Tamoxifen Chemoprevention Research Articles

Abstract SS02-03: Cancer risk associated with exogenous hormone use in BRCA mutation carriers

Abstract Women with a pathogenic vari ant (mutation hereafter) in the BRCA1 or BRCA2 gene face the highest known lifetime risks of developing breast cancer. Notably, incidence rates increase rapidly in early adulthood but remain high even after age 60. Thus, understanding how exogenous (anti)hormones impact these risks is important for the safe clinical management of high-risk women, especially following early surgical menopause. In this session, I will review the current data on the role of tamoxifen chemoprevention, as well as the impact of oral contraceptives, hormone replacement therapy and fertility medication on breast cancer risk. Where possible, I will also discuss associations with ovarian cancer, given that managing BRCA-cancer risks is a balancing act, and present findings by gene mutation. Gaps in the literature and opportunities for further research will also be described. Our goal should be to maximize survival while optimizing health following risk-reducing salpingo-oophorectomy. Citation Format: J. Kotsopoulos. Cancer risk associated with exogenous hormone use in BRCA mutation carriers [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 SS02-03.

Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07). Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management.

Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.

Metformin and Chemoprevention: Potential for Heart-Healthy Targeting of Biologically Aggressive Breast Cancer.

Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the “whole woman healthy.” To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.

Abstract P1-02-06: Effect of chemoprevention on convolutional neural network-based breast cancer risk model using a mammographic dataset of women with atypical hyperplasia, lobular and ductal carcinoma in situ

Abstract Background: Mammographic density (MD) is a strong predictor of breast cancer risk and has been shown to predict response to tamoxifen for chemoprevention. We have developed a novel convolutional neural network (CNN)-derived pixel-wise breast cancer risk model, which is a more accurate predictor of breast cancer risk than MD. Our objective was to investigate how chemoprevention use among women with atypical hyperplasia (AH), lobular or ductal carcinoma in situ (LCIS/DCIS) is associated with change in the CNN breast cancer risk model. Methods: We conducted a retrospective cohort study of patients diagnosed with AH, LCIS, or DCIS at Columbia University Irving Medical Center (CUIMC) in New York, NY between 2007 and 2015. We collected mammograms conducted at baseline (at diagnosis of AH/LCIS/DCIS or start of chemoprevention) and 3-5 years later. Demographic and clinical characteristics, chemoprevention use, and mammography images were extracted from the electronic health record. Briefly, each mammogram was normalized as a map of z-scores and resized to an input image size of 256x256. Then a contracting and expanding fully convolutional CNN architecture was composed entirely of 3x3 convolutions, a total of four strided convolutions instead of pooling layers, and symmetric residual connections. L2 regularization and augmentation methods were implemented to prevent over-fitting. High-risk was defined as an absolute CNN model score >0.5. Change in CNN breast cancer risk model from baseline to follow-up was defined as: 1) stay high risk; 2) stay low risk; 3) increase from low to high risk; 4) decrease from high to low risk. Unordered polytomous regression models were used to assess the association between change in CNN score with chemoprevention use. Results: Among 541 evaluable patients, the mean age was 60 years (SD, 9.56) and 69% were postmenopausal. About a third of women (N=184, 34%) initiated chemoprevention, including 72% on a selective estrogen receptor modulator (SERM), 19% on an aromatase inhibitor (AI), and 9% both. About 57% had high CNN breast cancer risk scores at baseline. Comparing women who initiated chemoprevention to those who did not, more women had a decrease in their CNN breast cancer risk model (33.7% vs. 22.9%) and fewer women had an increase in CNN score (11.4% vs. 20.2%). In multivariate analysis, those who were treated with chemoprevention were less likely to have an increase in CNN risk score (odds ratio=0.51, 95% confidence interval=0.28-0.92). Conclusions: We previously reported that our CNN based algorithm can predict breast cancer risk and we now demonstrate that the CNN breast cancer risk model is modifiable on serial mammograms from high-risk women with proven chemopreventive agents, such as SERMs and AIs. Future studies should focus on whether these CNN mammographic changes are associated with subsequent development of breast cancer and may serve as a pharmacodynamics surrogate endpoint for breast cancer chemoprevention trials. Citation Format: Haley Manley, Simukayi Mutasa, Richard Ha, Katherine Crew. Effect of chemoprevention on convolutional neural network-based breast cancer risk model using a mammographic dataset of women with atypical hyperplasia, lobular and ductal carcinoma in situ [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-02-06.

Risk versus Benefit of Chemoprevention among Raloxifene and Tamoxifen Users with a Family History of Breast Cancer.

Tamoxifen and raloxifene have been approved for the primary prevention of breast cancer in high-risk women, but are associated with an increased risk of serious side effects. Few studies have characterized risk-benefit profiles for chemoprevention among women who initiate tamoxifen or raloxifene outside of a clinical trial setting. Use of raloxifene and tamoxifen for chemoprevention was self-reported in 2014 to 2016 by participants in The Sister Study, a prospective cohort of women with a sister who had been diagnosed with breast cancer. After exclusions, 432 current raloxifene users and 96 current tamoxifen users were matched to 4,307 and 953 nonusers, respectively, on age and year of cohort enrollment. Conditional logistic regression was used to evaluate characteristics associated with chemoprevention use. Risk-benefit profiles were examined using published indices that assess the level of evidence (none, moderate, strong) that the benefits of chemoprevention outweigh the risk of serious side effects. Among current chemoprevention users, 44% of tamoxifen users and 5% of raloxifene users had no evidence of a net benefit. In analyses of factors associated with chemoprevention use, having strong evidence of benefit was a significant predictor of raloxifene use, but not of tamoxifen use. In our sample of women with a first-degree family history of breast cancer, raloxifene was more commonly used for breast cancer prevention than tamoxifen. Most raloxifene users, but <60% of tamoxifen users, were likely to benefit. Use of risk-benefit tables can help women and their healthcare providers make an informed decision about breast cancer chemoprevention.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 266,120 In 2018, along with 63,960 new cases of non-invasive (in situ) breast cancer. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Prevention of breast cancer.

Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

Risk-Benefit Index of Tamoxifen and Raloxifene for Chemoprevention of Korean Breast Cancer

ABSTRACT Aim: According to the NSABP-P1 and P2 studies, tamoxifen and raloxifene can protect breast cancer and hip fracture, but they can induce endometrial cancer, stroke, and pulmonary embolism. We estimated the risks and benefits of tamoxifen and raloxifene using a Korean database in order to evaluate the feasibility of using tamoxifen and raloxifene for breast cancer chemoprevention in Korean women. Methods: Data were reviewed on the incidences of breast cancer, hip fracture, endometrial cancer and stroke in the absence of tamoxifen and raloxifene treatment in Korean women. We also reviewed NSABP-P1 and P2 data on the effects of tamoxifen and raloxifene on these outcomes. A risk-benefit index was calculated according to age and specific risk of breast cancer. Sensitivity analyses were performed of assumptions regarding the effects of tamoxifen and raloxifene. Results: Compared to U.S. women, the numbers of hip fractures and endometrial cancers were lower, but the number of strokes was much higher. The net benefit of tamoxifen and raloxifene were reduced with increasing age because of a high risk of stroke in older women. Older Korean women had more risk than benefit from tamoxifen and raloxifene chemoprevention. Only women younger than age 40 had a positive risk-benefit index of tamoxifen with an average 5-year risk of breast cancer in Korea. Sensitivity analysis showed that this result was robust. Raloxifene has more favorable index in postmenopausal women with a uterus. Conclusions: Women under the age 40 had more benefit than risk from tamoxifen chemoprevention. In the postmenopausal women with a uterus, raloxifene has more favorable risk-benefit index than tamoxifen. Disclosure: All authors have declared no conflicts of interest.

Tamoxifen for women at high risk of breast cancer

Tamoxifen has been used as a treatment for women who have been diagnosed with breast cancer for roughly four decades and has been approved as chemoprevention for over ten years. Although tamoxifen has been proven to be beneficial in preventing breast cancer in high-risk women, its use has not been widely embraced. To some extent, this is due to several of its side effects, including an increased risk of endometrial cancer and pulmonary embolism, but these serious side effects are rare. The risks and benefits of tamoxifen chemoprevention should be considered for each patient.

