Improved Breast Cancer Survival Research Articles

Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer

BackgroundObesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases.MethodsHere, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study.ResultsMetformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism.ConclusionsThese findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.

Understanding Disparities in Breast Cancer Care in Memphis, Tennessee

Although significant progress has been made in improving breast cancer survival, disparities among racial, ethnic, and underserved groups still exist. The goal of this investigation is to quantify racial disparities in the context of breast cancer care, examining the outcomes of recurrence and mortality in the city of Memphis. Patients with a biopsy-proven diagnosis of breast cancer from January 1, 2002, through December 31, 2012, were obtained from the tumor registry. Black patients were more likely to have advanced (II, III, or IV) clinical stage of breast cancer at diagnosis versus white patients. Black breast cancer patients had a two times higher odds of recurrence (95% confidence interval: 1.4, 3.0) after adjusting for race and clinical stage. Black breast cancer patients were 1.5 times more likely to die (95% confidence interval: 1.2, 1.8), after adjusting for race; age at diagnosis; clinical stage; ER, PR, HER2 status; and recurrence. Black women with stages 0, I, II, and III breast cancer all had a statistically significant longer median time from diagnosis to surgery than white women. Black patients were more likely to have advanced clinical stages of breast cancer at diagnosis versus white patients on a citywide level in Memphis. Black breast cancer patients have higher odds of recurrence and mortality when compared with white breast cancer patients, after adjusting for appropriate demographic and clinical attributes. More work is needed to develop, evaluate, and disseminate interventions to decrease inequities in timeliness of care for breast cancer patients.

Prevalence of Cardiac Disease in Breast Cancer Patients at Time of Diagnosis Compared to the General Female Population in Germany

Background: Advances in oncological therapy have significantly improved breast cancer survival; therefore comorbid conditions are becoming more relevant. We investigated the prevalence of prior cardiovascular diseases and risk factors in patients with breast cancer compared to those in the general female population in Germany. Methods: The PASSOS heart study is a retrospective multicenter cohort study on cardiac late effects in breast cancer patients treated between 1998 and 2008. We analyzed the frequencies of cardiac diseases and cardiovascular risk factors in patients from this cohort as documented in anesthesia protocols compared to self-reported frequencies in the general female population in Germany. Results: 3,496 patients aged between 40 and 79 years who underwent breast surgery were considered for analysis. The age-standardized prevalence of cardiac diseases or cardiovascular risk factors was 6.75 versus 7.52% and 69 versus 80.92%, respectively. Coronary heart disease (3.96 vs. 5.18%) and angina pectoris (0.37 vs. 1.03%) prevalence was lower in breast cancer patients, while non-fatal myocardial infarction (2.06 vs. 1.81%) and stroke (2.64 vs. 2.34%) were more frequent (not statistically significant). Conclusion: Pre-existing cardiac diseases and cardiovascular risk factors are common in both study populations, being slightly less frequent in the PASSOS cohort. When making therapy decisions, the cardiac risk profile should be carefully monitored and taken into account.

Cost-effectiveness of breast cancer screening using mammography in Vietnamese women.

BackgroundThe incidence rate of breast cancer is increasing and has become the most common cancer in Vietnamese women while the survival rate is lower than that of developed countries. Early detection to improve breast cancer survival as well as reducing risk factors remains the cornerstone of breast cancer control according to the World Health Organization (WHO). This study aims to evaluate the costs and outcomes of introducing a mammography screening program for Vietnamese women aged 45–64 years, compared to the current situation of no screening.MethodsDecision analytical modeling using Markov chain analysis was used to estimate costs and health outcomes over a lifetime horizon. Model inputs were derived from published literature and the results were reported as incremental cost-effectiveness ratios (ICERs) and/or incremental net monetary benefits (INMBs). One-way sensitivity analyses and probabilistic sensitivity analyses were performed to assess parameter uncertainty.ResultsThe ICER per life year gained of the first round of mammography screening was US$3647.06 and US$4405.44 for women aged 50–54 years and 55–59 years, respectively. In probabilistic sensitivity analyses, mammography screening in the 50–54 age group and the 55–59 age group were cost-effective in 100% of cases at a threshold of three times the Vietnamese Gross Domestic Product (GDP) i.e., US$6332.70. However, less than 50% of the cases in the 60–64 age group and 0% of the cases in the 45–49 age group were cost effective at the WHO threshold. The ICERs were sensitive to the discount rate, mammography sensitivity, and transition probability from remission to distant recurrence in stage II for all age groups.ConclusionFrom the healthcare payer viewpoint, offering the first round of mammography screening to Vietnamese women aged 50–59 years should be considered, with the given threshold of three times the Vietnamese GDP per capita.

