Hormone Receptor-negative Breast Cancer Research Articles

Would 1.0cm be a more suitable cutoff to subdivide pT1 tumors in hormone receptor-negative and HER2-positive breast cancer?

BackgroundHER2+ and hormone receptor (HoR)‐negative breast cancer usually associated with poor outcome. However, it remained elusive for the prognosis of small (T1a‐T1c) HER2+/HoR‐ breast cancer. The present study retrospectively analyzed the Surveillance, Epidemiology, and End Results (SEER) database to explore the clinicopathological characteristics and prognosis of T1a‐T1c HER2+/HoR‐ breast cancer.Material and MethodsData for patients diagnosed with either HER2‐/HoR+or HER2+/HoR‐ T1a‐T1c breast cancer between 2010 and 2012 were obtained from SEER program. Survival analyses were conducted by Kaplan‐Meier method and Cox proportion hazard regression.ResultsTotally, 2648 HER2+/HoR‐ and 56387 HER2‐/HoR+T1a‐T1c breast cancer patients were enrolled. There was a clear trend that tumor size had a positive correlation with advanced AJCC stage (P < 0.001) and N‐stage (P < 0.001). T1a and T1b HER2+/HoR‐ breast cancer had great homogeneity in that these two subgroups had comparable survival and both showed no significant survival difference with its counterpart of HER2‐/HoR+subtype. Conversely, T1c HER2+/HoR‐ breast cancers revealed worse prognosis than T1a/T1b HER2+/HoR‐ and T1c HER2‐/HoR+tumors (BCSS HR 3.847, P < 0.001; OS HR 2.055, P < 0.001).ConclusionT1a and T1b HER2+/HoR‐ breast cancer had favorable prognosis and great homogeneity, indicating 1.0 cm may be a suitable cutoff for subclassification of T1 cancer. Future randomized clinical trials were warranted to verify this hypothesis and elucidate the biological behavior of small T1 tumor to facilitate precise medicine.

Effects of trastuzumab on locoregional recurrence in human epidermal growth factor receptor 2-overexpressing breast cancer patients treated with chemotherapy and radiotherapy.

In the present study, the ability of adjuvant trastuzumab to reduce locoregional recurrence in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer receiving adjuvant chemotherapy and radiotherapy (RT) was investigated. We retrospectively included 520 patients with HER2-overexpressing breast cancer who received surgery followed by adjuvant RT and cytotoxic chemotherapy from 2003 to 2011. Adjuvant trastuzumab was administered to 286 patients. Propensity score matching was conducted to compare trastuzumab-treated and non-treated cohorts. Median follow-up duration was 7.1years (range 1.1-14.1years). Propensity score matching yielded 171 matched pairs of patients with no significantly different clinical factors. An improved 7-year locoregional control (LRC) rate was observed in the trastuzumab-treated cohort compared with the non-treated cohort (95.6% vs. 89.9%, p = 0.014). Based on multivariate analysis, hormone receptor negativity (hazard ratio [HR] = 5.348, p = 0.007), positive lymph node ratio > 0.25 (HR = 2.549, p = 0.040), and lack of adjuvant trastuzumab (HR = 3.401, p = 0.017) were identified as significant risk factors for poor LRC. Adjuvant trastuzumab significantly reduced the locoregional recurrence rate in patients with one or two risk factors (7-year LRC = 95.0% vs. 84.2%, p = 0.007); however, the benefit of adjuvant trastuzumab was non-significant in patients with no risk factors (7-year LRC = 95.8% vs. 97.9%, p = 0.75). Adjuvant trastuzumab improved LRC in patients with HER2-overexpressing breast cancer receiving adjuvant RT and cytotoxic chemotherapy, especially in hormone receptor-negative, HER2-enriched subtype, and high positive lymph node ratio breast cancer.

