage of presentation in patients with ER/PR/Her2-neu receptor negative breast cancer.

Abstract Abstract #2097 Background: Estrogen receptor/progesterone receptor/Her2-neu receptor negative, or “triple negative” breast cancer (TNBC) is notable for its propensity to metastasize early and display a comparatively more aggressive course. Some estimates comprise approximately 15-20% of all breast cancers, and it is apparently more prevalent in African-American women, Hispanic women, and women younger than 40 years of age. There has been a continual decline in death rates due to breast cancer since 1990 attributed to both earlier detection, as well as better treatment modalities including hormonal blockade in estrogen- and progesterone-receptor positive cancers, as well as the anti-Her2/neu receptor antibody, Trastuzumab. These hormone receptors are not found in TNBC, and therefore the traditional targets for endocrine manipulation cannot be therapeutically exploited. While lower socioeconomic status and racial predisposition to this aggressive disease have been observed, there exists a paucity of research into other demographic risk factors or associations. Methods: We reviewed data between January 2000 to December 2005 from our tumor registry with particular attention to age, race, family history, tobacco use, and stage of presentation, comparing this subset of patients (n=39) to other records (n=303). We included only those patients in whom the status of all three receptors were recorded. Results: Comparisons were made for TNBC vs non-TNBC patients respectively as follows: mean age (59.87±15.67 yrs vs 60.09±13.98 yrs); Black, 58.97% vs 39.27%; White, 35.90% vs 57.76%; Other minorities, 2.56% vs 0.99%; Unknown, 2.56% vs 0.33%. Comparisons with respect to tobacco history for TNBC vs non-TNBC patients respectively: cigarettes, 15.38% vs 18.81%; non smokers, 71.79% vs 61.72%; ex smokers, 5.13% vs 8.91%; chewing tobacco, 0% vs 0.33% and unknown, 7.69% vs 10.23%. Positive family history of cancer, 30.77% vs 33.33%; no family history of cancer, 51.28% vs 51.82%, and unknown, 17.95% vs 14.85%. Pathologic stage at diagnosis for TNBC vs non-TNBC patients respectively: Stage 0, 15.79% vs 11.37%; stage 1, 34.21% vs 30.98%; stage 2, 28.98% vs 37.25%; stage 3, 18.42% vs 17.25%, and stage 4, 3.63% vs 3.14%. Analysis using χ2 test (χ2=0.855) and CMH test for Linear Trend analysis (p=0.4775) showed no difference in percentages in association with the 5 stages or TNBC status and no linear trend respectively. Conclusion: This data suggests that at our institution, TNBC is less prevalent (12.87%) than estimates of 15-20% published in other studies. There was no difference in age at diagnosis (p=0.9272), with black patients more likely to have TNBC (p=0.004, OR=2.755). There was no significant association between smoking status and TNBC (p=0.4385). There was no significant association between a family history of cancer and TNBC (p=0.8384). When accounting for samples size, TNBC was as prevalent as non TNBC at all stages of diagnosis (p=0.4332, p=0.6890, p=0.3205, p=0.8591, and p=0.8651 respectively). These results differ from other published data and may reflect differences in statistical analysis or patient population. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2097.

Genetic variants in fibroblast growth factor receptor 2 (FGFR2) contribute to susceptibility of breast cancer in Chinese women

