Fluorouracil, Epirubicin And Cyclophosphamide Research Articles

Abstract PO1-12-06: Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia?

Abstract Background: Febrile neutropenia (FN), a major hematologic adverse event in perioperative chemotherapy for breast cancer, is more prevalent among Asians than in Caucasian populations. Four main guidelines, i.e., ASCO, EORTC, NCCN, and ESMO, provide recommendations regarding the appropriate use of hematopoietic growth factors. These guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) based on the estimated incidence of FN, primarily defined by the chemotherapy regimen. G-CSF administration is recommended when the incidence of FN is ≥20% or 10–20% with risk(s). However, the incidence of FN varies depending on the trial and design, and patient-specific risk factors for FN remain unclear. We previously performed a multicenter prospective cohort study in Japan, the CSPOR-BC FN study, evaluating the incidence of FN during perioperative chemotherapy for breast cancer. Herein, we conducted an additional analysis to explore thresholds of patient-specific risk factors for FN that could be evaluated before chemotherapy. We analyzed the risk factors for FN and verified the appropriateness of patient selection for prophylactic G-CSF administration. Methods: The previously reported CSPOR-BC FN study (PubMed ID=33631458) consecutively enrolled 1005 patients with stage I–III breast cancer between August 2015 and July 2017. In the current additional analysis, we intended to have 477 patients in the visiting group that evaluated true-FN, defined as ≥37.5℃ and grade 4 neutropenia. Multivariate analysis of risk factors for FN was performed, followed by the determination of cutoff values for age and pretreatment absolute neutrophil count (ANC) as risk factors. Results: Chemotherapy regimens administered were FEC (fluorouracil, epirubicin, and cyclophosphamide) in 170 patients (36%), E(A)C (epirubicin (doxorubicin) + cyclophosphamide) in 165 patients (35%), and TC (docetaxel + cyclophosphamide) in 142 patients (30%). The incidence of FN was 28.7% (N = 137). To evaluate the risk factors for FN, we predefined regimens, age, performance status (PS), stage, chemotherapy or radiotherapy history, infectious wounds, open wounds, ANC, and renal and liver dysfunction as potential risk factors. Multivariate analysis of risk factors for FN identified regimen (TC), age (≥65), low pretreatment ANC, treatment setting, and no primary pegfilgrastim prophylaxis as significant risk factors. Two patient-specific risk factors (age and pretreatment ANC) were analyzed. Logistic regression analysis revealed that age≥65 years was a significant risk factor (odds ratio=2.24, 95% confidence interval: 1.34–3.75). Applying a cutoff of 65 years (age) to predict FN, the sensitivity and specificity were 28.4 and 83.8%, respectively, which were inaccurate. Despite applying a cutoff of 67 years optimized from the receiver operating characteristic (ROC) curve, the sensitivity (22.4%), specificity (90.7%), and area under the curve (0.519) indicated low discrimination for predicting FN. The incidence of FN by age group was as follows: < 45 years, 30.8%; 45–55 years, 26.4%; 55–64 years, 20.9%; ≥65 years, 39.6%. Additionally, applying a cutoff of 2436/µL (pretreatment ANC) optimized from the ROC curve, the observed sensitivity (27.6%) and specificity (83.8%), and area under the curve (0.558) also indicated low discrimination for predicting FN. The incidence of FN by stratum of pretreatment ANC was as follows: < 2000, 33.3%; 2000–3000, 30.7%; 3000–4000, 29.9%; and >4000, 24.6. Accordingly, setting a cutoff value to predict FN incidence using age and/or pretreatment ANC was deemed inappropriate. Conclusion: Selecting patients for primary prophylactic G-CSF based on the existing FN risk can be challenging. Primary prophylactic G-CSF would be considered for every patient undergoing perioperative chemotherapy for breast cancer, especially Asians. ROC curve for FN and age. The AUC was 0.519. ROC curve for FN and neutrophil count. The AUC was 0.558. Citation Format: Kazutaka Narui, Takashi Ishikawa, Ikumi Takashima, Kosuke Kashiwabara, Yukari Uemura, Yuichiro Kikawa, Naruto Taira, Hirofumi Mukai. Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-06.