Risk management options elected by women after testing positive for a BRCA mutation

ObjectiveTo assess the uptake of risk-reducing options for the management of ovarian and breast cancer risk in BRCA mutation carriers in a large community based integrated health system in Northern California. MethodsA retrospective cohort of deleterious BRCA mutation carriers (1995–2012) was evaluated for consistency with NCCN guidelines for risk reducing salpingo-oophorectomy (RRSO) by age of 35–40, risk reducing mastectomy (RRM), as well as surveillance practices, including pelvic ultrasound, CA 125, mammogram, and breast MRI. Secondary outcomes included the use of chemoprevention and hormone replacement. ResultsOf the 305 eligible women, 170 were BRCA1 positive, and 135 were BRCA2 positive. Seventy four percent underwent RRSO with only 17% under age 40, while 44% underwent RRM. The median time from the test to both RRSO and RRM was 6months. In the first year after BRCA diagnosis, 45% underwent a pelvic ultrasound, dropping to 2.3% by year 5. In year 1, 47% had a CA 125, dropping to 2% by year 5. The number of women undergoing annual MRI and mammogram fell similarly over time. Sixteen percent of BRCA carriers used oral contraceptives (OCPs) and only one patient used tamoxifen for chemoprevention. ConclusionUptake of RRSO in BRCA carriers in a population based health system is high, however the majority of women do not have RRSO by the NCCN recommended age. Compliance with surveillance is low and rapidly declines even 1year out from testing. Attention needs to be focused on the earlier identification of BRCA mutation carriers with consolidated and standardized care to improve risk reduction.

Breast cancer chemoprevention: little progress in practice?

Breast cancer chemoprevention: little progress in practice?

Abstract A03: Tumorigenesis involving expansion of CD24 high CD61 cells is abrogated by tamoxifen in mouse models of luminal breast cancer

Abstract The cells within the mammary gland that are altered by tamoxifen chemoprevention and correlate with abrogation of tumorigenesis are unknown. We have documented that a 60 day tamoxifen chemopreventive regimen reduces tumor incidence in NRL-TGFalpha and MMTV-c-neu mouse models of luminal breast cancer. For this study our goal was to identify the aberrant and/or altered mammary cell subpopulations typically found in the mammary gland of TGFalpha and c-neu mice and determine the effect of tamoxifen on their relative quantity. Mammary cell subpopulations were evaluated using flow cytometric analysis by labeling lineage negative cells with CD24, CD61 and CD49f fluorescently tagged antibodies. TGFalpha mice developed an expanded CD24high CD61positive fraction of cells coinciding with hyperplasia and tumor presence. Prior to tumor development c-neu mice had an expanded CD24medium CD49f high cell fraction and by the time tumors developed, both nontumorous glands and tumors also displayed an expanded CD24high CD61positive cell fraction. Mammary glands from mice that received a 60 day tamoxifen chemopreventive regimen did not display expanded cell fractions compared to placebo treated mice in both models. Our data indicate that tamoxifen chemoprevention abrogates tumorigenesis that involves expansion of CD24high CD61positive cells. Further investigations into tamoxifen effects on mammary cell subpopulations is critical for a clearer understanding of the utility of tamoxifen and other estrogen receptor modulators as chemopreventives. Citation Format: Olga Zhdankin, Melanie Bomier, Donna Parke, Jon Holy, Teresa Rose-Hellekant. Tumorigenesis involving expansion of CD24 high CD61 cells is abrogated by tamoxifen in mouse models of luminal breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A03.

PS3-42: Health Literacy and Cancer Prevention: It's Not What You Say It's What They Hear

Background/Aims: A growing body of literature documents the relationship between health literacy and important health behaviors and outcomes. Most research to date has focused on print literacy-few studies have examined literacy with respect to spoken information (spoken health literacy). We sought to examine the extent to which responses to physician advice about cancer prevention and screening were associated with spoken health literacy. Methods: Participants listened to 3 simulated physician-patient discussions addressing: 1) Prostate Specific Antigen (PSA) testing; 2) tamoxifen for breast cancer prevention; and 3) colorectal cancer (CRC) screening. The physician provided information on risks and benefits but did not endorse one course of action. Post-vignette questions assessed understanding and reactions to the physician's advice. Participants had previously completed the Cancer Message Literacy Test-Listening (CMLT-L), a measure of spoken health literacy. Bivariate analyses examined the relationship between CMLT-L scores and comprehension, attitudes, and behavioral intentions. Results: Four hundred thirty-eight adults from 3 HMORN sites participated. Comprehension: Post-vignette comprehension scores were correlated with CMLT-L scores (r = 0.62, P <.001) and those scoring in the lowest CMLT-L quartile scored significantly lower on the vignette-specific comprehension scales (P <.001). Attitudes: Participants scoring in the lowest CMLT-L quartile were more likely to report their views had become more favorable on PSA testing (P <.001) and CRC screening (P <.001) as a result of the vignette. Behavioral intentions: Participants who scored in the lowest CMLT-L quartile expressed stronger intent than higher scoring participants to undergo PSA testing (P = .028) and to take tamoxifen for chemoprevention (P = .017). Conclusions: The ability to understand spoken information is a critical component of health literacy. In this study, spoken health literacy influenced patients' comprehension of, and reaction to spoken health information provided by a physician. The findings that participants scoring in the lowest quartile on the CMLT-L were more likely to respond favorably to physician advice on cancer prevention but were less likely to comprehend content of the vignettes, may indicate that physician mention of a prevention

Abstract 4880: PELP1 localization as a biomarker for early mammary carcinogenesis and response to tamoxifen chemoprevention.

Abstract Progress in breast cancer prevention is currently limited by our lack of biological markers to identify which high-risk women will progress to develop breast cancer and which women will respond to chemoprevention therapies, such as tamoxifen (Tam). While Tam has proven to be effective for breast cancer chemoprevention, Tam therapy only reduces the risk of developing breast cancer by approximately 50%. Therefore, identification of biomarkers is essential to determine which women will benefit from Tam chemoprevention. We have been studying the role of PELP1 in early mammary carcinogenesis and response to Tam chemoprevention. PELP1 subcellular localization is primarily nuclear in normal mammary epithelium, but it has been shown to be localized to the cytoplasm of &amp;lt;50% of PELP1 positive breast tumors. Targeting PELP1 to the cytoplasm leads to activation of non-genomic signaling to ERK1/2 and AKT and promotes Tam-resistance breast cancer cells. Additionally, it has been shown that transgenic mice expressing cytoplasmic PELP1 develop mammary gland hyperplasia. We have developed human mammary epithelial cell (HMEC) lines that express either vector control, wild-type PELP1 or a mutant of PELP1 in which the nuclear localization sequence has been mutated and the protein is predominately cytoplasmic (PELP1-cyto). Data generated using these cells lines indicates that PELP1-cyto, but not wild-type PELP1, promotes Tam-resistance. Our data also suggest that Tam treatment results in non-apoptotic death of HMECs. We found that Tam treatment induces the expression of LC3, an autophagy marker, and that Tam-induced LC3 expression is blocked in HMECs expressing PELP1-cyto. Together these data suggest that Tam-induced autophagy may be the mechanism of death in the HMEC cell lines and that cytoplasmic PELP1 may inhibit autophagic death. The objective of our current research is to determine if cytoplasmic PELP1 expression promotes expression of a novel gene signature that predicts response to Tam chemoprevention. We are currently testing models of early mammary carcinogenesis (pre-stasis, post-stasis, and immortal) for their response to Tam in the presence and absence of cytoplasmic PELP1. Microarray analysis will be performed on RNA from cell line that represents the earliest point in mammary carcinogenesis in which we see an effect of PELP1 expression. We expect that these studies will provide us with gene signatures that can predict cytoplasmic PELP1 expression and Tam resistance in early mammary carcinogenesis. Gene signatures will then be validated using existing gene array databases. These studies have the potential to lead to additional targets for chemoprevention and benefit women who are resistant to Tam chemoprevention. Citation Format: Julie Hanson Ostrander, Brian Girard, Tarah M. Regan-Anderson, Siya Lem, Victoria L. Seewaldt. PELP1 localization as a biomarker for early mammary carcinogenesis and response to tamoxifen chemoprevention. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4880. doi:10.1158/1538-7445.AM2013-4880

Abstract B84: The association between germline genetic variants in the PI3K pathway and PI3K mutations in breast tumors.

