BrCa Mortality Research Articles

Preimplantation genetic testing for BRCA gene mutation carriers: A cost effectiveness analysis (340)

Objectives: To investigate the cost-effectiveness of preimplantation genetic testing for selection and transfer of BRCA negative embryo in BRCA mutation carriers compared to natural conception. Methods: The cost-effectiveness of two strategies, conception through IVF/PGT-M and BRCA negative embryo transfer versus natural conception with a 50% chance of BRCA positive newborn for BRCA mutation carriers, was compared using a Markovian process decision analysis model. Costs of the two strategies were compared using quality-adjusted life years (QALYs’). All costs were discounted by 3%. Incremental cost-effectiveness ratio (ICER) compared to the willingness to pay threshold was used for cost-effectiveness analysis. A probabilistic sensitivity analysis (Monte Carlo simulation) was conducted with all variables, using 100 trials, each included 10,000 couples, to evaluate model uncertainties. Results: IVF/ PGT-M is cost-effective with an ICER of 150,219 new Israeli Shekels, per QALY gained (equivalent to 44,480 USD), at a 3% discount rate. Discount rate and uptake of risk reduction salpingo- oophorectomy (RRSO) are the most influential parameters that affect the ICER. Increasing uptake of RRSO would make the ICER highly cost-effective. Conclusions: IVF/ PGT-M and BRCA negative embryo transfer compared to natural conception among BRCA positive parents is costeffective and may be offered for selected couples with high BRCA mutation-related morbidity or mortality. Our results could impact decisions regarding conception among BRCA positive couples and health care providers. Objectives: To investigate the cost-effectiveness of preimplantation genetic testing for selection and transfer of BRCA negative embryo in BRCA mutation carriers compared to natural conception. Methods: The cost-effectiveness of two strategies, conception through IVF/PGT-M and BRCA negative embryo transfer versus natural conception with a 50% chance of BRCA positive newborn for BRCA mutation carriers, was compared using a Markovian process decision analysis model. Costs of the two strategies were compared using quality-adjusted life years (QALYs’). All costs were discounted by 3%. Incremental cost-effectiveness ratio (ICER) compared to the willingness to pay threshold was used for cost-effectiveness analysis. A probabilistic sensitivity analysis (Monte Carlo simulation) was conducted with all variables, using 100 trials, each included 10,000 couples, to evaluate model uncertainties. Results: IVF/ PGT-M is cost-effective with an ICER of 150,219 new Israeli Shekels, per QALY gained (equivalent to 44,480 USD), at a 3% discount rate. Discount rate and uptake of risk reduction salpingo- oophorectomy (RRSO) are the most influential parameters that affect the ICER. Increasing uptake of RRSO would make the ICER highly cost-effective. Conclusions: IVF/ PGT-M and BRCA negative embryo transfer compared to natural conception among BRCA positive parents is costeffective and may be offered for selected couples with high BRCA mutation-related morbidity or mortality. Our results could impact decisions regarding conception among BRCA positive couples and health care providers.

Preimplantation genetic testing for BRCA gene mutation carriers: a cost effectiveness analysis

BackgroundGynecologic oncologists should be aware of the option of conception through IVF/PGT-M for families with high BRCA related morbidity or mortality. Our objective was to investigate the cost-effectiveness of preimplantation genetic testing for selection and transfer of BRCA negative embryo in BRCA mutation carriers compared to natural conception.MethodsCost-effectiveness of two strategies, conception through IVF/PGT-M and BRCA negative embryo transfer versus natural conception with a 50% chance of BRCA positive newborn for BRCA mutation carriers was compared using a Markovian process decision analysis model. Costs of the two strategies were compared using quality adjusted life years (QALYs’). All costs were discounted at 3%. Incremental cost effectiveness ratio (ICER) compared to willingness to pay threshold was used for cost-effectiveness analysis.ResultsIVF/ PGT-M is cost-effective with an ICER of 150,219 new Israeli Shekels, per QALY gained (equivalent to 44,480 USD), at a 3% discount rate.ConclusionsIVF/ PGT-M and BRCA negative embryo transfer compared to natural conception among BRCA positive parents is cost effective and may be offered for selected couples with high BRCA mutation related morbidity or mortality. Our results could impact decisions regarding conception among BRCA positive couples and health care providers.

Abstract 1176: Racial differences in circulating inflammatory cytokines and breast cancer disparities

