Outcome In Early Breast Cancer Research Articles

Recurrence in early breast cancer: Analysis of data from 3,765 Australian women treated between 1997 and 2015

BackgroundEvidence suggests recent improvements in outcome in early breast cancer (EBC). AimTo analyse recurrence in women with EBC from our region from 1997 to 2015. MethodsWe analysed recurrence in 3,765 women with EBC. Median follow up was 83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status, 72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple negative (TN) tumour. ResultsRecurrence occurred in 459 (12·2%), predominantly in distant sites (71·7%). In women entered from 2002 onwards, the five and 10 year recurrence rates were significantly lower in the luminal group than the HER2+ and the TN groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On multivariate analysis the following were associated with a significantly increased risk of recurrence: nodal involvement (p < 0·0001), tumour grade (p < 0·0001), symptomatic presentation (p < 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p < 0·0001) and tumour size >50 mm (p = 0·02). ConclusionThe recurrence rate in this series was much lower than in previous older series. Lymph node involvement, tumour grade, symptomatic presentation, presence of LVI, non-luminal tumour type and tumour size (>50 mm) were associated with an increased risk of recurrence. We strongly recommend that clinicians include the presence of LVI and symptomatic presentation as well as the other established tumour factors, when assessing the risk of recurrence in women with EBC.

Comorbidities, age and period of diagnosis influence treatment and outcomes in early breast cancer.

Survival for breast cancer (BC) is lower in eastern than northern/central Europe, and in older than younger women. We analysed how comorbidities at diagnosis affected whether selected standard treatments (STs) were given, across Europe and over time, also assessing consequences for survival/relapse. We analysed 7581 stage I/IIA cases diagnosed in 9 European countries in 2009-2013, and 4 STs: surgery; breast-conserving surgery plus radiotherapy (BCS + RT); reconstruction after mastectomy; and prompt treatment (≤6 weeks after diagnosis). Covariate-adjusted models estimated odds of receiving STs and risks of death/relapse, according to comorbidities. Pearson's R assessed correlations between odds and risks. The z-test assessed the significance of time-trends. Most women received surgery: 72% BCS; 24% mastectomy. Mastectomied patients were older with more comorbidities than BCS patients (p < 0.001). Women given breast reconstruction (25% of mastectomies) were younger with fewer comorbidities than those without reconstruction (p < 0.001). Women treated promptly (45%) were younger than those treated later (p = 0.001), and more often without comorbidities (p < 0.001). Receiving surgery/BCS + RT correlated strongly (R = -0.9), but prompt treatment weakly (R = -0.01/-0.02), with reduced death/relapse risks. The proportion receiving BCS + RT increased significantly (p < 0.001) with time in most countries. This appears to be the first analysis of the influence of comorbidities on receiving STs, and of consequences for outcomes. Increase in BCS + RT with time is encouraging. Although women without comorbidities usually received STs, elderly patients often received non-standard less prompt treatments, irrespective of comorbidities, with increased risk of mortality/relapse. All women, particularly the elderly, should receive ST wherever possible to maximise the benefits of modern evidence-based treatments.

Impact of Vitamin D on Breast Cancer Outcome

Studies demonstrate an association of low vitamin D (D) levels with worse outcomes in early breast cancer (EBC) patients (pts). Studies incorporating treatment details and assessing for Defect across molecular subtypes are of value.

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/− intravenous ZOL 4 mg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. ResultsWith a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84–1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82–1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67–1.00; HRIDFS = 0.78, 95%CI = 0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58–0.97) and OS HROS = 0.69, 95%CI = 0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63–0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. ConclusionsDisease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Evaluation of the effect of CXCL13 mRNA expression in early breast cancer outcome: A confirmatory study.

e24286Background: CXCL13 mRNA expression has been associated with subtype specific outcome in breast cancer and its prognostic markers. Methods: Early breast cancer patients with T1-4, N1-2, M0 wer...

