Hormone Receptor-negative Tumors Research Articles

Factors Associated With Follow-Up Care Among Women With Early-Stage Breast Cancer

Follow-up guidelines vary widely among national organizations for patients with early-stage breast cancer treated with curative intent. We sought to evaluate the patterns and predictors of provider follow-up care within the first 5 years after diagnosis. Using the SEER-Medicare linked data set, we evaluated patients who were diagnosed with stage I and II breast cancer who underwent breast-conserving surgery from 2002 to 2007 with follow-up until 2012. We defined discontinuation of follow-up as > 12 months from the previous physician visit without a visit claim from either a surgeon, medical oncologist, or radiation oncologist. We performed a multivariable logistic regression and Cox proportional hazards regression analysis to determine factors associated with the discontinuation of follow-up care. Of the 30,053 patients enrolled in our initial cohort, 25,781 (85.8%) saw a medical oncologist and 21,612 (71.9%) saw a radiation oncologist in the first year in addition to a surgeon. Over the 5 years, 6,302 patients (21.0%) discontinued follow-up visits. Discontinuation of physician visits increased with increasing age. Women with stage II cancer ( v stage I) were less likely to discontinue follow-up visits (odds ratio, 0.78; 95% CI, 0.73 to 0.83). Time to early discontinuation was greater for patients with hormone receptor-negative tumors (hazard ratio, 1.14; 95% CI, 1.05 to 1.24). Women who were diagnosed more recently were less likely to discontinue seeing any physician. Twenty-one percent of patients with early-stage breast cancer discontinued seeing any oncology provider over the 5 years after diagnosis. Coordination of follow-up care between oncology specialists may reduce discontinuation rates and increase clinical efficiency.

CIZ1-F, an alternatively spliced variant of the DNA replication protein CIZ1 with distinct expression and localisation, is overrepresented in early stage common solid tumours

ABSTRACTCIZ1 promotes cyclin-dependent DNA replication and resides in sub-nuclear foci that are part of the protein nuclear matrix (NM), and in RNA assemblies that are enriched at the inactive X chromosome (Xi) in female cells. It is subjected to alternative splicing, with specific variants implicated in adult and pediatric cancers. CIZ1-F is characterized by a frame shift that results from splicing exons 8–12 leading to inclusion of a short alternative reading frame (ARF), excluding the previously characterized C-terminal NM anchor domain. Here, we apply a set of novel variant-selective molecular tools targeted to the ARF to profile the expression of CIZ1-F at both transcript and protein levels, with focus on its relationship with the RNA-dependent and -independent fractions of the NM. Unlike full-length CIZ1, CIZ1-F does not accumulate at Xi, though like full-length CIZ1 it does resist extraction with DNase. Notably, CIZ1-F is sensitive to RNase identifying it as part of the RNA-fraction of the NM. In quiescent cells CIZ1-F transcript expression is suppressed and CIZ1-F protein is excluded from the nucleus, with re-expression not observed until the second cell cycle after exit from quiescence. Importantly, CIZ1-F is over-expressed in common solid tumors including colon and breast, pronounced in early stage but not highly-proliferative late stage tumors. Moreover, expression was significantly higher in hormone receptor negative breast tumors than receptor positive tumors. Together these data show that CIZ1-F is expressed in proliferating cells in an unusual cell cycle-dependent manner, and suggest that it may have potential as a tumor biomarker.

Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies.