Abstract Introduction Racial disparities in breast cancer (BrCa) mortality are well documented. We previously reported that African American (AA) women with estrogen receptor-positive (ER+) BrCa have a 4-fold higher rate of death compared to non-Hispanic whites (white) after controlling for stage at diagnosis and treatment initiation. This suggests that racial differences in tumor biology may contribute to the survival disparity. In preliminary work we found that AA BrCa cases have higher serum levels of C-reactive protein (CRP) compared to whites, and that increased CRP was associated with worse survival, suggesting that increased systemic inflammation in AA women drives aggressive tumor biology and contributes to the racial disparity in survival. The goal of this study is to identify specific inflammatory pathways that may be involved. Experimental Procedures Pre-treatment blood samples from women with stage I-III ER+ BrCa (AA, n=40; white, n=55) and from healthy controls (AA, n=51; white, n=38) were analyzed with the Olink® targeted proteomic assay, which measures 92 inflammatory proteins. Normalized data was log2 transformed, and generalized linear models compared the normalized intensities with covariates of interest. The fit of the model was tested with empirical Bayes methods. All p-values are corrected for multiple testing with the false discovery rate (FDR) method of Benjamini and Hochberg. Findings After adjustment for site of enrollment, plasma levels of 13 inflammatory cytokines showed a log2 fold-change (log2FC) ≥ 1.0 for AA compared to white women, i.e. at least a two-fold increase in the mean value on a linear scale (Table). The racial difference was evident among both cases and controls, and remained after adjusting for body mass index (BMI). There were no differences between AA cases and controls, indicating that cytokine elevation in AA BrCa patients is not an effect of the tumor. Several of the cytokines are known to promote tumor progression and aggressive biological features in breast tumors. ProteinLog2FCProteinLog2FCCXCL52.42**CCL81.13***CXCL12.06***EIF4EBP11.12**STAMBP1.91*CCL201.10**CXCL111.89**TNF141.06*CCL31.45**TGF beta1.04**CXCL61.40**CCL71.03***CCL131.16**FDR corrected p-values: * < 0.05, **< 0.01, ***< 0.001 Conclusion Systemic elevation of biologically relevant inflammatory cytokines in AA women with ER+ BrCa does not appear to be an effect of the tumor. This inflammatory phenotype may activate inflammatory programs in ER+ breast tumors that develop in AA women, leading to disproportionately aggressive tumor biology and worse outcomes. Supported by grants U54CA203000; U54CA2022995; and U54CA2022997 from the National Institutes of Health. Citation Format: Oana C. Danciu, George Chlipala, Zeynep Madak-Erdogan, Hariyali Patel, Landan Banks, Ayesha Zaidi, Ashlie Santaliz-Casiano, Lauren Schulte, Lauren Weller, Deanna Taiym, Natalie Pulliam, Elona Liko Hazizi, Elonia Martin, Anita Fareeduddin, Archana Bargaje, Carlos Garcia, Scott Hegerty, Sarah Friedewald, Seema Khan, J Julie Kim, William Gradishar, Garth Rauscher, Jonna Frasor, Kent F. Hoskins. Racial differences in circulating inflammatory cytokines and breast cancer disparities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1176.

Abstract D004: Beyond socioeconomic and racial composition: Association between neighborhood disorder and breast cancer survival

Abstract Background: U.S. women who identify as Black/African American (AA) or reside in socioeconomically disadvantaged neighborhoods have greater breast cancer (BrCa) mortality compared to White women or women in more affluent neighborhoods. While biologic factors – physiologic stress, epigenetics, etc. – possibly involved in these pathways are under study, few social mechanisms have been investigated. We hypothesized that neighborhood disorder (i.e., physical deterioration, lack of social control) might be a social mechanism potentiating poorer BrCa survival. Methods: Sociodemographic (age, race, ethnicity, health insurance, residential address), tumor (subtype, grade, stage), and vital status data were collected on primary, histologically-confirmed, invasive BrCa cases diagnosed among females from 2008-2013, age 20-74 years, from the New Jersey State Cancer Registry (NJSCR). Neighborhood auditing of Google Street View (GSV) scenes was conducted at 29,017 locations across NJ and neighborhood disorder scores were created from nine characteristics observed: Physical disorder (garbage/litter, graffiti, boarded/burned buildings, dumpsters, building conditions, yard conditions) and aesthetic engagement (team sports equipment, yard decorations, yard seating). Physical disorder and aesthetic engagement values were assigned to each BrCa case’s residential address at diagnosis by extracting values predicted by stochastic spatial interpolation (Universal Kriging). Census-based factors were census tract socioeconomic status (Yost Index), AA segregation (Gini and Isolation indices) and % AA. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (CI) of BrCa-specific mortality by physical disorder and aesthetic engagement. Median BrCa diagnosis date was 01/24/2011, median GSV image date was 09/2013, and follow-up was through 12/31/2014. Results: Of 22,390 women, 70.0% were White, 12.7% were AA, 10.4% were Latina, and there were 2,040 BrCa deaths. Over two-thirds of AA and Latina women lived in high physical disorder areas compared to 43% of White women. In models adjusted for all factors listed above, hazard of BrCa mortality was 24% higher (CI: 6-45) in areas of the greatest physical disorder quartile compared to the lowest physical disorder quartile. Adjustment for physical disorder and aesthetic engagement alone reduced the non-Latino AA vs non-Latino White HR by 13% (HRCrude=2.01, HRAdj = 1.75). Conclusions: Inequities in BrCa survival might be partially attributable to characteristics of “place” – physical disorder and aesthetics – that are beyond socioeconomic and racial composition. Future studies should collect additional data to enable robust bias investigation. Citation Format: Jesse J Plascak, Andrew G Rundle, Stephen J Mooney, Mario Schootman, Antoinette M Stroup, Adana A.M. Llanos. Beyond socioeconomic and racial composition: Association between neighborhood disorder and breast cancer survival [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D004.

154P Survival outcome of indigenous and non-indigenous women of Western Australia with breast cancer in relation to remoteness

Between 2001 and 2010 Indigenous Western Australian women who developed breast cancer (BrCa) were four times more likely to die of the disease than age-matched non-Indigenous women. With remoteness also an established factor in BrCa mortality delineating the interplay between Indigenous status and remoteness could advise healthcare policy allowing tailored development of culturally specific services with appropriate geographical distribution to reduce the mortality risk.

Breast cancer risk (un)awareness among women suffering from neurofibromatosis type 1 in Poland.