Impact of baseline telomere length on survival and chemotherapy related toxicity in breast cancer patients receiving (neo)adjuvant anthracycline containing chemotherapy

PurposeThe aim of this study is to assess baseline mean leukocyte telomere length (TL) as a potential predictive factor for chemotherapy toxicity and a prognostic marker for long-term outcome in early breast cancer (BC) patients. Methods445 BC patients were selected, diagnosed between 2007 and 2010 with early BC and treated with (neo)adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) or with FEC and Docetaxel (FEC-D). RT-qPCR was performed on germline DNA samples collected at diagnosis before any treatment, to measure mean leukocyte TL. Uni- and multivariable logistic regression or Cox proportional hazard regression analyses were carried out to assess correlation between baseline TL and toxicity parameters (derived from the medical chart) or longer-term outcome. ResultsBaseline TL correlated with age as expected (p = 0.005), but not with febrile neutropenia (n = 97), left ventricular ejection fraction >10% decrease (n = 17) nor other toxicity endpoints measured (all p > 0.05). TL was neither associated with overall survival, breast cancer specific survival or distant disease-free survival (all p > 0.05). ConclusionsBaseline TL is not associated with chemotherapy-related toxicity nor long-term outcome in BC patients.

Risk for relapse and death after adjuvant chemotherapy associated with SNPs in patients with breast cancer - A retrospective study.

For the women breast cancer (BC) patients included in this retrospective study, the first line of systemic treatment in adjuvant modality for breast cancer (BC) after surgery was fluorouracil, epirubicin and cyclophosphamide (FEC). The aim of our investigation was to analyze the prognostic biomarkers for relapse and death of patients eight to ten years after chemotherapy in association with nausea and vomiting.Method. This retrospective study included 114 patients treated between 2010 and 2013. Blood samples for Single Nucleotide Polymorphism (SNP) analysis before the chemotherapy treatment were collected. The medical records were used to determine relapses and death.Results. Sixteen percent relapsed and 9 % died during the follow-up period. SNPs located in the genes ESR and CASP9 were associated with both relapse and death.Conclusions. Relapse and death were at a relative moderate level and consistent with other studies. Two SNPs in the Estrogen hormone receptor gene ESR1 and the apoptosis execution gene Caspases 9 (Casp9) were found to be associated with a higher risk of relapse and death. These findings suggest the possible value of blood biomarkers in the selection of individual treatments in the clinical setting.

Abstract 3607: Quantitative dimensions of the PAM50 in breast tumors are prognostic and predict paclitaxel response