PO-234 Transwell co-culture with human breast adipocytes alters the proteome expression profiles of MCF-7 and MDA-MB-231 human breast cancer cells

IntroductionBreast tumours grow within adipose tissue, and stromal adipocytes are likely the first cell type encountered by breast cancer cells as they metastasize. Adipocytes at the invasive edge of human breast tumours exhibit a modified phenotype, and consequently these adipocytes have been named Cancer Associated Adipocytes (CAA). Previous in vitro research has shown that co-culture with CAA promotes breast cancer cell resistance to radiation and some therapeutic agents, as well as breast cancer cell invasiveness both in vitro and in vivo. The aim of the current research was to identify cellular proteins that are differentially regulated in breast cancer cells co-cultured with CAA.Material and methodsThis study collected human breast adipose tissue samples, from which pre-adipocytes were isolated, differentiated into mature adipocytes, and co-cultured with hormone receptor positive (MCF-7) and negative (MDA-MB-231) human breast cancer cells for 3 days in a transwell co-culture system. The proteomes of co-cultured and control breast cancer cells were compared quantitatively using iTRAQ labelling and LC-coupled LTQ-Orbitrap tandem mass spectrometry. Validation of iTRAQ results was performed by Western blotting.Results and discussionsThis study identified and quantified a total of 1126 and 1218 proteins expressed in MCF-7 and MDA-MB-231 cells, respectively. Of these, 85 in MCF-7 and 63 in MDA-MB-231 had a fold change >1.5 between co-culture and control breast cancer cell samples. Overall, MCF-7 cells had more proteins downregulated (n=53) than upregulated (n=32) after co-culture, whereas, more proteins were upregulated (n=51) than downregulated (n=12) in MDA-MB-231 cells. Enrichment analysis revealed an upregulation of proteins involved in metabolic pathways, namely TCA cycle proteins in MCF-7 cells and glycolysis proteins in MDA-MB-231 cells. The metabolic enzyme PGK1 was upregulated in response to co-culture with CAA in both cell lines, and is associated with poorer overall survival and resistance to the chemotherapy agent paclitaxel in breast cancer. Western blotting results validated mass spectrometry ratios for three candidate proteins.ConclusionOverall, this study describes for the first time the local effect CAA have on the expression of proteins in breast cancer cells in vitro, and provides a comprehensive platform for further research investigating local interactions between breast cancer cells and CAA.

Advances in chemotherapy for HER2-negative metastatic breast cancer.

Metastatic breast cancer cannot be curable, but significant improvement in overall survival has been observed with the appearance of new agents. The purpose of treatment is to prolong survival and to improve quality of life by reducing cancer-related symptoms. To achieve these goals, individualized approach is required. Chemotherapy is used for patients with hormone receptor negative breast cancer or hormone receptor positive patients who have cancer-related symptoms. The choice of regimen (single-agent or a combination), selection of a specific therapy and the duration of treatment depend on multiple factors, including the tumor burden, general health status, prior treatments and toxicities, and patient preferences.

Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy.

Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer. EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7-11, 2016, Copenhagen, Denmark (oral presentation).

119 (PB-020) - The impact of menstrual cycle recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer

119 (PB-020) - The impact of menstrual cycle recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer

Intake of bean fiber, beans, and grains and reduced risk of hormone receptor-negative breast cancer: the San Francisco Bay Area Breast Cancer Study.

High dietary fiber intake has been associated with reduced breast cancer risk, but few studies considered tumor subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status or included racial/ethnic minority populations who vary in their fiber intake. We analyzed food frequency data from a population‐based case–control study, including 2135 breast cancer cases (1070 Hispanics, 493 African Americans, and 572 non‐Hispanic Whites (NHWs)) and 2571 controls (1391 Hispanics, 557 African Americans, and 623 NHWs). Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with fiber intake were calculated using unconditional logistic regression. Breast cancer risk associated with high intake (high vs. low quartile) of bean fiber (p‐trend = 0.01), total beans (p‐trend = 0.03), or total grains (p‐trend = 0.05) was reduced by 20%. Inverse associations were strongest for ER‐PR‐ breast cancer, with risk reductions associated with high intake ranging from 28 to 36%. For bean fiber, risk was reduced among foreign‐born Hispanics only, who had the highest fiber intake, whereas for grain intake, inverse associations were found among NHWs only. There was no evidence of association with fiber intake from vegetables and fruits or total intake of vegetables and fruits. A high dietary intake of bean fiber and fiber‐rich foods such as beans and grains may lower the risk of ER‐PR‐ breast cancer, an aggressive breast cancer subtype for which few risk factors have been identified.

WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

BackgroundMetastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread.MethodsIn this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo.ResultsHigh WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential.ConclusionsOur data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients.

Abstract P1-07-01: HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative breast cancer

Abstract Background: Interactions between cancer cells and the host immune system influence tumor biology, response to therapy and patient survival and their modulation offers promising new approaches for cancer therapy. The downregulation or loss of HLA class I expression in breast cancer cells might be an effective mechanism to evade the recognition by the immune system facilitating malignant behavior. Aim: To evaluate the association of tumor-infiltrating lymphocytes (TILs) with HLA class I expression and its theranostic value for therapy response and survival after neoadjuvant chemotherapy. Methods: HLA class I expression was evaluated by immunohistochemistry in a cohort of 732 pre-therapeutic core biopsies from breast cancer patients treated within the neoadjuvant GeparTrio trial. Patients received anthracycline- and taxane-based neoadjuvant therapy and adjuvant endocrine treatment if hormone receptor-positive (HR+). A publicly available microarray dataset of pre-therapeutic core biopsies from 508 breast cancer patients that received neoadjuvant chemotherapy and endocrine treatment if HR+ was used for validation of the results. The association of HLA class I expression with predefined genomic signatures for immune cell populations was evaluated in publicly available data from the cancer genome atlas. Results: HLA class I expression was associated with TILs (p &amp;lt; 0.001) and was predictive of better response to neoadjuvant chemotherapy in the subgroup of patients with HR+/HER2- breast cancer (14 % in tumors with high HLA vs. 7 % in tumors with low HLA, p = 0.029). Interestingly, high HLA was also predictive for shorter progression-free survival in univariate analysis (HR 1.590, 95 % CI 1.062—2.380; p = 0.024) and after adjustment to clinical and pathological parameters (HR 1.701, 95 % CI 1.105—2.618; p = 0.016). The results could be validated in the independent microarray-based dataset (HR 1.521, 95% CI 1.088 – 2.129; p = 0.0142). HLA class I was not associated with therapy response or survival in hormone receptor-negative breast cancer. HLA class I was associated with a predefined signature for T-cells and cytotoxic T- cells in the cancer genome atlas dataset (rho = 0.546). Conclusion: HLA class I expression is associated with better response but shorter progression-free survival in HR+/HER2- breast cancer following neoadjuvant chemotherapy. The underlying mechanisms warrant further investigation. Citation Format: Sinn BV, Weber K, Denkert C, Fasching PA, Schmitt WD, Thomas K, Ingold-Heppner B, van Mackelenbergh M, Symmans WF, Marmé F, Taube E, Müller V, Kunze CA, Schem C, Pfitzner BM, Stickeler E, von Minckwitz G, Loibl S. HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative breast cancer [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 P1-07-01.

Abstract ES3-1: Drugging protein synthesis in cancer therapy

Abstract Translation of mRNAs that encode proteins with transforming, cell survival, DNA damage DNA repair and angiogenic functions requires increased levels of specific translation factors that are often overexpressed in many human cancers. Translation of these same classes of oncogenic mRNAs also requires increased activation of the protein synthesis machinery, which is stimulated by well-known signal transduction pathways, particularly the P3K-AKT-mTOR pathway and the ERK-MAPK-MNK pathway. Targeted inhibition of selective oncogenic mRNA translation through inhibition of translation-specific signal transduction pathways, or the specific inhibition of certain translation factors that are required in greater amounts for oncogenic mRNA translation, are emerging new areas in human cancer therapeutics and are in active clinical trials. Small molecule drugs have been developed that are highly specific for the key translation factors that are overexpressed in many human cancers, including breast cancers. In breast cancer, specific stage and grade-dependent alterations occur in the translation machinery and in its signal transduction pathways that correspond to locally advanced, inflammatory, endocrine-resistant ER+, hormone receptor negative and metastatic breast cancer. Many of these alterations provide actionable targets with existing drugs for exploitation of translation-specific vulnerabilities that do not target normal cells and can be synergistically combined with existing genotoxic chemotherapies, endocrine therapies, radiation therapy and immunotherapies. Current research has also begun to elucidate previously unknown translational control pathways that provide additional novel targets and potentially lower toxicity approaches. Targeting translational regulation and the protein synthetic machinery in cancer cells provides the advantage of being able to impair the expression of classes of mRNAs that are essential for cancer progression, metastasis and drug resistance, rather than targeting individual proteins or genes. These promising new therapeutics and clinical treatment strategies will be discussed. Citation Format: Schneider RJ. Drugging protein synthesis in cancer therapy [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 ES3-1.