The main goal of this study was to draw the attention of physicians to commonly undisclosed risk of breast cancer (BrCa) in women suffering from neurofibromatosis type 1 (NF-1), which is 5-fold higher than in the general population. NF-1 related BrCa arises earlier (< 50 years) and is more advanced, with an increased mortality. NF-1 is one of the most frequent monogenic diseases worldwide and a tumor predisposition syndrome. The Nf1 gene is an important negative regulator of the Ras oncogene and belongs to the family of the 12 the most important BrCa predisposition genes. Planning introduction of BrCa screening guidelines for NF-1 women in Poland we started with assessment of BrCa risk awareness and current preventive practices in this population by a survey published in an open access internet profile dedicated exclusively to patients with NF-1 in Poland, with 1928 participants. As a result, we revealed that the awareness of this specific risk was declared by only 30% out of 138 responders, and only 21% of them received this information from medical professionals. In all 4 (2.89%) women suffering from BrCa the cancer was diagnosed before the 50th year of age. It exceeds significantly the expected prevalence of BrCa in the general population of Polish women. We conclude that the limited awareness of NF-1 related BrCa risk in Polish patients warrants the educational effort directed both to the NF-1 patients by professional counseling and to the medical community, in order to increase the efficacy of preventive measures and decrease BrCa mortality.

A Comparison of Mortality-to-Incidence Ratio with Survival Analyses in Assessing Racial Breast Cancer Disparities Across South Carolina Counties

Abstract The mortality-to-incidence rate ratio (MIR) provides a population-based measure of survival which accounts for incidence. The use of MIR as a surveillance tool has shown that South Carolina (SC) exhibits more extreme racial differences in cancer incidence, mortality and MIR than other states or the nation. We assessed the effectiveness of MIR as a proxy for 5-year survival time (5YST) among breast cancer (BrCa) patients in South Carolina. Methods: The 5YST was computed from data on BrCA cases which were obtained retrospectively from the SC Central Cancer Registry from 2002 to 2010. The MIR was computed from Cancer incidence and mortality data which were obtained from the SC Community Access Network (SCAN). The underlying data for SCAN were generated from the SC Central Cancer Registry and SC DHEC Vital Records and used to construct MIRs. ArcGIS 10.2 was utilized to map BrCA MIRs by race for 46 counties within SC. Seven categories of MIR were derived using the national MIR for BrCA as reference. 5YST was computed for all BrCA cases in each county utilizing SAS software and this was mapped with MIR per county. Exploratory and geographically weighted regression analyses were conducted in ArcGIS to determine the relationship between MIR and MST. Results: A total of 2155 breast cancer patients (nWhites = 1557/72%; nBlacks = 598/28%) were reported in the study period. A visual inspection of the MIR maps by race showed that Blacks were in the highest MIR category while the MIR by 5YST map showed that higher MIR was likely associated with lower 5YST. By contrast, the MIRs for Whites were more evenly represented over the seven categories. Overall, the 5YST was 92.8% among blacks and 95.6% among whites. Assessment of MIR with MST in ArcGIS utilizing exploratory ArcGIS regression showed that there was statistically significant Global Moran's I p value indicative of clustering. Conclusions: The MIR proved useful for identifying disparities in BrCA incidence and mortality among Black and White women in SC. Cancer surveillance programs may use the MIR to monitor disparities across racial/ethnic groups and geographic regions going forward. MIRs have the potential to serve as an indicator of the long-term success of cancer surveillance programs.

Abstract P6-13-04: Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials

Abstract OBJECTIVE: To quantitate breast cancer incidence (BrCa-I) and mortality (BrCa-M) outcome differences between the two Women's Health Initiative (WHI) HRT trials,1,2 the ratio of hazards was calculated for estrogen-alone based hormone replacement therapy (E-HRT) vs. placebo (P), and E + progestin Provera (ProgProv) combination HRT vs. P trials. METHODS: Hazard ratios (HR) of BrCa-I and BrCa-M and 95% confidence intervals (CI) were obtained from both WHI HRT trials. Subsequently, to compare BrCa outcomes between E-HRT vs. E + ProgProv, the ratios of HRs between the trials (HR1/HR2) were estimated separately for i. BrCa-I all women, ii. BrCa-I low Gail score (Gail score &amp;lt;1.75*), and iii. BrCa-M. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Outcome Comparison, the two WHI HRT randomized trials. Ratio of Hazards, BrCa Incidence and BrCa mortality E-HRT vs. P, HR1 (95% CI)E-HRT + ProgProv vs. P, HR2 (95% CI)HR1/HR2 (95% CI)pBrCa-I All Woman10.77 (0.62-0.95)1.25 (1.07-1.46)0.62 (0.47-0.80)0.0004BrCa-I Low Gail Score* (Gail score &amp;lt;1.75)10.65 (0.50-0.86)1.24 (1.01-1.51)0.53 (0.38-0.74)0.0002BrCa-M20.55 (0.33-0.92)1.44 (0.97-2.15)0.38 (0.20-0.75)0.004*Gail score &amp;lt;1.75; HRs calculated from Reference 1, Figure 3 CONCLUSIONS: Our calculations show that the different outcomes between the two WHI HRT trials, estimated as ratio of hazards, are highly significant on statistical basis, both for BrCa incidence and for BrCa mortality. These findings highlight the potential carcinogenic impact of ProgProv and the major public health benefits of HRT based on E alone. REFERENCES: 1. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. The Lancet Oncology 2012;13:476-86. 2. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. Citation Format: Ragaz J, Qian H, Wong H, Wilson KS, Shakeraneh S, Spinelli JJ. Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-04.