Relationships between determinants of adjuvant endocrine therapy adherence in breast cancer

BackgroundInterventions that promote adjuvant endocrine therapy (AET) adherence are critical to improve breast cancer survival. The development of interventions would benefit from a better understanding of the reasons for adherence and the causal relationships of determinants using theoretical or model approaches. The aim of the present study was to identify reasons for AET adherence in breast cancer patients with sequential relationships and inter-relationships.MethodsA total of 210 participants with estrogen receptor positive breast cancer who received AET completed a questionnaire assessing demographic/medical, psychological, and endocrine therapy (ET)-specific factors. A descriptive analysis was performed to identify meaningful variables. Selected variables were subjected to hierarchical regression and path analyses. The path model was tested and modified based on the research framework and the results of regression weights and model fit.ResultsAnalysis of sequential effects showed that ET-specific factors contributed the largest proportion of variance (13.4%) to predict AET adherence, followed by psychological factors (4.6%) and demographic/medical factors (3.1%). Analysis of inter-relationships showed that demographic/medical factors such as AET regimen type and cancer stage have direct effects on AET adherence, whereas psychological factors contribute indirectly through the mediating effects of ET-specific factors.ConclusionAssessments and interventions that encompass the patient’s medication beliefs, self-efficacy, and depression are needed to promote AET adherence.

Abstract GS1-06: Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment: Phase III data from the SUCCESS A study

Abstract Background: A recent meta-analysis has reported benefits of adjuvant bisphosphonate treatment in early breast cancer patients with improved breast cancer survival and reduced rate of breast cancer recurrences in the bone, especially in postmenopausal patients. However, a comparison between bisphosphonate treatments duration is lacking. Therefore, we examined 2 and 5 years of zoledronate treatment following adjuvant chemotherapy in the SUCCESS A trial. Methods: The SUCCESS A trial is a randomized, open-label, 2x2 factorial design Phase III study in high-risk early breast cancer patients that were randomized to adjuvant chemotherapy treatment with 3 cycles of FEC followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. After chemotherapy, patients were subject to a second randomization of 5 years of zoledronate treatment (4 mg i.v. every 3 months for 2 years, followed by 4 mg i.v. every 6 months for 3 years) vs. 2 years of zoledronate treatment (4 mg i.v. every 3 months for 2 years). Outcome was analyzed using adapted disease-free survival (DFS) and adapted overall survival (OS), with survival times measured as of 2 years after the start of zoledronate treatment. Maximal observation time was set to 4 years. Median observation time was 2.95 years for DFS and 3 years for OS. Results: Overall, 3421 of the 3754 patients randomized in the SUCCESS A study received at least one zoledronate dose. 434 patients had a DFS event or were lost to follow up in the first two years after the start of zoledronate treatment; thus, 2987 patients were available for analysis (1540 and 1447 patients in the 5-year and 2-year zoledronate treatment arm, respectively). Both adapted DFS and adapted OS did not differ between the two treatment arms (5 vs. 2 years) as shown by multivariate cox regressions adjusted for patient and tumor characteristics as well as chemotherapy (DFS: hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.75 – 1.25, p = 0.81; OS: HR 0.98, 95% CI 0.67 – 1.42, p = 0.90). In addition, subgroup analyses according to menopausal status revealed no difference in DFS or OS between the two treatment arms in premenopausal women (DFS: HR 1.21, 95% CI 0.81 – 1.81, p = 0.35; OS: HR 0.93, 95% CI 0.57 – 1.53, p = 0.78) or postmenopausal women (DFS: HR 0.85, 95% CI 0.62 – 1.16, p = 0.30; OS: HR 0.96, 95% CI 0.67 – 1.39, p = 0.84). Conclusions: Our study showed no difference in DFS or OS between 5-years and 2-years of adjuvant zoledronate treatment in early breast cancer patients, irrespectively of menopausal status. Thus, our results indicate that extended treatment with zoledronate does not improve DFS or OS in high-risk early breast cancer patients. Citation Format: Janni W, Friedl TWP, Fehm T, Müller V, Lichtenegger W, Blohmer J, Lorenz R, Forstbauer H, Bauer E, Fink V, Bekes I, Jückstock J, Schneeweiss A, Tesch H, Mahner S, Brucker SY, Heinrich G, Beckmann MW, Coleman R, Rack B. Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment: Phase III data from the SUCCESS A study [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 GS1-06.