Abstract GS1-03: Peri-operative aromatase inhibitor treatment in determining or predicting longterm outcome in early breast cancer – The POETIC* Trial (CRUK/07/015)

Abstract Background Experimental evidence (Fisher et al, 1989) &amp; a small clinical trial (IMPACT) respectively suggested peri-operative endocrine therapy (ET) may improve long-term disease-related outcome in patients undergoing primary surgery for ER positive (ER+) breast cancer (BC) &amp; that tumor Ki67 levels after 2 weeks of peri-operative aromatase inhibitor (POAI) therapy might offer an effective way of predicting outcome &amp; the need for additional adjuvant treatment. POETIC (*Peri-Operative Endocrine Therapy - Individualising Care) is a phase III randomized controlled trial designed to test these hypotheses &amp; provide data to determine whether 2 week Ki67 improves prediction beyond that by baseline Ki67 of the group who have a higher risk of relapse in the first years after diagnosis in spite of best current standard of care. Patients &amp; methods Postmenopausal patients with ER+ BC were randomised 2:1 to either, POAI (centre choice: letrozole 2.5mg or anastrozole 1mg daily) for 14 days prior to &amp; 14 days following surgery or no POAI (Control). Randomization was stratified by treating center; adjuvant treatment was per UK routine practice. Tissue samples were collected at baseline &amp; surgery (FFPE) for blinded Ki67 testing. Primary endpoint was Time to Recurrence (TTR: time from randomization to loco-regional or distant recurrence or BC death). A secondary endpoint was Ki67 at baseline &amp; after 2 weeks of AI. Results Between 2008 &amp; 2014, 4480 patients (2976 AI, 1504 Control) were randomized from 130 UK centers. Median age was 67 (IQR 62-75), 18% had grade 3 tumors, 39% were node positive and 61% had tumor size&amp;gt;2cm. For adjuvant ET 314 patients (7.2%) received tamoxifen (Tam), 3695 (84.6%) an AI, 251 (5.7%) Tam changing to AI and 109 (2.5%) changing from AI to Tam. On 8 August 2017, median follow-up was 60.7 months (IQR 49.5 to 72.2). 408/4480 (9.1%) patients have had a TTR event; 263 (8.8%) allocated to POAI compared to 145 (9.6%) controls: HR=0.91 (95%CI: 0.74, 1.12) Log-rank p=0.37. Adjusted HR=0.91 (95%CI: 0.74, 1.11). The relationship of Ki67 (baseline &amp; after 2 weeks) with TTR in both the POAI &amp; control groups will be presented for the overall ER+ population &amp; HER2 defined sub-groups. Discussion There was no significant evidence that four weeks of POAI improved TTR compared with no POAI. POETIC will provide definitive evidence on the role of 2 week POAI-treated Ki67 to inform future practice &amp; trials in terms of the potential to identify a group of patients for whom current standard of care appears insufficient in the few years post diagnosis. Citation Format: Robertson JFR, Dowsett M, Bliss JM, Morden JP, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Kilburn L, Dodson A, Smith I. Peri-operative aromatase inhibitor treatment in determining or predicting longterm outcome in early breast cancer – The POETIC* Trial (CRUK/07/015) [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 GS1-03.

Abstract ES8-3: Circulating complexes of stromal and tumor cells in breast cancer metastasis

Abstract The establishment of breast cancer metastases at sites distant from the primary lesion site is predicated on the ability of breast cancer cells to mobilize from the primary tumor, survive in circulation, and colonize in a suitable and permissive metastatic niche. While quantitation of individual CTCs has prognostic value in breast cancer patients with metastatic disease, and elevated counts of CTCs may associate with poor outcome in early breast cancer, recent evidence from mouse models indicates that CTCs in clusters have a greater capacity to produce metastases than individual CTCs and new studies in breast cancer suggest that the presence of CTC clusters in patients can be prognostic. We have found in breast cancer patients, clusters of circulating cells that include CTCs, immune cells, and stromal cells found in the tumor microenvironment, specifically cancer associated fibroblasts (CAFs). Like CTC and circulating CAF (cCAF) counts, the incidence and number of CTC/cCAF clusters increases with disease stage. While the clinical significance of circulating complexes of CTCs and stromal cells remains to be fully elucidated, the recent identification of cCAFs in the peripheral blood of patients with metastatic breast cancer, traveling individually or in clusters with CTCs emphasizes the potential importance of stromal cells as circulating mediators of cancer metastasis. Preclinical murine models of breast cancer metastasis provide opportunities to observe the composition, dynamics, and behavior of these circulating CTC/stromal cell complexes, and to interrogate mechanisms driving their mobilization and clustering. Identifying the cellular components in these circulating complexes, and understanding the mechanisms by which they facilitate breast cancer metastasis, may provide novel therapeutic avenues for the treatment or prevention of metastatic breast cancer. Citation Format: El-Ashry D. Circulating complexes of stromal and tumor cells in breast cancer metastasis [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 ES8-3.