Abstract P6-13-06: Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm

Abstract OBJECTIVE: To compare, in the setting of breast cancer (BrCa) prevention, the impact of estrogen-based hormone replacement therapy (E-HRT) vs. tamoxifen (TAM) on breast cancer mortality (BrCa-M) and breast cancer case fatality ratio (BrCa-CFR), by analyzing data from the Women's Health Initiative Trial 2 (WHI HRT Trial 2, E-HRT vs. placebo [P])1 and the International Breast Cancer Intervention Study 1 (IBIS-1), TAM vs. P.2 METHODS: Hazard ratios (HR) and confidence intervals (CI) for BrCa incidence and mortality were extracted from the original WHI HRT Trial 2 and IBIS-1 trials.1,2 BrCa-CFRs were estimated by dividing the mortality HR by the incidence HR. Subsequently, to compare E-HRT vs. TAM outcomes, the ratios of HRs (HR1/HR2) between the two trials were estimated separately for BrCa-M and BrCa-CFR. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Mortality and Case Fatality Outcomes: Impact of E-HRT versus TAM, expressed as ratio of HRs E-HRT vs. Placebo, HR1TAM vs. Placebo, HR2HR1/HR2pMortality0.55 (0.33-0.92)1.19 (0.68-2.10)0.46 (0.22-0.99)0.046Case Fatality0.70 (0.40-1.20)1.68 (0.93-3.01)0.42 (0.18-0.94)0.040 CONCLUSIONS: While acknowledging between-trial comparisons including eligibility differences, E-HRT yields significant reductions in BrCa mortality and case fatality as compared with TAM (54% and 58% respectively). These unexpected breast cancer mortality reductions represent major public health gains, additional to the already known superiority of E-HRT over TAM in terms of skeletal fracture rates and Alzheimer's dementia mortality reduction, and, in women entering menopause, also of cardiac and all-cause mortality reductions. REFERENCES: 1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology 2015;16:67-75. Citation Format: Ragaz J, Shakeraneh S, Qian H, Wilson KS, Wong H, Spinelli JJ. Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-06.

Abstract P1-07-10: Increasing population rates of in-situ breast cancer [DCIS] are associated with reduced breast cancer (BrCa) mortality. A case for screening mammography and "overdiagnosis" linked to outcome benefits

Abstract INTRODUCTION: Following the first phase of this project [Ref 1], we correlate here the rates of DCIS with BrCaMOR, in two regions of Canada - British Columbia [BC] and Atlantic Provinces [Atl.P]. We previously reported higher compliance in screening mammography [ScreenMam] and therapeutic [TH*] guidelines [GUIDELINES] for both DCIS and invasive BrCa in BC compared with Atl.P [Ref. 2]. METHODS: Annual age-specific rates [cases / 100,000 population] of DCIS, and BrCaMOR between BC vs Atl.P, were obtained for 17 age groups of 5 years (years 0-4 to 85+) and averaged each 5-year period from 1975-1979 up to 2005-2009. To compare age distribution, DCIS rates and BrCaMOR between the two regions, we selected four birth cohorts, age 30-34, 35-39, 40-44 and 45-49 in 1975-1979. From those, we tabulated the DCIS incidence and BrCaMOR for each birth cohort when they reached ages 50-54 and 60-64. We assumed that the rates of DCIS reflect annual ScreenMam practices. Data were obtained from the Public Health Agency of Canada based on the Canadian Cancer Registry database at Statistics Canada. RESULTS [N/100,000 population]British ColumbiaAtlantic ProvincesAge / years DCISBrCaMORDCISBrCaMORAge 50 â– 54 1980-8413.152.24.056.41985-8921.246.68.056.11990â–9429.244.421.449.91995â–9945.543.830.050.1Age 60â – 64 1990-9428.072.123.186.21995-9949.361.935.276.62000-0449.365.845.669.42005â–0951.453.141.059.4 CONCLUSIONS: 1. Our study shows across all age cohorts higher rates of DCIS and lower BrCaMOR in BC compared to Atl.P - results consistent with higher ScreenMam rates in BC than Atl.P. 2. These data are compatible with the concept that a higher diagnostic rate for early lesions such as DCIS [i.e. frequently designated as "Overdiagnosis"] by ScreenMam, and subsequent earlier Guideline TH*, contributes to lower BrCaMOR. *TH Guidelines: surgery, radiation, Tamoxifen for DCIS; and the same + chemotherapy for early invasive disease. Citation Format: Ragaz J, Qian H, Shakeraneh S, Fox J, Wilson KS, Simpson JS, Yoon J-Y, Wong H. Increasing population rates of in-situ breast cancer [DCIS] are associated with reduced breast cancer (BrCa) mortality. A case for screening mammography and "overdiagnosis" linked to outcome benefits. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-10.