Abstract Standard of care for women with locally advanced breast cancer is aggressive chemotherapy with a combined anthracycline-taxane regimen. Multiple randomized clinical trials have shown survival benefit to adding a taxane, e.g., paclitaxel; however, this can cause serious toxicities such as peripheral neuropathy. Identifying patients who benefit from taxane would improve survival outcomes, reduce toxicities and allow future randomization to more effective agents. So far, gene expression signatures have proven prognostic in the adjuvant chemotherapy setting but not predictive to particular regimens. We recently described 5 breast tumor dimensions using principal components (PC1-5): orthogonal quantitative tumor traits capturing the majority of expression variance in the PAM50 genes. Here we evaluate these dimensions and disease-free survival (DFS) in 819 patients in the Grupo Español para la Investigación del Cáncer de Mama (GEICAM) trial 9906, which evaluated fluorouracil, epirubicin and cyclophosphamide (FEC) vs. FEC followed by weekly paclitaxel (FEC-P). To investigate prognosis, we first ignored trial arm. PC1 was significantly associated with DFS in a Cox regression analysis (p=6.7x10-7), outperforming other predictors including nodal status, tumor size, grade, ER/PR/HER2/ki67 status, age at diagnosis and intrinsic subtype. PC1 remained significant in multivariate Cox regression adjusted for nodal status, tumor size and grade (p=8.7 x 10-4). Modeled as quintiles in a Kaplan-Meier (KM) analysis, PC1 was not only significant (p=3.7 x 10-6) but quantitatively prognostic, with the proportion surviving to 4 years decreasing for each quintile: 91%, 88%, 79%, 71%, 66% for low to high PC1 quintiles, respectively. To investigate response we examined interactions between dimensions and trial arm. Interactions were seen for PC3* arm (p=0.05) and PC4* arm (p=0.05). KM curves showed women with low-PC3 tumors responded to the addition of paclitaxel (p=0.006, 85% survival on FEC-P vs 72% FEC at 4 years), but women with high-PC3 tumors did not (p=0.94, 81% FEC-P, 82% FEC). Survival rates suggest that cases with high-PC3 were FEC super-responders, gaining no benefit from paclitaxel. Response to paclitaxel was seen for low-PC4 tumors (p=0.003, 89% FEC-P, 75% FEC), but not high-PC4 tumors (p=0.92, 70% FEC-P, 71% FEC); cases with high-PC4 tumors were poor responders to either treatment. Combining orthogonal traits PC3 and PC4 defined 44% of women (high-PC3 or high-PC4) with no benefit from paclitaxel (both arms 76% at 4 years), and 56% with lower PC3/PC4 tumors and substantial survival gain (p=0.002, 90% FEC-P, 73% FEC). In conclusion, breast tumor dimension PC1 shows great promise for quantitative prognostics. Dimensions PC3 and PC4 predict paclitaxel response, in particular identifying a large proportion of women (44%) who may be overtreated with paclitaxel, a drug class currently part of standard of care. Citation Format: Nicola J. Camp, Michael J. Madsen, Jesus H. Valera, Eva Carrasco, Rosalia Caballero, Miguel Martin, Philip S. Bernard. Quantitative dimensions of the PAM50 in breast tumors are prognostic and predict paclitaxel response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3607.

Patterns of care and outcomes among triple-negative early breast cancer patients in South Western Sydney.

Triple-negative breast cancer (TNBC) represents 12-24% of all breast cancer and carries a poor prognosis upon recurrence. Little is known of the treatment, or timing and frequency of recurrences outside of a clinical trial. We describe the patterns of care and outcomes of women with TNBC treated at two cancer centres in Sydney, NSW, Australia, to help oncologists talk to women with this subtype of breast cancer about their likely prognosis. We searched the electronic medical record for women with stages I-III TNBC diagnosed from 2006 to 2014. For each woman, we recorded demographics, tumour characteristics, treatment details, recurrences and survival using the Kaplan-Meier method. We identified 137 women with a median age of 55 years (interquartile range (IQR) 44-63). The median tumour size was 25 mm (IQR 16-35). Most women had grade 3 (92%) and ductal carcinomas (89%), and 35% were node positive; 113 (82%) patients received (neo)adjuvant chemotherapy. The most prescribed regimens for node-negative tumours were: fluorouracil, epirubicin and cyclophosphamide (FEC) × 6 (23pts, 35%), and for node-positive tumours, FEC-Docetaxel (18pts, 40%). Adjuvant radiotherapy was delivered to 114 (83%) patients. After a median follow up of 40 months, 17 patients (12%) had a recurrence. All but one recurrence (94%) occurred within 3 years of diagnosis. Twelve women received palliative chemotherapy, and 14 women have died. The median survival from the time of recurrence was 18 months (IQR 5-26). Seven women (5%) had a documented BRCA1 mutation, and four women (3%) had a documented BRCA2 mutation. TNBC affects women at a relatively young age and tends to recur early. Survival following metastatic disease is short, and more effective therapies are needed.

Role of taxanes in chemotherapy-related cognitive impairment: A prospective longitudinal study.

