Cyclophosphamide, Methotrexate And 5-fluorouracil Research Articles

Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

IntroductionPredictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A copy number can be used to predict benefit from epirubicin (E) containing chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil (CMF) treatment.MethodsFor the purpose of this study, formalin fixed paraffin embedded tumor tissue from women recruited into the BR9601 clinical trial, which randomized patients to E-CMF versus CMF, were analyzed for TIMP-1 immunoreactivity. Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1 immunoreactive and HER2 negative) and anthracycline responsive (all other cases).ResultsIn total, 288 tumors were available for TIMP-1 analysis with (183/274) 66.8%, and (181/274) 66.0% being classed as 2T and HT responsive, respectively. TIMP-1 was neither associated with patient prognosis (relapse free survival or overall survival) nor with a differential effect of E-CMF and CMF. Also, TIMP-1 did not add to the predictive value of HER2, TOP2A gene aberrations, or to Ki67 immunoreactivity.ConclusionThis study could not confirm the predictive value of TIMP-1 immunoreactivity in patients randomized to receive E-CMF versus CMF as adjuvant treatment for primary breast cancer.

Concurrent chemo-radiotherapy in the treatment of early breast cancer: Current status

Concurrent chemo-radiotherapy (CCRT) in early cancer was investigated by few authors and remains controversial. This treatment is more commonly used for locally advanced cancer and showed high rate of complete pathological response. A search of articles published in English literature, between 1980 and November 2012, was conducted on Medline using the following terms: breast cancer, chemotherapy, radiotherapy, and Trastuzumab. We identified five phase I/II trials and three randomized phase three trials evaluating concurrent chemoradiotherapy in the adjuvant of cancer. In patients with early cancer having positive lymph nodes, phases III clinical trials showed that CCRT improved local control after conservative surgery. However, these randomized trials used non-standard regimen: Cyclophosphamide, methotrexate and fluorouracil (CMF) or fluorouracil, mitoxantrone and cyclophosphamide (FNC). In addition, in phases II clinical trials, concurrent use of taxanes and anthracycline with standard whole-breast irradiation showed high rate of toxicity: Pulmonary toxicity with taxane; and cardiac and skin toxicity with anthracycline. Consequentely, CCRT is not be used in practice because of concerns of toxicity with the standard drugs (anthracyclines and taxanes) and radiation. Anthracyclines with partial irradiation (PBI) was feasible according to one phase I clinical trial, and should be investigated in randomized clinical trials. Concurrent Trastuzumab plus radiotherapy is safe and can be used in HER2-positive cancer; in this case, cardiac volume sparing and patient selections for internal mammary chain irradiation are highly recommended. The present paper aimed to review the current data evaluating the efficacy and safety of CCRT in early cancer.

Abstract P1-13-10: Efficacy, toxicity and quality of life in older patients with early-stage breast cancer treated with oral Tegafur-uracil or classical CMF (cyclophosphamide, methotrexate, and fluorouracil): an exploratory analysis of National Surgical Adjuvant Study for Breast Cancer (N-SAS BC) 01 Trial

Abstract Background: It is critically important to consider the issue of treatment for older breast cancer patients in developed countries where aging has been rapidly advanced such as in Japan. According to Oxford Overview analysis of 15-year results, benefit of adjuvant chemotherapy in older than 70 years remains uncertain. Recently CALGB 49907 trial clearly showed standard chemotherapy of either cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin plus cyclophosphamide (AC) is superior to capecitabine in patients with early-stage breast cancer who are 65 years or older. In contrast, we demonstrated equivalent efficacy between six cycles of classical CMF and 2 years of oral Tegafur-uracil (UFT) in phaseIII randomized controlled trial: N-SAS BC01 (Watanabe T et al, JCO 2009). Of interest, UFT showed a trend toward better suppression of recurrence in patients over 50 years of age in this trial. In current exploratory analysis, we sought to examine whether UFT is not inferior to CMF in terms of efficacy, toxicity and quality of life (QOL) in older patients with early-stage breast cancer. Patients and Methods: N-SAS BC 01 trial was a randomly assigned trial comparing adjuvant oral UFT with classical CMF in patients with node negative, high risk breast cancer. In this exploratory analysis, patients of 65 years or older enrolled in N-SAS BC 01 trial were analyzed in terms of efficacy, toxicity and quality of life. Results: Of the 707 patients enrolled in N-SAS BC 01 trial, 97 patients (13.7%) were 65 years or older. Median age was 68 years (range, 65 to 75 years). The 5-year relapse-free survival (RFS) rate was 92.5% in the CMF arm and 93.0% in the UFT arm. Overall survival (OS) rate at 5 years were 98.1% and 97.7%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 1.07 for RFS (95% CI, 0.31 to 3.55) and for OS (95% CI, 0.15 to 10.25). However 95 % CIs were very wide due to the small sample size. Among patients who received CMF, frequency of grade 3/4 leukopenia (3.8%) and neutropenia (13.5%) were higher than 0% and 4.8% with UFT, respectively. Similarly, grade 3/4 increased liver enzyme and nausea/vomiting were more frequent with CMF than with UFT. In contrast, elevation of total bilirubin and diarrhea were more observed in UFT arm. Compared with patients received CMF, patients with UFT had better QOL scores assessed by EORTC QLQ-C30/BR23 and the FACT-B questionnaire. The rate of adherence was 79.2% (42/53) at 6 months in the CMF arm and 74.4% (32/43) at 2 years in the UFT arm. Conclusion: The result of this study indicated that UFT might not be inferior to CMF in patient with early stage breast cancer who are 65 years of age or older in terms of efficacy, toxicity and QOL. UFT would be a promising option for adjuvant chemotherapy in older women with node-negative, high-risk breast cancer. Further larger randomized clinical trial in this patient population would be warranted to validate these results. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-10.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials

Background:The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses.Methods:National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles.Results:In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65–0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65–0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours.Conclusion:Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

Adjuvant treatments for triple-negative breast cancers

Conventional chemotherapy is the mainstay of adjuvant systemic treatment for most patients with early triple-negative breast cancer (TNBC). At present, comparisons between adjuvant chemotherapy regimens are retrospective in nature, and so the optimal drugs or drug combinations have not been established for patients with early TNBC. In retrospective subgroup analyses, taxanes are more effective than 5-fluorouracil in combination with cyclophosphamide and doxorubicin. Classical CMF (cyclophosphamide, methotrexate and 5-fluorouracil) has shown efficacy, whereas few data on the role of anthracyclines are available. An unplanned subgroup analysis of one randomised study suggests that capecitabine adds efficacy to a taxane-anthracycline regimen, but this observation requires confirmation. High-dose adjuvant chemotherapy is considered experimental. Ongoing trials are comparing standard adjuvant regimens with regimens that integrate an anti-angiogenic agent, a platin or maintenance capecitabine. Inhibitors of DNA repair or specific tyrosine kinases have not yet been addressed in the adjuvant setting. In the absence of data from prospective trials that focus on adjuvant therapy of early TNBC, several regimens, such as a taxane and an anthracycline-containing regimen or classical CMF may be considered reasonable choices.

Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study

The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. High UBE2C mRNA expression was associated with poor DFS (Wald's P = 0.003) and OS (Wald's P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.

Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

Chromosome 17 centromere (CEP17) duplication as a predictor of anthracycline response: evidence from the NCIC Clinical Trials Group (NCIC CTG) MA.5 Trial

HER2 gene amplification and topoisomerase IIα gene (TOP2A) alteration have been associated with increased benefit from anthracycline compared to non-anthracycline containing adjuvant breast cancer chemotherapy in some but not other studies. Chromosome 17 centromere (CEP17) duplication was measured on TMAs from formalin-fixed paraffin-embedded specimens obtained from 639 of 716 premenopausal women with node positive breast cancer who received cyclophosphamide, epirubicin and fluorouracil (CEF) or cyclophosphamide, methotrexate and fluorouracil (CMF) in the randomized controlled mammary 5 (MA.5) adjuvant trial. The prognostic impact of CEP17 duplication and its interactions with treatment were studied for relapse-free survival (RFS) and overall survival (OS). Overall, CEP17 duplication was not significantly associated with RFS or OS in multivariate analysis. For patients whose tumours had normal CEP17 copy number there were no apparent benefits for CEF compared to CMF for RFS (HR 0.98; 95% CI 0.68-1.42) or OS (HR 1.10; 95% CI 0.72-1.69). For patients whose tumours had CEP17 duplication, there was significant benefit for CEF compared to CMF for RFS (HR 0.54; CI 0.33-0.89) and a trend towards significance for OS (HR 0.64; CI 0.37-1.09). The adjusted Pvalues for interaction between treatment and CEP17 duplication were 0.09 for RFS and 0.13 for OS. This study suggests that CEP17 duplication has a borderline association with clinical responsiveness to anthracycline containing chemotherapy similar to previous results seen with HER2 amplification and TOP2A alteration in MA.5. An appropriately powered meta-analysis is required to discriminate the predictive value of these three candidate markers.

Achieving Optimal Dose Intensity with Adjuvant Chemotherapy in Elderly Breast Cancer Patients: A 10-Year Retrospective Study in a UK Institution

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group.

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer

BackgroundThe International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. Patients and methodsFrom 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF→ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. ResultsFor the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF→ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). ConclusionsFor pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea.

Effect of neutropenia with adjuvant epirubicin-CMF on survival in patients with node-negative or 1 to 3 node-positive rapidly proliferating breast cancer.

e11566 Background: Patients who experience at least some degree of neutropenia whilst receiving adjuvant chemotherapy for breast cancer show improved survival. Tumor proliferation is a prognostic marker in breast cancer. We therefore hypothesized that patients with rapidly proliferating breast cancer and evidence of neutropenia whilst on adjuvant chemotherapy would have a better survival than that of similar patients in whom there was no evidence of myelotoxicity. Methods: We reviewed the case notes of 173 women treated in Wide Area of Romagna cancer centers with epirubicin followed by the intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) regimen or the inverse sequence for rapidly proliferating breast cancer, defined by thymidine labeling index (TLI) >3%, to identify patient- and treatment-related factors influencing outcome. Results: The actuarial 5-year overall survival for these women was 94%, with the anticipated poorer outcome for those with higher TLI (≥10% vs <10%, P=0.032). There was no evidence that ER-negative tumors, HER-2 positive disease or older age at presentation resulted in poorer survival. Of note, the absolute survival advantage was confined to the 47% of patients who had grade 3/4 neutropenia (P<0.001) with respect to those with grade 0-2 neutropenia (P=0.268). Conclusions: Our results suggest that neutropenia has a greater influence on outcome than age and tumor biological factors in patients with rapidly proliferating breast cancer.

Concomitant adjuvant chemo-radiation therapy with anthracyclinebased regimens in breast cancer: a single centre experience

This study was done to evaluate the toxicity related to concurrent radiotherapy and anthracycline (AC)-based chemotherapy in the adjuvant treatment of early breast cancer and to investigate the impact of treatment interruptions and the feasibility of this uncommon therapeutic approach. From September 2002 to December 2007, 60 patients were treated at our Centre. The mean age at presentation was 48.5 (range 38-64) years. All patients underwent conservative surgery, and radiotherapy to the entire breast (mean dose 50 Gy; range 46-52 Gy). AC-based regimens consisted of four cycles of AC (doxorubicin plus cyclophosphamide) or four cycles of epirubicin (EPI) followed by four courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Concomitant treatment caused acute skin G3 toxicity in 8.9% of patients and one case of G4 toxicity (1.7%). Concerning cardiac assessment, six of the 56 evaluable patients (10.7%) developed an asymptomatic decline of left ventricular ejection fraction >10% and <20% of the baseline value. Radiotherapy was temporarily stopped in 21.3% and chemotherapy in 57.1% of patients. In our experience, concomitant chemotherapy did not emerge as a significant factor in radiotherapy interruption. Moreover, no severe cardiac events were recorded.

