Eun-Sil Shelley Hwang

The Effect of Hospital Volume on Breast Cancer Mortality.

Objective: The aim of this study was to determine whether hospital volume was associated with mortality in breast cancer, and what thresholds of case volume impacted survival. Background: Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery. Methods: All adults (18 to 90 years) with stages 0-III unilateral breast cancer diagnosed from 2004 to 2012 were identified from the American College of Surgeons National Cancer Data Base (NCDB). A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital volume and overall survival, after adjusting for measured covariates. Intergroup comparisons of patient and treatment characteristics were conducted with X2 and analysis of variance (ANOVA). The log-rank test was used to test survival differences between groups. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) associated with each volume group. Results: One million sixty-four thousand two hundred and fifty-one patients met inclusion criteria. The median age of the sample was 60 (interquartile range 50 to 70). Hospitals were categorized into 3 groups using restricted cubic spline analysis: low-volume (<148 cases/year), moderate-volume (148 to 298 cases/year), and high-volume (>298 cases/year). Treatment at high volume centers was associated with an 11% reduction in overall mortality for all patients (HR 0.89); those with stage 0-I, ER+/PR+ or ER+/PR- breast cancers derived the greatest benefit. Conclusions: Treatment at high volume centers is associated with improved survival for breast cancer patients regardless of stage. High case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment.

Abstract P2-18-09: TBCRC 013: A prospective analysis of the role of surgery in stage IV breast cancer

Background: Retrospective studies suggest that primary breast surgery is associated with improved overall survival (OS) in Stage IV breast cancer. TBCRC 013 is a multi-center prospective registry study evaluating the role of surgery for the primary tumor in Stage IV disease. Methods: From 7/09 - 4/12, 128 eligible pts from 14 sites were enrolled in two cohorts (A: Stage IV with intact primary tumor (n = 112); B: metastases (mets) within 3 months of primary surgery (n = 16)). Baseline patient and tumor characteristics, and surgery of the primary were correlated with 2yr overall survival (OS) using log rank, Kaplan Meier and Cox regression for all patients. Comparisons were also made between cohorts A and B and within cohort A stratified by response to systemic therapy. Responders included those with any response (partial,complete) or stable disease at distant sites. Results: Median pt age was 52yrs(21-79) and median primary tumor size 3.2cm(0.7-15). Phenotypes were ER+ 106 (83%), HER2neg 91(71%), and triple neg 10(8%). 60(47%) had bone-only mets. The only significant baseline difference between cohorts A and B was the presence of palpable nodes (A:62% vs B:0%, p Conclusions: In this prospective registry study, patients diagnosed with mets within 3 months of primary breast surgery have an improved 2yr OS. When all pts having surgery (A + B) are examined, surgery is associated with improved OS on MVA, but when limited to Arm A responders, elective surgery does not improve OS. Given that the number of Arm A responders is small, results from the prospective randomized trial will be needed to address this question. These data also demonstrate that the need for surgical palliation of the primary tumor is uncommon in the modern era. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-09.

Abstract P6-05-03: Genomic diversity of ductal carcinoma in situ (DCIS) as a driver of invasion and metastasis

Background: Recent evidence indicates that breast cancers may have high levels of heterogeneity. Based on principles of tumor evolution, we are investigating whether DCIS with higher levels of intra-tumoral genetic heterogeneity are more likely to progress to invasive and/or metastatic disease. Methods: Cases (DCIS with co-existing invasive or metastatic cancer) and controls (pure DCIS) are identified from Duke Pathology archives. From cases and controls, we are analyzing two areas of DCIS separated by >1cm with germ line DNA from the same subject to measure allele frequencies of somatic mutations and copy number variation (CNV). Small amounts of FFPE derived DNA are made into NGS libraries for full exome sequencing and hybridization to a 4.2 million element SNP array. Comparison of allele frequencies and CNV is made between specimens from the same cancer to assess heterogeneity. Results: We identified a series of pure DCIS (controls for this study) and generated high coverage sequencing data from 20ng of FFPE DNA from 12 samples (4 subjects, germline + 2 DCIS containing areas from each subject) as proof of principle. We compared the occurrence of deletions, insertions and SNP9s after a 20X coverage filtration. From these data, we identified between 50 to greater than 600 sequence changes in these DCIS compared to normal DNA. Present/absent calls and allele frequencies indicate both significant and variable degrees of heterogeneity even in these pure DCIS samples. Additional data is now being gathered and analyzed based on this established technical approach. Conclusion: We have demonstrated the feasibility of acquiring high quality NGS data from archival DCIS specimens allowing us to test the hypothesis that genetic heterogeneity is a driving force in breast cancer progression. The degree and nature of this heterogeneity will be assessed in a panel of pure DCIS and DCIS co-existing with invasive and/or metastatic cancer. We are now generating and analyzing these data for Symposium presentation. Citation Format: King LM, Marks JR, Hall AH, Temko D, Graham TA, Mardis ER, Maley CC, Hwang E. Genomic diversity of ductal carcinoma in situ (DCIS) as a driver of invasion and metastasis. [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 P6-05-03.

Pediatric phyllodes tumors: A review of the National Cancer Data Base and adherence to NCCN guidelines for phyllodes tumor treatment

BACKGROUND Phyllodes tumors are fibroepithelial breast lesions that are uncommon in women and rare among children. Due to scarcity, few large pediatric phyllodes tumor series exist. Current guidelines do not differentiate treatment recommendations between children and adults. We examined national guideline adherence for children and adults. METHODS We queried the NCDB (2004-2014) for female patients with phyllodes tumor histology, excluding patients with missing age or survival data. Patients were stratified by age (pediatric <21, adult ≥21), and compared based on patient characteristics, treatment patterns, and survival. RESULTS We identified 2787 cases of phyllodes tumor (2725 adult, 62 pediatric). Median age was 17years in children and 52years in adults. Margin positivity rates and median tumor size were similar between adults and children. Treatment was discordant with NCCN guidelines in 28.6% of adults and 14.5% of children through use of axillary staging, chemotherapy, adjuvant endocrine therapy, and radiotherapy. Five-year and ten-year survival were comparable between both groups. CONCLUSION Children and adults present with similarly sized phyllodes tumors. Trends reveal high margin positivity rates, and overtreatment with regional axillary staging and systemic adjuvant therapies. Particularly in children, treatment decisions must consider risks of adjuvant therapy including radiation-related second primary cancers, given uncertain benefit. TYPE OF STUDY Retrospective Comparative Study. LEVEL OF EVIDENCE Level III.

Abstract P4-15-07: Quantifying the natural history and overtreatment rate of ductal carcinoma in situ

Background. Subsets of ductal carcinoma in situ (DCIS) are thought to be relatively indolent disease with long progression time to invasive cancer. Nevertheless, the vast majority of women diagnosed with DCIS undergo extirpative surgery, potentially leading to widespread overtreatment of patients who would not develop symptomatic breast cancer in absence of treatment. Due to a poor understanding of the natural history of untreated DCIS, it remains difficult to derive estimates of the true rate of overtreatment. The objective of this study was to quantify the natural history of untreated DCIS through synthesis of retrospective data sources and to estimate the associated rate of overtreatment. Methods. A systematic PubMed search was performed to identify published studies on ipsilateral invasive cancer-free survival in women who did not undergo surgery with curative intent after diagnosis with DCIS. Individual life histories from included studies were manually extracted and aggregated in a patient-level meta-analysis. Each lesion was assigned to one of three categories: DCIS precursor lesions, low-risk DCIS, and high-risk DCIS. Time-to-event analyses (Kaplan-Meier) and Cox proportional-hazards models were used to calculate absolute and relative progression rates for the three risk groups. For the low-risk group, overtreatment rates were estimated by means of a competing risk analysis. For this purpose, progression hazards were estimated by maximum likelihood inference of parametric mixture models, and non-breast cancer mortality rates were derived from standardized life tables (birth cohort: 1960). Results. A total of n=122 women from 3 retrospective studies were included in the patient-level meta-analysis. The median age at diagnosis was 47 years (interquartile range [IQR]: 41-57) and median follow-up was 17 years (IQR: 6-20). Compared to DCIS precursor lesions (n=38), relative rates of progression to invasive cancer were significantly higher for both low-risk DCIS (n=68; hazard ratio [HR]: 4.8, 95%-CI: 1.4-16.0) and high-risk DCIS (n=16; HR: 6.9, 95%-CI: 1.7-27.8). Among women with low-risk DCIS, the cumulative progression to ipsilateral invasive disease after 5, 10, and 20 years was found to be 16.9% (95%-CI: 9.7-28.5), 28.5% (95%-CI: 16.6-38.8) and 35.1% (95%-CI: 23.8-49.8), respectively. The corresponding overtreatment rates for low-risk DCIS were estimated to be of the order of 56%, 63% and 72% for ages at diagnosis of 55, 65 and 75 years respectively. Conclusion. To our knowledge, this study constitutes the most comprehensive quantitative analysis of the natural history of incompletely treated DCIS. The estimated propensity to progress to invasive disease suggests overtreatment among some women diagnosed with low-risk DCIS, especially in older patients with comorbidities. The extent to which this cohort resembles those currently diagnosed with DCIS is unclear. However, these results underscore the importance of clinical trials in evaluating active surveillance and/or anti-estrogen therapy as alternative management strategies for women diagnosed with low-risk DCIS. Citation Format: Ryser MD, Weaver DL, Marks JR, Hyslop T, Hwang ES. Quantifying the natural history and overtreatment rate of ductal carcinoma in situ [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 P4-15-07.