Abstract P1-15-01: Final analysis of SWOG S0230/Prevention of early menopause study (POEMS)

Abstract BACKGROUND: The SWOG S0230/POEMS study demonstrated a 70% reduction in ovarian failure (OF) with goserelin coadministration during chemotherapy (CT) for ER-negative early breast cancer (BC; Moore H et al, NEJM 2015). Goserelin use was also associated with more pregnancies as well as favorable disease free survival (DFS) and overall survival (OS). Here we report the final analysis after 5 years of follow-up. METHODS: Premenopausal women age &amp;lt;50 with stage I-IIIA ER/PR-negative BC to be treated with cyclophosphamide-containing CT were randomized to receive standard CT with or without monthly goserelin 3.6 mg SQ starting at least 1 week prior to the first CT dose. The primary endpoint was OF at 2-years, defined as amenorrhea for the prior 6 months and post-menopausal FSH. Secondary endpoints included pregnancies, disease free survival (DFS) and overall survival (OS). An unplanned analysis of rate of menses recovery at 2 years (presence of menses within 6 months of the 2 year time-point or pregnancy within the first 2 years) was also conducted. OF and pregnancy endpoints were analyzed using multivariable logistic regression adjusting for stratification factors (age and CT regimen); DFS and OS were examined using multivariable Cox regression, adjusting for stratification factors and stage. Two-sided p-values are reported unless otherwise specified in accordance with protocol design. RESULTS: Among 257 randomized participants, 218 were eligible and evaluable. One hundred thirty-six eligible and evaluable patients had OF data and 186 had menstrual data. Median age was 37.7 years. Among the 136 patients with OF data, the odds ratio (OR) for OF at 2 years was 0.30 (95% CI 0.1-0.98; one-sided p=0.023) comparing CT with goserelin to standard CT alone. Among 186 patients with menstrual data, 80% recovered menses by 2 years in the goserelin arm compared with 70% in the standard arm (OR=1.74, 95% CI: 0.83-3.66, p=0.15). Pregnancies, DFS and OS are reported for all 218 eligible and evaluable patients. With a median follow-up of 5.1 years, 22% of patients in the goserelin group had at least one pregnancy compared with 12% in the standard group (OR 2.38, 95% CI 1.08-5.26, p=0.03). Cumulative incidence of pregnancy at 5 years is 23% in the goserelin arm compared with 12% in the standard group. Five-year Kaplan-Meier DFS estimates are 88% in the goserelin arm compared with 79% in the standard arm (HR=0.50, p=0.05). Five-year OS is 92% with goserelin versus 83% in the standard arm (HR=0.47, p=0.06). Including all 257 randomized patients, HR for DFS and OS are 0.67 and 0.48 (p=0.18 and p=0.05). CONCLUSION: Ovarian suppression with goserelin during chemotherapy for hormone receptor-negative breast cancer reduces OF risk and, after 5 years of follow-up, continues to be associated with more pregnancies and improved survival compared with chemotherapy without goserelin. SUPPORT: NIH/NCI grant awards CA189974, CA180888, CA180819, CA074362; AstraZeneca Citation Format: Moore HCF, Unger JM, Phillips K-A, Boyle F, Hitre E, Moseley A, Porter D, Francis PA, Goldstein LJ, Gomez HL, Vallejos CS, Partridge AH, Dakhil SR, Garcia AA, Gralow J, Lombard JM, Forbes JF, Martino S, Barlow WE, Fabian CJ, Minasian L, Meyskens FL, Gelber RD, Hortobagyi GN, Albain KS. Final analysis of SWOG S0230/Prevention of early menopause study (POEMS) [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 P1-15-01.