The aim of this study is to elucidate the role of taxanes on cognition when they are administered as a part of the treatment with a fluorouracil, epirubicin and cyclophosphamide (FEC) regimen for breast cancer (BC). Two groups of women (n=51) with a novel diagnostic of BC that were treated with a combination of FEC alone (6 cycles of FEC) or with taxanes (4 cycles of FEC plus 8 cycles of taxanes) were compared at three moments: before chemotherapy, after its completion (short-term evaluation) and at a mean of 74.5weeks from baseline as a long-term evaluation. Both groups showed worsening in tests of attention and executive functions on the short-term assessment, with the group treated with taxanes showing more number of affected cognitive measures at this time point, including verbal learning and speed measures. At the long-term evaluation, cognitive dysfunction was still found in attention and executive functions in both groups. Our results suggest that chemotherapy for BC with a FEC regimen can have a negative effect on cognition. Acute deficits seem to be larger when taxanes are added, but treatment seems to affect cognition also at long term.

Single nucleotide polymorphisms might influence chemotherapy induced nausea in women with breast cancer

BackgroundWomen receiving FEC (5 fluorouracil, epirubicin and cyclophosphamide) chemotherapy (CT) for breast cancer (BC) often experience side effects such as nausea and vomiting. Individual variations of side effects occur in patients despite similar cancer therapy. The purpose of this study was to investigate a possible genetic background as a predictor for individual variations in nausea induced by CT. Methods114 women were included in the study. All women received adjuvant CT for BC. Self-reported nausea and vomiting was recorded in a structured diary over ten days following treatment. Blood samples were collected before the treatment and used for the detection of 48 single nucleotide polymorphisms (SNPs) in 43 genes. SNPs from each individual woman were analyzed for their relation to the patient-reported frequency and intensity of nausea and vomiting. ResultsEighty-four percent (n=96) of the women reported acute or delayed nausea or combined nausea and vomiting during the ten days following CT. Three out of the forty-eight SNPs in the following genes: FAS/CD95, RB1/LPAR6 and CCL2 were found to be associated with a risk of nausea. ConclusionSNPs in the FAS/CD95, RB1/LPAR6 and CCL2 genes were found to be associated with nausea among women treated with adjuvant FEC for BC. SNPs analysis is fast and cost effective and can be done prior to any cancer therapy. The association between individual SNPs and severe side effects from FEC may contribute to a more personalized care of patients with BC.

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10mg/kg, epirubicin at 2.5mg/kg and 5-flurouracil at 10mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.

Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2- breast cancer patients: results from the GEICAM 9906 trial.

IntroductionEndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial.MethodsThe patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.ResultsThe molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.ConclusionsEP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.

Abstract S5-06: Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil, epirubicin and cyclophosphamide (FEC) followed by T, all given every 3 weeks or 2 weeks, in node-positive early breast cancer (BC) patients (pts). Final results of the gruppo Italiano mammella (GIM)-2 randomized phase III study