Overexpression of the HER2 gene is predictive of treatment benefit with trastuzumab therapy for breast cancer (BC) patients. The study objective was to investigate whether all eligible patients with HER2-positive BC initiated trastuzumab therapy. A systematic search was conducted through PubMed, Web of Science PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library. From 2651 studies identified, 107 observational studies were included for full text review, of which 26 met the inclusion criteria and an additional 7 studies were identified through citation searching. Two independent reviewers extracted data for accuracy and completeness. From 33 observational studies, 14,644 patients were exposed to trastuzumab therapy. Age range varied across studies; the youngest cohort had a median age of 50 and the oldest had a median age of 84. Sample sizes ranged from 11 to 1928 and included patients from 10 countries. Studies were heterogenous and few studies accounted for confounders. We identified large variability in uptake of trastuzumab in HER2-positive early BC patients (9.1-100%) and metastatic BC patients (50.8-84.0%). The pooled uptake was 71.3% (95% CI 64.6-77.9%), with high heterogeneity (I2 = 99.05%). The most conservative predictors of higher uptake included younger age (OR 2.09; 95% CI 1.36-3.20) and lower Charlson Comorbidity Index of patients (OR 1.62; 95% CI 1.32-1.99). In addition, tumour characteristics including higher tumour grade (OR 1.73; 95% CI 1.23-2.45), larger tumour size (OR 1.80; 95% CI 1.54-2.10), advanced tumour stage (OR 2.07; 95% CI 1.44-2.96) and hormone receptor negative tumor (OR 1.54; 95% CI 1.35-1.77) were associated with higher uptake. The uptake of trastuzumab therapy varied widely between studies and across subgroups suggesting that there may be some inequalities in the use of this agent. However, our findings should be interpreted with caution due to study heterogeneity and potential confounding, and thus additional studies of individual level data which control for confounders are needed to understand more about inequalities in uptake.

Subtype‐specific clinical and prognostic relevance of tumor‐expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study

Background Tumor expression of certain coagulation factors has been linked to cancer progression. Single nucleotide polymorphisms (SNPs) in F5 (encoding the FV protein) have been found to be associated with breast cancer; however, the role of coagulation factor V (FV) in cancer pathogenesis remains undiscovered. Objectives We aimed to investigate the clinical significance of FV and the regulatory role of F5 gene variants in breast cancer. Patients/Methods A Scandinavian 503-sample breast cancer cohort and three public breast cancer datasets (GOBO, TCGA and KM plotter) were used to determine associations between F5 gene expression (tumor-specific), circulating FV, F5 SNPs, clinical characteristics and breast cancer survival. Immunohistochemistry (IHC) was used to detect FV antigen in tumors. Results F5 expression was 2-fold higher in breast tumors compared with normal tissue, and the presence of FV antigen in breast tumors was confirmed by IHC staining. F5 expression was increased in patients with hormone receptor negative tumors, triple negative tumors, HER2-enriched and basal-like tumors. In patients with basal tumors, high expression of F5 was associated with improved overall survival (hazard ratio, HR = 0.52, 95% confidence interval, 0.31-0.86). SNPs in F5 were associated with tumor size and luminal A tumors. The rs6427202-rs9332542 C-G haplotype, previously associated with breast cancer, displayed a cis-regulatory effect on F5 expression in tumors and plasma FV antigen levels. In silico mining supported this regulatory function. Conclusions FV was a possible marker of aggressive breast cancer, yet also a predictor of favorable outcome. Evaluation of FV expression may be clinically useful for prognosis and treatment decisions in aggressive breast cancer.