Lapatinib.

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastrointestinal cancer, and at lower rates also in additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexpressing HER2 have a more aggressive course of their disease. The poor prognosis associated with HER2 overexpression can be substantially improved by adding HER2-targeted therapy to standard of care using the monoclonal antibody trastuzumab. Lapatinib, an oral dual tyrosine kinase inhibitor, blocks HER1 and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor's intracellular domain, resulting in inhibition of tumor cell growth. Lapatinib is generally well tolerated with diarrhea being the most common adverse effect. However, although being mainly of mild to moderate severity, interruption or discontinuation of treatment has been reported in a substantial proportion of patients in clinical trials. In 2007, lapatinib has been approved in combination with capecitabine in patients with advanced HER2-positive breast cancer upon progressive disease following standard therapy with anthracyclines, taxanes, and trastuzumab. In 2013, the approval was extended to a chemotherapy-free combination with trastuzumab for patients with metastatic HER2-positive, hormone receptor-negative breast cancer progressing on prior trastuzumab and chemotherapy. Since 2010, lapatinib is approved in combination with letrozole in the treatment of postmenopausal women with advanced HER2- and hormone receptor-positive breast cancer. In contrast, in first-line cytotoxic-based therapy of both early and advanced HER2-positive breast cancer, data from clinical trials did not provide evidence of additional benefit of lapatinib compared to trastuzumab. Moreover, over the past few years, novel HER2-targeted drugs, either alone or as a combined anti-HER2 approach, have been extensively evaluated, demonstrating a more favorable outcome. Also, neither in first- nor second-line treatment of advanced gastric cancer, lapatinib has been proven to be superior compared to trastuzumab as hitherto standard of care HER2 blockade. Therefore, lapatinib has become somewhat less important in patients with HER2-positive breast cancer during the past 10years since its first introduction. Nevertheless, consideration of treatment with lapatinib appears to be reasonable in selected patients not only in the approved applications but also beyond, and further indications such as HER2-positive refractory metastatic colorectal cancer may arise in future. Also, lapatinib may have distinct advantages over antibodies in targeting truncated HER2 and crossing the blood-brain barrier. Finally, the favorable cardiac toxicity profile of lapatinib makes it an attractive alternative to trastuzumab-based regimens in patients at risk for cardiac events.

Breast cancer statistics, 2017, racial disparity in mortality by state.

In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 252,710 new cases of invasive breast cancer and 40,610 breast cancer deaths are expected to occur among US women in 2017. From 2005 to 2014, overall breast cancer incidence rates increased among Asian/Pacific Islander (1.7% per year), non-Hispanic black (NHB) (0.4% per year), and Hispanic (0.3% per year) women but were stable in non-Hispanic white (NHW) and American Indian/Alaska Native (AI/AN) women. The increasing trends were driven by increases in hormone receptor-positive breast cancer, which increased among all racial/ethnic groups, whereas rates of hormone receptor-negative breast cancers decreased. From 1989 to 2015, breast cancer death rates decreased by 39%, which translates to 322,600 averted breast cancer deaths in the United States. During 2006 to 2015, death rates decreased in all racial/ethnic groups, including AI/ANs. However, NHB women continued to have higher breast cancer death rates than NHW women, with rates 39% higher (mortality rate ratio [MRR], 1.39; 95% confidence interval [CI], 1.35-1.43) in NHB women in 2015, although the disparity has ceased to widen since 2011. By state, excess death rates in black women ranged from 20% in Nevada (MRR, 1.20; 95% CI, 1.01-1.42) to 66% in Louisiana (MRR, 1.66; 95% CI, 1.54, 1.79). Notably, breast cancer death rates were not significantly different in NHB and NHW women in 7 states, perhaps reflecting an elimination of disparities and/or a lack of statistical power. Improving access to care for all populations could eliminate the racial disparity in breast cancer mortality and accelerate the reduction in deaths from this malignancy nationwide. CA Cancer J Clin 2017;67:439-448. © 2017 American Cancer Society.

Racial Differences in Adjuvant Endocrine Therapy Use and Discontinuation in Association with Mortality among Medicare Breast Cancer Patients by Receptor Status.

Background: There are racial disparities in breast cancer mortality. Our purpose was to determine whether racial/ethnic differences in use and discontinuation of adjuvant endocrine therapy (AET) differed by hormone receptor status and whether discontinuation was associated with mortality.Methods: We conducted a retrospective cohort study with SEER/Medicare dataset of women age ≥65 years diagnosed with stage I-III breast cancer in Medicare Part-D from 2007 to 2009, stratified by hormone receptor status. We performed multivariable logistic regressions to assess racial differences for the odds of AET initiation and Cox proportional hazards models to determine the risk of discontinuation and mortality.Results: Of 14,902 women, 64.5% initiated AET <12 months of diagnosis. Among those with hormone receptor-positive cancer, 74.8% initiated AET compared with 5.6% of women with negative and 54.0% with unknown-receptor status. Blacks were less likely to initiate [OR, 0.76; 95% confidence interval (CI), 0.66-0.88] compared with whites. However, those with hormone receptor-positive disease were less likely to discontinue (HR, 0.89; 95% CI, 0.80-0.98). Women who initiated with aromatase inhibitors had increased risk of discontinuation compared with women who initiated tamoxifen (HR, 1.12; 95% CI, 1.05-1.20). Discontinuation within 12 months was associated with higher risk of all-cause (HR, 1.75; 95% CI, 1.74-2.00) and cancer-specific mortality (HR, 2.76; 95% CI, 1.74-4.38) after controlling for race/ethnicity.Conclusions: There are racial/ethnic differences in AET use and discontinuation. Discontinuing treatment was associated with higher risk of all-cause and cancer-specific mortality regardless of hormone receptor status.Impact: This study underscores the need to study factors that influence discontinuation and the survival benefits of receiving AET for hormone receptor-negative breast cancer. Cancer Epidemiol Biomarkers Prev; 26(8); 1266-75. ©2017 AACR.

Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population

BackgroundPrevious population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history.MethodsThe Women’s Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations.ResultsLobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0–1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1–1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0–9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen.ConclusionsHaving a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.

Abstract 2427: Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben

Abstract Parabens are a group of chemical compounds extensively used as preservatives in consumer products such as cosmetics, pharmaceuticals and processed food. Parabens have been shown to have endocrine disrupting properties, to accumulate in breast tissue and to increase the proliferation of hormone receptor positive breast cancer cell lines through competitive binding to the estrogen receptor. Studies have shown that isobutylparaben has the highest binding affinity for the aryl hydrocarbon receptor (AhR), reported to bind environmental toxins. This study examined the alterations in gene expression correlated to exposure of the hormone receptor negative breast cancer cell line MDA-MB-231 to isobutylparaben over a 72 hour time frame. Exposure of the cells to concentrations of isobutylparabens commonly found in consumer products alters the genetic expression profile of the cells. In our study, detectable expression levels of AhR mRNA decreased, while cytochrome P450 (CYP1A1) and receptor activator of NFκB ligand (RANKL) mRNA levels increased, as analyzed by qPCR. The downregulation of AhR and altered expression levels of invasion related genes is suggestive of an increased metastatic phenotype with exposure to isobutylparaben. Citation Format: Christine Strelchuk, Holly Jones Taggart. Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben [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 2427. doi:10.1158/1538-7445.AM2017-2427

Abstract 3461: The Nek2 mitotic kinase drives centrosome amplification, mitotic dysfunction, and invasion in mammary epithelial and breast cancer cells