Abstract Background: Gene mutations in the PI3K pathway in breast tumors are associated with resistance to tamoxifen and poorer prognosis. Differences in host susceptibility to developing breast cancers with PI3K pathway mutations may explain the heterogeneity in response to tamoxifen for chemoprevention and breast cancer outcomes. The objective of the study was to evaluate the association between host germline single nucleotide polymorphisms (SNPs) and activation of the PI3K pathway in breast tumors. Methods: We extracted tumor and germline DNA from 386 women with stages I-II breast cancer treated at the MD Anderson Cancer Center. Nine PI3K mutation sites were evaluated using the Sequenom assay and 57 tagging single nucleotide polymorphisms (SNPs) of candidate genes in the PI3K pathway were genotyped using the Illumina Golden Gate Platform. Results: 36 patients (10%) had at least one mutation in the PI3K pathway. There was no association between PI3K mutation status by age at diagnosis or ethnicity. In univariate analysis, there was a statistically significant association between PI3K gene mutation status and 3 tagging SNPs in the genes, PTEN (rs123421, rs1234213) and IGF-1 (rs2033178). Conclusion: PI3K mutations are rare in breast tumors but represent a druggable target for prevention and treatment. Host genetics may play a role in contributing to tumor biology and serve to identify individuals at risk for tumors with PI3K pathway activation and tamoxifen resistance. Citation Format: Abenaa M. Brewster, Melissa Bondy, Kim-anh Do, Aysegul Sahin, Katherine Hale, Caimiao Wei, Gordon Mills, Patricia Thompson. The association between germline genetic variants in the PI3K pathway and PI3K mutations in breast tumors. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B84.

Estimating the Risks and Benefits of Tamoxifen for Prophylactic Breast Cancer Chemoprevention in Korea

PurposeAccording to the National Surgical Adjuvant Breast and Bowel Project P1 (NSABP-P1) study, tamoxifen can prevent 49% of invasive breast cancers in patients who have a 5-year risk of 1.67% or more. Because tamoxifen is associated with both adverse effects (endometrial cancer, stroke, pulmonary embolism) and protective effect (fracture prevention), it is necessary to weigh the risks and benefits of using tamoxifen for prevention in Korean women. This study weighed those risks and benefits.MethodsData were reviewed on the incidences of breast cancer, hip fracture, endometrial cancer and stroke in the absence of tamoxifen treatment in Korean women. We also reviewed NSABP-P1 data on the effects of tamoxifen on these outcomes. A risk-benefit index was calculated according to age and specific risk of breast cancer. Sensitivity analyses were performed with assumptions regarding the effects of tamoxifen.ResultsCompared to U.S. women, the numbers of hip fractures and endometrial cancers were lower, but the number of strokes was much higher. The net benefit of tamoxifen was reduced with increasing age because of a high risk of stroke in older women. Older Korean women had more risk than benefit from tamoxifen chemoprevention. Only women younger than age 40 had a positive risk-benefit index with an average 5-year risk of breast cancer in Korea. Sensitivity analysis showed that this result was robust.ConclusionWomen under the age 40 had more benefit than risk from tamoxifen chemoprevention. Tamoxifen chemoprevention should be limited to Korean women younger than age 40.

CHEK2 mutations as markers for high risk of breast cancer

Genetic testing for the two major breast cancer susceptibility genes, BRCA1 and BRCA2 is widely available in North America and Europe. A few other highly-penetrant breast cancer genes have been found, including p53, BRIP1 and PALB2, but families with mutations in these are exceedingly rare. Arguably, the most relevant of the post-BRCA genes, from a clinical point of view, is CHEK2, which was first linked to breast cancer susceptibility in 2002. In Poland, there are four founder mutations of CHEK2. Three of these (IVS2+1G>A, del5395 and 1100delC) are protein-truncating mutations and one (I157T) is a missense variant. We estimated the lifetime risk of breast cancer for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree-relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both first- and one-second degree relative affected in the Polish population. In addition we estimated that the lifetime risk for breast cancer for women who carried two different CHEK2 mutations (a truncating mutation and the missense mutation) to be 42%. Our results confirm that CHEK2 mutation screening detects a clinically meaningful risk of breast cancer, and women with a truncating mutation in CHEK2 and a positive family history of breast cancer, and women who carry two different CHEK2 mutations (the missense mutation I157T and a truncating mutation) face a lifetime risk of breast cancer above 25% and are candidates for MRI screening and for tamoxifen chemoprevention.