Fibroblast growth factor receptor 2 (FGFR2) belongs to the FGFR family, which plays an important role in cell growth, invasiveness, motility and angiogenesis. In human breast cancer, expression of FGFR2 is estrogen receptor (ER)-dependent and correlates with a lower rate of apoptosis. Recently, whole-genome association studies have identified several single-nucleotide polymorphisms (SNPs) of FGFR2 as novel breast cancer susceptibility loci. In the present study of 1049 breast cancer patients and 1073 cancer-free controls, we assessed whether polymorphisms of FGFR2 are associated with breast cancer risk in Chinese women and whether these associations are stronger in women with a reproductive history suggestive of greater exposure to endogenous estrogens. We genotyped three FGFR2 polymorphisms (rs2981582C/T, rs1219648A/G and rs2420946C/T) using the SNPstream 12-plex platform. Each of the three SNPs was significantly associated with increased breast cancer risk in a dose-dependent manner. Compared with women with 0-2 risk loci, those with 3 risk loci had a 1.36-fold increased odds of breast cancer (95% confidence interval = 1.13-1.62, P = 0.001). In stratified analyses, associations between the presence of 3 risk loci and breast cancer were stronger among women with ER- and/or progesterone receptor-positive cancers, premenopausal women and women with an older age at first live birth. Furthermore, there was a significant additive interaction between risk genotypes and menopausal status (P for multiplication interaction/additive interaction: 0.083/0.037). These findings indicate that genetic variants in FGFR2 may contribute to breast cancer occurrence in Chinese women, possibly through pathways related to estrogen and/or progesterone.

A prospective study of grapefruit and grapefruit juice intake and breast cancer risk

Sir, In a recent interesting study by Monroe et al (2007), grapefruit intake was associated with an increase in breast cancer risk, and they hypothesised that this might be mediated by an effect on endogenous oestrogen levels. However, the researchers were unable to examine grapefruit juice intake. Therefore, we examined grapefruit and grapefruit juice intake and breast cancer risk in the Nurses' Health Study. Briefly, the Nurses' Health Study is a prospective cohort consisting of women aged 30–55 years in 1976 (Kim et al 2006). Medical and lifestyle information was obtained with general follow-up questionnaires every 2 years and with semi quantitative food frequency questionnaires that included intakes of grapefruit and grapefruit juice in 1984, 1986, 1990, 1994, and 1998. In both age-adjusted (not shown) and multivariate analyses adjusted for standard breast cancer risk factors, we found no overall association with either grapefruit or grapefruit juice intake and breast cancer risk among all women in the cohort, and among postmenopausal women only (Table 1). Furthermore, our results did not change once additional covariates – alcohol, saturated fat, dietary fibre, and soluble fibre – included by Monroe et al were added to our models. Table 1 Multivariate relative risks of breast cancer incidence between 1984 and 2002 by cumulatively averaged grapefruit and grapefruit juice intake Stratification by BMI did not alter the breast cancer risk with either grapefruit or grapefruit juice intake. However, stratification by hormone therapy showed a significant decrease in risk of breast cancer with greater intake of grapefruit in women who never used hormone therapy (multivariate RR comparing ¼ grapefruit or more per day to none=0.78, 95% CI, 0.59–1.04, P trend=0.03). This is contrary to the findings of Monroe et al, who observed a significant increase in risk of breast cancer with greater consumption of grapefruit in this subgroup. Furthermore, the association between grapefruit (not grapefruit juice) intake and breast cancer risk differed significantly by oestrogen and progesterone receptor status of the tumours. No association was observed in women with oestrogen and progesterone receptor positive cancers. However, in women with oestrogen and progesterone receptor negative cancers, there was a significant decrease in breast cancer risk with increased consumption of grapefruit (multivariate RR comparing ¼ grapefruit or more per day to none=0.60, 95% CI, 0.37–0.98, P trend=0.03). We also examined cross-sectionally the relationship between consumption of grapefruit and grapefruit juice and plasma levels of oestrogens among 701 postmenopausal women not using hormone replacement. No significant correlation was observed (grapefruit, grapefruit juice) for plasma oestradiol (r=0.02, −0.04), oestrone (r=0.00, −0.02), or oestrone sulphate (0.09, 0.01). Our findings do not support an adverse effect of consumption of grapefruit or grapefruit juice on risk of breast cancer or on endogenous hormone levels.