Abstract A24: Triple-negative breast Cancer risk: Ancestry and immune response

Abstract Background: Blacks in the U.S. have the worst breast cancer survival outcomes of any racial/ethnic group in the nation. However, blacks are not a monolithic group but are comprised of several ethnic groups. One such group in particular is the Sea Island or Gullah population of coastal South Carolina, North Carolina, Georgia, and Florida, whose ancestors came from coastal rice-growing areas of Africa. Sea Islanders (SI) have the lowest rates of European (non-Hispanic white) genetic admixture of any U.S. blacks, and are thus a special population who provide a rare opportunity to investigate genetic contributions to the profound ancestrally linked disparities in BC. Purpose: The purpose of this study was to identify, for the first time, frequencies of selected single nucleotide polymorphisms (SNPs) associated with triple-negative breast cancer (TNBC) in these three non-Hispanic population groups: whites, African Americans without Sea Island ancestry (AA), and African Americans with Sea Island ancestry (SI). Methods: Saliva samples were obtained using a mailed kit from a sample of 90 women in SC who had been diagnosed with TNBC in the past 1.5 years, recruited from the three population groups (30 women per group). Four SNPs on the 19p13 locus of BRCA 1 (rs8170, rs4808611, rs2363956, and rs3745185) were evaluated. Results: The percentage of TNBC cases was 6.7% among whites, 4.2% among SI blacks, and 22% among non-SI blacks. After controlling for TNBC status, similar allele frequencies for each SNP were seen in whites and SI blacks, compared to non-SI blacks (p<0.01). The less genetically admixed groups (SI and whites) had a lower percentage of triple-negative breast cancer (AA vs. whites, p=0.02; AA vs. SI, p=0.03; whites vs SI: p=0.99) Discussion: The prevalence of triple-negative breast cancer is significantly higher in African American women, and at younger ages, than in white women. Findings by Mukhtar et al. (2011) implicate immune function in the development of this aggressive breast cancer, as higher proliferating cellular nuclear antigen counts and tumor-associated macrophages were associated with hormone receptor-negative tumors and non-white ethnicity. Human populations differ in their transcriptional responses to immune challenges, and immune-responsive regulatory variants have participated in human adaptation by positive selection. Regulatory variants affecting steady-state gene expression and transcriptional responsiveness to immune challenges, particularly those that were viral related, may have been preferentially introduced into African genomes through admixture with Europeans, which may have conferred a natural selection disadvantage to modern blacks without SI ancestry. Such a natural selection disadvantage may mean that different immunologic therapeutic approaches are required for blacks with cancer than for whites with cancer, particularly for more aggressive disease. Citation Format: Marvella E. Ford, Erika T. Brown, David P. Turner, Victoria J. Findlay, Nestor F. Esnaola, Anthony J. Alberg, Susan Bolick, Deborah Hurley, Rita Kramer, Judith D. Salley, Joan E. Cunningham. Triple-negative breast Cancer risk: Ancestry and immune response [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A24.

Associations between genomic stratification of breast cancer and centrally reviewed tumour pathology in the METABRIC cohort

The integration of genomic and transcriptomic profiles of 2000 breast tumours from the METABRIC [Molecular Taxonomy of Breast Cancer International Consortium] cohort revealed ten subtypes, termed integrative clusters (IntClust/s), characterised by distinct genomic drivers. Central histopathology (N = 1643) review was undertaken to explore the relationship between these ten molecular subtypes and traditional clinicopathological features. IntClust subtypes were significantly associated with histological type, tumour grade, receptor status, and lymphocytic infiltration (p < 0.0001). Lymph node status and Nottingham Prognostic Index [NPI] categories were also significantly associated with IntClust subtype. IntClust 3 was enriched for tubular and lobular carcinomas, the latter largely accounting for the association with CDH1 mutations in this cluster. Mucinous carcinomas were not present in IntClusts 5 or 10, but did not show an association with any of the remaining IntClusts. In contrast, medullary-like cancers were associated with IntClust 10 (15/26). Hormone receptor-positive tumours were scattered across all IntClusts. IntClust 5 was dominated by HER2 positivity (127/151), including both hormone receptor-positive (60/72) and hormone receptor-negative tumours (67/77). Triple-negative tumours comprised the majority of IntClust 10 (132/159) and around a quarter of IntClust 4 (52/217). Whilst the ten IntClust subtypes of breast cancer show characteristic patterns of association with traditional clinicopathological variables, no IntClust can be adequately identified by these variables alone. Hence, the addition of genomic stratification has the potential to enhance the biological relevance of the current clinical evaluation and facilitate genome-guided therapeutic strategies.

Use of Breast Imaging After Treatment for Locoregional Breast Cancer(AFT-01).

Annual mammography is recommended after breast cancer treatment. However, studies suggest its under-utilization for Medicare patients. Utilization in the broader population is unknown, as is the role of breast magnetic resonance imaging (MRI). Understanding factors associated with imaging use is critical to improvement of adherence to recommendations. A random sample of 9835 eligible patients receiving surgery for stages 2 and 3 breast cancer from 2006 to 2007 was selected from the National Cancer Database for primary data collection. Imaging and recurrence data were abstracted from patients 90days after surgery to 5years after diagnosis. Factors associated with lack of imaging were assessed using multivariable repeated measures logistic regression with generalized estimating equations. Patients were censored for death, bilateral mastectomy, new cancer, and recurrence. Of 9835 patients, 9622, 8702, 8021, and 7457 patients were eligible for imaging at surveillance years 1 through 4 respectively. Annual receipt of breast imaging declined from year 1 (69.5%) to year 4 (61.0%), and breast MRI rates decreased from 12.5 to 5.8%. Lack of imaging was associated with age 80years or older and age younger than 50years, black race, public or no insurance versus private insurance, greater comorbidity, larger node-positive hormone receptor-negative tumor, excision alone or mastectomy, and no chemotherapy (p < 0.005). Receipt of breast MRI was associated with age younger than 50years, white race, higher education, private insurance, mastectomy, chemotherapy, care at a teaching/research facility, and MRI 12months before diagnosis (p < 0.05). Under-utilization of mammography after breast cancer treatment is associated with sociodemographic and clinical factors, not institutional characteristics. Effective interventions are needed to increase surveillance mammography for at-risk populations. ClinicalTrials.gov Identifier: NCT02171078.

Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa

BackgroundBreast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa.MethodsIn this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases.ResultsThe distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer.ConclusionThe present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

Breast cancer-specific survival in patients with HER2-positive, node-negative T1a and T1b breast cancer

PurposeThere is limited data on prognosis of node-negative (N0), HER2-positive (HER2+) small breast cancers. We evaluated breast cancer-specific survival (BCSS) among women diagnosed with T1a/T1b, N0 tumors in California between 2000–2004 and 2005–2012, eras before and after approval of adjuvant trastuzumab. Patients and Methods45,346 women diagnosed with T1a/b, N0 tumors between January 1, 2000 and December 31, 2012 were identified in the California Cancer Registry (CCR); approximately 10% were HER2 + , and 80% hormone receptor positive (ER and/or PR+). Primary outcome was BCSS, analyzed in 2000–2004 and 2005–2012. Multivariable Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for mortality, and separately conducted for hormone receptor positive and negative tumors. Kaplan-Meier curves compared BCSS by HER2 status. ResultsWhile BCSS in this cohort exceeded 90%, a significantly higher hazard of breast cancer death was observed in women with HER2+ tumors in the 2000–2004 era. There was no difference in outcomes between T1a and T1b tumors. Women with ER/PR+ tumors had lower hazards of death in both eras, but HER2+ tumors were associated with a higher hazard of death in the 2000–2004 era. Among women with hormone receptor negative tumors, HER2 positive disease was associated with a lower hazard of death in the 2005–2012 era. ConclusionWithin this large cohort of T1a/b N0 breast cancers from the CCR, HER2+ tumors were associated with a significantly worse BCSS in the era before adjuvant trastuzumab. A balanced discussion regarding HER2-directed therapies is needed between patient and clinician.

Breast cancer in a tertiary cancer center in India - An audit, with outcome analysis.

Survival studies may serve as benchmarks to develop cancer-related policies and estimate baseline survival rates in a given patient population. We carried out a retrospective audit of cases managed in 2009 and now report the disease-free survival (DFS) in early breast cancer (EBC) and locally advanced breast cancer (LABC) in patients registered at a tertiary cancer center in India. The study included 2192 patients with breast cancer with ages ranging from 18 years to 94 years with a median of 50 years. Of these, 888 (40.5%) were EBCs Stage I and II, 833 (38%) were LABCs (Stage III), and 471 (21.5%) were de novo metastatic or relapsed cancers at presentation. The 5-year DFS in the women with EBC was 85.5% and in LABC, it was 67.7%, P < 0.001. The factors adversely affecting DFS in EBC were node metastasis (P < 0.001), higher metastatic nodes (P < 0.001), hormone receptor negativity (P = 0.001), and human epidermal growth factor receptor 2 (Her2neu) positivity (P = 0.033). In the multivariate Cox regression analysis in EBC, node-positive status (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.51-3.45, P < 0.001) and hormone receptor negative tumors (HR 1.96, 95% CI 1.30-2.94, P = 0.001) significantly affected DFS in EBC. The factors adversely affecting DFS in LABC in the univariate analysis were node metastasis (P < 0.001), increasing numbers of nodes (P < 0.001), presence of lymphovascular emboli (LVE) (P < 0.01), mastectomy (P < 0.001), and Her2neu positivity (P = 0.03). In the multivariate Cox regression analysis, node positivity (HR 2.96, 95% CI 2.04-4.29, P < 0.0001), presence of LVE (HR 1.47, 95% CI 1.06-2.04, P = 0.023), and mastectomy (HR 1.49, 95% CI 1.06-2.10, P = 0.023) adversely impacted DFS in LABC. The survival rates in this study are equal to the documented global rates; nodal disease burden emerged as the most important prognostic factor. In addition, in EBCs, a lack of hormone receptor expression and in LABC, Her2neu overexpression appear to worsen the outcome.

FcrR3A-158 Polymorphism and Stromal Tumor-Infiltrating Lymphocytes and Survival among Patients with Metastatic HER2-Positive Breast Cancer Receiving Trastuzumab-Based Treatment.

PurposeThe prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has markedly improved since the introduction of trastuzumab. We aimed to evaluate the association between stromal tumor-infiltrating lymphocyte (sTIL) or FcrR polymorphisms and survival among patients with metastatic HER2-positive breast cancer who were treated with trastuzumab.MethodsA total of 56 women with recurrent or metastatic HER2-positive breast cancer who received the trastuzumab-taxane combination as first-line treatment were included in this retrospective analysis. The single-step multiplex allele-specific real-time polymerase chain reaction technique was employed for FcrR3A genotyping. sTILs were identified via immunohistochemical analysis of surgical (n=34, 60.7%) or biopsy specimens of metastatic lesions (n=22, 39.3%).ResultsWe classified patients based on the sTIL level (≤10% [n=44] or >10% [n=12]); high sTIL counts were more commonly observed in patients with hormone receptor-negative tumors than in those with hormone receptor-positive tumors (34.8% vs. 12.1%, p=0.02). There was a significant association between high sTIL levels and longer progression-free survival in comparison to low sTIL levels (median, 28.4 months vs. 16.8 months; p=0.03). With regard to the FcrR3A-158 genotype, patients were classified into the Phenylalanine/Phenylalanine group (23 patients, 41.1%), Phenylalanine/Valine group (23 patients, 41,1%), or Valine/Valine group (10 patients, 17.9%); these classifications were not associated with clinical outcomes.ConclusionHigh sTIL expression may be associated with better efficacy of trastuzumab-containing therapy in patients with metastatic HER2-positive breast cancer. However, this finding warrants further evaluation in the larger population.

Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions.

Glucocorticoid receptor (GR) has emerged as an important steroid nuclear receptor in hormone dependent cancers, however few data are available regarding a potential role of GR in endometrial cancer. The aim of this study was to investigate expression of GR in primary and metastatic endometrial cancer lesions, and to assess the relationship between GR expression and clinical and histopathological variables and survival. Expression of GR was investigated by IHC in 724 primary tumors and 289 metastatic lesions (from 135 patients), and correlations with clinical and histopathological data and survival were explored. Expression of GR was significantly increased in non-endometrioid tumors compared to endometrioid tumors, and was associated with markers of aggressive disease and poor survival both in univariate and multivariate analysis after correcting for age, FIGO stage and histologic grade. Within the subgroups of hormone receptor negative tumors (loss of androgen receptor, estrogen receptor or progesterone receptor) expression of GR was highly significantly associated with poor disease specific survival. There was an overall increase in GR expression from primary to metastatic lesions, and the majority of metastases expressed GR. GR expression in primary endometrial cancer is associated with aggressive disease and poor survival. The majority of metastatic endometrial cancer lesions express GR; therefore GR may represent a therapeutic target in the adjuvant therapy of poor prognosis early-stage as well as metastatic endometrial cancer.

