Anthracycline-based Adjuvant Chemotherapy Research Articles

Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis

BackgroundAdjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes.MethodsPubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (between January-1 1978 and January-29, 2013) were searched for eligible studies. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (β) corresponding to a continuous representation per 4-week delay of AC. Most used regimens of chemotherapy in included studies were CMF (cyclophosphamide, methotrexate, and fluorouracil) or anthracycline-based. Individual adjusted β were combined using a fixed-effects or random-effects model depending on heterogeneity.ResultsWe included 7 eligible studies with 9 independent analytical groups involving 34,097 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 4 hospital-/population-based retrospective study. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.15; 95% confidence interval [CI], 1.03-1.28; random-effects model) and DFS (HR = 1.16; 95% CI, 1.01-1.33; fixed-effects model). One study caused a significant between-study heterogeneity for OS (P < 0.001; I2 = 75.4%); after excluding that single study, there was no heterogeneity (P = 0.257; I2 = 23.6%) and the HR was more significant (HR = 1.17; 95% CI, 1.12-1.22; fixed-effects model). Each single study did not fundamentally influence the positive outcome and no evidence of publication bias was observed in OS.ConclusionsLonger time to AC is probably associated with worse survival in breast cancer patients.

Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials

BackgroundThe HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy.MethodsFormalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated.ResultsHER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death.ConclusionHER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202

A Three-Arm Randomized Phase II Study of Oral Vinorelbine Plus Capecitabine Versus Oral Vinorelbine and Capecitabine in Sequence Versus Docetaxel Plus Capecitabine in Patients with Metastatic Breast Cancer Previously Treated with Anthracyclines

Owing to the increased number of patients treated with anthracycline-based adjuvant chemotherapy, there is a need for new effective and tolerable nonanthracycline regimens in metastatic breast cancer. Patients with HER2-negative metastatic breast cancer previously treated with anthracyclines in (neo)adjuvant setting were randomized to fully oral 3 weekly cycles of the combination of oral vinorelbine with capecitabine (V + C), to the same drugs alternating every three cycles (V↔C), or to the combination of docetaxel and capecitabine (D + C). V was given at 80 mg/m(2) (after the first cycle at 60 mg/m(2)) on days 1 and 8 in the V + C arm and weekly in the V↔C arm, C at 1,000 mg/m(2) bid from days 1 to 14, and D on day 1 at 75 mg/m(2). The primary end point was disease control rate (CR + PR + NC ≥ 3 months). A total of 139 patients were randomly assigned to V + C (44 patients), V↔C (47 patients), and D + C (48 patients). After an independent review, the disease control rate in the intent-to-treat population in the V + C, V↔C, and D + C arms [95% CI] was 70.5% [54.8-83.2], 37.0% [23.2-52.5], and 70.8% [55.9-83.1], and the median overall survival 22.2, 19.4, and 24.2 months, respectively. When taken into account the disease control rate, the alternating V↔C regimen seems to be less effective compared with V + C or D + C combinations. Combinations of V + C or D + C showed similar efficacy and a different toxicity profile; V + C induced less neutropenia, infection, hand-foot syndrome, fatigue/asthenia, and alopecia, whereas D + C - less gastrointestinal toxicity. V + C combination constitutes a valuable fully oral alternative option to D + C in patients with metastatic breast cancer previously treated with anthracyclines in (neo)adjuvant setting, while offering the advantages of an all-oral treatment.

Comparison of the prognostic value of genomic grade index, Ki67 expression and mitotic activity index in early node-positive breast cancer patients

Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.