Abstract Background. Using a 2 × 2 factorial design, we compared the efficacy of two different schedules of chemotherapy (CT), dose-dense (DD) every 2 weeks versus standard duration every 3 weeks and the role of Fluorouracil (F) in addition to EC, in the adjuvant treatment of node positive BC pts. Patients and Methods. Node positive early BC pts younger than 70 years were eligible and randomly assigned to one of the following treatment arms: ARM A (4 courses of EC [90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM B (4 courses of FEC [600/90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM C (4 courses of EC [90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]); ARM D (4 courses of FEC [600/90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]). Pts enrolled in the DD arms (ARM C and D) received subcutaneous pegfilgrastim (6 mg) 24 hours after CT. HER2-positive pts enrolled after April 2006 received trastuzumab for 1 year at the end of CT. The primary study endpoint was disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. All analyses were conducted according to the intention-to-treat principle. Results. From April 2003 to July 2006, 2091 pts were enrolled (545 in ARM A, 544 in ARM B, 502 in ARM C, 500 in ARM D). The planned number of CT cycles was completed in 89% of pts in the DD group and in 88.1% of pts in the standard duration group. Pts treated with DD CT (ARM C + ARM D) experienced more frequently anemia (all grades: 67.2% vs 49.5%, p &amp;lt; .0001; G3-G4: 0.2% vs 1.4%, p = .004) and bone pain (53.5% vs 39.2%, p &amp;lt; .0001). Neutropenia occurred more frequently in standard duration arms (ARM A + ARM B): 66.7% vs 28.0%, p = &amp;lt; .0001. At a median follow up of 7.0 years, multivariate analysis, showed that DD treatments (ARM C + ARM D vs ARM A + ARM B) improved the primary endpoint, DFS (hazard ratio [HR] = 0.78; 95% CI 0.66-0.94; p = .007), and OS (HR = 0.68; 95% CI 0.52-0.87; p = .002). Conversely, the addition of F to EC did not improve clinical outcomes: the HR for DFS and OS (ARM A + ARM C vs ARM B + ARM D) were respectively 0.98 (95% CI 0.83-1.17; p = .85) and 0.93 (95% CI 0.73-1.19; p = .578). Subgroup analyses revealed that the benefits associated with DD CT were independent of hormone receptor status: in hormone receptor positive the HRs for DFS and OS were 0.80 (0.65-0.98) and 0.69 (0.51-0.93) respectively; in hormone receptor negative the HRs for DFS and OS were 0.67 (0.47-0.95) and 0.57 (0.36-0.92) respectively (p for interaction for DFS: 0.339; p for interaction for OS: 0.495). Pathological tumor size, nodal status (1-3 vs ≥ 4 positive nodes), histological grade and hormone receptor status were independently associate with DFS and OS. Conclusions. DD CT as adjuvant treatment in node positive BC pts, improves DFS and OS significantly. Conversely, the addition of F to EC does not improve clinical outcomes. (ClinicalTrials.gov number, NCT00433420). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-06.

Interstitial pneumonia associated with neoadjuvant chemotherapy in breast cancer

Interstitial pneumonia (IP) is a critical adverse event that may occur during anticancer chemotherapy. Physicians should be aware of the possibility of IP, particularly when dealing with patients on neoadjuvant chemotherapy (NAC) since delays in diagnosis and treatment interfere with the scheduled operation. In our institution, fluorouracil, epirubicin and cyclophosphamide (FEC) followed by weekly paclitaxel is the standard NAC regimen for operable breast cancer cases. In the present study, 95 patients with breast cancer were treated with this regimen, 5 of whom (5.3%) developed IP during NAC. All 5 cases were diagnosed when anticancer therapy was withdrawn and steroid pulse therapy was initiated. Consequently, the standard operation was immediately performed. In conclusion, physicians should be aware that IP may occur at any point during NAC and that it should be immediately diagnosed and treated to avoid delay of the therapeutic plan.

Differential Pathological Response to Preoperative Chemotherapy across Breast Cancer Intrinsic Subtypes

Background: Breast cancer is a heterogeneous disease with a diversity of clinical behaviors. The purpose of this study was to evaluate the utility of breast cancer intrinsic subtypes in the prediction of pathological complete response (pCR) in a cohort of breast cancer patients receiving preoperative chemotherapy. Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine and docetaxel) followed by 4 cycles of FEC (fluorouracil, epirubicin, and cyclophosphamide) as preoperative chemotherapy. Tumors were classified as luminal A, luminal B, luminal/HER2, HER2, basal-like, or non-basal-like triple negative by immunohistochemical analysis in core needle biopsy samples at baseline. Results: The overall pCR rate was 11.9% (12/101). Multivariate analysis showed that intrinsic subtype was an independent factor to predict pCR. With luminal A patients as the reference group, luminal B (OR = 16.39; 95% CI 1.44–185.88; p = 0.024), HER2 (OR = 14.73; 95% CI 1.19–180.84; p = 0.035), and basal-like (OR = 13.27; 95% CI 1.27–138.79; p = 0.031) patients had a significantly higher likelihood of pCR. Conclusion: The present data indicate that intrinsic subtypes may be useful predictive biomarkers of pCR in breast cancer patients treated with preoperative chemotherapy.

