Breast Cancer Risk Evaluation Research Articles

Abstract PD10-03: Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes

Abstract BACKGROUND: TNBC is among the most aggressive subtypes of invasive breast cancer (BC), and accounts for approximately 10-15% of incidental BC diagnoses. TNBC is associated with early age of onset (median age of diagnosis <50) and disproportionately affects African American women. Breast MRI is currently recommended to screen for BC in women with at least a moderate-to-high lifetime risk of BC (a 2-fold or higher increased risk), and may also be superior to mammogram to screen for TNBC. TNBC has been most closely associated with germline PVs in BRCA1. However, recent studies have suggested that PVs in other genes previously associated with invasive BC may specifically confer high risks of the TNBC subtype. METHODS: Results were analyzed from 627,219 women undergoing clinical multi-gene panel testing at a single US-based commercial laboratory between 5/2013 and 2/2020, including genes associated with hereditary BC and other cancers. Demographic and personal/family history data were collected on a test requisition form. Individuals who had single- or founder-site testing, or prior BRCA1 or BRCA2 testing, were excluded. Multivariable regression analysis was used to examine the association between PVs/suspected PVs and personal history (PHx) of TNBC. Models were adjusted for age, personal/family cancer history, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. RESULTS: In total, 22.4% (140,467/627,219) of women tested reported PHx of BC, of whom 12.8% (17,951/140,467) reported PHx of TNBC. Elevated risks of TNBC were identified in carriers of PVs in 10 genes (see Table). While the highest TNBC risk was associated with PVs in BRCA1 (OR 21.24, 95% CI 19.71-22.88), high risks were also seen for BARD1 (OR 7.05, 95% CI 5.71-8.71), TP53 (OR 5.64, 95% CI 3.08-10.33), PTEN (OR 5.52, 95% CI 2.35-13.00) and PALB2 (OR 5.27, 95% CI 4.55-6.10). Moderate-to-high risks (2-5-fold increased risk) of TNBC were also seen for carriers of PVs in RAD51C, RAD51D, BRCA2, and CDKN2A/P16. By contrast, PVs in NBN, ATM, and CHEK2 were all associated with an apparent decreased risk of TNBC. CONCLUSIONS: PVs in several hereditary cancer genes routinely tested on multi-gene panel tests are associated with high risks (OR>5.0) and moderate-to-high risks (OR 2.0-5.0) of TNBC. These findings can inform practice guidelines about which genes to test when evaluating breast cancer risk and which PV carriers may benefit from intensive breast screening with magnetic resonance imaging (MRI). Odds ratios for TNBC in germline carriers of PV in hereditary cancer risk genesRisk GenePV Positive with TNBCOR95% CIp-valueHigh RiskBRCA1119321.2419.71-22.88<0.001BARD11257.055.71-8.71<0.001TP53125.643.08-10.33<0.001PTEN65.522.35-13.00<0.001PALB22315.274.55-6.10<0.001Moderate-to-High RiskRAD51C864.923.86-6.26<0.001RAD51D454.643.34-6.45<0.001BRCA24884.434.02-4.89<0.001CDKN2A (p16)172.521.52-4.18<0.001Moderate-to-Low RiskBRIP1771.921.51-2.44<0.001Protective EffectNBN140.550.32-0.940.030ATM400.510.37-0.70<0.001CHEK2490.440.33-0.58<0.001HOXB1350.330.14-0.810.015 Citation Format: Michael J Hall, Eric Rosenthal, Susana San Roman, Ryan Bernhisel, John Kidd, Elisha Hughes, Thomas Slavin, Allison Kurian. Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-03.

Association of the Differences in Average Glandular Dose with Breast Cancer Risk

Objectives. To compare the differences in normalized average glandular dose (NAGD) between the breasts of healthy subjects and those of cancer patients and to determine if the NAGD difference is associated with breast cancer risk and improves breast cancer classification. Materials and Methods. Craniocaudal view and mediolateral view full-field digital mammography (FFDM) images were obtained from 1682 healthy subjects whose breasts were categorized as Breast Imaging-Reporting and Data System (BI-RADS) I or II and from 811 biopsy-confirmed unilateral breast cancer patients whose breasts on the contralateral side were category I or II. Both populations were randomized into training and test sets. Multivariate logistic regression analysis was used to build the breast cancer risk assessment model, and the area under the receiver operating characteristic curve ( A z ) was used to evaluate the model. Twenty-two breast cancer patients who were originally categorized as BI-RADS I or II for both breasts, but were diagnosed with unilateral biopsy-confirmed breast cancer subsequently, were included to validate the model. Results. The NAGD differences in both FFDM images between tumor-bearing breasts and the healthy breasts of patients were significantly higher than those in healthy subjects ( P < 0.001 ). The model with NAGD differences had a higher A z value than the model without NAGD differences. While there was no NAGD differences between originally healthy breasts of breast cancer patients, significant NAGD differences between now tumor-bearing breasts and the then previously healthy breasts were found in both FFDM images. Conclusions. NAGD differences between both breasts can be included in the breast cancer risk assessment model to evaluate breast cancer risk.