Trends and variations in postmastectomy radiation therapy for breast cancer in patients with 1 to 3 positive lymph nodes: A National Cancer Data Base analysis: PMRT in Patients With 1-3 + Lymph Nodes

High‐level evidence is lacking to guide treatment decisions about postmastectomy radiation therapy (PMRT) in patients who have breast cancer with 1 to 3 positive lymph nodes who receive contemporary systemic therapies, leading to potential variations in PMRT delivery. The objective of this study was to examine nationwide trends in PMRT use in this group.

Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival

PurposeThe purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS).MethodsWe collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease.ResultsThe presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22–8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size.ConclusionsIntra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.

Abstract B44: Immune pathway dysregulations in inflammatory breast cancer health disparity

Background: Inflammatory breast cancer (IBC) is a distinct, aggressive and the most lethal form of breast cancer. Furthermore, data from population-based registries, when stratified by race and compared to other locally advanced breast cancers, suggest that IBC has a disproportionately high incidence, prevalence & shorter median survival time in African Americans (AA) compared to Caucasian American (CA) patients. IBC health disparities that are independent of external factors like differences in income, screening rates, and access to health care suggest a biological component to poor outcomes. IBC pathobiology is also unique wherein instead of a solid tumor, tightly packed tumor cell clusters/emboli are formed with a propensity for lymphatic dissemination. The underlying mechanisms for this extremely aggressive breast cancer phenotype are largely unknown and, therefore, present a major impediment to identifying the molecular underpinnings for health disparities in IBC patients. Methods and Results: In order to understand how IBC cells evade cell death signals in the host microenvironment, we conducted comparative analysis of the largest collection of untreated primary tumor samples of IBC (N=137), along with stage- and subtype-matched non-IBC (N=252) and normal breast tissue. Results reveal that pretreatment tumor tissue samples from IBC patients have a heightened expression of adaptive stress response genes comprised of high levels of the nuclear transcription factor, NFkappaB, and its target genes in the anti-apoptotic and immune/inflammatory pathways that correlate with cell survival. In addition, guided by analysis based on presence of tumor infiltrating leukocytes in IBC (N=69) and non-IBC (N=62) patient samples, we have identified a set of pathways and genes that have the ability to distinguish the immune responses in IBC and non-IBC patients in a subtype independent manner. In particular, interferon alpha/beta and NFκB signaling pathways were differentially regulated in IBC vs. non-IBC. Gene expression driven analysis of enrichment of leukocyte subsets reveal specific differences in plasma cells and effector memory CD8 cells in IBC bulk tumor samples. Preliminary data analysis of gene expression data sets from laser microdissected epithelium and stromal compartments of AA and CA breast cancer patients also show enrichment of plasma cells, effector memory CD4+, and M1 macrophages. Studies are ongoing to characterize these immune profiles that are unique and distinguishable in IBC patients and further identify race-related differences. Most importantly, we discovered that the constitutive NFκB hyperactivation observed in IBC tumor cells is driven by stress-mediated translational upregulation of the most potent anti-apoptotic protein, XIAP. Interestingly, XIAP:NFκB overexpressing cells are highly resistant to immunotherapy mediated cell death. These data strongly suggest that in IBC, host immune phenotype promotes outgrowth of cell death resistant population and specific tumor cell pro-survival signaling mechanisms that enhances invasion and lymphatic dissemination. We have developed novel in vitro IBC tumor emboli culture model and a transgenic mouse bearing red fluorescent lymphatic vasculature that allow recapitulating host factors to define tumor cell signaling mechanisms on immune effector function and the resultant invasive phenotype. Conclusions: As the incidence is rising and targets for therapy are scant, IBC has the potential to become a major public health disparity concern. This study reveals that the immune factors in the host microenvironment may interact with underlying IBC genetics to promote the aggressive nature of the tumor, and more specifically, these factors may be one of the sources of biologic variation between patients of different ethnicities leading to IBC disparity outcomes. Supported in part by Duke IBC Consortium, DCI NIH CAO14236 development funds (GRD), DoD W81XWH-13-1-0047 (GRD). Citation Format: Gayathri R. Devi, Eun-Sil Shelley Hwang, John Stewart, Michael A. Morse, Steven Van Laere. Immune pathway dysregulations in inflammatory breast cancer health disparity. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B44.

Abstract P1-15-10: Low utilization of hypofractionated radiotherapy for the treatment of early-stage breast cancer in the US

Background: Large randomized controlled trials have shown that hypofractionated whole breast irradiation (HF-WBI) is not inferior to or more toxic than conventionally fractionated whole breast irradiation (CF-WBI) for the treatment of early-stage breast cancer. Royal Marsden data were published in 2006 (10-yr), the Ontario trial was reported in 2002 (5-yr) and 2010 (10-yr), and the UK START trials were published in 2006 (5-yr) and 2013 (10-yr). We utilized the National Cancer Data Base (NCDB) to evaluate patterns of radiotherapy fractionation for early-stage, node-negative breast cancer in the U.S. We hypothesized that HF-WBI use would increase over time in response to emerging data supporting its use in this population. Methods: We conducted a retrospective, population-based cohort study of women >18 years diagnosed with T1-2N0 invasive breast carcinoma and treated with breast-conserving surgery between 2004 and 2011. Radiotherapy was categorized as accelerated partial breast irradiation (APBI; 38-40 Gy/1-10 fractions), HF-WBI (40-56 Gy/15-24 fractions) or CF-WBI (50-66 Gy/25-40 fractions). Patients treated with alternate fractionation were excluded. Patterns of breast radiotherapy fractionation were compared using the chi-square test. Multivariable logistic regression was performed for patients diagnosed in 2011, the year with the highest levels of HF-WBI utilization. Results: 217,789 patients in the NCDB met inclusion criteria. HF-WBI use increased over time, rising from 2.1% among eligible patients in 2004 to 15.1% in 2011, while APBI use remained low at 30 years. Table 1 shows frequency of HF-WBI use over time by center type. On multivariate analysis of patients diagnosed in 2011, the following factors were associated with higher use of HF-WBI: treatment at an academic center, older patient age, hormone receptor positivity, pT1 tumor size, and rural residence (Table 2). Conclusions: Utilization of HF-WBI in the US is rising, but remains low overall despite level I evidence showing its non-inferiority to CF-WBI. Given the advantages of HF-WBI in terms of patient convenience and potential healthcare system costs, further research is indicated to explore disparities in HF-WBI utilization in the US and to guide education of breast cancer providers. Citation Format: Yvonne M Mowery, Rachel A Greenup, Kevin Houck, Manisha Palta, Janet K Horton, Eun-Sil S Hwang, Julie A Sosa, Rachel C Blitzblau. Low utilization of hypofractionated radiotherapy for the treatment of early-stage breast cancer in the US [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 P1-15-10.