Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics.
ABSTRACT: BACKGROUND:Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS:Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS:Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated?=?11-27%, p???0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+?, PR+?, and HER2- breast cancer; percent MD partially mediated these associations (percent mediated???31%, p???0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+?breast cancer (percent mediated?=?16%, p???0.05). CONCLUSION:Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.
Project description:INTRODUCTION:Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models. METHODS:Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (<55, 55-64, and ? 65 years). RESULTS:MD was positively associated with risk of invasive tumors across all ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55-64 and ? 65 years (P(age-interaction) = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P's < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55-64 and ? 65 years (P(age-interaction) = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group. CONCLUSION:MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.
Project description:PURPOSE:To update and expand the Rosner-Colditz breast cancer incidence model by evaluating the contributions of more recently identified risk factors as well as predicted percent mammographic density (MD) to breast cancer risk. METHODS:Using data from the Nurses' Health Study (NHS) and NHSII, we added adolescent somatotype (9 unit scale), vegetable intake (servings/day), breastfeeding (months), physical activity (MET-h/week), and predicted percent MD to the Rosner-Colditz model to determine whether these variables improved model discrimination. We evaluated all invasive as well as ER+/PR+, ER+/PR-, and ER-/PR- breast cancer. RESULTS:In the NHS/NHSII, we accrued over 5200 cases of invasive breast cancer over more than 20 years of follow-up with complete data on the risk factors. Adolescent somatotype and predicted percent MD significantly improved the original Rosner-Colditz model for all invasive breast cancer (change in age-adjusted AUC = 0.020, p < 0.001). The relative risk (RR) of invasive breast cancer for a 4-unit increase in adolescent somatotype was 0.62 (95% CI 0.56, 0.70), whereas the RR for a 20-unit increase in predicted percent MD was 1.32 (95% CI 1.28, 1.36). Adolescent somatotype and predicted percent MD also significantly improved the ER+/PR+model (change in age-adjusted AUC = 0.020, p < 0.001) as well as the ER+/PR- model (change in age-adjusted AUC = 0.012, p = 0.007). Adolescent somatotype, predicted percent MD, breastfeeding, and vegetable intake improved the ER-/PR- model (change in AUC = 0.031, p < 0.0001). The RR of ER-/PR- disease for 5 vegetable servings/day increase was 0.83 (95% CI 0.70, 0.99), while the RR for every 12 months of breastfeeding was 0.88 (95% CI 0.77, 1.01). Physical activity did not improve risk classification in any model. CONCLUSION:Adolescent somatotype and predicted percent MD significantly improved breast cancer risk classification using the Rosner-Colditz model. Further, risk factors specific to ER- disease, such as breastfeeding and vegetable intake, may also help improve risk prediction of this aggressive subtype.
Project description:A prior analysis of postmenopausal breast cancer patients linked a decline in mammographic density (MD) following the initiation of tamoxifen treatment with improved survival, but excluded premenopausal women, for whom tamoxifen is the primary anti-endocrine therapy. Therefore, we evaluated change in MD after tamoxifen and breast cancer death among patients age 32 to 87 years.This case-control study included 349 estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen at Kaiser Permanente Northwest (1990-2008): 97 who died from breast cancer (case patients) and 252 who did not (control patients), matched on age and year at diagnosis and disease stage. Percent MD in the unaffected breast was measured at baseline (mean six months before tamoxifen initiation) and follow-up (mean 12 months after initiation). Associations between change in MD and breast cancer death were estimated using conditional logistic regression.Patients in the highest tertile of MD decline had a lower risk of breast cancer death when compared with women in the lowest tertile (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.22 to 0.88); results were similar after adjustment for baseline MD (OR = 0.49, 95% CI = 0.23 to 1.02). Reductions in death were observed only among patients in the middle and upper tertiles of baseline MD. Associations did not differ by age, tamoxifen use duration, estrogen and/or progestin use, body mass index, or receipt of chemotherapy or radiotherapy.These data suggest that younger and older ER-positive breast cancer patients who experience large reductions in MD following tamoxifen initiation have an improved prognosis.
Project description:The preoperative endocrine prognostic index (PEPI) predicts survival after neoadjuvant endocrine therapy (NAE) using aromatase inhibitors (AIs) for women with postmenopausal estrogen receptor (ER)-positive breast cancer irrespective of the human epidermal growth factor receptor 2 (HER2) status. Although the progesterone receptor (PgR) is also a prognostic factor for ER-positive breast cancer, the PgR status was not considered a prognostic factor in the original PEPI scoring system. In this study, we investigated the utility of a modified PEPI including the PgR status (PEPI-P) as a prognostic factor after NAE for postmenopausal patients with ER-positive and HER2-negative breast cancer. We enrolled 107 patients with invasive ER-positive and HER2-negative breast cancer treated with exemestane for ?4 months as NAE. We initially assessed PEPI and compared survival between the groups. Additionally, we obtained an effective cutoff for PgR through survival analysis. Then, we assessed the survival significance of PEPI-P. A PgR staining rate of 50% was the most significant cutoff for predicting recurrence-free survival (RFS) and cancer-specific survival (CSS). PEPI was a significant prognostic factor; moreover, PEPI-P was the most significant prognostic indicator for RFS and CSS. PEPI-P is a potent prognostic indicator of survival after NAE using AIs for postmenopausal patients with ER-positive and HER2-negative breast cancer. This modified PEPI may be useful for therapeutic decision-making regarding postmenopausal ER-positive and HER2-negative breast cancer after NAE.
