Receptor-positive Breast Cancer Risk Research Articles

Abstract 3464: Development and prospective validation of an estrogen receptor positive breast cancer risk model to identify women who could benefit for risk-reducing therapies

Abstract Background: Breast cancer risk-reducing therapies such as tamoxifen and aromatase inhibitors are effective for ER-positive (ER+) but not for ER-negative disease. As these therapies have side effects it is important to identify women at risk of ER+ disease. We developed and validated ER-specific risk prediction models in a prospective cohort and evaluated the expected gains of predicting ER+ vs overall disease. Methods: The iCARE-Lit model integrates established questionnaire-based risk factors and a 313 variant polygenic risk score. We reparametrized the iCARE-Lit model to estimate risk of ER+ and ER- disease separately by obtaining relative risks from published literature for ages at menarche, menopause, first childbirth, and parity to account for their heterogeneous associations with risk of ER-defined subtypes. We estimated 5-year (yr) absolute risk (AR) for ER+ disease using an overall and ER+ model. We evaluated model performance in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial prospective cohort. This included evaluation of calibration (expected-to-observed (E/O) ratio) and discrimination (area under the receiver operating characteristic curve (AUC)), among 46,571 self-reported non-Hispanic White women aged 50-75 yrs (1,052 ER+ cases with 5 yrs of follow-up from enrollment). We compared projected risk stratification of the overall and ER+ models among eligible US women in terms of proportions of women and future ER+ cases identified above the 3% 5-yr AR threshold recommended for risk-reducing interventions in the US. Results: In predicting ER+ disease in PLCO, on average the overall and ER+ AR were well calibrated; however, models overpredicted risk at the ≥3% 5-yr AR threshold, (E/O = 1.31 (1.20, 1. 42) and 1.23 (1.13, 1.34), respectively. Risk discrimination was similar from the overall and ER+ models (AUC=0.65 (0.64-0.67) and 0.66 (0.64-0.67), respectively. The overall model projected that 16% of women in the US could be eligible for risk-reducing therapies, compared to 11% when using ER+ model, resulting in ~1.4 million less women crossing the risk threshold when using the ER+ score. However, the percentage of ER+ cases in the US population projected to occur within 5-yrs among eligible women was larger for the overall (38%) than ER+ (32%) risk score. Conclusion: Findings suggest that ER-specific risk scores might not offer a substantial advantage compared to overall risk scores to identify women eligible for risk-reducing therapies. Further risk-benefit analyses are needed to quantify the potential gains of predicting ER+ vs overall breast cancer. Citation Format: Thomas U. Ahearn, Srijon Mukhopadhyay, Jeya Balasubramanian, Nilanjan Chatterjee, Montserrat García-Closas, Parichoy Pal Choudhury. Development and prospective validation of an estrogen receptor positive breast cancer risk model to identify women who could benefit for risk-reducing therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3464.

Gut and Breast Microbiota as Endocrine Regulators of Hormone Receptor-positive Breast Cancer Risk and Therapy Response.

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor-positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential antitumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine-targeting therapies may influence or be influenced by the microbiota and how that may affect carcinogenesis initiation and tumor recurrence.

Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort.

Endocrine-disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidémiologique auprès de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925-1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05-4.69]; 4th quartile: OR = 2.33 [CI = 1.11-4.90]); Ptrend = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07-5.65]; 4th quartile: OR = 2.76 [CI = 1.21-6.30]; Ptrend = 0.02). When considering receptor-negative tumors, only the 2nd quartile of PFOS was associated with risk (ER-: OR = 15.40 [CI = 1.84-129.19]; PR-: OR = 3.47 [CI = 1.29-9.15]). While there was no association between PFOA and receptor-positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor-negative tumors (ER-: OR = 7.73 [CI = 1.46-41.08]; PR-: OR = 3.44 [CI = 1.30-9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor-positive tumors, only low concentrations of PFOS and PFOA were associated with receptor-negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC.