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.

Concurrent administration of chemo-endocrine therapy for postmenopausal breast cancer patients

We have been treating hormone receptor-positive, postmenopausal women with breast cancer with a regimen of neoadjuvant chemotherapy (NAC), FEC (fluorouracil, epirubicin, and cyclophosphamide), followed by weekly doses of paclitaxel combined with the concurrent administration of anastrozole. In this article, we compared our results retrospectively with those of past trials. Twenty-six patients that were postmenopausal and were younger than 70 years of age were selected. They all had primary operable tumors that were ≥2 cm in diameter (clinical T2-3, Nx, M0). All patients received four cycles of 500 mg/m² cyclophosphamide, 500 mg/m² 5-fluorouracil, and 80 mg/m² epirubicin (from April 2006, the dose was increased to 100 mg/m²) that were administrated on day 1 of every 3rd week and followed by 12 cycles of 80 mg/m² paclitaxel on day 1 of each week. From the beginning of NAC the aromatase inhibitor, anastrozole, was concomitantly administered at a dose of 1 mg/day. After surgery, the clinical and pathological responses were examined. Among the 26 patients, 5 (17.9%) achieved clinical complete response, 16 (57.1%) clinical partial response, and 4 (14.3%) clinical stable disease. If the nodal status was counted, the pathological complete response (pCR) rate of our chemo-endocrine therapy was 11.5%. The pCR rate of the concurrent administration of chemo-endocrine therapy was not lower than those of past trials, but it remains uncertain whether this positive result was due to the administration of the aromatase inhibiter or our NAC regimen. In order to answer this, we need to make a direct comparison between the concurrent versus sequential administration of the aromatase inhibitor during NAC in a prospective study.

Use of BRCA1 mRNA expression levels to predict survival in breast cancer patients (p) treated with neoadjuvant chemotherapy

11510 Background: A fraction of sporadic breast cancers have low BRCA1 expression. These p can respond to DNA damage-based chemotherapy but not to antimicrotubule drugs. In addition, DNA damage-based chemotherapy confers a significant survival advantage to BRCA1 mutation carriers compared to non-mutation carriers. Also ovarian cancer p with low levels of BRCA1 mRNA have improved survival following platinum-based chemotherapy compared to p with high levels of BRCA1 mRNA (Quinn et al, CCR 2007). Methods: Tumor biopsies were obtained from 86 p with locally advanced breast cancer who were treated with four cycles of neoadjuvant fluorouracil, epirubicin and cyclophosphamide (FEC). Estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 6/7, vimentin, Huntingtin interacting protein 1 (HIP1) and BRCA1 were examined by tissue microarray. HER2 was also assessed by CISH, and BRCA1 mRNA was analyzed in samples of 41 p by quantitative PCR. Results: Pathological response was attained in 57% of p. Median disease-free survival (DFS) was 30 months (m) and median survival (MS) was 41 m. There was no correlation between BRCA1 protein expression by immunohistochemistry and BRCA1 mRNA expression. In the multivariate analysis for DFS and MS, low levels of BRCA1 mRNA, positive PR and negative lymph node involvement predicted significantly lower risk of relapse, and low levels of BRCA1 mRNA and positive PR were the only variables associated with significantly better survival (table). Conclusions: We provide evidence to support a major role for BRCA1 mRNA expression as a predictive marker of DFS and MS in sporadic breast cancers. These findings can be useful for customizing chemotherapy. DFS MS N HR (95% CI) p HR (95% CI) p BRCA1 mRNA Low 13 1 1 by terciles Intermediate 14 7.68 (2.41-24.55) 0.001 4.52 (1.51-13.46) 0.007 High 12 4.52 (1.50-13.63) 0.007 2.94 (0.99-8.71) 0.05 PR Negative 26 4.15 (1.61-10.69) 0.003 2.43 (0.99-5.93) 0.05 Positive 13 1 1 Lymph node involvement Negative 6 1 Positive 33 12.01 (1.51-95.16) 0.02 No significant financial relationships to disclose.