Economic evaluation of a standard dosage system for an outpatient breast cancer chemotherapy regimen

Abstract Objective To develop and validate a standard dosage system for use with the cyclophosphamide, methotrexate and 5-fluorouracil (CMF) breast cancer chemotherapy regimen, and to conduct a pharmacoeconomic evaluation of the standard dosage system in the outpatient clinic. Method The standard dosage system was developed using data collected retrospectively from patients treated with the CMF chemotherapy regimen. The objective was to establish a standard dosage system that did not vary from individually calculated doses by more than 5 per cent, which was considered clinically to be of no significant consequence. The pharmacoeconomic evaluation involved a control and study period. Outcome measures were time taken for patients to progress through the clinic, time taken to dispense a prescription, and number of pharmacy staff involved in the process. Setting Two outpatient clinics in the chemotherapy unit at a large district general hospital in the West Midlands region of England. Key findings It is possible to develop a clinically acceptable standard dosage system for use with the CMF chemotherapy regimen. Doses of chemotherapy were pre-prepared and there was a significant reduction in the time that a prescription spent within pharmacy and the time taken to dispense the prescription. The overall time that a patient spent at the clinic was reduced significantly. As a result of implementing this system, it was possible to use pre-filled syringes in the pharmacy cytotoxic reconstitution unit, producing a drug cost saving of £20.13 per cycle for a typical CMF patient, with a projected annual saving to the Trust of almost £10,000. Furthermore, the system resulted in more efficient utilisation of staff time in the pharmacy, allowing 55.7 per cent more CMF chemotherapy cycles to be produced without additional investment. Conclusion This project has illustrated that a clinically acceptable standard dosage system can be developed for a chemotherapy regimen. This resulted in savings in drug costs, better utilisation of staff time in the pharmacy department, and a reduction in the overall time that a patient spends at an outpatient clinic.

Are current development programs realising the full potential of new agents?

Following the seminal introduction of CMF (cyclophos-phamide, methotrexate, and fluorouracil) for adjuvant breast cancer treatment more than three decades ago [1], the efficacy of adjuvant chemotherapy has gradually improved by the introduction of the anthracyclines [2] and, more recently, the taxanes [3]. However, while anthracycline-containing regimens have become standard treatment for oestrogen receptor (ER)-positive as well as ER-negative tumours, conflicting evidence has linked the use of adjuvant taxanes to improved outcome in patients with ER-positive tumours. This uncertainty has now, to a large extent, been resolved with the results from a recent study [4] revealing a benefit for ER-positive tumours with a high growth rate as evaluated by KI67 status, but no benefit for ER-positive tumours with a low KI67 score. These results indicate a way forward; while studies three decades ago centred on identifying prognostic factors in breast cancer, we are now starting to learn predictive factors identifying which tumours may achieve optimal benefit from defined therapeutic regimens [5]. This relates to established drug regimens and also to new experimental therapies in particular. While this is conventional wisdom with respect to targeted therapies, such as endocrine agents and anti-human epidermal growth factor receptor 2 (anti-HER-2) strategies, current data illustrate the need for predictive factors to enable optimal use of chemotherapy as well. Realizing the need to identify predictive factors and, ideally, to understand the mechanisms causing drug resistance [6], translational research aiming at identifying such biological parameters should be part of most phase I to III trials [7]. Before discussing future perspectives and the implementation of novel drugs, a brief summary of the state of the art for predictive factors in breast cancer therapy is provided.

CEF is superior to CMF for tumours with TOP2A aberrations: a Subpopulation Treatment Effect Pattern Plot (STEPP) analysis on Danish Breast Cancer Cooperative Group Study 89D

The aim of this study was to examine TOP2A gene copy number changes as a means to identify groups of breast cancer patients with superior benefit from treatment with anthracyclines. Tumour tissue was retrospectively collected and successfully analysed for TOP2A in 773 of 980 Danish patients randomly assigned to receive intravenous CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil) in DBCG trial 89D. Subgroup analyses on this material published by Knoop et al. (J Clin Oncol 23:7483-7490, 2005) and updated by Nielsen et al. (Acta Oncol 47:725-734, 2008) demonstrated that superiority of CEF over CMF is limited to patients with TOP2A aberrations, defined as patients whose tumours have TOP2A ratio below 0.8 or above 2.0. The Subpopulation Treatment Effect Pattern Plot (STEPP) technique was applied to these data to explore the pattern of treatment effect relative to TOP2A and to compare that pattern to the ranges previously used to define 'aberrations'. The pattern of treatment effect illustrated by the STEPP analysis confirmed that the superiority of CEF over CMF is indeed limited to patients whose tumours have high or low TOP2A ratios. The hypothesis of no treatment effect-covariate interaction was rejected (P = 0.02). Furthermore, results indicated that the interval of TOP2A ratios hitherto denoted as 'normal' could be narrower than previously assumed. A more optimal separation of TOP2A subgroups could be obtained by altering cut-points currently used to define TOP2A amplified and TOP2A deleted tumours by narrowing the TOP2A normal interval, and consequently enlarging the population with TOP2A aberrated tumours.

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

The authors examined the long-term cognitive implications of cancer treatment among breast cancer survivors over 65 years old who received treatment during midlife. Thirty women survivors were matched with 30 noncancer, healthy older adults in terms of age, education, and IQ. The cancer survivors scored significantly lower in the cognitive domains of executive functioning, working memory, and divided attention, reflecting potential dysfunction in frontal-subcortical brain regions. Our findings suggest that among breast cancer survivors who remain disease-free for more than a decade, the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes.

Microtubule Associated Protein Tau Expression as a Predictive and Prognostic Marker in a Trial Assessing Sequential Docetaxel as Adjuvant Chemotherapy for Early Breast Cancer (TACT).

Abstract Objective: TACT, which compared sequential anthracycline-taxane (FEC-D) adjuvant chemotherapy with an anthracycline regimen of similar duration (Lancet 2009:373, 1681-1692) provides an opportunity to correlate tau expression levels with disease-free survival (DFS) and to explore the interaction between tau expression and docetaxel benefit. Patients and Methods: 4162 patients were randomized to FE60C (fluorouracil, epirubicin and cyclophosphamide,- 4 cycles) followed by docetaxel (4 cycles) or control. Control, determined by local centres, was FE60C (8 cycles) or epirubicin (4 cycles) followed by classical CMF (cyclophosphamide, methotrexate and fluorouracil - 4 cycles). Patients with hormone receptor positive tumours also received adjuvant endocrine treatment. Tissue blocks were obtained for 3610 TACT patients (87 % of total) to create tissue microarrays (TMA). Tau protein expression was assessed by immunohistochemistry (IHC). Tau was successfully scored by 2 observers (blinded to treatment allocation and clinical outcome), scoring 2 cores from separate TMAs for each of 2977 patients. Intensity (negative, weak, moderate or strong) and the proportion of tumour cells stained (in 5% increments) were recorded. Results: A very strong association was observed between level of intensity and proportion of staining (p&amp;lt;0.001), subsequent analysis used tau intensity only. Fifty one percent of tumors were tau-positive defined as demonstrating weak or greater intensity of staining. Tau expression was positively correlated with ER status (p&amp;lt;0.001), negatively correlated with grade (p&amp;lt;0.001) and negatively correlated with HER2 status (p&amp;lt;0.001). In absence of overall treatment benefit for docetaxel, significant factors predicting DFS on univariate analysis were tau, ER and HER-2 expression in addition to nodal status, grade, tumour size and age. With the exception of age these variables were also significant on multivariate analysis. No significant interaction between tau expression and efficacy of docetaxel was observed in all patients or in patients within the ER+HER2-ve, HER2 +ve and ER -ve HER2 –ve subsets. Exploratory analyses to assess interactions using tau intensity and proportion IHC staining as continuous variables are underway and will be reported. Conclusion: Tau expression was associated with improved DFS but there was no evidence of an interaction between tau and docetaxel benefit. These results are similar to NSABP-B28, which evaluated addition of paclitaxel to doxorubicin/cyclophosphamide. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 607.

A Retrospective Review of Patients with Adenoid Cystic Breast Cancer Treated at Mayo Clinic.

Abstract Background: Adenoid cystic carcinoma of the breast is a rare type of breast cancer accounting for approximately 0.1% of all breast cancer and less than 200 cases are reported in the literature. Hence, data for treatment and outcome are limited. This retrospective review reports the Mayo Clinic's experience.Methods: We identified 30 patients between 1971 and 2009 who were diagnosed with adenoid cystic breast cancer at Mayo Clinic Rochester, Arizona or Florida. Median follow-up was 62 months with a range of 1 to 424 months. Data regarding demographics (age, gender, and race), tumor characteristics (size, grade, and margin status), biological features (Estrogen receptor (ER), Progesterone receptor (PR) status, HER2 status) and clinical course (recurrence, secondary treatment) were collected. Disease free survival was calculated using Kaplan Meier estimates.Results: The median age of all patients was 58 (range, 22 – 78 years). All were female. Median tumor size was 1.3 cm (range, 0.6 – 8.5cm). Axillary lymph node sampling (sentinel or complete dissection) was performed in 15 patients. No patient had lymph node positive disease on presentation. The majority of patients had hormone receptor negative disease. Only 3 patients (10%) had weak hormone receptor (1-10%) positivity. No tumors were HER2 positive. Only two patients had high grade disease. Initial surgical data only available in twenty one patients: fifteen (50%) were treated with lumpectomy and adjuvant radiation, and 6 (20%) were treated with mastectomy. There were no local recurrences. Only one patient was treated with adjuvant chemotherapy (with cyclophosphamide, methotrexate and fluorouracil (CMF) followed by tamoxifen) but still suffered a distant recurrence within 5 years. There were a total of five patients that recurred. The 5-year disease free survival (DFS) rate for the entire cohort was 90%, and 10 year DFS was 83%. Median time to recurrence was 47.5 months (Range, 23-77 months). Recurrence occurred almost exclusively in patients with ≥ T2 disease. The primary site of metastases was lung (80%) and bone (20%) but subsequent liver and brain metastases were also seen. Treatments at relapse included surgical resection, radiosurgery and chemotherapy.Conclusion: Adenoid cystic carcinomas of the breast are rare but have overall good prognosis. This review confirms that the majority of these patients present with node negative disease, low to intermediate histologic grade and endocrine unresponsive tumors. Primary treatment is surgery (mastectomy or lumpectomy plus radiation) and there seems to be no role of any adjuvant therapy at the present time. In general, recurrences (80%) occurred with tumors larger than 2 cm and adjuvant chemotherapy and/or targeted therapy could be explored for selected patients in the context of a clinical trial. Overall mortality after recurrence was 50% but median overall survival was variable in years (1-14 years). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2055.

Tissue inhibitor metalloproteinase type-1 (TIMP-1), a novel cancer biomarker predicting response of adjuvant anthracycline-based chemotherapy in patients afflicted with primary breast cancer

A central question relating to adjuvant systemic treatment of early breast cancer patients has been whether anthracyclines should be part of chemotherapy or whether it is appropriate to recommend the cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen instead.1 CMF chemotherapy was considered the standard adjuvant therapy for a long time but in a series of meta-analyses the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has established the importance of anthracyclines in the adjuvant setting.