Dose-Dense Epirubicin and Cyclophosphamide Followed by Docetaxel as Adjuvant Chemotherapy in Node-Positive Breast Cancer

Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement particularly in node-positive patients, but optimal dose and schedule remain undetermined. Objectives. This study aimed to assess the feasibility of dose-dense epirubicin and cyclophosphamide followed by docetaxel in node-positive breast cancer. Methods. All Patients first received 4 cycles of epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) at 2-week interval then followed by docetaxel (100 mg/m2) at 2-week interval for 4 cycles, with daily Pegfilgrastim (G-CSF) that was administered in all patients on days 3–10 after each cycle of epirubicin and cyclophosphamide infusion. Results. Fifty-eight patients with axillary lymph node-positive breast cancer were enrolled in the study, of whom 42 (72.4%) completed the regimen. There were two toxicity-related deaths, one patient due to grade 4 febrile neutropenia and the other due to congestive heart failure. Grade 3/4 neutropenia and febrile neutropenia were 13.8% and 5.1%. The most common grade 3/4 nonhematological complications were as follows: skin-nail disorders (48.3%), hand-foot syndrome (34.4%), paresthesia (38%), arthralgia (27.5%), and paresis (24.1%). Conclusions. Dose-dense epirubicin and cyclophosphamide followed by docetaxel with G-CSF support are not feasible, and it is not recommended for further investigation.

Abstract P6-07-18: Identification of Sperm Associated Antigen 5 (SPAG5) as a novel biological and predictive biomarker in Breast cancer

Abstract Introduction: SPAG5 has been found to be involved in the functional and dynamic regulation of mitotic spindles, and to be essential for chromosome segregation fidelity. Recently we found by using neural network and pathways analysis of a gene expression array data that SPAG5 was among top 10 ranked genes out of 48,000 of transcripts, that accurately predicted worse clinical outcome based on a 10-fold external cross-validation analysis with an average classification accuracy of &amp;gt;99.999%. Moreover we found that 5% of BC showed amplification of SPAG5 locus at chromosome 17q11.2 and SPAG5 mRNA expression levels displayed a statistically significant correlation with its copy number. Methods: In the current study the molecular and clinicopathological features of SPAG5 expression and its effect on management of BC have been investigated in 2800 BC patients with primary operable invasive BCs constituted four cohorts: 1) A series of 1650 BC patients received adjuvant endocrine and/or CMF chemotherapy according to NPI.2) A series of 256 BC received adjuvant anthracycline-based chemotherapy (ATC-CT)3) A series of 140 primary BC HER2+ patients treated with ATC-CT+ Herceptin 4) To validate SPAG5 as a predictor factor for ATC-CT, 260 patients with locally advanced primary breast cancer treated with neoadjuvant ATC-CT were included and the pathological complete response (pCR) was used to evaluate the response to chemotherapy. Immunohistochemical staining was performed using Anti–SPAG5 rabbit polyclonal (HPA022479; Sigma). Results: i) By using dual immunoflurescent in BC cell lines, co-expression of SPAG5 and proliferating cell nuclear antigen (PCNA) was detected in 4 out of 5 of the breast cancer cell lines screened (MCF7, T47D, MDA468 and MDA231) providing evidence for the importance of SPAG5 in cell proliferation. ii) 20% of breast cancer showed SPAG5 protein overexpression. SPAG5 overexpression showed a statistically significant association with ER−, PR−, triple negative phenotype, high grade tumour, high ki67, basal like phenotype and epithelial mesenchymal transition phenotype, p53 mutation and absence of DNA repair genes (BRCA1, ATM and XRCC1); p values &amp;lt;0.0001. iii) In high risk ER− BC patients who did not received any adjuvant therapy or received ineffective CMF chemotherapy, SPAG5+ protein expression had a similar risk of death and recurrence. Receiving ATC-CT had a positive impact on high risk ER− BC patients with SPAG5 protein + expression as SPAG5+ protein expression showed 72–65% less of death, recurrence and metastases compared to SPAG5−; p &amp;lt; 0.0001. The positive impact of ATC-CT on SPAG5+BC has also been confirmed in HER2+ who either received ATC-CT only or ACT-CT plus Herceptin. iv) Moreover, BC received neoadjuvantATC-CT, SPAG5+ BC achieved 39% pCR vs., 6% of SPAG5-negative BC (p &amp;lt; 0.00001). After controlling to other validated predictors for pCR, SPAG5 remained as a powerful independent predictor (HR; 2.4, CI 95%; 1.5–3.9; p = 0.00001). Conclusion: SPAG5 is an important novel gene implicated in the survival of BC cells and its protein expression is an independent predictor for ATC- CT. SPAG5 may provide new avenues for the discovery of new predictive marker to guide therapeutic intervention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-18.

Abstract P6-07-09: Identification of Trophinin associated protein (TROAP) as a novel biological marker in breast cancer (BC): Co-expression of TROAP and TOPO2A predicts response of anthracycline based chemotherapy (ATC-CT)

Abstract Introduction: Recently, TOPO2A alteration was found to be a predictor for ATC-CT and by using neural network and pathways analysis of gene expression array data, TROAP gene was revealed as a major hub in TOPO2A pathway and strongly related to genes that are involved in mitotic cell cycle regulation. In addition, we found that TROAP gene was among top 10 ranked genes out of 48,000 of transcripts, that accurately predicted worse clinical outcome, and differentiated between low and high grade based on a 10-fold external cross-validation analysis with an average classification accuracy of &amp;gt;99.999%. TROAP protein is essential for centrosome integrity and proper bipolar organisation of spindle assembly during mitosis and plays essential role in cell proliferation. In the current study the molecular and clinicopathological functions of TROAP expression and its effect on management of breast cancer have been investigated. Methods: The co-expression of TROAP and TOPO2A protein was evaluated by using dual immunoflurescent in BC cell lines. In addition both TROAP and TOP2A protein expressions were immunohistochemically (IHC) assessed in 40 normal breast tissues and a well characterised series of 1650 primary BC and were correlated to clinicopathological and other biomarkers. IHC staining was performed using Anti-TROAP rabbit polyclonal (HPA044102; Sigma). The association between TROAP and response to chemotherapy was investigated in 350 ER negative BC treated with adjuvant ATC-CT and 260 locally advanced BC treated with neoadjuvant ATC-CT. In addition the clinical outcome of TROAP expression was evaluated in a series of 180 ER− high risk BC patients who did not received any CT. Results: No expression of TROAP protein was observed in normal breast tissue while, 25% of BC showed TROAP protein overexpression. By using dual immunoflurescent in BC cell lines, The MCF7 cells showed strong cytoplasmic TROAP staining with no TOPO2A expression, while The T47D cells did not express TROAP but expressed TOPO2A. SKBr3, MDA468 and MDA231 cell lines showed co-expression of TROAP and TOPO2A. TROAP overexpression was significantly associated with aggressive clinico-pathological features including; high grade, high mitotic rate, absence of hormonal receptors, overexpression of HER2, TOP2A and EGFR (p &amp;lt; 0.001), Triple negative phenotype (p &amp;lt; 0.001), basal-like BC (p &amp;lt; 0.001), p53 mutation (p &amp;lt; 0.001) and inactive p16 (p &amp;lt; 0.001). With regard to outcome, receiving anthracycline chemotherapy had a positive impact on high risk ER− BC patients with TROAP protein over-expression as TROAP protein overexpression showed 50% less risk of recurrence compared to TROAP negative expression; p &amp;lt; 0.0001. Moreover, in locally advanced BC who received anthracycline-based neoadjuvant chemotherapy, 31/81 (39%) of BC with co-expression of TROAP+/TOPO2A+ achieved pCR while none of those with absence of both TROAP−/TOPO2A− (0/51) had achieved pCR (p &amp;lt; 0.00001). Conclusion: TROAP is an important novel gene implicated in the survival of BC cells and its protein expression is a predictor for Anthracycline CT. TROAP may provide new avenues for the discovery of new predictive marker to guide therapeutic intervention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-09.

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial

Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.

Differential Response of Immunohistochemically Defined Breast Cancer Subtypes to Anthracycline-Based Adjuvant Chemotherapy with or without Paclitaxel

BackgroundThe aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC).Materials and MethodsFormalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low); luminal B (ER/PgR-positive, HER2-negative, Ki67high); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive).ResultsAfter a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31–2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62–3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors.ConclusionsTriple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.

BCL2 protein in prediction of relapse in triple-negative breast cancer (TNBC) treated with adjuvant anthracycline-based chemotherapy.

1087 Background: Preclinical data show an association of BCL2 expression and resistance to anthracyclines. The absence of BCL2 expression in prechemotherapy samples is associated with a higher probability of pathological complete response to neoadjuvant doxorubicin-based chemotherapy. The aim of our research is identification of markers predicting sensitivity to adjuvant treatment in TNBC. Here we focus on BCL2 protein as a putative predictor of sensitivity to adjuvant anthracycline-based chemotherapy. The objective was to determine whether BCL2 expression predicts relapse in TNBC patients treated with anthracycline-based regimens. Methods: The study included 187 patients with TNBC, 178 of whom were treated with adjuvant chemotherapy (164 had anthracyclines). BCL2 analysis was performed using IHC, proportion score and intensity score were counted. The data were analysed with software Statistica and R. Results: High BCL2 expression predicts poor relapse free survival (RFS) in patients treated with adjuvant anthracycline-based regimens (logrank p=.035, hazard ratio, HR 2.37, 95%CI 1.04-5.41). High BCL2 predicts trend to poor overall survival (OS) in patients treated with adjuvant anthracycline-based regimens (logrank p=0.075, HR 2.31, 95%CI 0.90-5.97). In univariate analysis of anthracycline treated patients, stage (RFS p=.0004, OS p=.0005), size (RFS p=.003, OS p=.00009) and nodal status (RFS p=0.018, OS p=.028) were associated with outcome, as well. In multivariate analysis of athracycline treated patients, BCL2, size and nodal status had an independent predictive significance for both RFS (p=.005, p=.056, p=.003) (logrank test, p=0.0004) and OS (p=.014, p=.006, p=.012) (logrank test p=0.0007). Conclusions: This study is the first to prove that high BCL2 expression predicts poor outcome in TNBC treated with adjuvant anthracycline-based chemotherapy. BCL2 expression could facilitate decision making on adjuvant treatment in TNBC patients and its assessment should be included in standard diagnostics. In patients with high BCL2 expression other types of adjuvant treatment should be considered. Grants: IGA NS10286,IGA NS10357-3 and Biomedreg CZ.1.05/2.1.00/01.0030.

Trastuzumab-induced cardiotoxicity in early breast cancer: Evaluation of possible risk and protective factors.

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF &lt;50%. The term heart failure (HF) referred to the New York Heart Association classification III or IV. Logistic regression was used to assess relative risks. Results: A total of 179 HER2-positive EBC pts (median 54 years, range 30-84) were evaluated. 154 (86%) were treated with anthracycline-based adjuvant chemotherapy. 78 (44%) did not show any risk factors, whereas 101 (56%) had at least one: hypertension (24%), smoking habit (16%), dysthyroidism (18%), obesity (12%), hypercholesterolemia (9%) and diabetes mellitus (4%). Among the 179 EBC pts, 78 (44%, 95% confidence intervals (CI) 37-51%) experienced TIC during their 12-month trastuzumab treatment and only 4 (2%, 95% CI 0-4%) developed HF. 14 pts stopped trastuzumab due to TIC. None of the risk factors described above was correlated with TIC development. A previous anthracycline cumulative dose &gt; 240 mg/m2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.

Impact of the delivery of adjuvant anthracycline-based nontaxane chemotherapy schedules on the outcome of breast cancer patients: Results from a retrospective database analysis.

1074 Background: A dose-response effect has previously been observed with CMF and anthracycline-based schedules. The objective of this post-hoc analysis was to give additional information on the impact of chemotherapy delivery on patients’ outcome. Methods: Selection criteria were to have early breast cancer (stage I-IIIA) from Jan 1980 to Dec 2000, to undergo surgery as primary treatment and to receive an anthracycline-based non-taxane schedule in the adjuvant setting. G-CSF support was not given to any patient. Chemotherapy delivery was assessed based on ≥ 2 vs. &lt; 2 delayed cycles, ≥ 15 vs. &lt;15 delayed days and &lt; 85% vs. ≥ 85% of the relative dose intensity (RDI) given. Patients’ outcomes were assessed based on 5- and 10-year disease-free survival (DFS) and overall survival (OS) rates. Results: 793 breast cancer patients with a median age of 51 years (21-79) were analyzed of whom 27% had stage IIIA and 23% had stage I disease. As shown in the table, 5- and 10-year rates of DFS and OS significantly improved when adjuvant chemotherapy was optimally delivered. Conclusions: The dose-response effect is a key factor that should be taken into account when an anthracycline-based non-taxane chemotherapy is administered in the adjuvant setting. Delays and/or reductions of chemotherapy should be avoided in order to achieve the maximal benefit for the patient. This study was partially funded by Amgen SA. [Table: see text]

Validation of NAD(P)H quinone oxidoreductase (NQO1) expression as a predictive factor for adjuvant chemotherapy benefit in patients with early breast cancer.

1091 Background: NAD(P)H:quinone oxidoreductase-1 (NQO1) has important antioxidant functions by stabilizing p53 from proteasomal degradation. NQO1 knockdown is associated with higher susceptibility to oxidative stress. Polymorphisms suppressing NQO1 are predictors of poor survival in patients with breast cancer (BC) treated with anthracyclines. BC cell lines with impaired NQO1 function showed resistance to epirubicin chemotherapy (CT) independently of p53 status suggesting NQO1 as predictive factor for anthracycline benefit. In this study we hypothesized that lack of NQO1 could predict resistance to anthracycline-containing CT in patients with early breast cancer (EBC). Methods: Patients were identified from two French multicentric trials that randomized patients with EBC to adjuvant anthracycline-based CT vs no CT between 1988 and 1995. NQO1 was determined in TMAs by automated quantitative assessment of immunofluorescence (On-Q-ity Inc, Waltham). Cut-off for positivity was the median value of NQO1 expression. Univariate and multivariate Cox regression models were performed. Treatment effect was assessed on long term overall survival (OS). Results: NQO1 expression was assessed in 600 patients. 75% were postmenopausal, had more often grade II (62%), LN-negative (58%) and ER-positive (67%) BC. Higher NQO1 expression was observed in postmenopausal (P=0.02) patients. No relation with other clinicopathological factors (grade, LN or ER) was observed. Effect of adjuvant CT on death rates was dependant on NQO1 level. Hazard ratio (HR) for treatment efficacy at the four quartiles of NQO1 were 1.07 (95%CI: 0.69-1.7), 0.87 (0.64-1.19), 0.66 (0.45-0.97), 0.46 (0.22-0.95) (interaction test: 0.1). Interaction test was statistically significant (0.02) when NQO1 expression was considered as binary variable with median value taken as cut-off. NQO1 remained predictive among ER+ patients only. HR for OS was 0.61 (0.36-1.02) and 1.25 (0.79-1.99) in patients with high and low NQO1 respectively. Conclusions: This study adds to the existing data suggesting NQO1 expression as an independent predictor of efficacy for adjuvant anthracycline-containing CT.

Chemotherapy-Induced Nausea and Vomiting in Asian Women With Breast Cancer Receiving Anthracycline-Based Adjuvant Chemotherapy

Chemotherapy-induced nausea and vomiting (CINV) remain among the most frequently reported distressing side effects associated with anthracycline-based chemotherapy despite significant advances in antiemetic management. The main risk factor for severity of CINV is the emetogenic potential of the chemotherapeutic agents. However, patient-related risk factors have been identified, including genetic makeup. Although studies have noted that ethnicity influences nausea and vomiting in other contexts, there is a paucity of research regarding the impact of ethnicity on CINV. This study was undertaken to evaluate whether Asian women receiving anthracycline-based chemotherapy experience more CINV than non-Asians. A retrospective, comparative, correlational chart review was performed to abstract the relevant variables. Data from a convenience sample of 358 women with breast cancer who received chemotherapy with doxorubicin between 2004 and 2008 at City of Hope in Duarte, California, were evaluated. The sample consisted of Caucasians (45%), Hispanics (27.7%), Asians (19.8%), and African Americans (7.5%). The results indicate that Asian women with breast cancer undergoing anthracycline-based chemotherapy experienced statistically significantly more clinically important CINV than their non-Asian counterparts. The data were collected retrospectively, with a certain population distribution at a specific time. This study provides interesting preliminary evidence that Asian ethnicity plays a role in the development of severe CINV. When managing chemotherapy toxicities in women with breast cancer, health-care providers should tailor therapy to individual risk profiles. Specifically, consideration of antiemetic therapy should accommodate patient characteristics, such as Asian descent.

Prediction of Anthracycline Cardiotoxicity after Chemotherapy by Biomarkers Kinetic Analysis

Anthracyclines are active drugs against breast cancer, but can exert cardiotoxic effects. We analyzed the association between the kinetics of various biomarkers during chemotherapy, and the risk of subsequent cardiac toxicity. 50 patients (49 women) with early breast cancer surgically treated and eligible to anthracycline-based adjuvant chemotherapy were analyzed. The left ventricular ejection fraction (LVEF) together with the plasma concentration of several blood markers was measured at the beginning of anthracycline chemotherapy (t (0)), 5months (t (1)), 16months (t (2)), 28months (t (3)), and 40months later (t (4)). A single measured LVEF value less than 50% or a clinically overt congestive heart failure (CHF) was considered cardiotoxic effects. We tested whether the kinetics of LVEF and blood biomarkers measured during chemotherapy was predictive of subsequent cardiotoxicity and overall cardiac fitness. The left ventricular ejection fraction measured at the end of treatment as well as the rate of change of hemoglobin concentration during anthracycline-based chemotherapy predicted cardiotoxicity in a 3-year follow-up period. When LVEF at the end of chemotherapy was lower than 53% or hemoglobin blood concentration declined more than 0.33g/dL/month during chemotherapy, the odds ratio of subsequent cardiotoxicity was 37.3 and 18, respectively. The specificity of these two tests was 93.3% and 80%, whereas the sensitivity was 90.9 and 81.2%, respectively. Testing the rate of change of hemoglobin concentration during anthracycline-based chemotherapy, as well as the left ventricular ejection fraction at the end of treatment, seems a powerful method to assess the effects of anthracyclines on cardiac fitness and identify patients at high risk of CHF. Further validation of these tests on a large cohort of patients and cost-benefit analysis should be encouraged.

P5-01-11: Small Node-Negative (T1b-cN0) Invasive Hormone Receptor (HR)-Positive Breast Cancers: Is There a Population Which Might Have Benefit from Adjuvant Chemotherapy?

Abstract Background It has been widely accepted that small and node-negative breast cancers have an excellent prognosis and do not generally have clinical benefit from adjuvant chemotherapy. Recently, the role of adjuvant chemotherapy for small node negative breast cancers has been justified in some high-risk patients, which include HER2−positive and triple negative breast cancers. However, the question has been raised as to whether there are some patients who might have benefit from adjuvant chemotherapy in small node-negative HR-positive breast cancers. According to the current 2011 NCCN guideline, 21-gene RT-PCR assay can be considered for tumor size of more than 0.5 cm in HR-positive, HER2−negative cancers. In cases of high recurrence score (≥ 31), adjuvant chemotherapy in addition to endocrine therapy is recommended as category 2B. Because gene array cannot routinely be used in clinical practice and has not been validated in prospective randomized trials and the usefulness of it still needs to be defined, it would be better if there were valuable markers to determine risk for relapse in this setting. We hypothesized that there could be a population who might have clinical benefit from adjuvant chemotherapy in this small node-negative HR-positive tumors. Patients and Methods We retrospectively analyzed the clinicopathologic characteristics and outcomes of 538 postoperative HR-positive (ER-positive and/or PgR-positive) T1b-cN0 breast cancer patients between 2004 and 2007 at the Samsung Medical Center. We performed Cox regression multivariate analysis for relapse using variables from univariate analysis by log-rank test for relapse. Results: The median age at diagnosis was 46 years (range, 22–79). During the median 60.5 months of follow-up, the 5-year recurrence rate was 5.2%. Anthracycline-based adjuvant chemotherapy was administered to 44.8% of the patients. Adjuvant endocrine and radiation treatment were administered to 94.6% and 63.7% of the patients. There were significant differences according to histologic grade (HG), Ki67 index, and age of less than 35 years in univariate analyses regarding RFS (p=0.003, p&amp;lt;0.0001, and p=0.003, respectively by log-rank test). There was no significant difference according to tumor size of subcentimeter (&amp;lt; 1cm) (p=0.826). In Cox regression multivariate analysis, high Ki67 index and young age of less than 35 years were identified as independent risk factors for relapse (p&amp;lt;0.0001 for Ki67 index and 0.015 for young age). The high risk patients (n=24, 4.5%) who have high Ki67 index (more than 75%, 4+) or young age of less than 35 and more than 50% of Ki67 index showed better RFS with statistical significance for anthracycline-containing adjuvant chemotherapy (p=0.029). Conclusion: A patients’ population may exist who have clinical benefit from adjuvant chemotherapy in T1b-cN0 HR-positive breast cancer patients. Ki67 index and age are useful as valuable surrogate markers to predict recurrence and to have benefit from adjuvant chemotherapy in this population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-11.

P5-19-01: Final Results of a Three-Arm Randomised Phase II Study of Oral Vinorelbine Plus Capecitabine Versus Oral Vinorelbine and Capecitabine in Sequence Versus Docetaxel Plus Capecitabine in Patients with Metastatic Breast Cancer Previously Treated with Anthracyclines.

Abstract Purpose: Owing to the increasing number of patients treated with anthracycline-based adjuvant chemotherapy, there is a need for new effective and tolerable non-anthracycline based regimens in metastatic breast cancer. Patients and methods: Patients with HER2−negative metastatic breast cancer previously treated with anthracyclines in (neo) adjuvant setting were randomised to fully oral 3-weekly cycles of the combination of oral vinorelbine with capecitabine (V+C), to the same drugs alternating every 3 cycles (V ⇔ C), or to the combination of docetaxel and capecitabine (D+C). V was given at 80 mg/m2 (after the first cycle at 60 mg/m2) on days 1 and 8 in the V+C arm and weekly in the V ⇔ C arm, C at 1,000 mg/m2 bid from days 1 to 14, and D on day 1 at 75 mg/m2. The primary endpoint was disease control rate (CR+PR+NC ≥ 3 months). Results: A total of 139 patients were randomly assigned to V+C (44 patients), V ⇔ C (47 patients) and D+C (48 patients). After an independent review, the disease control rate in the intent-to-treat population in the V+C, V ⇔ and D+C arms [95% CI] was 70.5% [54.8−83.2], 37.0% [23.2−52.5] and 70.8% [55.9−83.1]. The response rate was 31.8% [18.6−47.6], 8.7% [2.4−20.8] and 35.4% [22.2−50.5], respectively. The median duration of progression-free survival in the V+C, V ⇔ C and D+C arms [95% CI] was 7.2 months [5.3−8.9], 3.4 months [2.6−5.6] and 8.9 months [7.2−12.0]; the median overall survival [95% CI] was 22.2 [18.8; 29.9], 19.4 [12.5; 35.4] and 24.2 [14.2; 38.5] months, respectively. Lower efficacy observed in the sequential arm could be due to higher prevalence of patients with visceral disease in this arm (91.3% in comparison to 65.9% in V+C and 64.6% in D+C arm). Combinations of V+C or D+C showed similar efficacy and a different toxicity profile; V+C induced less neutropenia, infection, hand-foot syndrome, fatigue/asthenia and alopecia, whereas D+C- less gastrointestinal toxicity. Conclusions: V+C combination constitutes a valuable fully oral alternative option to D+C in patients with metastatic breast cancer previously treated with anthracyclines in (neo)adjuvant setting, while offering the advantages of an all-oral treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-01.

PD03-08: BRCA1-Like Triple Negative Tumors: Clinicopathological Variables and Chemosensitivity to Alkylating Agents.

Abstract Background Our group has previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of BRCA1-mutated breast cancers. It is reasonable to assume that this pattern indicates ‘BRCAness’ and thus serves as a marker for homologous recombination deficiency. This BRCA1-like aCGH profile is also present in about half of all triple negative sporadic breast cancers and has been shown to be predictive for benefit from intensive chemotherapy with DNA crosslinking agents. To study BRCA1-like tumors and conventional dose chemotherapy sensitivity in more detail, we compared clinical factors and survival rates in a uniform cohort of triple negative breast tumors treated with alkylating agents. Patients and methods 103 patients with triple negative tumors received conventional dose adjuvant chemotherapy with doxorubicin/cyclophosphamide. DNA was extracted from tumor samples and BRCA1-like profiles were assessed. Tumors were classified as BRCA1 -like or non-BRCA1-like. Standard clinical and histopathological factors were determined and compared between both groups. Relapse free survival (RFS), disease specific survival (DSS) and overall survival (OS) after diagnosis were compared between BRCA1-like and non-BRCA1-like tumors. Results 66 tumors (65%) had a BRCA1-like profile, while 35 tumors (35%) did not show such a profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease compared to the patients with non-BRCA1-like tumors (p=0.058 and p=0.034, respectively). There was no significant difference in survival between BRCA1-like and non BRCA1-like patients after treatment with alkylating agents: the median RFS was 121 vs. 109 months, median DSS was 129 vs. 114 months and OS was 127 vs. 110 months, for BRCA1-like versus non-BRCA1-like tumors. T-stage was the only variable significantly associated with survival. Conclusion BRCA1-like tumors occurred in younger patients and were more often node negative, which are features shared with tumors in BRCA1-mutation carriers. We did not observe a difference in survival between BRCA1-like and non-BRCA1-like triple negative breast cancers after treatment with conventional dose chemotherapy with alkylating agents. These results confirm our previous findings that BRCA1-like tumors have similar sensitivity to anthracycline-based adjuvant chemotherapy as other triple-negative tumors. It will be important to establish whether BRCA1-like tumors also share the exquisite sensitivity of BRCA-mutated tumors to PARP-inhibitors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-08.

P5-13-13: The Role of Topoisomerase IIa in Predicting Sensitivity to Anthracyclines in Breast Cancer Patients: A Meta-Analysis of Published Literatures.

Abstract Topoisomerase IIα is not only a proliferation marker of tumor cells but also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there was a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα is still controversial in breast cancer patients. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy (RR = 1.93, 95%CI: 1.27−2.94, P=0.002; RR =1.98, 95%CI: 1.37−2.86, P&amp;lt;0.001). In early breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification(HR = 0.64, 95%CI: 0.49−0.83, P=0.001; HR = 0.59, 95% CI: 0.35−1.01, P=0.056) or deletion (HR = 0.82, 95%CI: 0.67−1.00, P=0.051; HR =0.58, 95%CI: 0.35−0.97, P=0.036) of topo IIα was significantly associated with better RFS and OS. The subgroup analysis in the early breast cancer patients indicated that taxane could be an interference for evaluation of the predictive role of topo IIα. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who received anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-13.

Evaluation of Peripheral Blood Smear for Myelodysplasia in Breast Cancer Patients who Received Adjuvant Antracycline.

Therapy-related myeloid neoplasms (t-MN) account for approximately 10% to 20% of all cases of AML (acute myeloid leukemia), MDS (myelodysplastic syndrome) and MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasms), MDS, and MDS/MPN. In our study, we evaluated peripheral blood smear samples and hemogram values in breast cancer patients who were receiving adjuvant anthracycline regimens and were in remission. A total of 78 patients receiving anthracycline-based adjuvant chemotherapy treatment from Kayseri Research and Training Hospital and Mersin State Hospital were enrolled in the study. Their adjuvant treatments had been completed at least 18 months prior to the study. Two patients complained of anemia (2.2%) (Hb<11 mg/dl), leukopenia was observed in seven patients (7.7%) (leukocytes<4000/ mm(3)), and thrombocytopenia was observed in four patients (4.4%) (PLT<150.000/mm(3)). In the blood smear samples, the following were observed: ovalomacrocytes (14%), macrocytes (37%), acanthocytes (1%), stomatocytes (12%), teardrops (12%), nucleated erythrocytes (1%), basophilic stippling (14%), and Howell-Jolly bodies (1%). Additionally, hypo-granulation (38%), Pelger-Huet abnormalities (26%), hypersegmentation (20%), immature granulocytes (8%), and blasts (6%) were observed. We also confirmed the presence of giant platelets (50%) and platelet hypogranulation (19%). According to the peripheral blood smear assessments in our study, we suggest that breast cancer patients should be evaluated for MDS in the early stages, starting from month 18, even if the automated blood counts are normal.