171P - Composite index of risk shows that benefit from adjuvant dose dense chemotherapy is not confined to triple negative breast cancer

Background: Compared with the standard interval adjuvant chemotherapy, dose-dense schedule is proved to increase disease-free survival (DFS) in node-positive early breast cancer (EBC) patients (pts). To date, GIM2 is the only trial supporting the role of dose-dense chemotherapy in pts with hormone receptor-negative (HR-) or hormone receptor-positive tumours (HR+) (Del Mastro et al. Lancet 2015). To further refine the evidence of treatment effect in the HR+ subgroup, a composite index of risk was developed including clinico-pathological features. Methods: The randomized phase III GIM2 trial enrolled 2091 pts with node-positive EBC (primary endpoint: DFS). A continuous, composite measure of treatment benefit was determined from a Cox model incorporating potential predictive factors (age: 25-40/41-55/56-71; histological grade: 1 + 2/3; HR status: positive/negative; ki-67 levels: ≤20%/>20%). Subpopulation treatment effect pattern plot methodology was used to reveal differential treatment effects on DFS according to composite index. The study analyzed the cohort of pts with HER2- (N = 1127) disease with a special focus on HR+ disease (N = 980). Results: On average, the magnitude of benefit with dose dense chemotherapy versus standard chemotherapy widely varied according to composite measure of specific features. In the HER2- subgroup, the highest benefit was observed in pts with G3, HR-, >10 positive nodes, age <40 yrs, ki-67 > 20% (hazard ratio for DFS 0.57, 95% CI 0.35-0.94). Notably, among pts with HR+ disease, the following clinic-pathological characteristics conferred the highest benefit: G3, ≥4 positive nodes, age ≥56 yrs, ki-67 > 20% (hazard ratio for DFS 0.66, 95% CI 0.38-1.15). Conclusions: Composite risk evaluation and corresponding subpopulation treatment effect pattern plot methodology suggest that benefit of dose dense adjuvant chemotherapy is not confined to triple negative EBC. Legal entity responsible for the study: Gruppo Italiano Mammella Funding: None Disclosure: All authors have declared no conflicts of interest.

Abstract 2971: The prognostic relevance of inflammatory cytokines and growth factors elaborated from adipose-derived stem cells in breast cancer

Abstract Introduction: Given the high rates of obesity and aggressive breast cancers, it is paramount to understand how adipose tissue supports the tumor microenvironment. We previously found that adipose-derived stem cells cultured with triple-negative tumor cells enhanced the expression of numerous pro-inflammatory cytokines. This finding is significant as it could explain, in part, how obesity contributes to worse outcomes in breast cancer. To further expand this study, we probed the Cancer Genome Atlas (TCGA) breast invasive carcinoma dataset for the expression profiles of the inflammatory cytokines we found to be highly up-regulated in vitro. We predicted TCGA data would demonstrate a correlation between cytokine overexpression and worse clinical scenarios. Methods: Cytokines and growth factors were measured in the media of adipose stromal cells and MDA-MB-231 tumor cells via membrane-based antibody array. To validate clinical significance, we compared each cytokine’s mRNA expression profile, available from primary tumor samples of TCGA breast invasive carcinoma dataset (n = 1,005), to indices of tumor progression and survival status. For survival analysis, samples were dichotomized as high or low expression by individual cytokines (z score ≥ 1.5). Cytokine and growth factor expression was further stratified according to molecular subtype of breast cancer (luminal A, luminal B, HER2, triple negative) and receptor status. Ingenuity pathway analysis (IPA) was performed to identify candidate markers related to obesity or inflammation. Results: High levels of FGF7 and CCL5 protein were found in the conditioned media of tumor and adipose stem cell co-cultures and together they showed a significant impact on breast cancer survival within TCGA data. FGF7, CCL5, together with CCL2, IL6, and IL6R were further analyzed for expression across molecular subtypes of breast cancer. IL6R, CCL5, and CCL2 expression varied significantly between breast cancer subtypes, with mean expression highest in triple-negative tumors. After dichotomizing the samples for estrogen receptor status, IL6R, CCL5, and CCL2 showed significantly higher mean expression in ER negative tumors. Greater expression of these cytokines in tumors was correlated with reduced patient survival in triple-negative tumors and ER negative subtypes. IPA analysis indicated IL6, IL6R, CCL5, and CCL2, but not FGF7, cooperate through inflammatory pathways to promote tumor progression. Conclusions: Genomic data analysis supports in vitro findings that IL6R, CCL5, and CCL2 overexpression, either independently or synergistically, predict a worse prognosis in breast cancer. For adipose-driven, hormone receptor negative breast tumors, these cytokines and growth factors could serve as novel therapeutic targets. (Supported by NIH P20GM103434 and NIGMS U54GM104942) Citation Format: Nicole Werwie, Kelsey Sadlek, Eric Lundstrom, Daniel Berrebi, Gerald Hobbs, Linda Vona-Davis. The prognostic relevance of inflammatory cytokines and growth factors elaborated from adipose-derived stem cells in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2017-2971