Combination of phenotype and polygenic risk score in breast cancer risk evaluation in the Spanish population: a case \u2013control study

BackgroundIn recent years, the identification of genetic and phenotypic biomarkers of cancer for prevention, early diagnosis and patient stratification has been a main objective of research in the field. Different multivariable models that use biomarkers have been proposed for the evaluation of individual risk of developing breast cancer.MethodsThis is a case control study based on a population-based cohort. We describe and evaluate a multivariable model that incorporates 92 Single-nucleotide polymorphisms (SNPs) (Supplementary Table S1) and five different phenotypic variables and which was employed in a Spanish population of 642 healthy women and 455 breast cancer patients.ResultsOur model allowed us to stratify two groups: high and low risk of developing breast cancer. The 9th decile included 1% of controls vs 9% of cases, with an odds ratio (OR) of 12.9 and a p-value of 3.43E-07. The first decile presented an inverse proportion: 1% of cases and 9% of controls, with an OR of 0.097 and a p-value of 1.86E-08.ConclusionsThese results indicate the capacity of our multivariable model to stratify women according to their risk of developing breast cancer. The major limitation of our analysis is the small cohort size. However, despite the limitations, the results of our analysis provide proof of concept in a poorly studied population, and opens up the possibility of using this method in the routine screening of the Spanish population.

Risk of Breast Cancer Revealed by Mammographic Screening in Czech Women Aged 40-45 Years, a Monocentric Cohort Study.

The aim of the present study was to evaluate breast cancer risk in women aged 40–45 years not included in the routine mammographic screening programme in the Czech Republic and to assess the suitability of the screening interval. Our cohort study was conducted using registry data of one mammography centre (Bulovka Hospital in Prague) between 1 January 2008 and 31 December 2017. The risk of breast cancer was evaluated using a positive predictive finding (PPF) corresponding to the Breast Imaging-Reporting and Data System (BI-RADS) scores of 4 and 5. The annual PPF incidence rate achieved 2.25 per 1000 women aged 40–45 years and was not significantly different from that (3.31) of women of 45–50 years of age as demonstrated by an adjusted hazard ratio of 0.75 (95% confidence interval: 0.42–1.33). It was found that a screening interval longer than 3 years increased the chance of PPF occurrence 1.7 times independently of the women’s age, signalling a risk of failure of early detection of breast cancer. The same PPF incidence rates both in women aged 40–45 years and in older ones indicates that even younger women should be eligible for enrolment in the routine mammographic screening programme in the Czech Republic.

Abstract PR05: Utilizing electronic fertility clinic records and registry linkage to establish a retrospective population-based cohort study to evaluate the association between in vitro fertilization (IVF) and subsequent cancer risk in women

Abstract Background: Since the introduction of in vitro fertilization (IVF) in 1978, the use of assisted reproduction technology (ART) has increased annually with an estimated 240,000 ART-conceived children born each year worldwide. Despite its widespread use, the impact on subsequent maternal and child health is not well understood. Specifically, cancer risk in women receiving IVF treatment has not been adequately evaluated, in part due to the complex nature of the research question and the need for large numbers of exposed women with long follow-up to evaluate rare cancer outcomes. Methods: To address this research question, we designed a country-wide retrospective medical record linkage study that utilizes electronic records from all IVF units in operation in Israel between 1997 and 2014. Linkage to cancer registry is facilitated via unique national identification numbers. We selected Israel for this study because it has the highest rate of ART/IVF exposure in the world, with 24 IVF units in the country that perform more than 45,000 ART cycles annually. Fertility treatment is fully covered by national health insurance with no restriction on the number of cycles or type of procedure, thus reducing potential selection issues related to access to care that may exist in other populations. We are currently collecting medically documented and detailed exposure information from the IVF units, including causes of infertility, hormonal treatments, procedures (e.g., IVF), and important covariates (e.g., parity, body mass index, etc.). To date we have collected exposure and covariate information from 18,470 women receiving treatment at 9 IVF clinics and conducted an interim linkage with the cancer registry through December 2014, providing on average 15 years of follow-up. We calculated standardized incidence ratios (SIRs) for all cancers combined and separately for breast cancer and further evaluated breast cancer risk with number of treatment cycles using Cox proportional hazards regression. Results: Based on interim registry linkage we identified 611 invasive cancers including 272 breast cancers among 18,470 women with more than 236,000 woman-years of follow-up. The incidence of cancer [SIR (95% confidence interval (CI)): 0.96 (0.88-1.04)] or breast cancer [0.98 (0.87-1.11)] was not elevated compared to the general population. Further, breast cancer risk was not associated with increased number of IVF treatment cycles [adjusted hazard rate ratio (RR) (95% CI) per IVF cycle: 1.01 (0.96-1.09)]. Conclusions: With this data we have demonstrated the feasibility of linking IVF clinic data with the nationwide cancer registry to evaluate cancer risk. In our preliminary analyses, IVF treatment was not associated with risk of incident invasive cancer or breast cancer. Given that continued linkage with the cancer registry is feasible, we will be able to monitor long-term cancer risks associated with IVF treatment using the enumerated data. This abstract is also being presented as Poster A15. Citation Format: Britton Trabert, Galit Hirsh-Yechezkel, Adel Farhi, Inna Zaslavsky, Shai E. Elizur, Arik Kahana, Raoul Orvieto, Hananel Holzer, Ilan Calderon, Shevach Friedler, Einat Shalom-Paz, Raphael Ron-El, Arie Raziel, Louise A. Brinton, Liat Lerner-Geva. Utilizing electronic fertility clinic records and registry linkage to establish a retrospective population-based cohort study to evaluate the association between in vitro fertilization (IVF) and subsequent cancer risk in women [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr PR05.