Abstract IS-3: Breast Imaging in Resource Constrained Regions: Lessons from Uganda

Abstract Breast cancer is the leading cause of cancer death in women and the most common cancer among women world-wide. Five-year survival rates in patients with breast cancer in the United States, Australia and Canada approach 90%, while in parts of Africa survival rates are less than 15%. In October 2013 the international New York Times front page reported on “Uganda's Neglected Epidemic of Breast Cancer.” In December 2013 the WHO International Agency for Research on Cancer (IARC) issued an update on the world's cancer statistics with the headline including the alarm that “marked increase in breast cancers must be addressed.” In Uganda, resources for surgical intervention (mastectomy) and medical oncology (hormonal therapy and limited chemotherapy) are available. Strong recent efforts by the National Cancer Institute, American Cancer Society, and global partners will increase the availability of affordable chemotherapy. In parallel, there is a growing community of breast cancer survivors in Uganda who are sharing their stories and emphasizing the importance of early detection and prompt treatment. Women with palpable breast lumps, identified by themselves or their healthcare providers, are encouraged to seek treatment. But with so many women having palpable breast lumps, and no efficient way to sort the majority of lumps that are benign from the minority of lumps that are malignant, systems are overwhelmed. Clinics do not have the capacity to detect the cancers amongst all the women who present with palpable lumps, and breast cancers remain undiagnosed and untreated, and mortality rates continue to rise. The delays in diagnosis can be significantly reduced with ultrasound (US) technology placed in the hands of non-physician healthcare providers, to streamline the diagnostic process and separate women with lumps that have features warranting biopsy from lumps that can be safely followed clinically in the patient's local, healthcare clinic. Mammography has little added value in countries with limited resources. With so many women who have clear symptoms of breast cancer, and with a significantly higher pre-test probability of cancer in women with (rather than without) symptoms, interventions targeted to asymptomatic women are neither logical nor feasible. The need is not to screen for breast cancers in asymptomatic women but rather to detect the breast cancers in women with symptoms, most notably palpable lumps. Innovative, effective, affordable strategies that emphasize prompt and accurate diagnostic methods in women with palpable breast lumps are needed to improve breast cancer survival in LMICs. These programs can be based on inexpensive, portable ultrasound machines that support triage of patients with palpable lumps to those that need biopsy and those that don't. These technologies are already being used by local health care personnel in developing countries for other prenatal and urgent care purposes. Going forward, novel ultrasound techniques for automated sonogram acquisition and machine learning and deep learning methods can combine to extend the impact of ultrasound imaging in breast cancer diagnosis by reducing the need for highly specialized breast imagers in both acquisition and interpretation. Citation Format: Lehman CD. Breast Imaging in Resource Constrained Regions: Lessons from Uganda [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 IS-3.

Chronological Improvement in Survival of Patients with Breast Cancer: A Large-Scale, Single-Center Study.

PurposeThis study aimed to chronologically evaluate survival of patients with breast cancer in Korea and investigate the observed changes during the last 20 years. We also sought to determine factors that may influence outcomes and changes in the duration of survival over time.MethodsWe retrospectively analyzed a total of 10,988 patients with breast cancer who were treated at our institution between January 1993 and December 2008. We divided the study period into three periods (P1, 1993–1997; P2, 1998–2002; and P3, 2003–2008). We retrospectively reviewed the collected data from the Asan database, including age at diagnosis, clinical manifestations, pathology report, surgical methods, types of adjuvant treatment modalities, type of recurrence, and follow-up period.ResultsAt a median follow-up of 8.2 years, we observed that survival outcomes have improved recently. The 5-year breast cancer-specific survival (BCSS) rate also increased from 82.8% in P1 to 92.6% in P3 (p<0.001). The survival rate in patients with tumors at each stage increased in similar patterns in all patients, and, remarkably, there was a significant survival improvement in patients with stage III breast cancer (P1 vs. P3: 5-year BCSS, 57.4% vs. 80.0%, p<0.001). The time period was a significant prognostic factor in multivariate analysis (P1 vs. P2: hazard ratio [HR], 0.83, p=0.035; P1 vs. P3: HR, 0.75, p=0.015).ConclusionThe study results suggest an improvement in breast cancer survival in Korea, which is consistent with the development of treatments and early detection.