Abstract Despite findings reported by The Cancer Genome Atlas (TCGA) that the most common human tumors have undergone at least one genomic doubling, the roles of polyploidy and chromosome instability (CIN) in cancer are poorly understood. Defective mitosis, and centrosome amplification (CA) are major sources of CIN, which generally associates with poor prognosis of patients. Prevalence of CA and CIN in hormone receptor negative (ER-PR-Her2- or ER-PR-Her2+) breast cancer patients, who have the poorest outcomes among all intrinsic subtypes, suggest that CA and CIN play major roles in the disease. CA in breast cancers correlates with poor survival, metastasis and high tumor grade, suggesting roles in tumor progression. Our laboratory, using an inducible K-RasG12D transgenic mouse that directed its expression to mammary epithelial cells, demonstrated CA appeared in precancerous mammary epithelial lesions, suggesting a role in tumor initiation. Despite these observations, the role of CA as cancer driver or promoter has not been tested experimentally. To understand that role, drivers of CA in cancer must be identified, and our laboratory showed that dysregulated E2F1, E2F2 and E2F3a, and their mitotic targets, including Nek2, TTK, and SgoI sustain CA and CIN in mammary epithelial and breast cancer cells. In fact, orthotopic models of breast cancer demonstrated that silencing of E2F3 leads to slow tumor growth that correlates with reduced mitosis, CA and Nek2 levels. We find that overexpression of the E2F target Nek2 in non-transformed mammary epithelial cells results in large acinar structures, CA, CIN, and changes in relevant EMT markers that include vimentin. Our findings indicate that deregulated E2F pathway contribute to mammary tumorigenesis in part by deregulating kinases that control mitosis, including Nek2, and in turn these affect mitotic progression, CIN, EMT and invasion. Thus, centrosome/kinases downstream of the E2F pathway may represent future targets for intervention in highly-malignant HR- breast cancers. Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Miyoung Lee, Harold I. Saavedra. The Nek2 mitotic kinase drives centrosome amplification, mitotic dysfunction, and invasion in mammary epithelial and breast cancer cells [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 3461. doi:10.1158/1538-7445.AM2017-3461

Abstract 2761: Adjuvant chemotherapy outcomes of node negative, T1a,T1b,T1c hormone receptor-negative HER2-positive breast cancer patients

Abstract Background: Patients (pts) with early stage HER2neu-positive breast cancers have a higher risk of recurrence and death compared to hormone receptor positive patients. NCCN guidelines recommends adjuvant chemotherapy for Stage II and above HER2-positive breast cancer patients. It is unclear what benefit patients with Stage I HER2-positive breast cancer receive from adjuvant chemotherapy. The current study evaluates the effects of adjuvant chemotherapy on the survival of early stage ER/PR negative, HER2-positive breast cancer patients registered to the National Cancer Data base (NCDB) from 2010-2012. Patients and Methods: 3416 women from the NCDB were identified with Stage I ER, PR negative, HER2-positive breast cancer diagnosed between 2010-2012. The primary measured outcome was overall survival. Pts were grouped by tumor size (T1a,T1b,T1c) and adjuvant chemotherapy or no adjuvant chemotherapy. Additionally, patients were also grouped into lumpectomy with radiation and mastectomy with or without radiation. Adjusted variables included age, race, Charlson Comorbidity Index (CCI), payer status, income, education, distance travelled, diagnosing/treating facility and treatment delay. Multivariate Cox regression was used to investigate the effect of adjuvant chemotherapy on overall survival while adjusting for other factors. Results: There were a total of 3416 patients, mean age at diagnosis of 57.9 (range 22-90). The mean age was 56.2 years for the chemotherapy group and 61.8 for the no chemotherapy group. Pathological stage distribution was T1a (24.9%), T1b (24.7%) and T1c (50.2%). Adjuvant chemotherapy was received by 49.5% of T1a, 83.5% of T1b and 95% of T1c pts. Mean patient follow up was 2.7 years (range 0.05-5 years) In univariate analysis, the hazard ratio (HR) of death for chemotherapy vs no chemotherapy in each T stage was: T1a; 1.22 (0.46-3.28), T1b; 0.221 (0.095-0.512), T1c; 0.217 (0.094-0.498). In multivariate analysis, adjusting for other factors in the model, HR of death was 0.51 (95%CI: 0.26-1.03) for chemotherapy vs no chemotherapy. The HR of death was 1.92 (95%CI: 1.11-3.32) for pts who received mastectomy without radiation compared to lumpectomy with radiation. In addition, we observed a HR of 5.16 for CCI score of 2 or above as compared to score of 0. There was no difference in outcome based on payer status or race. Conclusion: Patients with early stage T1 a-c HER2-positive breast cancer had a marginal improvement in overall survival with the addition of chemotherapy. Patients who underwent lumpectomy with radiation were also found to have better overall survival compared to mastectomy without radiation. However, the relatively short follow up and the lack of cancer recurrence information preclude making definitive conclusions relative to adjuvant therapy for pts with these tumors. Longer follow-up and prospective controlled trials will be needed to quantify these potential benefits. Citation Format: Anu Paul, Runhua Shi, Prakash Peddi, Gary Burton. Adjuvant chemotherapy outcomes of node negative, T1a,T1b,T1c hormone receptor-negative HER2-positive breast cancer patients [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 2761. doi:10.1158/1538-7445.AM2017-2761

Abstract 1767: Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study)

Abstract AIM: We compared 6 cycles of docetaxel and cyclophosphamide (TC6) with 3 cycles of 5-fluorouracil and epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FEC-D) as neoadjuvant chemotherapy for patients with hormone receptor (HR)-negative breast cancer (BC) to identify biomarkers requiring anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were administered TC6 or FEC-D. Triple-negative BC was subdivided by CK5/6 and EGFR into basal- and non-basal BCs. The primary endpoint was pathological complete response (pCR). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (Ki-67, P-53, ALDH1 and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: Of the 103 patients, 97 completed the study. Overall pCR was higher for patients treated with FEC-D (36%) than for those treated with TC6 (25.5%) (P=0.265). FEC-D was significantly superior to TC6 in basal BC (42.9% vs 13.6%; P=0.033), while no differences in HER2 and non-basal BCs. Aldehyde dehydrogenase 1 (ALDH1) positivity was inversely associated with pCR for both regimens, significantly for FEC-D (FEC-D: p=0.047, TC6: p=0.085). Patients who achieved pCR tended to have longer DFS (P = 0.287) and OS (P = 0.069). Patients with basal and non-basal BC treated with FEC-D had significantly better DFS (P = 0.016) and OS (P = 0.034) than those with TC6. Conclusion: We found TC6 was less effective than FEC-D for HR-negative BC because it was not sufficient to treat basal-BC. This suggests that DNA damaging agents like anthracyclines are required for treating basal-BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Mari S. Oba, Akimitsu Yamada, Kumiko Kida, Mikiko Tanabe, Yasushi Ichikawa. Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study) [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 1767. doi:10.1158/1538-7445.AM2017-1767

INFLUENCE OF EXOGENOUS LACTOFERRIN ON THE OXIDANT/ ANTIOXIDANT BALANCE AND MOLECULAR PROFILE OF HORMONE RECEPTOR-POSITIvE AND -NEGATIvE HUMAN BREAST CANCER CELLS IN VITRO

To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro. The study was performed on receptor-positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low-temperature electron paramagnetic resonance, and the Comet assay were used. Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p < 0.05), NO generation rate by inducible NO-synthase (p < 0.05) and the level of "free" iron (p < 0.05) were observed. Moreover, the effects of lactoferrin were more pronounced in receptor-negative MDA-MB-231and MDA-MB-468cells. These changes resulted in increased expression of proapoptotic Bax protein (p<0.05), reduced expression of the antiapoptotic Bcl-2 protein (p < 0.05) and level of not-oxidized mitochondrial cardiolipin (1.4-1.7-fold, p< 0.05). This, in turn, caused an increase in the percentage of apoptotic cells (by 14-24%, p < 0.05). Cytotoxic effects of lactoferrin were accompanied by an increase in the percentage of DNA in the comet tail and blocking cell cycle at G2/M phase, especially in receptor-negative cell lines. The study showed that exogenous lactoferrin causes a violation of an antioxidant balance by increasing the level of ROS, "free" iron and NO generation rate, resalting in the blocking of cell cycle at G2/M-phase and apoptosis of malignant cells.