Abstract P2-05-19: Breast cancer dormancy, re-emergence, and treatment

Abstract Breast cancer (BrCa) mortality continues to result predominately from distant metastases that can emerge years after successful treatment of the primary disease. Metastatic resistance to agents that eradicate the primary mass is likely due to protection from the metastatic microenvironment and the quiescent state of dormant BrCa cells. Advancements for the treatment of metastatic tumors have been made, but significant progress has been hampered by the lack of relevant model systems, particularly for dormancy. We address this gap with an innovative all-human 3D liver microphysiological system (MPS). The liver is both a major site for BrCa metastasis (and other solid tumors) and the primary site of drug metabolism and limiting toxicities, an important consideration in evaluating cancer therapy efficacy and availability. Primary hepatocytes and non-parenchymal cells (NPC) from human liver resections were seeded into the MPS. Following tissue formation on day 3, tagged BrCa cells were seeded and allowed a minimum of 4 days to integrate into the tissue before interventions were initiated. On day 7, chemotherapy treatment of micrometastases was initiated for 72h. Cultures were allowed 3 days to recover before the MPS was challenged with inflammatory factors (LPS/EGF) for 48h. BrCa cells were then re-treated with chemotherapy (either the same or alternate therapy) on day 21 for 72h. Hepatocyte function and injury were measured by urea, AST, ALT, A1AT, fibrinogen and CYP P450 assays. BC proliferation was monitored by quantification, Ki67 staining, and EdU incorporation. Communication networks within the metastatic microenvironment during different stages of metastatic BrCa progression were identified using Luminex assays (55 analytes). The metastatically aggressive MDA-MB-231 BrCa cells demonstrated growth attenuation after 12d of culture in a subpopulation of cells (Ki67-/EdU-). Treatment of BrCa cells with doxorubicin for 72h eradicates the cycling cells, leaving behind a dormant cell population (Ki67-/EdU-) that can be subsequently stimulated to cycle by addition of inflammatory stimuli. A second dose of doxorubicin or cisplatin reduced the BrCa load but did not eradicate the BrCa. Luminex analysis of culture supernatants identified signaling molecules potentially involved in metastatic progression. In addition, we present the use of adjuvant therapy in the MPS to prevent this outgrowth of the dormant tumor cells. In parallel, we have piloted hydrogel scaffolds that better support tissue formation and produce signals consistent with a healthier liver physiology. Hydrogels enhanced MDA-MB-231 cell entry into dormancy, resulting in reduced efficacy of doxorubicin treatment with greater persistence of tumor load. The MPS provides a mechanism to close the gap in understanding metastatic dormancy. We demonstrate spontaneous dormancy for the first time in an all-human system and mimicked the dormancy and outgrowth observed in patients. Namely, that dormant BrCa are resistant to chemotherapy and can be stimulated to reemerge following an inflammatory insult. The completion of these studies will provide insights into the tumor biology of metastatic seeding, dormancy, and re-emergence and provide an accessible tool for testing therapeutics against metastatic BrCa in a metabolically competent system capable of evaluating dose-limiting toxicity. Citation Format: Beckwitt C, Wheeler SE, Clark AM, Pillai VC, Young CL, Stolz DB, Lauffenburger DA, Venkataramanan R, Griffith LG, Wells A. Breast cancer dormancy, re-emergence, and treatment. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-19.

Abstract P1-07-01: Modeling breast cancer dormancy and re-emergence

Abstract Most breast cancer (BrCa) mortality results from distant metastases. Current evidence strongly suggests that in some instances these disseminated cells remain dormant for long periods of time. Both the non-proliferative state and protective microenvironment of the metastatic niche likely contribute to the observed resistance of metastases to chemotherapies that are otherwise effective against the primary tumor. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model systems for metastases has hindered the development of therapies against this stage. To address this gap, we developed an innovative all-human 3D ex vivo hepatic microphysiological system (MPS) to faithfully reproduce human physiology and thereby facilitate the investigation of BrCa behavior in a micrometastatic niche. The liver is a major site of metastasis for carcinomas and is also the primary site of drug metabolism (activation and/or detoxification), which is a significant factor in determining efficacy and limiting toxicities of cancer therapies. The MPS incorporates hepatocytes and nonparenchymal cells (NPC) isolated from fresh human liver resections. BrCa cells (RFP+) are seeded on day 3 and afforded time to intercalate into the hepatic tissue until treatment with chemotherapy on day 7 for 72h. Surviving BrCa cells are stimulated on day 13 with LPS/EGF and cultured through day 15. Proliferation is monitored by RFP quantification, Ki67 staining and EdU incorporation. Physiological function of the hepatic tissue is monitored throughout the experiment by protein catabolism (urea), active metabolism (glucose, CYP P450) and injury markers (AST, ALT, A1AT, fibrinogen). Luminex assays (55 analytes) were used to provide insights into the communication networks in the hepatic metastatic milieu during different stages of dormancy and progression, and identify potential metastatic biomarkers via computational approaches. The MPS maintains the physiologic function of the hepatic niche through 15 days and BrCa cells effectively integrate into the established niche. Spontaneous dormancy is observed amongst a subpopulation of BrCa cells, indicated by the absence of Ki67 staining and EdU incorporation after 12 days of culture. Further, we demonstrate that the BrCa cells surviving chemotherapy (doxorubicin) are non-proliferating (Ki67-/EdU-). Notably, ‘re-awakening’ of the surviving non-proliferating cancer cells is observed in the presence of physiological inflammatory stressors (LPS/EGF). Luminex analyses of the milieu effluent identified signaling molecules from NPC influenced the metastatic cell fraction entering dormancy. This MPS provides unprecedented insights into the tumor biology of dormant micrometastases. We demonstrate the recreation of spontaneous, rather than engineered, BrCa dormancy in an all-human ex vivo hepatic MPS. Mimicking the dormancy and outgrowth observed in patients, we found that dormant breast cancer cells that are resistant to chemotherapy can be stimulated to re-emerge following an inflammatory insult. Ultimately, this MPS provides an accessible tool to identify new therapeutic strategies for metastasis during initial seeding, dormancy and re-emergence, while concurrently evaluating agent efficacy for metastasis, metabolism and dose-limiting toxicity. Citation Format: Amanda M Clark, Sarah E Wheeler, Donald P Taylor, Carissa L Young, Venkateswaran C Pillai, Donna B Stolz, Raman Venkataramanan, Douglas A Lauffenburger, Linda G Griffith, Alan Wells. Modeling breast cancer dormancy and re-emergence [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-01.