A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p &lt; 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF &lt; 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( &lt; 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.

Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression

BackgroundThe underlying mechanisms for breast cancer (BC) are largely unknown. We investigated possible correlations between the expression levels of human cytomegalovirus (HCMV) proteins and established histopathological markers of BC, including expression of estrogen receptor (ER)-α, the progesterone receptor (PgR), and HER2. Materials and MethodsWe retrospectively examined paraffin-embedded biopsy specimens of BC (n = 62), ductal carcinoma in situ (n = 19), and adjacent normal breast tissue (n = 42) for HCMV immediate-early protein (IE), HCMV late antigen, HCMV DNA and RNA, and investigated possible correlations between them and expression of ER-α, PgR, and HER2. ResultsHCMV DNA and RNA were detected in all examined infiltrating BCs. High-grade positivity for HCMV-IE was detected in 77% of infiltrating BCs, 39% of ductal carcinomas in situ, and 7% of tumor-free breast tissue samples. HCMV expression correlated inversely with ER-α (P = .02) and PgR (P = .003) expression. HER2 expression was also reduced in HCMV-positive samples without reaching a level of statistical significance (P = .09). ConclusionThe negative correlation between high-grade expression HCMV-IE and hormone receptor expression suggests a role for HCMV in hormone receptor-negative BC tumors, possibly by forcing BC cells into a more aggressive phenotype.

Determining breast cancer recurrence following completion of active treatment: A novel approach using linked administrative health data.

ABSTRACTObjectivesAlthough outcomes for the majority of women diagnosed with primary breast cancer are good, with five-year survival exceeding 90%, some women will experience cancer recurrence and ultimately die from the disease. It is important for patients, clinicians and health service planners to know the risk of recurrence once initial treatment for primary breast cancer is completed. However, none of Australia’s State or Territory cancer registries routinely report on cancer recurrence which could be used to evaluate this issue. To address this absence of direct reporting, we aimed to determine the incidence of cancer recurrence in Australian clinical practice after completion of treatment for primary breast cancer, using a range of linked health data sources.&#x0D; ApproachWe performed a retrospective cohort study using linked health data from New South Wales (NSW), Australia. Data were linked from six data collections: i) Cancer Registry, ii) Admitted Patient Data Collection, iii) Pharmaceutical Benefits Scheme claims, iv) Medicare (outpatient) claims, v) Death Registry; and the vi) NSW 45 and Up Study. We identified 2416 women diagnosed with primary invasive breast cancer during 2003-2008 in NSW who had not had a recurrence by 18 months post-diagnosis. Unit-level hospital, pharmacy and outpatient claims were used to identify services indicative of recurrence. Incidence of recurrence was calculated and multivariate Cox regression used to identify baseline and active treatment characteristics predictive of cancer recurrence up to six years post-diagnosis.&#x0D; ResultsA total of 217 women (9.0%) had a hospital, pharmacy or outpatient claim indicating breast cancer recurrence between 18 months and six years post-diagnosis. Overall annual cumulative incidence of recurrence was 3.3%. Recurrence was significantly higher for women with node-positive (4.8% vs. 2.5% annually, adjHR=1.7, 95%CI=1.3-2.3) or hormone receptor-negative (3.8% vs. 3.1% annually, adjHR=1.3, 95%CI=1.0-1.7) tumours. Women with tumours &gt;2cm at diagnosis were more likely to experience recurrence within six years compared with those with a smaller initial tumour (4.8% vs. 2.7 annually, adjHR=1.5; 95%CI=1.1-2.0).&#x0D; ConclusionsWomen with breast cancer in this Australian cohort experienced recurrence at 3.3%pa in the years following completion of treatment. Those at greatest risk of recurrence were women with node-positive or hormone-receptor negative tumours, or tumours &gt;2cm at initial diagnosis, consistent with international findings. This method for ascertaining breast cancer recurrence can be used to assess population-level changes over time and to investigate the impact of specific treatments on outcomes in the absence of available Cancer Registry data.