The Institute of Cancer Research, Clinical Trials and Statistics Unit (ICR-CTSU)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by The Institute of Cancer Research, Clinical Trials and Statistics Unit (ICR-CTSU). Clinical trials include: The NCRI Adjuvant Breast Cancer (ABC) trial. ISRCTN31514446The UK randomized trial of hormone replacement therapy (HRT) in women with a history of early stage breast cancer. ISRCTN29941643NCRI Standardisation of Breast Radiotherapy (START) trial. ISRCTN59368779TACT: A randomized trial of standard anthracycline-based chemotherapy (fluorouracil, epirubicin and cyclophosphamide (FEC) or epirubicin and CMF (Epi-CMF)) versus FEC followed by sequential docetaxel in women with early breast cancer. ISRCTN 79718493SoFEA: Study of Faslodex with or without concomitant Arimidex versus Exemestane following progression on non-steroidal Aromatase inhibitors. ISRCTN: 44195747TACT2: Trial of accelerated adjuvant chemotherapy with Capecitabine in early breast cancer. ISRCTN68068041FAST trial: Prospective randomized clinical trial testing 5.7 Gy and 6.0 Gy fractions of whole breast radiotherapy in terms of late normal tissue responses and tumour control.IMPORT low trial.IMPORT high trial.Adjuvant chemotherapy in older women (ACTION).

Inflammatory breast cancer outcome with epirubicin‐based induction and maintenance chemotherapy

The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen. One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed. The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome. FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC.

Effects of adjuvant chemotherapy on the protein C anticoagulant pathway in patients with early stage breast cancer

8563 Background: Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms are poorly understood. We have previously shown that treatment of endothelial cells with adriamycin and epirubicin impairs the protein C anticoagulant pathway by downregulating EPCR (endothelial protein C receptor), an endothelial receptor required for the conversion of protein C to the anticoagulant enzyme activated protein C (APC). In this study, we examined the effects of adriamycin- and epirubicin-containing chemotherapy on the protein C anticoagulant pathway in early stage breast cancer patients. Methods: We collected blood samples from 20 patients patients with early stage breast cancer undergoing adjuvant CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy on days 1, 2 and 8 for the first 2 cycles of treatment. Markers of protein C generation (protein C, thrombin-antithrombin (TAT) complexes, and APC) were measured on these days. Results: Plasma protein C levels were significantly lower at cycle 2 day 8 (0.88 ± 0.14 U/ml) compared to pre-chemotherapy levels (1.07 ± 0.23 U/ml) (p=0.0036). Plasma TAT levels were significantly higher at cycle 2 day 8 (2.87 ± 0.79 μg/L) compared to pre-chemotherapy levels (2.01 ± 1.24 μg/L) (p=0.02). Based on the APC levels, the patients appear to fall into two categories in terms of their ability to generate APC. The first group (n=16) has elevated APC levels that parallel the elevated TAT levels, whereas the second group (n=4) has low APC levels despite elevated TAT levels. Conclusions: Impaired ability to generate APC in a subpopulation of patients may reflect chemotherapy-induced impairment of the protein C pathway through the downregulation of EPCR. This pilot study provides new mechanistic insights into the prothrombotic effects of chemotherapy agents. No significant financial relationships to disclose.

Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer

Background: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many.Patients and methods: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation.Results: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02).Conclusions: The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.

Trends in endocrine therapy and chemotherapy for early breast cancer: a focus on the premenopausal patient

The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting.