Risk Of Invasive Breast Cancer Research Articles

Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial

BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov, NCT00470236. Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05-0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06-0·20; p=0·00021), persisting at 24 months (0·13 [0·06-0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03-0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [-0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference -1·10 [95% CI -1·79 to -0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.

Adolescent Use of Hair Dyes, Chemical Straighteners and Perms in Relation to Breast Cancer Risk in the Sister Study

Abstract Hair products may contain hormonally active and carcinogenic compounds. We evaluated the risk of breast cancer associated with adolescent use of hair dyes, chemical straighteners and perms in a large prospective U.S. cohort. Methods: Sister Study participants (n = 47,833) were ages 35–74 years and had a sister who had been diagnosed with breast cancer at the time of enrollment (2003–2009). Enrollment questionnaires obtained information on demographics and lifestyle factors as well as frequency of use of hair dyes, chemical straighteners, and perms at ages 10–13 years. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between adolescent hair product use and breast cancer risk (invasive cancer and ductal carcinoma in situ). We considered whether associations varied by invasiveness, estrogen receptor (ER) status of the tumor, menopause status and race. Results: Over an average of 8.3 years of follow-up, 2,829 cases were diagnosed. Hair dye use at ages 10–13 years was uncommon and not associated with breast cancer risk (e.g. permanent hair dye, <3%; HR = 0.96, 95% CI: 0.76–1.22). Use of perms (34% non-Hispanic white vs. 8% black women) and straighteners (10% non-Hispanic white vs 75% black women) at ages 10–13 years varied by race. An elevated HR for breast cancer was observed for frequent use of chemical straighteners (HR = 1.27, 95% CI: 0.98–1.65). Though based on small numbers, this association was most pronounced for ER- invasive (HR = 2.04, 95% CI: 0.98–4.24) and premenopausal breast cancer (HR = 2.18, 95% CI 1.27–3.74). Frequent use of perms was also associated with a higher risk of invasive breast cancer and ER- tumors (HR = 1.25, 95% CI: 1.00–1.57 and HR = 1.69, 95%CI: 0.96–2.98, respectively). Although product use varied by race, associations with breast cancer did not. Conclusions: Frequent use of chemical straighteners or perms during the ages of 10–13 years was associated with a higher risk of breast cancer. These results suggest that exposure to the chemicals in these hair products, especially during adolescence which may be an important biological window of susceptibility, may play a role in breast carcinogenesis.

Dietary advanced glycation end products and the risk of postmenopausal breast cancer in the National Institutes of Health-AARP Diet and Health Study.

Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism and are consumed through the diet in high-fat and highly processed foods. They are associated with chronic inflammatory diseases, and evidence suggests that they play a role in carcinogenesis. The authors evaluated the association of dietary AGE intake and the risk of postmenopausal invasive breast cancer. This was a prospective cohort study of 183,548 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. The main outcome was incident invasive breast cancer. AGE intake was estimated from food-frequency questionnaires. Incident breast cancer cases were identified through state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals for developing breast cancer according to AGE intake quintiles. Multivariable regression models were adjusted for breast cancer risk factors. The mean follow-up was 12.8years, and 9851 breast cancers (1978 advanced stage) were identified. The median AGE daily intake was 5932kilo units per 100kilocalories (KU/1000kcal). Women with higher intake tended to have lower education levels, higher body mass index, less physical activity, were current smokers, and had higher fat and meat intake. The highest quintile of AGE intake (compared with the lowest) was associated with an increased risk of breast cancer (HR, 1.09; 95% CI, 1.02-1.16; P=.03) after adjusting for breast cancer risk factors and particularly was associated with 37% of advanced-stage tumors (HR, 1.37; 95% CI, 1.09-1.74; P<.02) after adjusting for risk factors and fat and meat intake. Dietary AGEs may play a role in the development of postmenopausal breast cancer.

Abstract PD3-04: Classic lobular carcinoma in situ in the Netherlands: A population-based analysis

Abstract Background: Lobular carcinoma in situ (LCIS) is a non-invasive proliferation of epithelial cells of the terminal-duct lobular unit. Although LCIS is non-invasive itself, studies in the past showed that patients with LCIS have a 4-12 times higher risk of developing invasive breast cancer than the general population. Therefore, the optimal management of LCIS is still subject of debate. Despite lack of information about LCIS in the Dutch population, the Dutch guidelines recommend active surveillance for classic LCIS. This study aims to describe incidence and management of classic LCIS over time in the Netherlands, and to understand its behavior in terms of survival and the risk of developing subsequent ductal carcinoma in situ (DCIS) or invasive breast cancer. Methods: All female patients diagnosed with classic LCIS between 1989-2017 in the Netherlands were identified from the nationwide population-based Netherlands Cancer Registry. Patients previously diagnosed with DCIS or invasive breast cancer were excluded. Standardized incidence ratios (SIR) were calculated to estimate the risk of subsequent DCIS and invasive breast cancer, using data on population size from Statistics Netherlands (CBS). Multivariable Cox proportional hazards regression was performed to estimate hazard ratios (HR) of overall mortality and risk of subsequent invasive breast cancer for different patient-, tumor- and treatment-related characteristics. Competing risks were taken into account. Relative survival was estimated using the Ederer II method, with expected mortality of the general population (matched by age, gender, calendar year) as a reference. Results: We included 1,890 patients. The median age at diagnosis was 51 years (range 24-91 years). The incidence of classic LCIS increased from 186 patients between 1989-1993 to 497 patients between 2014-2017. Of all patients, 50.5% were treated with breast-conserving surgery, 10.2% were treated with mastectomy, 12.6% were treated with an unknown type of surgery and 26.7% did not receive surgery. While in 1989 all patients were surgically treated, only 41% were surgically treated in 2017. Radiotherapy was administered in 3.1% and endocrine therapy in 0.2% of the patients. Median follow-up to death, and subsequent DCIS or invasive breast cancer was 8.5 years (range 0-29 years) and 6.9 years (range 0-27 years). Unadjusted 10- and 20-year overall survival rates were 91% (95%CI:90-93%) and 76% (95%CI:73-79%). Unadjusted 10- and 20-year relative survival rates were 99% (95%CI:97-100%) and 95% (95%CI:91-99%). In total, 270 patients was diagnosed with subsequent invasive breast cancer and 48 were diagnosed with DCIS. Of these, 60% were ipsilateral and 40% were contralateral. The SIRs for DCIS and invasive breast cancer were 4.4 (95%CI:3.2-5.8) and 24.4 (95%CI:21.6-27.5) as compared to the general population, respectively. The SIR was higher for younger patients than for older patients, and the SIR of ipsilateral invasive breast cancer was higher in case no surgical management was performed. In multivariable analysis, increasing age was the most important predictor for overall mortality, while no surgical management was related to a higher incidence of subsequent invasive breast cancer. Conclusion: LCIS incidence has increased over time, while surgical management has decreased. This study shows that the mortality risk is very low compared to the general population. In contrast, the incidence of invasive breast cancer, over a median follow-up of 6.9 years (range 0-27 years), is over 24 times more common in LCIS patients than in the general population. These results suggest that LCIS patients have a good prognosis, even when a subsequent invasive breast cancer is diagnosed. However, the high incidence of second tumors suggest that we carefully monitor these patients. Citation Format: Marissa Corine van Maaren, Agustin Ortega Avila, Jos Bart, Pieter J Westenend, Sabine Siesling. Classic lobular carcinoma in situ in the Netherlands: A population-based analysis [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 PD3-04.

Abstract P5-03-02: Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene

Abstract Background: Germ-line pathogenic variants (PV) in ATM are often considered low-to-moderate penetrance risk factors for breast cancer (BC), conferring a two-fold increased BC risk among heterozygous PV carriers. Several other cancers have been associated with ATM PV such as melanoma, thyroid cancer, prostate cancer, pancreatic cancer, gastro-esophageal cancers, colorectal cancer, and ovarian cancer. Estimating the diverse cancer risks attributable to ATM PVs may present challenges due to the low-to-moderate penetrance of ATM PV for some cancers, requiring large samples of tested patients to estimate risk with precision, and the potential for substantial variability in penetrance of particular ATM PV such as the c.7271T&amp;gt;G PV reported by previous studies. We investigated cancer risks with ATM PV in a large clinical testing dataset. Methods: Results of 614,344 individuals undergoing clinical analysis of ATM as part of a multi-gene hereditary cancer gene panel between 09/2013 and 06/2019 were reviewed. Patient age, sex, ancestry, personal and family cancer history were extracted from a test requisition form. PV included variants classified as suspected deleterious or deleterious (hereafter referred to as pathogenic). Risk estimates are estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: PV in ATM were identified in 4,372/614,344 (0.7%) individuals: 4,155/592,881 (0.7%) females and 217/21,463 (1.0%) males. 1,603/4,155 (38.6%) of female ATM PV carriers had invasive BC or DCIS. Overall, ATM PV were associated with a 2-fold increased risk for invasive BC [OR 2.01, 95% CI 1.86-2.16] and DCIS [OR 1.82, 95% CI 1.62-2.04]. A prevalent missense PV c.7271T&amp;gt;G, predicted to lead to inactivation of ATM kinase activity and that has previously been described as high penetrance (Goldgar DE et al, Breast Cancer Res 2011), represented 5.1% (n=223) of all ATM PV, and was associated with a particularly high risk of invasive BC [OR 3.80, 95% CI 2.78-5.19] but no increased risk of DCIS. Significantly elevated risks of pancreatic cancer, gastric cancer, prostate cancer, ovarian cancer, colon cancer and melanoma were also observed among ATM PV carriers (see Table 1). Median age of invasive BC diagnosis was similar in carriers and non-carriers of ATM PV. Conclusions: ATM PV are associated with 1.5-fold to &amp;gt;4-fold increased cancer risks across a variety of disease sites, including invasive BC (2-fold increased risk). Cancer risks also demonstrate mutation-specific variability, as suggested by the 4-fold increased risk of invasive BC in carriers of the ATM PV c.7271T&amp;gt;G. Larger and/or pooled studies are critical to further refine the breadth and magnitude of ATM-associated cancer risk and to improve clinical management guidelines for ATM PV carriers. Table 1: Odds ratios for cancer risks in c.7271T&amp;gt;G and all other ATM PV carriersAll ATM PVs (excluding c.7271T&amp;gt;G)c.7271T&amp;gt;GCancer OR (95% CI)p-valueOR (95% CI)p-valueBreast, Invasive1.94 (1.79, 2.09)&amp;lt;0.00013.80 (2.78, 5.19)&amp;lt;0.0001Breast, DCIS1.83 (1.62, 2.05)&amp;lt;0.00011.63 (0.97, 2.74)0.0624Breast, Lobular invasive0.94 (0.73, 1.21)0.62330.84 (0.27, 2.64)0.7671Breast, Male1.44 (0.86, 2.42)0.16884.24 (0.46, 39.15)0.2032Ovarian1.55 (1.32, 1.82)&amp;lt;0.00011.99 (0.99, 4.02)0.0532Colorectal1.51 (1.25, 1.82)&amp;lt;0.00011.67 (0.67, 4.18)0.2693Endometrial1.10 (0.88, 1.39)0.39610.89 (0.28, 2.81)0.8401Melanoma1.44 (1.14, 1.81)0.00182.16 (1.00, 4.64)0.0491Prostate2.61 (1.93, 3.52)&amp;lt;0.00014.37 (0.70, 27.26)0.1146Pancreatic4.18 (3.17, 5.49)&amp;lt;0.00012.50 (0.34, 18.21)0.3660Gastric3.09 (1.73, 5.53)0.0001—— Citation Format: Michael J Hall, Katie Larson, Ryan Bernhisel, Elisha Hughes, Eric Rosenthal, Nanda Singh, Johnathan M Lancaster, Allison W Kurian. Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene [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 P5-03-02.

Abstract OT3-09-02: A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS)

Abstract Background: TSECs were developed to treat menopausal symptoms after progesterone containing hormone replacement therapy was found to significantly increase the risk of invasive breast cancer (IBC). The first of this class of agents combines conjugated estrogens (CE), a collection of steroidal estrogens that collectively have both estrogen receptor (ERα) agonistic and antagonistic activity, and bazedoxifene (BZA), a third generation selective estrogen receptor modulator that does not stimulate the mammary gland or endometrium. The FDA approved CE/BZA for treatment of menopausal symptoms and osteoporosis after five randomized placebo controlled trials demonstrated the safety, efficacy and tolerability of CE/BZA in healthy postmenopausal women. Since then, a substantial body of evidence has emerged suggesting that CE/BZA may have additional therapeutic benefits in women. It is widely accepted that progression to IBC occurs through both epithelial and stromal mechanisms. Recent in vitro and in vivo data provide support that CE/BZA prevents progression to IBC through its effects on both epithelium and stroma. In epithelial cells, CE/BZA antagonizes estrogen-induced proliferation and expression of markers of ERα activity and also degrades ERα protein. In the stroma, CE/BZA increases expression of the scavenger receptor CD36 and consequently, reduces expression of extracellular matrix proteins (ECM) and pro-inflammatory cytokines that have been shown to contribute to the development of pro-tumorigenic microenvironment. Based on these preliminary data, we hypothesized that CE/BZA will have an anti-tumorigenic effect in the breast. Our ultimate objective is to provide postmenopausal women diagnosed with DCIS a novel and safe therapeutic option to prevent progression to IBC. Specific Aims: Aim 1: To assess epithelial contributions by determining if a short intervention of CE/BZA will have antagonistic activity in breast epithelium of postmenopausal women with ER + DCIS. Aim 2: To assess stromal contributions by determining if a short intervention of CE/BZA will alter expression of stromal markers of progression in breast tissue of postmenopausal women with ER + DCIS. Aim 3: To determine if a short intervention of CE/BZA is well tolerated and safe in postmenopausal women with ER + DCIS. Trial Design: We are currently conducting a multicenter randomized placebo controlled window of opportunity trial with CE/BZA in post-menopausal women with DCIS, a non-obligate precursor to IBC. The duration of intervention is 28 ± 7 days prior to surgical resection to enable comparison of CE/BZA on the breast using the diagnostic core biopsy and surgical sample. To date 33/166 women have enrolled in the trial. Eligibility Criteria: Post-menopausal women between 18-79 years of age diagnosed with ER (+) DCIS (&amp;gt;1cm on imaging) undergoing surgery are eligible. Women must not be on current hormonal therapy, have a current or past diagnosis of IBC, other ER sensitive tumors or have recurrent DCIS. Statistics: Results will be compared between diagnostic biopsy and surgical resection specimens and contrasted between the CE/BZA intervention group and placebo group using Fisher’s exact test for categorical variables and independent sample t-tests, or rank sum tests for continuous data. For RNAseq data, transcripts that have &amp;gt;1.5-fold expression change (at 20% FDR) between control and experimental samples will be used for downstream analysis, such as to plot heat maps, pathway and gene ontology analysis. Summary: At the conclusion of this study, we will have the first direct evidence of the potential benefits of CE/BZA therapy on DCIS lesions in the human breast, along with an initial assessment of symptoms and pharmacogenomics that will inform the design of future studies. Citation Format: Swati A. Kulkarni, Geoffrey Greene, Thea Tlsty, Luis Blanco, Judy Garber, Al George, Fred Rademaker, Seema A Khan, Nora Hansen, Kevin Bethke, Rebecca Aft, Julia Tchou. A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS) [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 OT3-09-02.

Abstract P2-08-04: Bilateral mastectomy in ductal carcinoma in situ: 10-year analysis of national inpatient sample database

Abstract Background: The utilization of bilateral (B/L) mastectomy for ductal carcinoma in situ (DCIS) has been rising within the last two decades. This is occurring despite the lack of convincing evidence to support the positive impact of this approach on disease-specific or overall survival (OS.) Notably, the estimated annual risk of developing a contralateral breast cancer is only 0.1% per year. Method: This is a retrospective cohort analysis of National Inpatient Sample database between the years 2005 and 2014 of adult females who underwent B/L mastectomy. ICD-9-CM procedure codes were used to identify two subpopulations; those who had only DCIS without invasive breast cancer or high risk genetic syndrome (DCIS mastectomy) and all others. The aim of this study is to assess the demographic predictors of undergoing B/L mastectomy for DCIS. Statistical analysis done using STATA. Results: The total number of B/L mastectomies performed within the study period was 144,754, of which 24,766 (17.1%) were performed for DCIS with no invasive cancer and no high risk genetic syndrome. There was no significant difference between the two groups in age (average 52.8 years), length of stay (average 2.34 days) and total charge for hospitalization (average $51,209). Among DCIS mastectomy patients, 56.3% were &amp;gt;50 year-old and only 0.7% were 18-30 year-old, 80.7% were Caucasian and 7.5% were African American, 42% were from highest income quartile neighborhoods and 12.6% were from lowest income quartile neighborhoods and 77.8% had private insurance while 15.9% and 5.2% had Medicare and Medicaid, respectively. Interestingly, 95.6% of B/L mastectomies for DCIS were performed at urban centers, 63.6% in teaching hospitals and 64.2% were in large hospital by bed size. Univariate regression showed no significant predictive value for undergoing B/L mastectomy for DCIS indication by age, race, hospital geographic region, teaching status of hospital or hospital size. The odds of undergoing B/L mastectomy for DCIS was higher for age category for 30-50 year-old compared to 18-30 year-old (OR=2.6, p&amp;lt;0.001), highest income quartile compared to lowest (OR=1.28, p &amp;lt;0.001) and private insurance compared to Medicare (OR=1.3, p&amp;lt;0.001) and was lower for Charlson Comorbidity Index (CCI) ≥3 compared to 0 (OR=0.008, p&amp;lt;0.001). On multivariate analysis, age (OR=1.05, p&amp;lt;0.001), race (OR=1.5 for African American compared to Caucasian, p&amp;lt;0.001), highest income quartile (OR=1.19, p=0.03), higher CCI ≥3 (OR=0.005, p&amp;lt;0.001) and private insurance (OR=1.3, p=0.004) were independent predictors of undergoing B/L mastectomy for the diagnosis of DCIS. This disparity could be explained by the variability in anxiety levels among different groups and access to the financial resources needed to perform these procedures. In addition, we noted a progressive rise in charge of hospitalization for B/L mastectomy over the years (table). Conclusion: A significant proportion of B/L mastectomies are being performed for DCIS. While this approach has not convincingly yielded an OS benefit, it has significant clinical and psychological morbidity along with considerable financial toxicity. We found inequity in populations that receive this procedure by age, race, insurance status, income quartile and urban or rural location of center. Further studies would be helpful to delineate this disparity among patients and assess the utility of B/L mastectomy in the era of molecular prediction and superior therapeutic modalities. YearTotal charge of hospitalization ($)200528,722.3200632,192.5200738,492.2200845,168.5200945,752.2201053,326.5201156,128.0201259,118.7201372,193.6201473,783.9 Citation Format: Sindhu Janarthanam Malapati, Sunny RK Singh, Rohit Kumar, Jason Mouabbi, Ahmed Abdalla, Carrie Dul, Tarik Hadid. Bilateral mastectomy in ductal carcinoma in situ: 10-year analysis of national inpatient sample database [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 P2-08-04.

External validation of a mammographic texture marker for breast cancer risk in a case-control study.

.Purpose: The pattern of dense tissue on a mammogram appears to provide additional information than overall density for risk assessment, but there has been little consistency in measures of texture identified. The purpose of this study is thus to validate a mammographic texture feature developed from a previous study in a new setting.Approach: A case–control study (316 invasive cases and 1339 controls) of women in Virginia, USA was used to validate a mammographic texture feature (MMTEXT) derived in a independent previous study. Analysis of predictive ability was adjusted for age, demographic factors, questionnaire risk factors (combined through the Tyrer-Cuzick model), and optionally BI-RADS breast density. Odds ratios per interquartile range (IQ-OR) in controls were estimated. Subgroup analysis assessed heterogeneity by mode of cancer detection (94 not detected by mammography).Results: MMTEXT was not a significant risk factor at 0.05 level after adjusting for classical risk factors (, 95%CI 0.92 to 1.46), nor after further adjustment for BI-RADS density (, 95%CI 0.76 to 1.10). There was weak evidence that MMTEXT was more predictive for cancers that were not detected by mammography (unadjusted for density: , 95%CI 0.99 to 2.15 versus 1.03, 95%CI 0.79 to 1.35, Phet 0.10; adjusted for density: , 95%CI 0.70 to 1.77 versus 0.76, 95%CI 0.55 to 1.05, Phet 0.21).Conclusions: MMTEXT is unlikely to be a useful imaging marker for invasive breast cancer risk assessment in women attending mammography screening. Future studies may benefit from a larger sample size to confirm this as well as developing and validating other measures of risk. This negative finding demonstrates the importance of external validation.

Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank.