Impact of adjuvant chemotherapy on survival of women with T1N0M0, hormone receptor negative breast cancer

BackgroundThe benefit of adjuvant chemotherapy in women with T1N0M0 breast cancers is unclear. While gene expression-based prognostic assays may aid management of women with early estrogen receptor (ER) positive tumors, therapeutic decision-making in women with early stage ER negative tumors remains fraught with difficulties. We investigated the association between adjuvant chemotherapy and overall survival in women with T1N0M0, hormone receptor negative breast cancers. MethodAll newly diagnosed breast cancer patients with node-negative and hormone receptor negative tumors measuring≤2cm at the University Malaya Medical Centre (Malaysia) from 1993 to 2013 were included. Mortality of patients with and without adjuvant chemotherapy were compared and adjusted for possible confounders using propensity score. ResultsOf 6732 breast cancer patients, 341 (5.1%) had small (≤2cm), node-negative and hormone receptor negative tumors at diagnosis. Among them, only 214 (62.8%) received adjuvant chemotherapy. Five-year overall survival was 88.1% (95% confidence interval (CI): 82.0%–94.2%) for patients receiving chemotherapy and 89.6% (95% CI: 85.1%–94.1%) for patients without chemotherapy. Chemotherapy was not associated with survival following adjustment for age, ethnicity, tumor size, tumor grade, HER2 status, lympho-vascular invasion, type of surgery and radiotherapy administration. However, chemotherapy was associated with a significant survival advantage (adjusted hazard ratio: 0.35, 95%CI: 0.14–0.91) in a subgroup of women with high-grade tumors. ConclusionAdjuvant chemotherapy does not appear to be associated with a survival benefit in women with T1N0M0, hormone receptor negative breast cancer except in those with high-grade tumors.

Abstract P6-07-19: An alteration of hormonal receptor status throughout tumor progression related to prognosis in breast cancer patients

Abstract Purpose We aimed to identify whether hormonal receptors change throughout tumor progression, because this may influence management and influence prognosis in breast cancer patients. Patients and Methods From the institution's database, we collected data of 963 patients who developed relapse during their follow-ups. To determine estrogen receptor(ER) and progesterone receptor (PR), we retrospectively reviewed immunohistochemical(IHC) results in both primary and relapsed tumors. Results Among a total of 963 patients, 280 and 683 patients experienced locoregional relapse only and distant metastasis irrespective of locoreginal relapse, respectively. ER in 650 patients and PR in 590 patients from both primary tumor and relapse were identified, revealing a change in 157 (24.2%) and 154 (26.1%) patients, respectively. In patients with distant metastasis, assessment of ER and PR showed an alteration in 86 and 56 patients, respectively. The overall survival related to the change of ER and PR status in primary tumor and relapse was significantly different (log rank, P&amp;lt;0.001 in both ER and PR status). In addition, women with hormone receptors negative primary tumors that changed to hormone receptors positive tumors who received anti-hormonal therapy after relapse showed a statistically significant good overall survival (p&amp;lt;0.001) compared with women who had constant ER-negative tumors.(cox regression, hazard ratio 2.32 ; 95% CI, 1.91 to 3.01) Conclusion The breast cancer showed alterations of hormone receptor status throughout tumor progression, hat were related to the strategy of treatment and significantly influences survival. Therefore, investigations of hormone receptor at relapse are essential and helpful in breast cancer patient management. Citation Format: Lee E-S, Kim J, Yoo T-K, Kim Y, Han J, Kang YJ, Choi J, Rhu J, Lee H-B, Han W, Noh D-Y, Moon H-G. An alteration of hormonal receptor status throughout tumor progression related to prognosis in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-19.