Survival Analysis: A Hospital Based Retrospective Life Span Study of Breast Cancer Patients after First Recurrence

Background Overall survival of breast cancer patients has been calculated many times but there is no precise research available regarding the survival time of breast cancer patients after recurrence. We investigated the effects factors on mortality due to breast cancer. Methods All Factors were analyzed using statistical tools and techniques to find out rate of mortality after recurrence. Descriptive statistics, cox proportional hazard models were used to find statistical significant variables. In the present study recurrence is considered as an important event which may play a role in study of breast cancer progression. In this study, we evaluated breast cancer risk factors in relation to mortality due to this disease among 1028 women with breast cancer in Lahore, Pakistan. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between risk factors and mortality due to breast cancer were estimated in subtype-specific Cox regression models. Results Survival of breast cancer patients depends upon many factors. A total of 581 alive and 447 deaths due to breast cancer occurred during a median follow-up period of 1977 days. Median survival time after recurrence was 3 years. Significant factors were included post- menopausal women who diagnosed and had recurrence at the age < 45 of molecular subtype estrogen receptor positive, progesterone receptor negative, Her2.neu positive with tumor size ≥ 3 & involved lymph nodes >5. Radiotherapy has increased life span of patients even after recurrence. Conclusion Younger women had higher risk of mortality after recurrence even gone through chemotherapy while lower grade tumor had good prognosis. Radiotherapy played a major role in increasing life time of breast cancer women after recurrence. Our findings are consistent with those from previously published data.

Abstract P5-08-06: NSAID use and breast cancer risk in a retrospective cohort of women with benign breast disease

Abstract Background Prior epidemiologic studies have shown an inverse relationship of aspirin and NSAID use with breast cancer (BC) risk in the general population. Women with benign breast disease (BBD) are at an increased BC risk compared with women in the general population, and we have shown that BBD biopsies contain increased numbers of immune cells compared with normal breast tissues donated for research in the Komen Tissue Bank. We hypothesized that NSAID use among women with BBD is associated with reduced risk of BC. Methods We evaluated BC risk in relation to aspirin and NSAID use in a single institution retrospective cohort of 4,498 women who received a biopsy diagnosis of BBD between 1/1/1992 and 12/31/2001. Information on usual medication use, including average number of days used per month (0, 1-7, 8-28 and >28), was collected via questionnaires mailed after identification of participants. NSAIDs were categorized into three classes: 1) Aspirin, 2) Ibuprofen (plus other prostaglandin synthesis inhibitors), and 3) COX inhibitors. BC events were captured via medical record, questionnaires, and Tumor Registry records. Medication use was evaluated for associations with clinical and pathology features. Hazard ratios (HR) and 95% confidence intervals (CI) examining associations between medication use and BC risk were estimated using Cox regression analyses, with adjustment for age and BMI at biopsy, years between biopsy and questionnaire, and pathologic features related to BC risk (severity of BBD and degree of involution in background lobules). Tests for trend examining frequency of use were calculated from ordered values (lowest to highest) in Cox models with a one degree-of-freedom linear term. We assessed BC associations with any type of NSAID use, as well as the three subclasses. Results Information on NSAID use was available for 3,089 (69%) of the participants in the cohort; these women had a median age of 49 and did not differ in BC risk from women who did not provide data on NSAID use (p=0.46). Of the 3,089 respondents, 313 (10.1%) subsequently developed BC with median follow-up of 17 years. Age was significantly associated with use of all types of NSAIDs, with increasing use in older women. BMI at the time of biopsy, severity of BBD findings, and involution in background lobules were also associated with NSAID use; thus these factors and age were adjusted for in risk association analyses. Ever users of NSAIDs (any type) had a significantly lower risk of BC than never users (HR 0.76, CI 0.59-0.98, p=0.03), and increasing frequency of NSAID use was significantly associated with lower BC risk (HRs 0.81, 0.79, and 0.70 for regular use 1-7, 8-28, and >28 days/month), trend p=0.02. Analyses of drug classes revealed that ever use of ibuprofen (HR 0.61, CI 0.42-0.89, p=0.01) and ever use of COX inhibitors (HR 0.59, CI 0.39-0.89, p=0.01) were associated with decreased BC risk. COX inhibitors in particular showed a strong dose response effect with increasing use (HRs 0.97, 0.52, and 0.47 for regular use 1-7, 8-28, and >28 days/month), trend p<0.01. Use of aspirin was not associated with BC risk (HR 0.88, CI 0.64-1.21, p=0.44). Conclusions In this exploratory analysis, we found use of ibuprofen and other NSAIDs to be associated with decreased BC risk among women who had undergone a BBD biopsy. These findings suggest that anti-inflammatory approaches may have value in chemoprevention among women with BBD. Citation Format: Amy Degnim, Robert Vierkant, Stacey Winham, Marlene Frost, Daniel Visscher, Jodi Carter, Suneetha Kaggal, Julie Cunningham, Teresa Allers, Tanya Hoskin, Ethan Heinzen, Celine Vachon, Keith Knutson, Keith Knutson, Derek Radisky, Mark Sherman. NSAID use and breast cancer risk in a retrospective cohort of women with benign breast disease [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 P5-08-06.