Abstract C66: Insulin-like growth factor binding protein-6 is differentially methylated in African American, African, and Amish HapMap cell lines

Abstract African American women, while having lower lifetime incidence of breast cancer (BrCa) than Caucasian women, have higher BrCa mortality rates, partially due to a higher incidence of the more aggressive, basal-like molecular subtype of BrCa. Correlations of this subtype within African ancestral groups suggest a potential link to African Ancestry and basal-like BrCa. While socioeconomic factors may also play a role in higher mortality rates, there is mounting evidence that the differential epigenetic regulation of cancer genes may also contribute to this disparity. To address this, our lab is investigating the epigenetic regulation of genes in the insulin-like growth factor pathway using qPCR, Immunohistochemistry (IHC) and Bisulfite-DNA Sequencing. This presentation specifically highlights novel data on the expression of insulin-like growth factor binding protein-6 (IGFBP-6), an IGF-II regulator and agent of cell proliferation, which has been shown previously to be epigenetically modified in cancer cells. Our qPCR and IHC data demonstrates higher IGFBP-6 transcription and protein expression in basal-like BrCa cells when compared to normal breast and ER+ BrCa cells. To address potential ancestry-specific expression, we also evaluated IGFBP-6 expression in African and African-American HapMap lymphoblast cell lines compared to CEPH-European (Amish) cell lines. Both qPCR and IHC data indicate higher overall expression of this gene in African lineages. Lastly, we have measured the differential methylation in two regions of the IGFBP-6 CpG island among African, African-American, and Amish cell lines. We show that IGFBP-6 methylation correlates with the expression patterns. Differential methylation could be due to Ancestral-Specific polymorphisms in this region, altering potential methylation sites. We conclude that the distinct levels of IGFBP-6 expression and promoter methylation in African and African-American cell lines may correspond to the increased incidence of basal-like BrCa in these populations, due to prolonged half-life and activity of the IGF-II growth signal. Our future studies include evaluation of whether this epigenetically-mediated up-regulation of IGFBP-6 directly leads to the excessive proliferation of basal-like tumors. Citation Format: DeJuana Ford, Briana Bennett, Myrielis Rivera, Rupali Hire, Melissa Davis. Insulin-like growth factor binding protein-6 is differentially methylated in African American, African, and Amish HapMap cell lines. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C66. doi:10.1158/1538-7755.DISP13-C66

Competing risks of death in younger and older postmenopausal breast cancer patients

To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality. We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Competing risks of death in NCIC CTG MA.27 adjuvant exemestane versus anastrozole.

564 Background: Our group previously examined if baseline patient/tumor characteristics, or prior treatment affected cause of death in MA.17, a placebo controlled extended adjuvant trial of the aromatase inhibitor (AI) letrozole. We now examine factor effects on all cause mortality in MA.27. Methods: MA.27 was an adjuvant phase III superiority trial of 5 yrs of exemestane vs anastrozole, in ER+ postmenopausal breast cancer accrued between 2003 and 2008; event free survival was similar. We examined by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa), cardiovascular (Cardio), and other causes (OT) of death with log-normal survival analysis adjusted by treatment and stratification factors (lymph node status, adjuvant chemotherapy, celecoxib, aspirin, and trastuzumab). We tested whether factors were associated with 1) all cause mortality, and if so, 2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. Results: 7,576 women (median age 64.1 years; 5417 (71.5%) &lt;70 yrs and 2159 (28.5%) &gt;70 yrs) were enrolled and followed for a median of 4.1 yrs. The 432 deaths comprised: 187 (43.3%) BrCa, 66 (15.3%) Cardiovascular, and 179 (41.4%) OT MA.27 therapy was not associated with mortality (p=0.84). Five baseline factors were differentially associated with cause of death. Older age was associated with greater BrCa (p=0.03), Cardio (p&lt;0.001), and OT (p&lt;0.001) mortality. Pre-existing cardiovascular history led to worse Cardio mortality (p&lt;0.001). Worse ECOG performance status led to worse OT death (p&lt;0.001). T1 tumors were associated with less BrCa mortality (p&lt;0.001). PgR+ tumors were also associated with less BrCa mortality (p&lt;0.001). There were fewer BrCa deaths with Node –ve disease (p&lt;0.001), ER+ tumors (p=0.001) and without adjuvant chemotherapy (p=0.005); there was worse Cardio mortality (p=0.01) with receipt of trastuzumab; worse OT (p=0.03) for non-whites, and without adjuvant radiotherapy (p=0.003). Conclusions: 56.7% of deaths in MA.27 patients were non-breast cancer related. We showed baseline patient and tumor characteristics, and prior treatment differentially affected cause of death. Clinical trial information: NCT00066573.

Impact of county-level surgical specialist density on breast (BrCa) and lung cancer (LuCa) mortality.