Aberrant expression of HOX genes in human invasive breast carcinoma

HOX genes are known not only as master genes that control the morphogenesis, but also as regulator genes that maintain tissue or organ specificity in the adult body. We hypothesized that dysregulated expression of HOX genes was associated with tumor development and malignant progression such as invasion and metastasis. In this study, we analyzed the expression patterns of 39 HOX genes in human invasive ductal breast cancer tissues and normal tissues by the real-time RT-PCR method. We found 11 HOX genes (HOXA1, A2, A3, A5, A9, C11, D3, D4, D8, D9 and D10) expression levels of which were significantly different between cancerous and normal tissues. All 10 genes except HOXC11 were expressed at lower levels in cancerous tissues than normal tissues. Comparing expression levels of each HOX gene among the different types of cancer tissues, the expression level of HOXB7 was lower in lymph node metastasis-positive cancer tissues than negative cancer tissues; those of HOXD12 and D13 were higher in progesterone receptor-positive cancer tissues than negative cancer tissues; and the expression level of HOXC5 was lower in cancerous tissues with mutated-type p53 than in normal and cancerous tissues with wild-type p53. These results suggest that the aberrant expression of HOX genes is related to the development of breast cancer and malignant behavior of cancer cells.

抗がん剤のｍｏｌｅｃｕｌａｒ ｔａｒｇｅｔｉｎｇ 女性ホルモン受容体を標的とした癌治療

Estrogen and progesterone, female sex hormones, are known to play important roles in female reproductive health via their nuclear receptors. Some cancers and tumors show these female sex hormones(especially estrogen)dependent growth and development. Therefore, various types of drugs, which modulate these hormonal effects, have been developed and used for treatment of estrogen receptor(ER) and/or progesterone receptor(PR) positive cancers since 1960 s. In this decade. the researches on structures and functions of ER and PR isoforms have rapidly been promoted by the progress of molecular biology. The researches and developments of new drugs against ER and/or PR positive cancers(e.g. pure antiestrogen, progesterone receptor modulators) are also in progress. In this review, we will introduce the functions of ER and PR, endocrine therapy for ER and/or PR positive cancers, and recent researches on new compounds and natural products which show antitumor effects against ER and/or PR positive cancers.

MYEOV: a candidate gene for DNA amplification events occurring centromeric to CCND1 in breast cancer.

Rearrangements of chromosome 11q13 are frequently observed in human cancer. The 11q13 region harbors several chromosomal breakpoint clusters found in hematologic malignancies and exhibits frequent DNA amplification in carcinomas. DNA amplification patterns in breast tumors are consistent with the existence of at least 4 individual amplification units, suggesting the activation of more than 1 gene in this region. Two candidate oncogenes have been identified, CCND1 and EMS1/CORTACTIN, representing centrally localized amplification units. Genes involved in the proximal and distal amplicons remain to be identified. Recently we reported on a putative transforming gene, MYEOV, mapping 360 kb centromeric to CCND1. This gene was found to be rearranged and activated concomitantly with CCND1 in a subset of t(11;14)(q13;q32)-positive multiple myeloma (MM) cell lines. To evaluate the role of the MYEOV gene in the proximal amplification core, we tested 946 breast tumors for copy number increase of MYEOV relative to neighboring genes or markers. RNA expression levels were studied in a subset of 72 tumors for which both RNA and DNA were available. Data presented here show that the MYEOV gene is amplified in 9.5% (90/946) and abnormally expressed in 16.6% (12/72) of breast tumors. Amplification patterns showed that MYEOV was most frequently coamplified with CCND1 (74/90), although independent amplification of MYEOV could also be detected (16/90). Abnormal expression levels correlated only partially with DNA amplification. MYEOV DNA amplification correlated with estrogen and progesterone receptor-positive cancer, invasive lobular carcinoma type and axillary nodal involvement. In contrast to CCND1 amplification, no association with disease outcome could be found. Our data suggest that MYEOV is a candidate oncogene activated in the amplification core located proximal to CCND1.