Abstract P2-10-12: Relationship between predicted risks of carrying breast cancer susceptibility genes and the presence of germline variants in Japanese patients with primary breast cancer

Abstract Background: Breast cancer risk models are used to predict the risk of carrying a variant, for one of the most common breast cancer susceptibility genes such as BRCA1 and BRCA2, and the lifetime risk of developing breast cancer. The prediction of harboring a germline variant of the BRCA gene and the development of breast or ovarian cancer over time affects the decision-making for undergoing genetic testing and screening using imaging techniques as the common practice. For instance, the American Cancer Society and the National Comprehensive Cancer Network (NCCN) recommends screening using MRI in women with 20% or greater lifetime risk of having breast cancer. We aimed to investigate the prediction of these risks in Japanese women, particularly on the relationship between the presence of pathogenic germline variants and breast cancer susceptibility genes, using a cohort of 1016 primary breast cancer patients. Patients and Methods: We analyzed a cohort of Japanese patients with primary breast cancer who were treated at the Kyoto University Hospital and the related institutions or hospitals from the period of 2011 to 2016. The germline variants were examined for a set of 13 breast cancer susceptibility genes, using targeted-capture sequencing of pooled DNA, and it was found that 66 out of 1016 patients had pathogenic variants. These included 11 functionally well-established genes (BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, and NBN) and two additional genes (BARD1 and BRIP1), which are recommended for the screening of high-risk patients with hereditary breast cancer in the NCCN guidelines. Using this cohort, we studied the association of the calculated risk of carrying a germline variant of BRCA1/ BRCA2, using the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool, within the laboratory germline test results. Results: Pathogenic germline variants of BRCA1/ BRCA2 were carried by 54 (5.3%) out of the 1016 patients (12 cases of BRCA1 and 42 cases of BRCA2). According to the NCCN guidelines, which focus on Genetic/ Familial High-Risk Assessment: Breast and Ovarian, it was found that 500 out of 1016 (49.2%)patients were categorized for considering germline testing. In fact, 38 (7.6%) of the 500 patients, harbored a pathogenic germline variant of BRCA1/ BRCA2. In the remaining 516 patients, 16 (3.1%) harbored the pathogenic germline variant of BRCA1/ BRCA2. The predictive risks of the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool were recorded as follows: Area under the ROC curve, BRCA1 (area 0.750, 95% CI- 0.581-0.919), BRCA2 (area 0.741, 95% CI- 0.661-0.820), BRCA1 or BRCA2 (Area 0.749, 95% CI: 0.675-0.822), suggesting that the Tyrer-Cuzick model may be useful for the Japanese population. In the mammography breast density analysis, 484 patients showed almost entirely fat or scattered fibroglandular breast tissue, and 362 cases had heterogeneous or extreme fibroglandular breast tissue. In this study, the correlations of breast tissue density with age and breast or ovarian cancer familial history have been reported in greater detail. Discussion and Conclusions: In a retrospective cohort of 1016 Japanese patients with primary breast cancer, 5.3% had pathogenic germline variants of BRCA1/ BRCA2. In a group recommended by NCCN guidelines for considering genetic testing, the BRCA1/ BRCA2 variant rate was 7.6%. Predictive risks calculated by the Tyrer-Cuzick model similar with the known data. Further data are reported. Citation Format: Noriko Senda, Nobuko Kawaguchi-Sakita, Masahiro Kawashima, Yukiko Inagaki-Kawata, Kenichi Yoshida, Tomomi Nishimura, Masahiro Takada, Eiji Suzuki, Yuki Kataoka, Fumiaki Sato, Yoshiaki Matsumoto, Masae Torii, Hiroshi Yoshibayashi, Kazuhiro Yamagami, Shigeru Tsuyuki, Akira Yamauchi, Nobuhiko Shinkura, Hironori Kato, Yoshio Moriguchi, Ryuji Okamura, Norimichi Kan, Hirofumi Suwa, Shingo Sakata, Susumu Mashima, Fumiaki Yotsumoto, Tsuyoshi Tachibana, Mitsuru Tanaka, Takashi Inamoto, Masahiro Sugimoto, Seishi Ogawa, Masakazu Toi. Relationship between predicted risks of carrying breast cancer susceptibility genes and the presence of germline variants in Japanese patients with primary breast cancer [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 P2-10-12.

Abstract P3-08-28: Tissue sound speed is more strongly associated with breast cancer risk than mammographic percent density: A comparative case-control study