Breast cancer is considered to result from a combination of genetic and lifestyle-related factors, but the degree to which an overall healthy lifestyle may attenuate the impact of multiple genetic variants on invasive breast cancer risk remains equivocal. Using Cox proportional hazards regression models, we examined the association of a modified healthy lifestyle index (HLI) with risk of invasive breast cancer by genetic risk group among 146 326 women from the UK Biobank. We generated an HLI score based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry, and a polygenic risk score (PRS) using 304 breast cancer-associated genetic loci. Among premenopausal and postmenopausal women, a favorable lifestyle (highest tertile) was associated with 22% and 31% reductions in invasive breast cancer risk, respectively (hazard ratio [HR]high vs low = 0.78, 95% confidence interval [CI] = 0.64 to 0.94; HRhigh vs low = 0.69, 95% CI = 0.63 to 0.77, respectively), whereas a high PRS (highest tertile) was associated with more than a doubling in the risk in both groups. For premenopausal women, the greatest risk reduction in association with the HLI was seen among those with a high PRS (HRhigh vs low = 0.73, 95% CI = 0.75 to 0.95). In postmenopausal women, those with a favorable lifestyle had 30%, 29%, and 32% reductions in risk of invasive breast cancer in the low, intermediate, and high PRS groups, respectively (HRhigh vs low = 0.70, 95% CI = 0.56 to 0.88; HRhigh vs low = 0.71, 95% CI = 0.59 to 0.84; and HRhigh vs low = 0.68, 95% CI = 0.59 to 0.78, respectively). There was an additive but not multiplicative interaction between the HLI score and PRS for postmenopausal and, to a lesser extent, premenopausal women. Our findings support the view that an overall healthy lifestyle may attenuate the impact of genetic factors on invasive breast cancer risk among women of European ancestry.

Breast cancer risk reduction: Notable achievements and remaining challenges.

Millions of women in the United States are at increased risk of breast cancer. Multiple prospective, randomized clinical trials have demonstrated both the efficacy and safety of selective estrogen receptor modulators and aromatase inhibitors in reducing substantially the risk of invasive breast cancer in women at increased risk. Published tables are available to aid clinicians in shared decision-making regarding drug interventions with their patients who are at increased risk of breast cancer. Both professional and governmental agencies have advised that these interventions should be offered to women at increased risk of breast cancer. Doing so would reduce breast cancer morbidity substantially.

The association between DXA-derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative.

BackgroundMost studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk.MethodsCox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years.ResultsExcess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses.ConclusionThese findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.

Risk factors for ductal carcinoma in situ of the breast in the UK Biobank cohort study

Ductal carcinoma in situ of the breast (DCIS) is considered to be a non-obligate precursor of invasive breast cancer (IBC). This suggests that risk factors for DCIS should be a subset of those for IBC. To this end, we investigated whether demographic, lifestyle, and reproductive factors that have been linked to IBC risk are also associated with DCIS risk. This study was conducted in 263,788 women aged 40–69 years at enrolment into the UK Biobank population-based cohort. Information on demographic, reproductive and health factors was collected at baseline using computerized questionnaires, while incident DCIS was ascertained through linkage to UK cancer registries. Age-adjusted and multivariable hazard ratios were estimated using Cox proportional hazards models in the total sample and by menopausal status. During an average of 7 years of follow-up, 1,016 women developed DCIS. Multivariable analysis indicated that age, physical activity, height, family history of breast cancer, menopausal status, parity, and years between menarche and first live birth had associations with DCIS risk. Among post-menopausal women not using hormone replacement therapy, body mass index ≥30 kg/m2 was associated with increased DCIS risk. This study, the largest to date including both pre-menopausal and post-menopausal women, confirms previous findings indicating correspondence between risk factors for DCIS and IBC and highlights the potential contribution to DCIS risk of anthropometric measures not previously reported to be associated with the disease, such as height and BMI amongst post-menopausal women.

Identifying Women at High Risk for Breast Cancer Using Data From the Electronic Health Record Compared With Self-Report.

A barrier to chemoprevention uptake among high-risk women is the lack of routine breast cancer risk assessment in the primary care setting. We calculated breast cancer risk using the Breast Cancer Surveillance Consortium (BCSC) model, accounting for age, race/ethnicity, first-degree family history of breast cancer, benign breast disease, and mammographic density, using data collected from the electronic health records (EHRs) and self-reports. Among women undergoing screening mammography, we enrolled those age 35 to 74 years without a prior history of breast cancer. Data on demographics, first-degree family history, breast radiology, and pathology reports were extracted from the EHR. We assessed agreement between the EHR and self-report on information about breast cancer risk. Among 9,514 women with known race/ethnicity, 1,443 women (15.2%) met high-risk criteria based upon a 5-year invasive breast cancer risk of 1.67% or greater according to the BCSC model. Among 1,495 women with both self-report and EHR data, more women with a first-degree family history of breast cancer (14.6% v 4.4%) and previous breast biopsies (21.3% v 11.3%) were identified by self-report versus EHR, respectively. However, more women with atypia and lobular carcinoma in situ were identified from the EHR. There was moderate agreement in identification of high-risk women between EHR and self-report data (κ, 0.48; 95% CI, 0.42-0.54). By using EHR data, we determined that 15% of women undergoing screening mammography had a high risk for breast cancer according to the BCSC model. There was moderate agreement between information on breast cancer risk derived from the EHR and self-report. Examining EHR data may serve as an initial screen for identifying women eligible for breast cancer chemoprevention.

Associations of race and ethnicity with risk of developing invasive breast cancer after lobular carcinoma in situ

BackgroundLobular carcinoma in situ (LCIS) of the breast is a risk factor of developing invasive breast cancer. We evaluated the racial differences in the risks of subsequent invasive breast cancer following LCIS.MethodsWe utilized data from the Surveillance, Epidemiology, and End Results registries to identify 18,835 women diagnosed with LCIS from 1990 to 2015. Cox proportional hazards regression was used to estimate race/ethnicity-associated hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of subsequent invasive breast cancer.ResultsDuring a median follow-up of 90 months, 1567 patients developed invasive breast cancer. The 10-year incidence was 7.9% for Asians, 8.2% for Hispanics, 9.3% for whites, and 11.2% for blacks (P = 0.046). Compared to white women, black women had significantly elevated risks of subsequent invasive breast cancer (HR 1.33; 95% CI 1.11, 1.59), and invasive cancer in the ipsilateral breast (HR 1.37; 95% CI 1.08, 1.72) and in the contralateral breast (HR 1.33; 95% CI 1.00, 1.76). Black women had significantly higher risks of invasive subtypes negative for both estrogen receptor and progesterone receptor (HR 1.86; 95% CI 1.14, 3.03) and invasive subtypes positive for one or both of receptors (HR 1.30; 95% CI 1.07, 1.59). The risk of subsequent invasive breast cancer was comparable in Asian women and Hispanic women compared with white women.ConclusionsBlack women had a significantly higher risk of developing invasive breast cancer, including both hormone receptor-positive and hormone receptor-negative subtypes, after LCIS compared with white counterparts. It provides an opportunity to address health disparities.

Association of Microcalcification Clusters with Short-term Invasive Breast Cancer Risk and Breast Cancer Risk Factors

Using for-presentation and for-processing digital mammograms, the presence of microcalcifications has been shown to be associated with short-term risk of breast cancer. In a previous article we developed an algorithm for microcalcification cluster detection from for-presentation digital mammograms. Here, we focus on digitised mammograms and use a three-step algorithm. In total, 253 incident invasive breast cancer cases (with a negative mammogram between three months and two years before diagnosis, from which we measured microcalcifications) and 728 controls (also with prior mammograms) were included in a short-term risk study. After adjusting for potential confounding variables, we found evidence of an association between the number of microcalcification clusters and short-term (within 3–24 months) invasive breast cancer risk (per cluster OR = 1.30, 95% CI = (1.11, 1.53)). Using the 728 postmenopausal healthy controls, we also examined association of microcalcification clusters with reproductive factors and other established breast cancer risk factors. Age was positively associated with the presence of microcalcification clusters (p = 4 × 10−04). Of ten other risk factors that we studied, life time breastfeeding duration had the strongest evidence of association with the presence of microcalcifications (positively associated, unadjusted p = 0.001). Developing algorithms, such as ours, which can be applied on both digitised and digital mammograms (in particular for presentation images), is important because large epidemiological studies, for deriving markers of (clinical) risk prediction of breast cancer and prognosis, can be based on images from these different formats.

Considerations When Using Breast Cancer Risk Models for Women with Negative BRCA1/BRCA2 Mutation Results.

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.

Air Pollution, Clustering of Particulate Matter Components, and Breast Cancer in the Sister Study: A U.S.-Wide Cohort.