Project description:The response to neoadjuvant chemotherapy (NAC) varies by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) statuses, with responses being lower in ER-positive, HER2-negative tumors as compared with ER-negative, HER2-positive or triple-negative tumors. Neoadjuvant endocrine therapy (NET) is an attractive alternative to NAC for ER-positive, HER2-negative cancer. However, a prior trial comparing NET with standard NAC in ER-positive tumor showed that the difference of response was not significant. Studies demonstrated that the mTOR inhibitor everolimus could sensitize breast tumors to endocrine therapy. A pilot open-label, randomized trial has been designed to evaluate the feasibility, efficacy and tolerability of neoadjuvant everolimus plus letrozole versus NAC in treating postmenopausal women with ER-positive, HER2-negative breast cancer.Forty postmenopausal women with non-metastatic ER-positive, HER2-negative invasive breast cancer with a primary tumor > 2 cm or positive axillary lymph node(s) proved by biopsy will be randomly (1:1) enrolled from Sun Yat-Sen Memorial Hospital to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for six cycles before surgery. Primary outcome is the feasibility of the trial. Secondary outcome measures include ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, and changes in the percentages of peripheral blood CD4+ T cells, CD8+ T cells, T helper cells, regulatory T cells, and NK cells.This is the first study to determine the feasibility, efficacy and tolerability of head-to-head neoadjuvant everolimus plus letrozole versus neoadjuvant FEC in treating postmenopausal women with ER-positive, HER2-negative breast cancer. The trial will provide evidence to assess the feasibility of a future multicenter, randomized controlled trial, and will provide valuable clinical data of the immunoregulatory effect of everolimus in breast cancer.ClinicalTrials.gov registry, ID: NCT02742051 . Registered on 7 April 2016.
Project description:<h4>Introduction</h4>Breast cancer comprises clinically distinct subtypes, but most risk statistics consider breast cancer only as a single entity. To estimate subtype-specific lifetime breast cancer risks, we took advantage of population-based data for which information regarding tumor expression of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu (HER2) was newly available.<h4>Methods</h4>We included women whose breast cancer was diagnosed in the state of California from 2006 to 2007 and was reported to the National Cancer Institute's Surveillance, Epidemiology and End Results Program (N = 40,936). We calculated absolute lifetime and age-specific probabilities (percent, 95% confidence interval) of developing breast cancer subtypes defined by ER, PR, and HER2 status - luminal (ER and/or PR-positive, HER2-negative), HER2-positive (ER and PR-positive or negative, HER2-positive), and triple-negative (ER-negative, PR-negative, and HER2-negative) - separately for white, black, Hispanic, and Asian women.<h4>Results</h4>The luminal breast cancer subtype predominates across racial/ethnic groups, with lifetime risk lowest in Hispanic women (4.60%, 4.41-4.80%) and highest in white women (8.10%, 7.94-8.20%). HER2-positive breast cancer varies less by race (1.56-1.91%). Lifetime risk of triple-negative breast cancer is highest in black women (1.98%, 1.80-2.17%), compared to 0.77% (0.67-0.88%) for Asians, 1.04% (0.96-1.13%) for Hispanics and 1.25% (1.20-1.30%) for whites. Across racial/ethnic groups, nearly half of all luminal breast cancers occur after age 70.<h4>Conclusions</h4>These absolute risk estimates may inform health policy and resource planning across diverse populations, and can help patients and physicians weigh the probabilities of developing specific breast cancer subtypes against competing health risks.
Project description:HER2+/ER+ breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers. The bidirectional crosstalk between HER2 and estrogen receptor (ER) in HER2+/ER+ breast cancer contributes to resistance towards both anti-estrogens and HER2-targeted therapies. TFF3 promotes breast cancer progression and has been implicated in anti-estrogen resistance in breast cancer. Herein, we investigated the cross-regulation between HER2 and estrogen-responsive TFF3, and the role of TFF3 in mediating trastuzumab resistance in HER2+/ER+ breast cancer. TFF3 expression was decreased by HER2 activation, and increased by inhibition of HER2 with trastuzumab in HER2+/ER+ breast cancer cells, partially in an ER?-independent manner. In contrast, the forced expression of TFF3 activated the entire HER family of receptor tyrosine kinases (HER1-4). Hence, HER2 negatively regulates its own signalling through the transcriptional repression of TFF3, while trastuzumab inhibition of HER2 results in increased TFF3 expression to compensate for the loss of HER2 signalling. In HER2+/ER+ breast cancer cells with acquired trastuzumab resistance, TFF3 expression was markedly upregulated and associated with a corresponding decrease in HER signalling. siRNA mediated depletion or small molecule inhibition of TFF3 decreased the survival and growth advantage of the trastuzumab resistant cells without re-sensitization to trastuzumab. Furthermore, TFF3 inhibition abrogated the enhanced cancer stem cell-like behaviour in trastuzumab resistant HER2+/ER+ breast cancer cells. Collectively, TFF3 may function as a potential biomarker and therapeutic target in trastuzumab resistant HER2+/ER+ breast cancer.
Project description:BACKGROUND:Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens and mammographic density (MD), an intermediate marker of breast cancer risk, have been inconsistent. We investigated the cross-sectional associations of urinary estrogens, and their 2-, 4-, and 16-hydroxylated metabolites with MD. METHODS:Postmenopausal women without breast cancer (n = 194), ages 48 to 82 years, and reporting no current menopausal hormone therapy use were enrolled at a clinic in Western NY in 2005. Urinary estrogens and estrogen metabolites were measured using mass spectrometry. Percent MD and dense area (cm(2)) were measured using computer-assisted analyses of digitized films. Linear regression models were used to estimate associations of log-transformed estrogen measures with MD while adjusting for age, body mass index (BMI), parity, and past hormone therapy use. RESULTS:Urinary concentrations of most individual estrogens and metabolites were not associated with MD; however, across the interdecile range of the ratio of parent estrogens (estrone and estradiol) to their metabolites, MD increased by 6.8 percentage points (P = 0.02) and dense area increased by 10.3 cm(2) (P = 0.03). Across the interdecile ranges of the ratios of 2-, 4-, and 16-hydroxylation pathways to the parent estrogens, MD declined by 6.2 (P = 0.03), 6.4 (P = 0.04), and 5.7 (P = 0.05) percentage points, respectively. All associations remained apparent in models without adjustment for BMI. CONCLUSION:In this study of postmenopausal women, less extensive hydroxylation of parent estrogens was associated with higher MD. IMPACT:Hydroxylation of estrogens may modulate postmenopausal breast cancer risk through a pathway involving MD.
Project description:Mammographic density (MD) is a strong risk factor for breast cancer, but the biological mechanism underlying this association is not clear. Current adult body mass index (BMI) is inversely associated with percent MD; however, few studies have included Hispanic women or evaluated associations with measures of body fatness earlier in life. ESMaestras was established in 2006, when 28,345 women ages ?35 responded to a detailed questionnaire that assessed possible disease risk factors, including body fatness in childhood, adolescence, and young adulthood. In 2007, 2084 ESMaestras participants underwent a clinical examination, which included measurements of weight, height, and sitting height and a mammogram. We measured percent MD using a computer-assisted method. The current analysis includes 972 premenopausal and 559 postmenopausal women. We used multivariable linear regression to evaluate associations between measures of body size and MD, independent of current BMI. Among pre- and postmenopausal women, we observed no significant associations between body fatness during childhood, adolescence, or young adulthood and percent MD. Among postmenopausal women, we observed a modest positive association between body fatness immediately before first pregnancy and between ages 25 and 35 after adjustment for current BMI, with differences of 4.9 and 3.6 % points, respectively, in percent MD between the heaviest and leanest women (p-trend = 0.02). There were no significant associations between height, sitting height, and percent MD among pre- or postmenopausal women in multivariable models adjusting for BMI. In general, we found no clear associations between measures of body size in early life, current sitting height, or current height, and percent MD, after adjusting for current BMI, in this population of Mexican women. Our observation of a positive association between early adult body fatness (i.e., before first pregnancy and ages 25-35) and percent MD among postmenopausal women is inconsistent with prior research and requires confirmation in other studies.
Project description:PURPOSE:Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS:MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A?=?reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS:The mean age at diagnosis was 51.7 years (SD?=?10.7) and the average BMI was 24.7 kg/m2 (SD?=?3.8). The distribution of BI-RADS categories was 7.4% A?=?almost entirely fat, 24.2% B?=?scattered fibroglandular dense, 49.4% C?=?heterogeneously dense, and 19.0% D?=?extremely dense. Compared to women with BI-RADS?=?A/B, women with BI-RADS?=?D were more likely to have HER2-enriched tumors (OR?=?1.81, 95% CI 1.08-3.06, p?=?0.03), regardless of menopausal status. The association was only observed in women with normal (<?25 kg/m2) BMI (OR?=?2.43, 95% CI 1.24-4.76, p?<?0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38-2.52, p?=?0.96). CONCLUSIONS:Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+?tumors previously reported in Asian women.