Abstract PURPOSE. Increased mammographic percent density (MPD) is a strong independent risk factor for developing breast cancer. Previous studies have shown that tissue sound speed, derived from ultrasound tomography, is a surrogate biomarker of MPD. We examined associations of sound speed and MPD with breast cancer risk in a case-control study. METHOD AND MATERIALS. We evaluated breast cancer risk associated with sound speed and MPD in a case-control study involving 59 participants with recent breast cancer diagnoses (cases, aged 30-70 years) and 150 participants with no history of breast cancer (controls), who were matched to cases on age, race, and menopausal status. The cases and controls were imaged with both ultrasound tomography (UST) and mammography. In cases, breast density was measured pre-treatment in the contralateral breast to avoid potential influences of tumor-related changes on MPD or sound speed. In controls, a randomly selected breast was imaged. The ultrasound tomography images were used to estimate the volume averaged sound speed of the breast, and the Cumulus software package was applied to mammograms to determine MPD. Odds Ratios (ORs) and 95% Confidence Intervals (CIs), adjusted for matching factors, were calculated for the relation of quartiles of MPD and sound speed with breast cancer risk. OR differences were tested using a bootstrap approach. RESULTS. MPD was associated with elevated breast cancer risk compared to controls, consistent with previous studies, although the trend did not reach statistical significance (OR per quartile=1.28, 95%CI: 0.95, 1.73; ptrend=0.10). In contrast, elevated sound speed was significantly associated with increased breast cancer risk in a dose-response fashion (OR per quartile=1.79, 95%CI: 1.30, 2.48; ptrend=0.0004). The OR-trend for sound speed was statistically significantly different from that observed for MPD (p=0.01). DISCUSSION. Our case-control study showed that increasing quartiles of whole breast sound speed were consistently and more strongly associated with increasing breast cancer risk than quartiles of MPD. These results show promise for UST’s role in breast cancer risk stratification. CONCLUSION. Elevated breast density strongly increases breast cancer risk. UST has the potential to provide a more accurate, non-ionizing method for assessing breast density and its associated breast cancer risk. Citation Format: Mark Sak, Neb Duric, Ruth Pfeiffer, Mark Sherman, Peter Littrup, Michael Simon, David Gorski, Teri Albrecht, Haythem Ali, Rachel Brem, Rachel Brem, Sharon Fan, Gretchen Gierach. Tissue sound speed is more strongly associated with breast cancer risk than mammographic percent density: A comparative case-control study [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 P3-08-28.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use

Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Odds ratios (ORs) for subsequent breast cancer by ER status. A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population‐based cohort study

We aim to evaluate breast cancer risk relating to PPIs usage in women with peptic ulcer. From 2000 to 2013, incidence rates of breast cancer were compared between the two cohorts (with or without PPIs). Each study cohort consisted of 4838 women. The incidence density rate of breast cancer in the PPI cohort was 0.29 that in the comparison cohort (10.0 vs 31.6 per 10000 person-years), with an adjusted HR (hazard ratio) of 0.32 (95% CI=0.20-0.49) for the PPI cohort. In conclusion, the medication of PPIs is associated with reduced breast cancer risk for women with gastric ulcer.

Quantitative assessment of breast density using transmission ultrasound tomography.

PurposeBreast density is important in the evaluation of breast cancer risk. At present, breast density is evaluated using two‐dimensional projections from mammography with or without tomosynthesis using either (a) subjective assessment or (b) a computer‐aided approach. The purpose of this work is twofold: (a) to establish an algorithm for quantitative assessment of breast density using quantitative three‐dimensional transmission ultrasound imaging; and (b) to determine how these quantitative assessments compare with both subjective and objective mammographic assessments of breast density.MethodsWe described and verified a threshold‐based segmentation algorithm to give a quantitative breast density (QBD) on ultrasound tomography images of phantoms of known geometric forms. We also used the algorithm and transmission ultrasound tomography to quantitatively determine breast density by separating fibroglandular tissue from fat and skin, based on imaged, quantitative tissue characteristics, and compared the quantitative tomography segmentation results with subjective and objective mammographic assessments.ResultsQuantitative breast density (QBD) measured in phantoms demonstrates high quantitative accuracy with respect to geometric volumes with average difference of less than 0.1% of the total phantom volumes. There is a strong correlation between QBD and both subjective mammographic assessments of Breast Imaging ‐ Reporting and Data System (BI‐RADS) breast composition categories and Volpara density scores — the Spearman correlation coefficients for the two comparisons were calculated to be 0.90 (95% CI: 0.71–0.96) and 0.96 (95% CI: 0.92–0.98), respectively.ConclusionsThe calculation of breast density using ultrasound tomography and the described segmentation algorithm is quantitatively accurate in phantoms and highly correlated with both subjective and Food and Drug Administration (FDA)‐cleared objective assessments of breast density.

Breast cancer risk factors, survival and recurrence, and tumor molecular subtype: analysis of 3012 women from an indigenous Asian population

BackgroundLimited evidence, mostly from studies in Western populations, suggests that the prognostic effects of lifestyle-related risk factors may be molecular subtype-dependent. Here, we examined whether pre-diagnostic lifestyle-related risk factors for breast cancer are associated with clinical outcomes by molecular subtype among patients from an understudied Asian population.MethodsIn this population-based case series, we evaluated breast cancer risk factors in relation to 10-year all-cause mortality (ACM) and 5-year recurrence by molecular subtype among 3012 women with invasive breast cancer in Sarawak, Malaysia. A total of 579 deaths and 314 recurrence events occurred during a median follow-up period of ~ 24 months. Subtypes (luminal A-like, luminal B-like, HER2-enriched, triple-negative) were defined using immunohistochemical markers for hormone receptors and human epidermal growth factor receptor 2 (HER2) in conjunction with histologic grade. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between risk factors and ACM/recurrence were estimated in subtype-specific Cox regression models.ResultsWe observed heterogeneity in the relationships between parity/breastfeeding, age at first full-term pregnancy (FFP), family history, body mass index (BMI), and tumor subtype (p value < 0.05). Among luminal A-like patients only, older age at menarche [HR (95% CI) ≥15 vs ≤ 12 years = 2.28 (1.05, 4.95)] and being underweight [HRBMI < 18.5kg/m2vs. 18.5–24.9kg/m2 = 3.46 (1.21, 9.89)] or overweight [HR25–29.9kg/m2vs. 18.5–24.9kg/m2= 3.14 (1.04, 9.50)] were associated with adverse prognosis, while parity/breastfeeding [HRbreastfeeding vs nulliparity = 0.48 (0.27, 0.85)] and older age at FFP [HR > 30 vs < 21 years = 0.20 (0.04, 0.90)] were associated with good prognosis. For these women, the addition of age at menarche, parity/breastfeeding, and BMI, provided significantly better fit to a prognostic model containing standard clinicopathological factors alone [LRχ2 (8df) = 21.78; p value = 0.005]. Overall, the results were similar in relation to recurrence.ConclusionsOur finding that breastfeeding and BMI were associated with prognosis only among women with luminal A-like breast cancer is consistent with those from previously published data in Western populations. Further prospective studies will be needed to clarify the role of lifestyle modification, especially changes in BMI, in improving clinical outcomes for women with luminal A-like breast cancer.

A Reliability Comparison of Cone-Beam Breast Computed Tomography and Mammography: Breast Density Assessment Referring to the Fifth Edition of the BI-RADS Atlas

To evaluate the reliability of cone-beam breast computed tomography (CBBCT) in visual assessment of breast density referring to the fifth edition of the Breast Imaging Reporting and Data System compared to digital mammography. Breast density assessments of 130 female patients were performed by five radiologists referring to the fifth edition of Breast Imaging Reporting and Data System atlas both on two-view mammograms and CBBCT images. Assessments were repeated by three radiologists with different experience more than 1 month after the initial evaluation. The inter- and intrareader agreements were compared by using the Cohen's weighted Kappa statistic and intraclass correlation coefficient. Weighted Kappa statistic was also used to analyze the agreement between CBBCT images and mammograms. The influence of radiologist experience for breast density assessment was analyzed using a chi-square test. For CBBCT images, the inter-reader agreement was 0.781, whereas the agreement on mammograms was 0.744, both demonstrating moderate agreement. The level of intrareader reliability was higher on the CBBCT images than mammograms for breast density evaluation, 0.856 versus 0.786. Based on the majority report, the agreement between these two modalities was on substantial agreement degree. There was a statistically significant difference among radiologists with different levels of experience, and higher density categories were reported more often by experienced reader. CBBCT showed equal aptitude and better agreement for the breast density evaluation compared to mammography. CBBCT could be an effective modality for breast density assessment and breast cancer risk evaluation in routine diagnosis and breast cancer screening.

Use of Receiver Operating Characteristic (ROC) Curve Analysis for Tyrer-Cuzick and Gail in Breast Cancer Screening in Jiangxi Province, China.

BackgroundBreast cancer is a malignant tumor derived from breast gland epithelium. The screening and early diagnosis of breast cancer in high-risk populations can effectively suppress its threat to women’s health and improve treatment efficiency, and thus has critical importance. Using various evaluation models, the present study evaluated cancer risk in 35–69-year-old women, and the usefulness of models in breast cancer prevention was compared.Material/MethodsA total of 150 infiltrative breast cancer patients who were diagnosed with breast cancer at our hospital were recruited, along with 130 healthy women as the control group. A retrospective study was performed to collect information. The 5-year risk of breast cancer was evaluated using the Gail and Tyrer-Cuzick models. Diagnostic results were analyzed to plot ROC curves for comparing the value for screening between Gail and Tyrer-Cuzick models.ResultsThe Gail model has 53.33% sensitivity and 77.69% specificity, with 73.39% positive prediction value, 59.06% negative prediction value, 64.64% accuracy, and 0.31 Jordon index. The Tyrer-Cuzick model had 66.00% sensitivity, 86.92% specificity, 85.34% positive prediction value, 68.90% negative prediction value, 75.71% accuracy, and 0.53 Jordon index. The area under the curve (AUC) was 0.665 for the Gail model (95% CI: 0.629~0.701) and 0.786 for the Tyrer-Cuzick model (95% CI: 0.757~0.815).ConclusionsBoth Gail model and Tyrer-Cuzick models can be used to evaluate breast cancer risk. The Gail model has relatively lower accuracy in evaluating breast cancer risk in Jiangxi province of China and the Tyrer-Cuzick model had relatively higher accuracy.

Evaluation of Breast Cancer Risk in Relation to Occupation

Background: Breast cancer is the most common cancer in females. At present, evidence exists to support an association of breast cancer with several risk factors such as occupational risk factors. The aim of this study is to further characterize potential associations between breast cancer risk and occupation.Methods: In this case-control study, we reviewed records from 965 histologically confirmed breast cancer cases. From these, 104 employed women were chosen. The control group consisted of 112 age-matched employed women. Required data were gathered through in-person interviews and medical records reviews. Occupations were classified into four categories: teachers, administrative/clerical workers, healthcare workers, and miscellaneous jobs. Data analysis was performed using the chi-square, t-test, and logistic regression model.Results: A higher proportion of cases (60.6%) were teachers. Physical activity, smoking, and family history of cancer significantly differed between the case and control groups. After adjustment for potential confounders, we found that teachers had a higher risk for breast cancer compared to other occupations (P<0.001).Conclusion: The teaching profession can be an important risk factor for breast cancer. Emphasis on early screening programs seems necessary. According to the high percent of female teachers, we recommend a detailed evaluation of exposures in this occupation.

Prospective evaluation of body size and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

Although evidence suggests that larger body size in early life confers lifelong protection from developing breast cancer, few studies have investigated the relationship between body size and breast cancer risk among BRCA mutation carriers. Therefore, we conducted a prospective evaluation of body size and the risk of breast cancer among BRCA mutation carriers. Current height and body mass index (BMI) at age 18 were determined from baseline questionnaires. Current BMI and weight change since age 18 were calculated from updated biennial follow-up questionnaires. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI). Among 3734 BRCA mutation carriers, there were 338 incident breast cancers over a mean follow-up of 5.5 years. There was no association between height, current BMI or weight change and breast cancer risk. Women with BMI at age 18 ≥22.1 kg/m2 had a decreased risk of developing post-menopausal breast cancer compared with women with a BMI at age 18 between 18.8 and 20.3 kg/m2 (HR 0.49; 95% CI 0.30-0.82; P = 0.006). BMI at age 18 was not associated with risk of pre-menopausal breast cancer. There was no observed association between height, current BMI and weight change and risk of breast cancer. The inverse relationship between greater BMI at age 18 and post-menopausal breast cancer further supports a role of early rather than current or adulthood exposures for BRCA-associated breast cancer development. Future studies with longer follow-up and additional measures of adiposity are necessary to confirm these findings.

Phthalate Metabolites and Postmenopausal Breast Cancer Risk

Abstract Mounting laboratory and animal model evidence supports the potentially carcinogenic effects of phthalates, chemicals used as plasticizers in a wide variety of consumer products (e.g., cosmetics, medications, vinyl flooring). Phthalate metabolites (PMs) are measurable in nearly 100% of the U.S. population, though levels vary widely, and also have been reported in human breast milk. However, prospective data on whether phthalates affect human breast cancer risk is lacking. Methods We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (N = 419 invasive cases and 838 matched controls). Controls were matched 2:1 on age, enrollment date, follow-up time, and study group (WHI clinical trial or observational study). We measured a panel of thirteen PMs and creatinine in two or three urine samples per participant over 1 to 3 years. Multivariable conditional logistic regression analysis was used to estimate risk ratios and 95% confidence intervals (RR, 95% CI) for breast cancer risk associated with each PM, with incorporation of measurement error correction approaches to account for the moderate within-participant variability of PMs. Results Overall, we did not observe statistically significant associations between individual PMs and breast cancer risk in analyses adjusted for matching factors, creatinine, body mass index, smoking status, and race/ethnicity: e.g., mono-2-ethylhexyl phthalate (MEHP; p trend = 0.31; e.g., RR 0.91, 95% CI, 0.62–1.33), monoethyl phthalate (MEP; p trend = 0.16; e.g., RR 0.80, 95% CI, 0.55–1.16 for 4th quartile vs. 1st quartile), monohydroxy-isobutyl phthalate (MHiBP; p trend = 0.11; e.g., RR 0.78, 95% CI, 0.51–1.18 for 4th quartile vs. 1st quartile, and monobenzyl phthalate (MBzP; p trend = 0.11; e.g., RR 0.86, 95% CI, 0.57–1.28 for 4th quartile vs. 1st quartile). Conclusions These results indicate that urinary phthalate metabolite levels are not related to increased breast cancer risk. However, some phthalate metabolites may be associated with decreased risk, possibly through anti-estrogenic actions. Future analyses will explore grouping metabolites by parent phthalate and also will separately evaluate breast cancer risk by tumor estrogen receptor status and explore potential effect modification.

Abstract P3-10-12: Breast cancer risk assessment and evaluation of risk-based screening practices by primary care providers: A single institution experience

Abstract Background: Risk reduction intervention for primary prevention of breast cancer (BC) with tamoxifen, raloxifene, exemestane, and anastrazole has been well studied in high risk women. Despite this established risk reduction strategy, chemoprevention (CP) remains underutilized. In this retrospective chart review, we describe the utilization of BC risk assessment, prevention awareness, and adherence to BC screening recommendations among primary care providers in Internal Medicine (IM), Family Medicine (FM), and Obstetrics and Gynecology (OB) in our institution. Methods: A total of 1220 electronic charts of women aged ≥35 and ≤78 who came for preventive visits in 2014 (n=1076, OB; n=59, IM; n=80, FM) were reviewed. Charts were evaluated for pertinent histories related to BC risk assessment. Gail scores were calculated for all patients based on available histories with conservative estimates in those with incomplete data recorded. Screening compliance with annual or biennial mammography was recorded. Results: The percentage of patients having adequate histories in the chart to allow calculation of Gail score was 56.9% in OB, 9.4% in FM, and 1.7% in IM, χ2(2)=131.08, p&amp;lt;0.001. Age at menarche was not documented in 29.5% of OB patients, 56.5% of FM patients, and 94.5% of IM patients, χ2(2)=123.78, p&amp;lt;0.001. Age at first live birth or parity was not documented in 17.8%, 85.9%, and 97.7% of OB, FM, and IM patients respectively, χ2(2)=286.89, p&amp;lt;0.001. Calculation of the Gail score yielded a total of 149 patients (12.2%) who are considered high-risk and potentially eligible for CP. No patients were offered CP as part of their care. IM physicians had significantly higher adherence to BC screening recommendations by NCCN, ACS, and USPSTF (55.36%-81%) compared with OB (45.74%-68.3%), and FM physicians (45.88%-68.6%), (p&amp;lt;0.001). No patients had documented risk-based BC screening even among those found to be high-risk. Differences between low vs high-risk patients by Gail score High Risk (Gail ≥ 1.67 Total (n=1220)Yes (n=149)No (n=1071)pGail score, M (SD)1.101 (0.68)2.36 (0.86)0.82 (0.37)&amp;lt;0.001Age, M (SD)48.51 (9.17)56.74 (7.99)47.36 (8.73)&amp;lt;0.001Age at 1st mammogram, M (SD)45.13 (7.77)49.15 (7.69)44.41 (7.56)&amp;lt;0.001Age at menarche, M (SD)12.62 (1.49)12.36 (1.49)12.65 (1.48)0.105Age at first live birth, M (SD)24.34 (5.85)26.39 (6.37)24.06 (5.73)&amp;lt;0.001Number of first degree relatives with history of BC, n (%) &amp;lt;0.00101036 (84.9)55 (36.9)981 (91.6) 1143 (11.7)84 (56.4)59 (5.5) 29 (0.7)8 (5.4)1 (0.1) Unknown32 (2.6)2 (1.3)30 (2.8) History of breast biopsy, n (%) &amp;lt;0.001No1150 (94.3)128 (85.9)1022 (95.4) Yes64 (5.3)21 (14.1)43 (4) Unknown6 (0.5)0 (0)6 (0.6) Number of biopsies 0.021157 (89.1)16 (76.2)41 (95.4) 27 (10.9)5 (23.8)2 (4.7) P-value compares two groups based on Gail score cutoff (≥1.67). Conclusions: BC risk assessment, risk-based screening, and use of BC chemoprevention is not adequately practiced by primary care providers. Primary care providers' adherence to BC screening recommendations was closest to USPSTF guidelines (68.3% to 81.1%) and did not follow risk-based screening recommendations. Rates of adherence to chemoprevention and mammogram screening recommendations approximated national data. Citation Format: Igid HP, Payne JD, Sultan A, Kow SY, Hobart KL, Payne TN, Jones C. Breast cancer risk assessment and evaluation of risk-based screening practices by primary care providers: A single institution experience [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-12.

Abstract P3-09-09: Assessing utility of breast cancer risk assessment tool in comparison to Tyrer-Cuzick model for determination of breast cancer risk and implications for chemoprevention

Abstract Background Despite findings that the Tyrer-Cuzick (IBIS Breast Cancer Risk Evaluation Tool or TC) model is more predictive of breast cancer risk than the Gail model (NCI maintained Breast Cancer Risk Assessment Tool or BCRAT), BCRAT is commonly clinically used as per the United States Preventive Services Task Force (USPSTF), with a 5-year risk for breast cancer (BC) of greater than 3% on BCRAT, the benefits of preventive medication likely outweigh the risks. We aimed to compare the models, 1: to see if a 10 year risk estimate per the TC model reliably correlated with the 3% 5 year risk per BCRAT, and 2: to analyze the subset of patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) who are known both to be at high risk for breast cancer and to benefit from chemoprevention. Our hypothesis is that BCRAT has limited utility in risk estimation, and the most comprehensive model for risk estimation and clinical decision making is TC. Methods 200 women ages 35-64 women followed in benign breast clinic were included. Risk estimations were run using BCRAT, TC version 7 (v7) and TC version 8 (v8). A Pearson's Correlation test was conducted to investigate the relationship between the TC models and the BCRAT model. A p-value &amp;lt; 0.05 was considered statistically significant. Results Analysis showed a positive moderate-strength relationship between the TC v7 10-year risk and the 5-year BCRAT risk for this population (R = 0.468, P&amp;lt;0.001) and a positive moderate-strength relationship between the TC v8 10-year risk and the 5-year BCRAT risk (R = 0.550, P&amp;lt;0.001). A TC v7 risk of 8.09% (95% confidence interval (CI): 7.42-8.75) and a TC v8 risk of 8.54% (95% CI: 7.85-9.24) corresponded to a BCRAT risk of 3%. However, much error was present when assessing consistency and correlation between the models. A total of 36 patients were diagnosed with AH, 2 patients were diagnosed with LCIS and 7 patients were diagnosed with both AH and LCIS. 11 patients who had AH had an estimated 5-year risk per the BCRAT model of &amp;lt;3%. Two of these patients were pre-menopausal and African American and one was pre-menopausal and Hispanic. Of the remaining 8 patients, all were under the age of 60. Of the 30 patients who had a BCRAT 5-year estimated risk of BC of &amp;gt;3% but no AH or LCIS, 12 had two first degree relatives with breast cancer and 16 had a first-degree relative with BC and at least two benign breast biopsies. Conclusion BCRAT is limited and caution is warranted with its use in assessing risk and for counseling around chemoprevention benefit. There is not reliable correlation between the 5 year BCRAT risk estimate and the 10 year TC risk estimate. Chemoprevention should be discussed for patients with AH, LCIS or 2+ first degree relatives with breast cancer. Further, BCRAT may underestimate risk in minority populations and others with AH. For a limited group of patients with moderate risk, dual modeling may be clinically useful in making chemopreventive recommendations. Citation Format: Pederson HJ, Yanda C, Kline M, Stephens M, Goraya ST, Grobmyer SR, Kattan MW. Assessing utility of breast cancer risk assessment tool in comparison to Tyrer-Cuzick model for determination of breast cancer risk and implications for chemoprevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-09.