Background:Particulate matter (PM) is a complex mixture. Geographic variations in PM may explain the lack of consistent associations with breast cancer.Objective:We aimed to evaluate the relationship between air pollution, PM components, and breast cancer risk in a United States-wide prospective cohort.Methods:We estimated annual average ambient residential levels of particulate matter and in aerodynamic diameter ( and , respectively) and nitrogen dioxide () using land-use regression for 47,433 Sister Study participants (breast cancer–free women with a sister with breast cancer) living in the contiguous United States. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk associated with an interquartile range (IQR) increase in pollutants. Predictive k-means were used to assign participants to clusters derived from component profiles to evaluate the impact of heterogeneity in the mixture. For , we investigated effect measure modification by component cluster membership and by geographic region without regard to air pollution mixture.Results:During follow-up (), 2,225 invasive and 623 ductal carcinoma in situ (DCIS) cases were identified. and were associated with breast cancer overall [ (95% CI:0.99, 1.11) and 1.06 (95% CI:1.02, 1.11), respectively] and with DCIS but not with invasive cancer. Invasive breast cancer was associated with only in the Western United States [ (95% CI:1.02, 1.27)] and only in the Southern United States [ (95% CI:1.01, 1.33)]. was associated with a higher risk of invasive breast cancer among two of seven identified composition-based clusters. A higher risk was observed [ (95% CI: 0.97, 1.60)] in a California-based cluster characterized by low S and high Na and nitrate () fractions and for another Western United States cluster [ (95% CI: 0.90, 2.85)], characterized by high fractions of Si, Ca, K, and Al.Conclusion:Air pollution measures were related to both invasive breast cancer and DCIS within certain geographic regions and PM component clusters. https://doi.org/10.1289/EHP5131

Breast Cancer Chemoprevention: A Practical Guide for the Primary Care Provider.

Several organizations, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the United States Preventive Services Task Force, recommend incorporation of breast cancer risk-based counseling and chemoprevention into routine well-woman care. However, primary care providers report both discomfort with and a lack of medical knowledge on this topic. In this review we present a practical, evidence-based guide for incorporating breast cancer risk assessment and chemoprevention into routine care. We advocate a stepwise approach consisting of: (1) risk assessment and communication, (2) selection of appropriate chemoprevention based on risk-benefit analysis, (3) shared decision-making regarding chemoprevention, and (4) management of chemoprevention side effects. We encourage providers to identify high-risk women and refer them to genetic counseling or a high-risk breast cancer clinic. For women who are not considered high risk, we suggest using the Gail model to estimate a woman's 5-year risk of invasive breast cancer. Usually, the benefits of chemoprevention outweigh the risks of chemoprevention once a woman's 5-year risk of invasive breast cancer reaches 3%. For these women there are several factors that need to be considered when selecting a chemoprevention agent, including patient preference, thrombotic history, menopausal status, absence or presence of a uterus, and bone mineral density. We advocate an evidence-based shared decision-making approach that reflects the woman's individual preferences when communicating risk and counseling about chemoprevention. After starting a chemoprevention agent, close follow-up is important as side effects of chemoprevention are common, including vasomotor symptoms and arthralgias. We also review evidence-based management of chemoprevention side effects.

The Tyrer–Cuzick Model Inaccurately Predicts Invasive Breast Cancer Risk in Women With LCIS

The Tyrer-Cuzick model has been shown to overestimate risk in women with atypical hyperplasia, although its accuracy among women with lobular carcinoma in situ (LCIS) is unknown. We evaluated the accuracy of the Tyrer-Cuzick model for predicting invasive breast cancer (IBC) development among women with LCIS. Women with LCIS participating in surveillance from 1987 to 2017 were identified from a prospectively maintained database. Tyrer-Cuzick score (version 7) was calculated near the time of LCIS diagnosis. Patients with prior or concurrentbreast cancer, a BRCA mutation, receiving chemoprevention, or with pleomorphic LCIS were excluded. Invasive cancer-free probability was estimated using the Kaplan-Meier method. A total of 1192 women with a median follow-up of 6years (interquartile range [IQR] 2.5-9.9) were included. Median age at LCIS diagnosis was 49years (IQR 45-55), 88% were white; 37% were postmenopausal, 28% had ≥ 1 first-degree family member with breast cancer, and 13% had ≥ 2 second-degree family members with breast cancer. In total, 128 patients developed an IBC; median age at diagnosis was 54years (IQR 49-61). Five- and 10-year cumulative incidences of invasive cancer were 8% (95% confidence interval [CI] 6-9%) and 14% (95% CI 12-17%), respectively. The median Tyrer-Cuzick 10-year risk score was 20.1 (IQR 17.4-24.3). Discrimination measured by the C-index was 0.493, confirming that the Tyrer-Cuzick model is not well calibrated in this patient population. The Tyrer-Cuzick model is not accurate and may overpredict IBC risk for women with LCIS, and therefore should not be used for breast cancer risk assessment in this high-risk population.

Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool.

BackgroundiPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman’s risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data.MethodsiPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20–70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed.ResultsDuring the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and BRCA1/2-mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy.ConclusionsFor 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b.