Combined effect of obesity and diabetes on early breast cancer outcome: a prospective observational study

BackgroundPrevious studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients.Materials and MethodsOverall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test.ResultsAt diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post-menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for disease-free survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival.ConclusionsAt diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cancer.

Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer

PurposeAlthough adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs.MethodsThe SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18–65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up.ResultsA total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up.ConclusionsIn this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.

Adherence and persistence to adjuvant hormonal therapy in early stage breast cancer patients: A population-based retrospective cohort study in Israel.

e12051 Background: Adjuvant hormonal therapy has been consistently proven to improve multiple outcomes in early breast cancer. Nonetheless, data on rates of adherence and persistence with therapy outside West Europe and North America are scarce. We assessed the adherence and persistence with adjuvant hormonal in a retrospective population based cohort of breast cancer survivors in Maccabi Health Services (MHS), Israel. Methods: We identified women who were diagnosed with breast cancer and initiated adjuvant hormonal therapy between January 2000 and November 2008. Subjects were followed retrospectively from first dispensed tamoxifen or aromatase inhibitor (AI) and up to the earliest of the following events: disease recurrence (indicated by surgery, radiotherapy, chemotherapy or other related therapies), leaving MHS, death, or completion of 5 years of treatment. Discontinuation of therapy was defined as a 180-day or longer treatment gap. Adherence with therapy was assessed using proportion of days covered (PDC) during follow-up period. Survival analysis was used to determine the effect of adherence on all-cause mortality. Results: A total of 4178 women with breast cancer were followed for a median 7.8 years. Over 90% of patients received tamoxifen as the initial hormonal agent. Mean PDC was 84% with lower rates associated with younger age, smoking status, comorbidities and year of diagnosis. Residential area did not affect adherence. Differences were not found. Discontinuation of therapy occurred in 23% of study patients. Among persistent patients, 70% were optimally adherent with therapy (PDC&gt;=80%). Association between adherence with therapy and survival is investigated. Conclusions: Adherence to adjuvant hormonal therapy among Israeli breast cancer patients with national health insurance is high in comparison to international reports. Nevertheless, suboptimal adherence was identified among younger (&lt;45y) patients. Because of the efficacy of hormonal therapy in preventing recurrence and death in women with early-stage breast cancer, interventions are necessary to identify and prevent suboptimal adherence among high risk subgroups.

Long-term safety and survival outcomes from the Scandinavian Breast Group 2004–1 (SBG 2004-1) randomized trial of tailored dose adjuvant chemotherapy for early breast cancer.

e12036 Background: Although adjuvant polychemotherapy (ACT) improves outcomes for early breast cancer (BC), the significant interpatient variability in pharmacokinetics result in differences in efficacy and both short and long term toxicities. Dose tailored ACT has been shown to improve outcomes, while tailored and dose dense therapy improved 5-year event free survival in the phase 3 PANTHER trial. Methods: The SBG 2004-1 trial was a randomized feasibility/phase II study which assessed dose tailored epirubicin and cyclophosphamide (EC) followed by docetaxel (T), compared to the same fixed dose schedule and to the TAC regimen (table 1). Women aged 18-65 years old, ECOG PS 0-1 with at least one positive lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the administered treatment. The secondary endpoint of the study was to evaluate the dose-intensity of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term safety results of the trial have been previously published. Here, we report safety and efficacy data after 10 years follow-up. Results: A total of 124 patients were included and &gt;95% of patients without relapse were followed for 10 years.Five secondary malignancies but no myelodysplastic syndrome / acute myeloid leukemias were reported. Long term disease-free and overall survival results will be presented at the meeting. Conclusions: Long term safety results from this study in combination with efficacy results from the PANTHER trial imply the feasibility of a tailor-based approach for ACT in early BC. [Table: see text]

BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses

Background:The co-chaperone protein Bcl-2-associated athanogene-1 (BAG-1) is overexpressed in breast cancer and has been incorporated in the oncotype DX and PAM50 breast cancer prognostic assays. Bcl-2-associated athanogene-1 exists as multiple protein isoforms that interact with diverse partners, including chaperones Hsc70/Hsp70, Ser/Thr kinase Raf-1 and Bcl-2, to promote cancer cell survival. The BAG-1L isoform specifically binds to and increases the transcriptional activity of oestrogen receptor in cells, and in some, but not all studies, BAG-1 expression is predictive of clinical outcome in breast cancer.Methods:A systematic review of published studies reporting BAG-1 (mRNA and/or protein) expression and clinical outcome in early breast cancer. The REporting Recommendations for Tumour MARKer and Prognostic Studies (REMARK) criteria were used as a template against which data were assessed. Meta-analyses were performed for studies that provided a hazard ratio and 95% confidence intervals for clinical outcomes including disease-free survival or breast cancer-specific survival from univariate analysis.Results:Eighteen studies used differing methodologies and reported on differing outcomes. Meta-analyses were only possible on results from a subset of reported studies. Meta-analyses suggested improved outcome with high BAG-1 mRNA and high BAG-1 nuclear expression by immunohistochemisty.Conclusions:Increased levels of BAG-1 are associated with better breast cancer outcomes.

Relation between Hypofractionated Radiotherapy, Toxicity and Outcome in Early Breast Cancer.

To compare adjuvant conventional radiotherapy (C-RT) to hypofractionated schedule (HF-RT) in early breast cancer. Between May 2012 and September 2015, 120 patients were included in the analysis. All patients underwent conservative surgery and adjuvant RT. RT was delivered in C-RT (50 Gy; 2 Gy/fr) or HF-RT (42.5 Gy; 2.66 Gy/fr), followed by a tumor bed boost (10 Gy; 2 Gy/fr). RT-induced toxicity was recorded and compared between groups. Toxicity results were graded according to the Common Terminology Criteria for Adverse Events guidelines. A multivariate analysis was performed of the factors associated with acute toxicity onset. Mild acute skin toxicity was observed in 71.7% of patients. No grade 4 toxicity was observed. From the multivariate analysis, Breast volume and RT fractionation significantly affected acute radiation-related toxicity. No increase in late toxic effects has been reported between C-RT and HF-RT schedules. Overall, the 2-year disease free survival was 94.4%. HF-RT represents a valid adjuvant treatment option in early breast cancer patients, without negative impact on acute and late radiation sequelae, as well as tumor control.

Abstract P4-07-01: Profiling miRNA in high risk post-operative early breast cancer patients to detect possible association to correlation with immune system antitumor response

Abstract Aims: Identifying which patient will be the one who developes metastatis or relapses is still an unsolved problem in breast cancer research. Circulating free nuclei acids such as microRNA (miRNA) are very promising cancer biomarkers to detect those patients. Aim of this study was to unravel an association among whole blood miRNA profiling, circulating tumor cells (CTCs) and clinical outcome in early breast cancer (EBC) patients and to test the utility of miRNAs as prognostic and diagnostic markers in post-operative patients. Methods: 48 high risk EBC patients, a subsample of the German SUCCESS A trial, were included in this retrospective study together with 18 aged-matched healthy donors (HDs) as controls. Peripheral blood was drawn post-operatively before (T0), after (T1) and two years after (T2) chemotherapy directly in Tempus Blood RNA Tubes (ThermoFischer Scientific) to stabilize and isolate total RNA. miRNAs were quantified by qPCR and their relative expression was calculated according to the 2-DCt method. CTCs were detected by immunocytochemistry. Data were analyzed using non-parametric statistical tests and p-values below 0.05 were considered significant. Results: 8 different miRNAs, either with oncogenic (miR-10a, -19a, -21, -22) or tumor suppressive (miR-20a, -127, -155, -200b) properties, in most of the cases linked to immune system regulation (miR-19a, -20a, -21, -127 and -155) were tested. miR-19a, miR-21, miR-22 and miR-127 showed the most promising results as prognostic markers in our tests. They could differentiate patients from HDs (Patients vs. HD: miR-19a at T0, p=0.004), T1 ( p&amp;lt;0.0001), miR-21 at T0 (p=0.001), T1 (p=0.004), miR-22 at T1 (p=0.012), T2 (p=0.034)). Additionally they correlated with the post-operative detection of CTCs (miR-127) and the late development of metastasis (miR-19a). Kaplan-Meier analysis indicated a borderline association between a longer progression free survival and higher miR-19a levels (HR= 2.808, 95% confidence interval [CI] =0.904, p=0.074.) Conclusion: We found a panel of miRNAs that could discriminate post-operative patients from HDs and could predict patients' outcome. We suggest that whole blood miRNA profiling could unravel a correlation with the activation of the immune system, leading to an efficient antitumor response and a better clinical outcome. These findings could open new perspectives in immune oncology and personalized therapy already in the early phase of the disease. Citation Format: Tzschaschel MLJ, Rack B, Majunke L, Trapp EK, Mahner S, Fasching PA, Fehm T, Schneeweiss A, Friedl TWP, Polasik A, Janni W, Alunni-Fabbroni M. Profiling miRNA in high risk post-operative early breast cancer patients to detect possible association to correlation with immune system antitumor response [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 P4-07-01.

Demographic Characteristics, Survival and Prognostic Factors of Early Breast Cancer Patients with Type 2 Diabetes Mellitus: A Hospital-Based Cohort Study

Objective:With increasing prevalence of type 2 diabetes mellitus and breast cancer in Iran, we aimed to search hospital registries of breast cancer patients to investigate type 2 diabetes mellitus association with survival outcomes of early breast cancer after adjustment of confounding factors.Methods:In a retrospective cohort study conducted from July 2003 to Feb 2014 and followed up until death or December 2016, female patients with early breast cancer who have been treated for the first time at the Cancer Institute of Iran, were divided to diabetic and non-diabetic groups. Primary and secondary outcomes were relapse free survival (RFS) and overall survival (OS). SPSS version 23 was used for analysis of data. Other variables included age, tumor stage, hormone receptor status, tumor subtype, and patient’s body mass index (BMI).Result:From a total of 1021 patients, 218 (21.4%) had type 2 diabetes mellitus. Diabetic patients had a higher mean age (53.31 vs 47.00), higher mean BMI (31.13 vs 29.15), lower HER2 expression (20.8% vs 32.1%) and higher frequency of luminal A subtype (61.1% vs 51.0). Overall, after adjustment of other variables, diabetes status did not affect RFS or OS independently. However, in luminal A subgroup, patients with diabetes mellitus had significantly lower survival outcomes of OS (135.277 vs 154.701) and RFS (114.107 vs 133.612) as well as OS higher hazard ratio of 1.830 and RFS hazard ratio of 1.663 compared to non-diabetic patients. BMI, hormone receptor status and tumor stage significantly affected the survival of the patients.Conclusion:In the present study, in addition to known breast cancer risk factors, BMI and type 2 diabetes mellitus had an independent impact on survival of the patients, highlighting the importance of health issues such as obesity and diabetes suboptimal performance in the treatment outcomes of early breast cancer patients in Iran.

Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer

Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer – An AZURE (BIG 01/04) sub-study

PurposeAdjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid.Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy)±intravenous zoledronic acid, 4mg for 5 years. Serum from 865 patients taken at randomisation was stored at −80°C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. ResultsOestradiol in the postmenopausal range (<50pmol/l) was associated with a significantly shorter IDFS (HR 1.36 95%CI: 1.05–1.78 p=0.022), predominantly due to distant recurrence (HR 1.33 95%CI: 0.98–1.81 p=0.065), compared to oestradiol ≥50pmol/l. In contrast, FSH in the postmenopausal range (>26IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41–1.04 p=0.072) compared to an FSH ≤26IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54–1.22, non-postmenopausal HR=0.99; 95%CI: 0.69–1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). ConclusionOestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown.

Reproductive hormones in breast cancer bone metastasis: The role of inhibins

The spread of breast cancer cells to bone and survival in this new metastatic environment is influenced not only by the genetic signature of the cells, but also multiple host cells and soluble factors produced locally (paracrine) or from distant sites (endocrine). Disrupting this metastatic process has been evaluated in clinical trials of the bone targeted agents bisphosphonates and denosumab and have shown that these agents reduce the recurrence of breast cancer in postmenopausal women only, suggesting the efficacy of the drugs are influenced by levels of reproductive endocrine hormones. The molecular mechanism driving this differential effect has not been definitively identified, however, there is evidence that both reproductive hormones and bisphosphonates can affect similar paracrine factors and cellular components of the bone metastatic niche. This review focuses on how the ovarian endocrine hormone, inhibin, interacts with the paracrine factors activin and follistatin, abundant in the primary tumour and bone microenvironment, with subsequent effects on tumour cell survival. Inhibin also affects the cellular components of the bone microenvironment primarily the osteoblastic niche. Recent evidence has shown that bisphosphonates also alter this niche, which may represent a common mechanism by which inhibin and bisphosphonates interact to influence disease outcomes in early breast cancer. Further research is needed to fully elucidate these molecular mechanisms to enable understanding and future development of alternative bone targeted treatments with anti-tumour efficacy in premenopausal women.

Highlights of This Issue

Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biological mechanisms contributing to this health disparity are poorly understood. Knight and colleagues found that low-SES HCT recipients show up-regulation of a conserved transcriptional response to adversity (CTRA) gene expression profile at pretransplant testing. Up-regulated CTRA gene expression was also associated with increased relapse and decreased leukemia-free survival. These results suggest new strategies for mitigating social disparities in cancer treatment outcomes through targeted pharmacologic intervention in the signaling pathways that drive CTRA gene expression.Hatzis and colleagues developed a statistical model to help design the next generation of clinical trials for breast cancer that simultaneously test drug activity in the preoperative (neoadjuvant) treatment setting and the impact on patient survival. Neoadjuvant chemotherapy often completely eradicates the cancer from the breast and lymph nodes, but does not always result in improved survival. The team found higher expected survival benefit for cancers with high risk of recurrence when treated with more effective novel therapies, highlighting the importance of assessing novel treatments in patients that have high risk for recurrence despite current best therapies.Combinations of ibrutinib with anti-CD20 monoclonal antibodies (mAbs) are being evaluated in clinical trials; however, in vitro data identified potentially negative interactions between the two drugs. Skarzynski and colleagues provide conclusive evidence that ibrutinib leads to CD20 downregulation on chronic lymphocytic leukemia (CLL) cells in vivo, resulting in decreased complement-dependent cytotoxicity. Yet, concurrent CD55 (complement inhibitor) downregulation and partial inhibition of mAb-mediated shaving of CD20 from CLL cells by effector cells (trogocytosis) could enhance mAb activity. These positive and negative interactions between ibrutinib and anti-CD20 mAbs could determine the overall therapeutic efficacy of combination therapy and should be investigated further.The site of recurrence affects prognosis in metastatic breast cancer, but the events underlying organ-specificity of metastases are elusive. The authors explored the global transcriptional landscape of clinical breast cancer metastases, unraveling a liver metastasis-selective signature enriched for stromal genes that were predominantly downregulated in liver metastases. Downregulation of the signature was predictive of poor outcome in early breast cancer, with the strongest independent prognostic value within the luminal A subtype. This signature identifies patients with ER-positive breast cancer requiring closer disease monitoring who may be amenable to enrolment into clinical trials investigating novel therapeutics targeting features other than proliferation.

Fractal dimension and lacunarity of tumor microscopic images as prognostic indicators of clinical outcome in early breast cancer.

Research in the field of breast cancer outcome prognosis has been focused on molecular biomarkers, while neglecting the discovery of novel tumor histology structural clues. We thus aimed to improve breast cancer prognosis by fractal analysis of tumor histomorphology. This retrospective study included 92 breast cancer patients without systemic treatment. Fractal dimension and lacunarity of the breast tumor microscopic histology possess prognostic value comparable to the major clinicopathological prognostic parameters. Fractal analysis was performed for the first time on routinely produced archived pan-tissue stained primary breast tumor sections, indicating its potential for clinical use as a simple and cost-effective prognostic indicator of distant metastasis risk to complement the molecular approaches for cancer risk prognosis.