The R-Enantiomer of Ketorolac Delays Mammary Tumor Development in Mouse Mammary Tumor Virus-Polyoma Middle T Antigen (MMTV-PyMT) Mice

Epidemiologic studies report improved breast cancer survival in women who receive ketorolac (Toradol) for postoperative pain relief compared with other analgesic agents. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. The goal of this study was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor virus-polyoma middle T-antigen model. Mice were administered ketorolac orally at 1 mg/kg twice daily to approximate the typical human dose. Mammary glands were analyzed for tumor number and immunohistochemical markers of proliferation and differentiation. R-ketorolac treatment significantly reduced mammary epithelial proliferation, based on Ki67 staining, and suppressed tumor development. Proliferative mammary epithelium from R-ketorolac-treated mice displayed greater differentiation, based on significantly higher total E-cadherin and decreased keratin 5 staining than epithelium of placebo-treated mice. No differences were detected inestrogen receptor, progesterone receptor, β-catenin, or vimentin expression between placebo and R-ketorolac treatment groups. These findings indicate that R-ketorolac treatment slows tumor progression in an aggressive model of breast cancer. R-ketorolac may thus represent a novel therapeutic approach for breast cancer prevention or treatment based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor.

Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single "real-world" setting.

Management of human epidermal growth factor receptor-2-positive (HER2+) breast cancer patients includes the combination of adjuvant chemotherapy and trastuzumab. A meta-analysis reported that <5% of HER2+ breast cancer patients will develop trastuzumab-induced cardiotoxicity (TIC). Observational data suggest that incidence is much higher. We aimed to determine the incidence, time to development, and risk factors associated with TIC among less selected patients. A retrospective cohort study was carried out in 160 HER2+ breast cancer patients who received adjuvant chemotherapy with trastuzumab from January 2006 to June 2014 at St. Michael's Hospital, Toronto, Canada. Patient demographics, cardiovascular history, and TIC were recorded. TIC was defined as symptomatic (heart failure) or asymptomatic [decline in left ventricular ejection fraction (LVEF) by ≥10% or LVEF≤50%]. Of the 160 patients [median age 52 (IQR 45-60), 48.1% on anthracycline-based chemotherapy], 34 patients (21.3%) experienced TIC (median follow-up 55.4months). The median time to development of TIC was 28.5weeks during trastuzumab therapy. Those with TIC were more likely to have undergone a mastectomy (52.9 vs. 33.3%, p=0.04). However, after adjusting for anthracycline-based chemotherapy, and radiotherapy, mastectomy was not independently associated with TIC (HR 2.02; 95% CI 0.88-4.63). The incidence of TIC is higher in our "real-world" population compared to clinical trial data. The median time to development of TIC was 28weeks after trastuzumab initiation, approximately the 10th treatment of trastuzumab. Timely identification and management of patients is important to avoid irreversible cardiac toxicity and improve breast cancer survival.

Abstract 4828: Recapitulating mammary ductal carcinoma microenvironment in vitro using sacrificial bioprinting

Abstract American Cancer Society projects that 1,685,210 new cancer cases will be diagnosed and 595,690 death will occur in 2016, corresponding to about 1,600 deaths per day. In 2016, an estimated 246,660 and 2,600 new cases of invasive breast cancer (e.g. invasive ductal carcinoma) are expected to be diagnosed in women and men in the U.S., respectively, along with 61,000 new cases of non-invasive (i.e., in situ) breast cancer for women. Although tremendous improvements in breast cancer survival have been achieved, current drug administration procedures relying on chemotherapy followed by radiographic scans often lead to disparity in cancer care, necessitating the development of predictive models that can achieve personalized drug administration regimes. While patient-derived tumor graft models have achieved some success, the genetic difference between animal species and the human remains a critical barrier for accurate prediction of patient responses, in addition to their overly high cost. During the past few years, the organs-on-a-chip technologies have made tremendous progress thanks to their capability in modeling the physiology of the sophisticated human systems. Such capability has been further enhanced by advancements in tissue engineering and bioprinting, making it possible to recapitulate the architecture and functionality of tissues in vitro. Here we have utilized a sacrificial bioprinting strategy to generate biomimetic mammary duct-like structures within a hydrogel matrix, to model the genesis and of ductal carcinoma and its invasion. Sacrificial bioprinting has proved its utility in fabricating hydrogel constructs containing hollow microchannels mimicking the tubular structures in the human body. In a typical process we first deposit a mold consisting of sacrificial microfibrous structures using Pluronic from a computerized model and allow it to dry overnight; we subsequently fill the mold with a mixture of gelatin methacryloyl (GelMA)/collagen I solution and induce gelation using photocrosslinking; afterwards, the Pluronic fillers are removed by immersing the entire construct in a cold phosphate buffered saline to achieve hydrogel microchannels. These bioprinted microchannels could then be populated with mammary ductal carcinoma cells on their interior walls. The cells were able to proliferate and populate the surface of the microchannels in 3 weeks, followed by initiation of invasion from the microchannels into the surrounding matrix in the 4th week of culture. In the meantime the cells were observed to deposit basement membrane molecules such as collagen type IV. This bioprinted mammary ductal carcinoma model provides a proof-of-concept demonstration of using bioprinting technologies for engineering biologically relevant cancer models, which can be readily extended to other cancer types where duct-like structures are involved. Citation Format: Y. Shrike Zhang, Margaux Duchamp, Leif W. Ellisen, Marsha Moses, Ali Khademhosseini. Recapitulating mammary ductal carcinoma microenvironment in vitro using sacrificial bioprinting [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 4828. doi:10.1158/1538-7445.AM2017-4828

Abstract LB-253: Novel prognostic gene profiles in tumors for breast cancer survival

Abstract Recent development in molecular phenotyping of breast cancer to guide treatment strategy has improved breast cancer survival. While several prognostic panels, such as Oncotype DX (21 genes), MammaPrint (70 genes), ProSigna (50 genes), have been approved for clinical use with demonstrated utility, there is still room for improvement. Using a novel bioinformatics approach, we previously demonstrated that higher “activity” (instead of level of expression) of miR-500a-5p in tumor was associated with shorter survival of ER+ breast cancer patients. However, the activity of miR-500a cannot be directly measured and can only be inferred by the expression of its associated genes. Using NanoString platform, we profiled 162 miR-500a-related genes as well as PAM50 genes (22 genes overlapped between PAM50 set and miR-500a-related set) from tumors collected as part of the Long Island Breast Cancer Study Project, where a population-based sample of 1508 women, predominantly Caucasians aged 25-98 (median age 58), newly diagnosed with first primary breast cancer in 1996-1997, were followed up for 15+ years using the National Death Index. We were able to obtain sufficient RNA for profiling from paraffin-embedded tumors tissues for 609 cases, among which 119 breast cancer deaths were reported at the end of follow up. Survival analyses were carried out using Cox proportional hazards models adjusting for known prognostic factors. Consistent with our a priori hypothesis, most of the selected miR-500a related genes (81 out of 162) significantly associated with breast cancer-specific mortality. Co-expression analysis revealed two major clusters of genes with opposite associations with breast cancer-specific mortality. For example, expression of SUSD3 from the first cluster showed inverse associations with breast cancer-specific mortality [high vs low expression: Hazard Ratio (HR) 0.33, 95% CI: 0.23-0.47] while TPX2 from the second cluster showed the opposite [HR 2.64, CI: 1.84-3.80]. These associations were also confirmed in independent combined datasets (described in “KM-Plotter”, kmplot.com). Most importantly, these associations remained significant after adjusting for known prognostic factors including tumor hormonal receptor status and PAM50-derived risk of recurrence category, implicating they are independent markers for breast cancer survival. Our study identified novel predictors that may improve prognostic efficiency of current molecular phenotyping. In addition, these results shed light on molecular mechanism of breast cancer progression and may point to the targets for treatment of the disease. Citation Format: Vasily N. Aushev, Marilie D. Gammon, Humberto Parada, Davide Degli Esposti, Hector Hernandez-Vargas, Zdenko Herceg, Susan Teitelbaum, Jun Zhu, Eunjee Lee, Jia Chen. Novel prognostic gene profiles in tumors for breast cancer survival [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 LB-253. doi:10.1158/1538-7445.AM2017-LB-253

Role of Aspirin in Breast Cancer Survival.

Chemotherapy and hormonal therapy have significantly decreased breast cancer mortality, although with considerable side effects and financial costs. In the USA, over three million women are living after a breast cancer diagnosis and are eager for new treatments that are low in toxicity and cost. Multiple observational studies have reported improved breast cancer survival with regular aspirin use. Furthermore, pooled data from five large randomized trials of aspirin for cardiovascular disease showed that subjects on aspirin had decreased risk of cancer mortality and decreased risk of metastatic cancer. Although the potential mechanism for aspirin preventing breast cancer is not known, possible pathways may involve platelets, inflammation, cyclooxygenase (COX) 2, hormones, or PI3 kinase. This review article summarizes the current epidemiologic and clinical trial evidence as well as possible underlying mechanisms that justify current phase III randomized trials of aspirin to improve breast cancer survival.

Clinical trials: A key tool in improving breast cancer survival in Nigeria.

e18198 Background: Clinical trials has continued to sharpen the treatment guidelines in managing breast cancer in the United States. The trends in breast cancer management in developed countries and the shifts in treatment paradigms have impacted on breast cancer diagnosis from an incurable entity in the early 1900s’ to the situation today where most women are diagnosed in early stage and cured while advanced staged women are living with the disease for several years. Clinical research in breast cancer is in its infancy stage in Nigeria. There is an urgent need for more clinical trials in Nigeria geared towards developing treatment algorithms in a bid to increase survival in Breast cancer patients. Methods: A systematic review of all research published on breast cancer since 1963 till 2017 in Nigeria .We reviewed all articles found on PubMed and Google scholar search engines by searching “ Breast cancer in Nigeria”. Using the PRISMA and NIH guidelines, we reviewed classified them based on their study designs into different levels of evidence. Information extracted from studies include, year of publications, study designs and level of evidence. Studies selected were group into seven levels of evidence .Meta-analysis was not considered in the review due to vary study designs and difficulty n pooling then together. Results: Out of 430 published articles cited relating to Breast cancer, only 282 articles where eligible for the systematic review. 56.4%(159) of studies done on breast were cross sectional studies, followed by case – control studies 11.7% (33), then case reports &amp; series 10.4%(29) ,2.8%(8) , only 1.1% (3)of studies cited were clinical trials registered on Clinical Trials.gov on breast cancer treatment. On Levels of Evidence, Level 6 accounted for 54.9 %( 155) followed by Level 7, 18.1 %( 51), level 1, 2, 3 were 0%, 1.1%, 8.9%.Conclusions: A vast majority of research done on Breast Cancer done in the Country are still at the Levels 4, 6 and 7 of Evidence. Clinical trials in Breast cancer treatment are rare in Nigeria, they however provide Level 1, 2 or 3 evidence which helps to develop treatment protocols for Breast cancer Treatment in Nigeria. , it is pertinent to develop more clinical trials so as to improve quality of care and life in breast cancer patients.

ABC trial (A011502): A randomized phase III double blinded placebo controlled trial of aspirin as adjuvant therapy for node positive breast cancer.

TPS586 Background: In-vitro and in-vivo evidence suggest that aspirin, an inexpensive and widely available drug may have anti-tumor activity via effects on multiple pathways. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Furthermore, pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users, especially metastatic adenocarcinoma (RR 0.52 (95% CI 0.35-0.75). In order for aspirin to be considered standard of care, the exact benefits and risks for breast cancer survivors need to be confirmed in a randomized trial. Methods: The primary objective is to compare the effect of aspirin versus placebo upon invasive disease-free survival (iDFS) in stage II-III node-positive HER2 negative breast cancer patients. Secondary objectives include effects on overall survival and cardiovascular disease and to collect toxicity and adherence. A biospecimen repository will be created for future correlative analyses including tumor collection at baseline and blood and urine samples at baseline and 2 years. Questionnaires assessing lifestyle factors associated with inflammation (pain, sleep, stress, and depression) will also be collected at baseline and 2 years. Study design: Subjects will be randomized (1:1) to aspirin 300 mg vs placebo daily for 5 years in a double-blinded fashion. Stratification factors include hormone receptor status (positive vs negative), body mass index ( &lt; or ≥ 30 kg/m2), and stage (II vs III).Subjects will be followed every 6 six months while on study drug and then annually until 10 years from registration. 2936 patients will be enrolled with 80% power to detect HR 0.75. Eligibility: Eligible subjects include patients aged 18-70 diagnosed with a primary invasive stage II or III node positive HER2 negative breast cancer in the past year. Patients who currently use any oral or injectable anticoagulant or those with a prior history of GI bleeding, atrial fibrillation, myocardial infarction, or grade IV hypertension will be excluded. Patients who regular used aspirin over the past year will be excluded. Clinical trial information: NCT02927249.

Abstract P5-14-03: Adjuvant dose dense doxorubicin-cyclophosphamide (ddAC) or docetaxel-AC (TAC) for high-risk breast cancer: First results of the randomized MATADOR trial (BOOG-2004-04)

Abstract Background: Anthracycline-based adjuvant chemotherapy has substantially improved breast cancer survival. Both the addition of taxanes as well as using a dose dense treatment schedule can further ameliorate outcome, but inter-individual differences exist. Here we present the efficacy and toxicity of dose dense scheduled doxorubicin/cyclophosphamide (ddAC) versus docetaxel/doxorubicin/cyclophosphamide (TAC), which is, to our knowledge, the first direct comparison of these treatment regimens. Methods: In this Dutch, multicenter phase III trial (ISRCTN61893718), patients with pT1-3, pN0-3, M0 breast cancer were randomized between six cycles of either A60C600 every 2 weeks or T75A50C500 every 3 weeks. All patients received pegfilgrastim. Patients were evaluated for recurrence-free survival (RFS) and overall survival (OS). Survival was compared in a Cox regression analysis and adjusted for known prognostic factors. These factors include age, type of surgery, tumor size, histological grade, ER/PR status, HER2 status, and lymph node status. Adverse events were reported according to the common toxicity criteria (CTCAE version 3.0). Results: Between 2004 and 2012, 664 patients were enrolled of whom 531 (80%) had node positive disease. At a median follow up of 5 years, OS was 92% in the ddAC treated subgroup and 93% in the TAC treated subgroup (adjusted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.42-1.34, intention to treat population). Forty-two breast-cancer specific deaths were equally divided over both treatment arms. Similarly, no significant difference in RFS was observed between both treatment groups (adjusted HR 0.85, 95% CI 0.55-1.32). Molecular subtypes were defined by St. Gallen criteria: 548 patients (83%) had estrogen receptor positive disease and 102 patients (15%) triple negative disease. No heterogeneity regarding treatment efficacy was observed in these subtypes. In particular, there was no survival benefit for ddAC or TAC in the triple negative subtype. Both treatment regimens were well tolerated. Whereas anemia was more frequent in ddAC treated patients (19% vs 4.7%; p&amp;lt;0.001), peripheral neuropathy occurred more frequently in TAC treated patients (4.6% vs 14.4%; p&amp;lt;0.001). The frequency of febrile neutropenia was not significantly different between the treatment arms (11% vs 12.5%; n.s.). Six patients developed congestive heart failure: 2 ddAC treated patients, 4 TAC treated patients. One ddAC treated patient and one TAC treated patient were diagnosed with acute myeloid leukemia after study treatment; another patient in the ddAC treatment group developed myelodysplastic syndrome. Conclusions: At a median follow up of 5 years no significant survival differences were observed between adjuvant ddAC and TAC, in all patients and in molecular subgroups, including triple negative. Our findings are in line with the Oxford overview, which reported no significant differences between taxane-based chemotherapy and more, non-taxane based chemotherapy given in a dose dense schedule. ddAC could be a reasonable alternative for patients with a contra-indication for TAC. Citation Format: van Rossum AGH, Oosterkamp HM, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok E, van Tinteren H, Kok M, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Rodenhuis S, Linn SC. Adjuvant dose dense doxorubicin-cyclophosphamide (ddAC) or docetaxel-AC (TAC) for high-risk breast cancer: First results of the randomized MATADOR trial (BOOG-2004-04) [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 P5-14-03.

Demographic changes in breast cancer incidence, stage at diagnosis and age associated with population-based mammographic screening.

Breast cancer incidence and mortality are influenced by early-detection methods, including mammographic screening. Demographic changes in US statistics serve as a model for changes that can be anticipated in countries where mammographic screening has not been implemented. SEER statistics (1973-2013) for breast cancer mortality, incidence, stage at diagnosis, and age at diagnosis were examined. Temporal associations between screening changes and breast cancer demographics in the US were documented. Before 1982 (pre-screening), breast cancer incidence in the US remained stable, with similar incidence of localized and regional cancers, and with in-situ disease comprising <2% of diagnosed disease.1 During the transitional phase of mammographic screening, breast cancer incidence increased. In 1991, breast cancer age-adjusted mortality rates began decreasing and have continued to decrease. In the post-screening phase, stage distribution stabilized, but now with localized and in-situ disease representing the majority of diagnosed cases. The median age at diagnosis has increased to 61 years. Mammographic screening increases breast cancer incidence, shifts the stage distribution toward earlier stage disease, and in high-income countries, is associated with improved survival. Whether similar improvement in breast cancer survival can be achieved in the absence of mammographic screening has yet to be conclusively demonstrated.

Abstract C20: Racial Disparities in Breast Cancer Diagnosis-to-treatment Waiting Times in South Carolina

Abstract Background: Although incidence of breast cancer is higher among white females, mortality rates remain higher among black women. This disparity has widened despite improved breast cancer survival rates over time. The widening gap in black-white mortality for breast cancer may be related to differences in tumor biology, treatments received and access to care. The objective of this study was to assess racial disparities in breast cancer diagnosis-to-treatment waiting times in South Carolina (SC). Methods: Data for this analysis includes all female breast cancer cases in SC from 2002-2009 derived from linked files from the SC Central Cancer Registry and Office of Revenue and Fiscal Affairs (who maintains the administrative medical claims data for the South Carolina Public Employee Benefits plan and Medicaid). The main outcome variable was diagnosis-to-treatment time (overall and by cancer treatment type) which was defined as the interval between the date of diagnosis and the date of any first course of treatment or the date of receipt of breast cancer-related surgery, radiation, chemotherapy, and hormonal therapy. The main exposure variable was patient race (white vs black). Students' t test with a significance level of 0.05 was used to assess the difference in diagnosis-to-treatment time by patient race. Results: A total of 1611 breast cancer patients including 1205 white and 406 black females were reported in the study period. There was a consistent increase in the mean number of diagnosis to receipt of first course of treatment among blacks compared to whites overall (22.7 vs 18.4); from diagnosis to surgery (27.2 vs 23.1); from diagnosis to radiation therapy (142.2 vs 122.8 radiation); from diagnosis to chemotherapy (65.5 vs 62.3); from diagnosis to hormonal therapy (148.7 vs 85.3). There was also a consistent increase in the median number of days (18 vs 15; 18 vs 15; 140 vs 91; 56 vs 52; and 136 vs 115) from diagnosis to receipt of first course of treatment overall, and by type (surgery, radiation, chemotherapy and hormonal therapy respectively) among blacks compared to whites. This difference was statistically significant for time to any first course of treatment overall (p: &amp;lt;0.01) and by time from diagnosis to radiotherapy (&amp;lt;0.01). Conclusions: Black females experience consistently longer waiting times from diagnosis to treatment (overall and by all subtypes of treatments) than their white counterparts. Further exploration is needed to know the reasons why black females have persistent increase in diagnosis to treatment wait times and particular attention should be placed on reduction of the diagnosis to treatment wait times in an attempt to reduce already existing racial disparities in breast cancer outcomes among Blacks and Whites. Citation Format: Oluwole Adeyemi Babatunde, Swann Arp Adams, Jan Eberth, Erica Sercy, James Hebert. Racial Disparities in Breast Cancer Diagnosis-to-treatment Waiting Times in South Carolina. [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 C20.

Low glycemic index diet, exercise and vitamin D to reduce breast cancer recurrence (DEDiCa): design of a clinical trial

BackgroundMechanisms influencing breast cancer (BC) development and recurrence include hyperglycemia, hyperinsulinemia, high insulin-like growth factor-1, high circulating estrogen, inflammation and impaired cellular differentiation/apoptosis. A lifestyle program that targets all the above mechanisms may be warranted. Low glycemic index (GI) foods produce lower post-prandial glucose and insulin responses and have been associated with lower BC risk. Moderate physical activity post-diagnosis reduces BC recurrence and mortality, partly explained by reduced insulin and estrogen levels. Vitamin D increases cell differentiation/apoptosis and high serum vitamin D levels improve BC survival. Yet no trial has evaluated the combined effect of a low GI diet, moderate physical activity and vitamin D supplementation on BC recurrence in the context of a Mediterranean lifestyle setting.MethodsWomen (30-74 yr) who had undergone surgery for primary histologically confirmed BC (stages I-III) within the previous 12 months, in cancer centres in Italy, will be randomized to follow, for a maximum of 33 months, either a high intensity treatment (HIT) composed of low GI diet + exercise + vitamin D (60 ng/mL serum concentration) or a lower intensity treatment (LITE) with general advice to follow a healthy diet and exercise pattern + vitamin D to avoid insufficiency. Both interventions are on a background of a Mediterranean diet. Considering a 20% recurrence rate within 3 years for BC cases and a predicted rate of 10% in the HIT group, with power of 80% and two-sided alpha of 0.05, the subject number required will be 506 (n = 253 in each arm). Clinic visits will be scheduled every 3 months. Dietary and exercise counselling and vitamin D supplements will be given at each clinic visit when blood samples, anthropometric measures and 7-day food records will be collected.DiscussionDEDiCa study aims to reduce BC recurrence in women with BC using a lifestyle approach with additional vitamin D and to investigate possible cardio-metabolic benefits as well as epigenetic modifications according to lifestyle changes. Given the supporting evidence and safety of the components of our intervention we believe it is feasible and urgent to test it in cancer patients.Trial registrationMay 11, 2016; NCT02786875. EudraCT Number2015-005147-14

Endocrine Therapy for Early Breast Cancer: Updated Review.

Although breast cancer is still the second most common cause of cancer-related deaths, breast cancer mortality has been declining because of advances in the use of adjuvant therapies. We summarize clinical trials involving endocrine therapies used to treat early breast cancer and discuss their inception and recent advances. Endocrine therapies such as tamoxifen have revolutionized the treatment of breast cancer, resulting in significant decreases in cancer-related mortality. Aromatase inhibitors such as anastrozole and letrozole have further improved breast cancer survival. With the implementation of such therapies resulting in decreased mortality, patients with breast cancer are living longer than ever before. The focus of research is now directed toward the length of treatment and prediction models for recurrence.