Interaction between dietary acrylamide intake and genetic variants for estrogen receptor-positive breast cancer risk

PurposeThe association between dietary acrylamide intake and estrogen receptor-positive (ER+) breast cancer risk in epidemiological studies is inconsistent. By analyzing gene-acrylamide interactions for ER+ breast cancer risk, we aimed to clarify the role of acrylamide intake in ER+ breast cancer etiology.MethodsThe prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline, a random subcohort of 2589 women was sampled from the total cohort for a case–cohort analysis approach. Dietary acrylamide intake of subcohort members (n = 1449) and ER+ breast cancer cases (n = 844) was assessed with a food frequency questionnaire. We genotyped single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis, based on 20.3 years of follow-up.ResultsUnexpectedly, there was a statistically non-significant inverse association between acrylamide and ER+ breast cancer risk among all women but with no clear dose–response relationship, and no association among never smokers. Among the results for 57 SNPs and 2 gene deletions, rs1056827 in CYP1B1, rs2959008 and rs7173655 in CYP11A1, the GSTT1 gene deletion, and rs1052133 in hOGG1 showed a statistically significant interaction with acrylamide intake for ER+ breast cancer risk.ConclusionsThis study did not provide evidence for a positive association between acrylamide intake and ER+ breast cancer risk. If anything, acrylamide was associated with a decreased ER+ breast cancer risk. The interaction with SNPs in CYP1B1 and CYP11A1 suggests that acrylamide may influence ER+ breast cancer risk through sex hormone pathways.

Estrogen Effects on the Mammary Gland in Early and Late Life and Breast Cancer Risk.

A woman has an increased risk of breast cancer if her lifelong estrogen exposure is increased due to an early menarche, a late menopause, and/or an absence of childbearing. For decades, it was presumed that the number of years of exposure drove the increased risk, however, recent epidemiological data have shown that early life exposure (young menarche) has a more significant effect on cancer risk than late menopause. Thus, rather than the overall exposure it seems that the timing of hormone exposure plays a major role in defining breast cancer risk. In support of this, it is also known that aberrant hormonal exposure prior to puberty can also increase breast cancer risk, yet the elevated estrogen levels during pregnancy decrease breast cancer risk. This suggests that the effects of estrogen on the mammary gland/breast are age-dependent. In this review article, we will discuss the existing epidemiological data linking hormone exposure and estrogen receptor-positive breast cancer risk including menarche, menopause, parity, and aberrant environmental hormone exposure. We will discuss the predominantly rodent generated experimental data that confirm the association with hormone exposure and breast cancer risk, confirming its use as a model system. We will review the work that has been done attempting to define the direct effects of estrogen on the breast, which are beginning to reveal the mechanism of increased cancer risk. We will then conclude with our views on the most pertinent questions to be addressed experimentally in order to explore the relationship between age, estrogen exposure, and breast cancer risk.

Residential exposure to estrogen disrupting hazardous air pollutants and breast cancer risk: the California Teachers Study.

Some studies show increased breast cancer risk from exposure to xenoestrogens, but few have explored exposures via ambient air, which could impact large populations. This study explored the association between breast cancer risk and residential exposures to ambient estrogen disruptors among participants in a large cohort study, the California Teachers Study. Participants consisted of 112,379 women free of breast cancer and living at a California address in 1995/1996. Eleven hazardous air pollutants from the US Environmental Protection Agency 2002 list were identified as estrogen disruptors based on published endocrine disrupting chemical lists and literature review. Census-tract estrogen disruptor air concentrations modeled by the US Environmental Protection Agency in 2002 were assigned to participants' baseline addresses. Cox proportional hazards models were used to estimate hazard ratios associated with exposure to each estrogen disruptor and a summary measure of nine estrogenic hazardous air pollutants among all participants and selected subgroups, adjusting for age, race/birthplace, socioeconomic status, and known breast cancer risk factors. Five thousand three hundred sixty-one invasive breast cancer cases were identified between 1995 and 2010. No associations were found between residential exposure to ambient estrogen disruptors and overall breast cancer risk or hormone receptor-positive breast cancer risk, nor among targeted subgroups of participants (pre-/peri-menopausal women, post-menopausal women, never-smokers, non-movers, and never-smoking non-movers). However, elevated risks for hormone receptor-negative tumors were observed for higher exposure to cadmium compounds and possibly inorganic arsenic among never-smoking non-movers. Long-term, low-dose exposure to ambient cadmium compounds or possibly inorganic arsenic may be a risk factor for breast cancer.

Non-steroidal anti-inflammatory drug use, hormone receptor status, and breast cancer-specific mortality in the Carolina Breast Cancer Study.

Epidemiologic studies report a protective association between non-steroidal anti-inflammatory drug (NSAID) use and hormone receptor-positive breast cancer risk, a finding consistent with NSAID-mediated suppression of aromatase-driven estrogen biosynthesis. However, the association between NSAID use and breast cancer-specific mortality is uncertain and it is unknown whether this relationship differs by hormone receptor status. This study comprised 935 invasive breast cancer cases, of which 490 were estrogen receptor (ER)-positive, enrolled between 1996 and 2001 in the Carolina Breast Cancer Study. Self-reported NSAID use in the decade prior to diagnosis was categorized by duration and regularity of use. Differences in tumor size, stage, node, and receptor status by NSAID use were examined using Chi-square tests. Associations between NSAID use and breast cancer-specific mortality were examined using age- and race-adjusted Cox proportional hazards analysis. Tumor characteristics did not differ by NSAID use. Increased duration and regularity of NSAID use was associated with reduced breast cancer-specific mortality in women with ER-positive tumors (long-term regular use (≥8days/month for≥3years) versus no use; hazard ratio (HR) 0.48; 95% confidence interval (CI) 0.23-0.98), with a statistically significant trend with increasing duration and regularity (p-trend=0.036). There was no association for ER-negative cases (HR 1.19; 95%CI 0.50-2.81; p-trend=0.891). Long-term, regular NSAID use in the decade prior to breast cancer diagnosis was associated with reduced breast cancer-specific mortality in ER-positive cases. If confirmed, these findings support the hypothesis that potential chemopreventive properties of NSAIDs are mediated, at least in part, through suppression of estrogen biosynthesis.

Association of the single nucleotide polymorphism TNRC9 rs3803662 on mammographic density and estrogen receptor-positive breast cancer risk in Japanese women.

1523 Background: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We recently created risk prediction models for estrogen receptor (ER)-posi...

Update on Estrogen Receptor–Positive Breast Cancer Risk Reduction

Women who are at increased risk of breast cancer can be identified using individual risk factors or by using validated quantitative risk assessment models. There are millions of such women in the US population alone, and many additional millions of women at increased risk worldwide. Decades of randomized, prospective studies of these women using selective estrogen receptor modulators (SERMs) have shown that risk can be reduced safely and effectively by 50% for all invasive breast cancer and by nearly 70% or more for estrogen receptor–positive breast cancer. Safety and tolerability of the SERMs are acceptable in the published studies, and two SERMs, tamoxifen and raloxifene, are approved by the US Food and Drug Administration for breast cancer risk reduction. Nevertheless, the drugs are not widely used despite reasonable cost per year of life saved (or morbidity avoided). Clinicians must endeavor to identify women who are suitable candidates for these drugs and educate them about their safety and utility.

Meat Mutagens and Breast Cancer in Postmenopausal Women—A Cohort Analysis

Mutagenic compounds produced when meats are cooked at high temperatures have been hypothesized to increase risk of breast cancer. We examined the association between intakes of the heterocyclic amines (HCA) MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f]), and meat-derived mutagenic (MDM) activity and risk of breast cancer using a cooking method questionnaire administered in 1996 in the Nurses' Health Study. Between 1996 and 2006, 2,317 breast cancer cases were diagnosed during 533,618 person-years. Higher intake of HCAs or MDM was not associated with elevated risk of breast cancer [multivariate relative risk and 95% confidence interval for the highest versus lowest quintile: MeIQx: 0.90 (0.79-1.03); PhIP: 0.92 (0.80-1.05); DiMeIQx: 0.92 (0.80-1.05); and MDM: 0.98 (0.85-1.12)]. HCA or MDM was not associated with estrogen receptor-positive/progesterone receptor-positive breast cancer risk either. There was some suggestion of a decreased risk of estrogen receptor-negative/progesterone receptor-negative breast cancer with higher intakes of MeIQx, DiMeIQx, and PhIP, but none of the associations were statistically significant. There was little evidence for an interaction between intake of cruciferous vegetables and HCA or MDM intake and risk of breast cancer. Higher consumption of mutagens from meats cooked at higher temperature and longer duration was not associated with increased risk of postmenopausal breast cancer. Overall prospective data including results from our study do not provide support for a substantial increase in risk of breast cancer with higher intake of HCAs.

Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene.

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.