6064 Background: Variations in distribution of the surgical workforce may result in differential access to cancer screening and treatment. Our aim was to explore the relationship between county-level surgical specialist density and BrCa and LuCa mortality. Methods: Using data from Area Resource File, US Census and National Cancer Institute, regression models that controlled for cancer incidence, county demographics and socioeconomic factors were constructed to examine the association among a) general surgeon (GS) and radiation oncologist (RO) density with BrCa mortality and b) thoracic surgeon (ThS) and RO density with LuCa mortality. Plastic (PS) and transplant surgeons (TrS) were used as surgical controls as they were not expected to correlate significantly with BrCa or LuCa mortality. Results: A total of 1,557 and 2,044 US counties were analyzed for BrCa and LuCa, respectively: mean incidences were 119 and 75 and death rates were 25 and 59 per 100,000 people, respectively, for BrCa and LuCa. Mean specialist densities were 7.72 (GS), 0.80 (RO), and 0.97 (PS) [for BrCa counties] and 0.55 (ThS), 0.55 (RO), and 0.01 (TrS) [for LuCa counties] per 100,000. When compared to counties with no surgical specialist, those with at least one GS and RO for BrCa and at least one ThS and RO for LuCa were associated with decreased mortality (Table). Increasing the density of GS and RO beyond 9 and 1 per 100,000 did not result in significant reductions in BrCa mortality. Likewise, increasing the density of ThS and RO to above 1 each per 100,000 failed to yield further improvements in LuCa mortality. Counties with more elderly residents also correlated with worse BrCa and LuCa outcomes. Conclusions: The presence of specific surgical specialists is associated with lower BrCa and LuCa mortality. There appears to be a threshold at which point further increase in their density do not contribute to continued improvements in outcomes. Distributing the surgical workforce across all counties will offer population-based improvements in BrCa and LuCa mortality. [Table: see text]

Comparative Analysis of Breast Cancer (BrCa) Mortality Reduction among Regions of Canada between 1950 – 2004: Impact of Systemic and Diagnostic Guidelines after 1977, with Model Definition of Number of Potentially Avoided Annual Deaths (N-PAAD).

Abstract BACKGROUNDWe reported in the past the BrCa mortality trends in three Provinces of Canada with different Levels of Provincial Diagnostic and Therapy Guideline (ProvDgThGuide) implementation, reflecting access to optimum cancer care (LEVEL I, most uniform: British Columbia (B.C.); LEVEL II, medium: Ontario(ON); LEVEL III, least uniform (Atlantic Provinces AP), and have shown best outcomes in B.C. (Cancer Res 2009 69[S] 2:383).OBJECTIVETo estimate the number of BrCa deaths that potentially could have been avoided during the period 1978 – 2004 if the ProvDgThGuide Level I (i.e. of B.C.) had been implemented in Canada, Ontario and Atlantic Provinces, respectively.METHODSData were obtained from Statistics Canada.i. For each region, we calculated the average annual age-standardized mortality rate / 100,000 (aveASR) for the periods 1950-1977 (R1) and 1978-2004 (R2).ii. Subsequently, calculated was the Relative Change (RC, expressed in %) in mortality rate between the two time periods (RC = (R2-R1)/R1).iii. And for each region, the 1978 – 2004 expected rates (RE) based on RC from B.C. [i.e. calculated as "-13.8%" [(RE = 1- 0138) x R1].iv. These steps permitted estimates of Number of potentially avoided [annual] deaths (N-PAAD), based on the difference in observed mortality during the 1978-2004 period and the mortality that would have occurred if the regions had experienced the same relative change in mortality rate as observed in B.C. (R2-RE x # at risk).RESULTS R1(aveASR 1950-1977)R2(aveASR 1978-2004)RCREN-PAAD(N-AveAnnDeaths)BC30.025.8-13.8%----Ontario30.929.2-5.3%26.6137Atlantic27.528.8+4.7%23.760Canadaexcluding BC30.729.0-5.5%26.5315CONCLUSIONThis study confirms in most but not all regions of Canada a substantial mortality reduction after 1977, suggestive that implementation of optimum levels of Provincial Diagnostic and Therapy Guidelines (optimum access to cancer care) may affect mortality, and that their delay may prevent materialization of survival gains.Once the average annual rates of B.C. was applied to the rates of rest of Canada, the newly developed "Potentially Avoided Annual Deaths" model estimates over 8,000 avoided BrCa deaths in Canada (without B.C.) during the period 1978 – 2004 (26 [years] x 315).The model estimates over 3,500 (26 x 137) and 1500 (26 x 60) avoided deaths, respectively, for Ontario and Atlantic Provinces.These data are relevant to all world regions with differing access to optimum cancer care. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2063.

Using Ki67 To Improve and Simplify Outcome Modeling for Breast Cancer.

Abstract Ki67 is a marker of proliferation which has several advantages over histological grade. Ki67 is determined less subjectively and is a continuous rather than a categorical variable. Many studies that have looked at Ki67 have been small and underpowered. A large population based tissue microarray was used to: A) test the prognostic value of Ki67 in testing and validation sets, and B) construct an improved model including Ki67 and conventional prognostic variables to predict patient outcome. Methods: The cohort included 2,780 patients with early breast cancer diagnosed in British Columbia and a median follow up of 14.5yrs. Variables included were: tumor size (T), number of positive nodes (N), grade, lymphovascular invasion (LVI), estrogen receptors (ER), progesterone receptors (PR), Her2, Ki67, local treatment (surgery, radiation) and systemic treatment (chemotherapy, hormonal). Prognostic factors were balanced between the training and validation sets. Prognostic variables were identified in the testing set among ER positive and ER negative cohorts using Cox Regression analysis and tested in the validation set. Results: The inclusion of Ki67 in the Cox Regression analysis resulted in the elimination of grade as a predictor. For ER positive disease independent predictors were T, N, LVI, PR, HER2, Ki67, local treatment, chemotherapy and hormonal therapy. Independent predictors among ER- cases were T, N, LVI, Ki-67, and chemotherapy. Predicted 10-yr Breast Cancer Specific Survival in the validation set was 72.0% versus 72.4% [SE: 1.2] observed. As subtle prognostic differences may result in very disparate treatment recommendations for Stage I breast cancers, we specifically reviewed this group. In analysis of stage I patients, there were no statistically significant deviations between predictions and observation; agreement between the predicted and observed 10-yr BCSS was excellent (86.0% vs 87.6% (SE: 1.6) p = 0.3169). As well, elevated Ki67 was common (53%) and was a powerful prognostic variable with causing more than a doubling of the 10-yr BrCa mortality (elevated ≥ 10% vs low &amp;lt; 10%, 16.8% vs 6.8%) in this group (table). Conclusion: In this study the proliferation marker Ki67 replaced histologic grade as a predictor of outcome for patients with early breast cancer. Predictive models such as Adjuvant! could incorporate Ki67 as an input variable and this modification is being developed. If models that use Ki67 are validated they may be able to be used globally and be cost effective compared to more expensive genomic predictors.Table: Predicted versus observed 10yr BCSS, based on the new modelPatientsSubgroupNPredicted SurvivalObserved Survivalp-valueAll patientsOverall139772.072.40.75 ER+101277.276.40.56 ER-38558.461.20.27 HER2+19755.658.00.50 HER2-120074.874.80.99Stage IOverall45386.087.60.32 ER+35287.690.40.09 ER-10179.678.40.77 HER2+4378.882.40.55 HER2-41086.888.40.33 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4042.

Breast cancer mortality reduction in the western world: therapeutic versus diagnostic interventions. Implications for cancer care organization processes.

Abstract Abstract #6083 INTRODUCTION. Recent epidemiology data show a substantial Breast Cancer (BrCa) mortality reduction in the western countries over the last decade. The literature indicates that both Adjuvant systemic treatments (Adj. SystTh) and Screening mammography (ScrM) contribute, but their interaction is not clear.&amp;#x2028; Our study examines if contribution of Adj. SystTh separate from ScrM could be more clearly identified; and also, - as a second objective, - if organization of cancer care could be correlated with BrCa mortality outcomes.&amp;#x2028; METHODOLOGY:&amp;#x2028; The mortality trends were compared among three Provinces of Canada with different Levels of Provincial Diagnostic and Therapy Guidelines (PDTG):&amp;#x2028; LEVEL I: most uniform coordination of PDTG: British Columbia (Brit.Col.), with a single Provincial budget; earliest implementation of Provincial Community Oncology Program (since the mid-1970's); and a uniform start of Adj. SystTh (late 1970's); and of ScrM (late -1980's).&amp;#x2028; LEVEL II: medium (Ontario).&amp;#x2028; LEVEL III: least uniform (Atlantic Provinces)*.&amp;#x2028; BrCa annual age-standardized mortality rates per 100,000/population were obtained from Statistics Canada for the years 1950-2004, and expressed relative to the year 1950 (the baseline).&amp;#x2028; RESUTLS: The 1950 BrCa mortality rates were: 30.9 for Canada; 31.4 for BC; 30.7 Ontario; 26.1 for Atlantic Provinces*.&amp;#x2028; &amp;#x2028; CONCLUSIONS:&amp;#x2028; While both Adj. SystTh and ScrM contribute towards recent BrCa mortality reduction, the British Columbia data indicate that the impact of Adj. SystTh antedates that of ScrM, at least by a decade.&amp;#x2028; Our data support a correlation of BrCa mortality trends with the organization of cancer care: Effective implementation of PDTG (- i.e. incorporating early curative interventions into guidelines), will have a strong impact on mortality trends, particularly if executed&amp;#x2028; a. ongoingly,&amp;#x2028; b. uniformly, and&amp;#x2028; c. across the whole population.&amp;#x2028; Our data therefore indicate that early implementation of curative systemic therapy - or of any curative intervention - is essential, as their delay may prevent materialization of survival gains. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6083.

Breast cancer mortality trends in the WEST compared to the EAST: lives gained, lives lost.

Abstract Abstract #6082 INTRODUCTION: Breast Cancer (BrCa) Mortality trends between 1950 – 2005 were reviewed between the Western (WEST) and Eastern Asian (EAST) countries, with the objective to gain understanding between therapeutic and diagnostic interventions and underlying epidemiology factors determining BrCa outcomes.&amp;#x2028; METHODOLOGY: We compared BrCa mortality trends in the WEST (Canada, UK, USA) and in the EAST (Japan and China-Shanghai). Data were obtained from WHO - IARC, Lyon (Canada, USA, UK, Japan); and from the Shanghai Cancer Registry (China-Shanghai). We analyzed age-standardized annual mortality rates per 100,000 / population (as per 1960 world standard population). Mortality trends were expressed relative to the baseline (year 1950 for all, year 1973 for China-Sha).&amp;#x2028; RESULTS: The baseline mortality rates were: 22.5 for Canada; 23.5 for UK; 21.6 for USA, 4.1 for Japan; and 7.3 for China-Shanghai.&amp;#x2028; &amp;#x2028; CONCLUSION. These data confirm a substantial mortality reduction in the WEST evident after the 1980's - 1990's, likely reflecting the interaction of diagnostic and therapeutic interventions (mammography, education, systemic / locoregional therapies, etc). The different timing and extent of mortality reduction in the WEST probably reflect different degree of implementation of the interactive factors.&amp;#x2028; On the other hand, mortality is increasing in the EAST, in parallel with the “westernization” of those regions (industrialization, diet, etc, Ref. [NEJM; 2008:358;3)]. For the EAST, our data also support a correlation between the timing / extent of the “westernization” and mortality trend dynamics (i.e. mortality increase in Japan 20 years earlier than China). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6082.