Dietary acrylamide intake and estrogen and progesterone receptor-defined postmenopausal breast cancer risk

Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake and risk of postmenopausal breast cancer stratified by estrogen and progesterone receptor status. This study was embedded within the Netherlands Cohort Study on diet and cancer, which was initiated in 1986 enrolling 62,573 women aged 55-69 years at baseline. After 13.3 years of follow-up, 2225 incident breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status. No association was observed for overall breast cancer or receptor-negative breast cancer risk, irrespective of smoking status. A statistically non-significantly increased risk of ER positive, PR positive and joint receptor-positive breast cancer was found in never-smoking women. The multivariable-adjusted hazard ratios were 1.31 (95% CI: 0.87-1.97, P (trend) = 0.26) for ER+, 1.47 (0.86-2.51, P (trend) = 0.14) for PR+, and 1.43 (0.83-2.46, P (trend) = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 microg/day) to women in the lowest (median 9.5 microg/day). This study showed some indications of a positive association between dietary acrylamide intake and receptor-positive breast cancer risk in postmenopausal never-smoking women. Further studies are needed to confirm or refute our observations.

Chemoprevention of Breast Cancer

Trials with tamoxifen have clearly shown that estrogen receptor-positive breast cancer risk can be reduced at a late stage in the natural history with prophylactic agents. Approximately half of the cases were prevented. The current challenge is to achieve this or better efficacy, and reduce side effects. A recent trial found that the selective estrogen receptor modulator raloxifene has similar efficacy to tamoxifen but fewer side effects. Long-term Phase III trials are currently underway studying two aromatase inhibitors. Results from other studies suggest that these agents have a better side-effect profile and may prevent 70-80% of receptor-positive breast cancers. New agents are needed for receptor-negative breast cancer and several possibilities are currently under investigation.

Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women

Since it is well established that inactivation of p53 is involved in pathogenesis of breast cancer, it seems to be reasonable to assume that p53 genetic polymorphism at codon 72 (p53 Arg72Pro) which affects the function of p53 might have an influence on breast cancer risk. Thus, in the present study, we have studied the association of p53 Arg72Pro polymorphism with breast cancer risk. A case–control study was conducted with 191 breast cancer patients and 218 healthy female controls. p53 Arg72Pro polymorphism was examined in their association with breast cancer risk after adjustment for the epidemiological risk factors. Relationship between p53 Arg72Pro polymorphism and clinicopathological characteristics of breast cancers was also studied. In addition, frequency of somatic p53 mutation was compared according to the genotype of p53 Arg72Pro polymorphism. p53 72Pro/Pro homozygotes showed a significant increase in the risk of estrogen receptor (ER) positive breast cancer (adjusted odds ratio (OR)=2.04, P=0.04) as compared with p53 72Arg/Arg homozygotes, whereas such an association was not found between p53 72Pro/Pro homozygotes and ER negative breast cancer risk. Subset analysis according to menopausal status showed that p53 72Pro/Pro homozygotes were significantly associated with ER positive breast cancer risk in postmenopausal women (adjusted OR=3.42, P=0.01) but not in premenopausal women. Frequency of ER positive tumors was significantly ( p<0.01) higher in breast cancer patients with p53 72Pro/Pro genotype (82.8%) than those with p53 72Arg/Arg genotype (54.5%). Mutational analysis of p53 in tumors showed that p53 72Pro/Pro homozygotes had a lower frequency of p53 mutation (3.5%) than p53 72Arg/Arg homozygotes (10.5%). It is suggested that p53 Arg72Pro polymorphism is associated with ER positive breast cancer risk, especially, in postmenopausal women. The higher frequency of p53 somatic mutation in p53 72Arg/Arg homozygotes than p53 72Pro/Pro homozygotes is consistent with the thesis that the function of p53 72Pro/Pro is impaired so that a further alteration of p53 gene is less required in p53 72Pro/Pro homozygotes than p53 72Arg/Arg homozygotes.

Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk

Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis ( CYP19) and metabolism ( CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 ( TTTA repeats) in intron 4 and CYP1A1 6235 C/T in the 3′ non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 ( TTTA) 7( −3bp) allele carriers showed a significantly ( P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10–2.69), but not ER-negative breast cancers. CYP1A1 6235 C allele carriers showed a non-significant ( P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42–1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56–5.74) than the CYP19 ( TTTA) 7( −3bp) polymorphism alone. The combination of CYP19 ( TTTA) 7( −3bp) and CYP1A1 6235 C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen.