The impact of genetic variability on severe toxicity of (neo-) adjuvant chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, and cyclofosfamide (FEC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1020-1020
Author(s):  
Christof Vulsteke ◽  
Diether Lambrechts ◽  
Anne-Sophie Dieudonné ◽  
Sigrid Hatse ◽  
Barbara Brouwers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Variability ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Multi Drug Resistance ◽  
Hematological Toxicity ◽  
Severe Toxicity ◽  
Wild Type ◽  
Grade 3 ◽  
The Impact

1020 Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events. The panel of genes, genotyped using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, UGT1A6 and UGT2B7. These genes are involved in the metabolization of the studied chemotherapeutics. Because of multiple testing the false discovery rate (FDR) was calculated. Results: We identified 1089 patients treated between 2000-2010 with 3-6 cycles of FEC, for whom germline DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/MRP1), compared to wild-type (GG, 88.5%), were associated with febrile neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type (GG, 88%), were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). Conclusions: Genetic variation in the ABCC1 gene was strongly associated with severe hematological toxicity of FEC. Other previously described SNP were not validated. This is the largest bc study in which the impact of genetic variability on the adverse events of FEC chemotherapy was investigated.

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin, and cyclophosphamide as adjuvant chemotherapy for early-stage breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 604-604
Author(s):  
H. Abe ◽  
T. Umeda ◽  
Y. Kawai ◽  
M. Tanaka ◽  
T. Shimizu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Early Stage ◽  
Dose Intensity ◽  
Completion Rate ◽  
Early Stage Breast Cancer ◽  
Hematological Toxicity ◽  
Grade 3

604 Background: As adjuvant chemotherapy for breast cancer, the addition of docetaxel to regimens containing anthracyline has been shown to be effective. However, tolerance and safety associated with the administration order of the two drugs have not been evaluated. Methods: Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The treatment completion rate and toxicity were evaluated in 2 arms who underwent a total of 6 courses of the following regimens: Arm A: 3 courses of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100: q3w) followed by 3 courses of docetaxel (DOC100: 100 mg/m2, q3w); and Arm B: 3 courses of DOC100 (q3w) followed by 3 courses of FEC100 (q3w). Results: June 2006 to April 2008, 42 patients were registered. To the present, analysis has been completed in 21 patients in arm A and 21 in arm B. The mean age of patients was 49.1 years and 53.8 years, respectively. In arm A, the stage of cancer was 1 in 4 patients, 2a in 10, and 2b in 7, in arm B, the stage of cancer was 1 in 3 patients, 2a in 9, and 2b in 9. The adjuvant chemotherapy completion rate was 100 % for arm A and 95.2 % for arm B. The relative dose intensity (RDI) was 94.2 % for FEC100 and 97.8 % for DOC100 in arm A, and 98.9 % for DOC100 and 95.2 % for FEC100 in arm B. In arm A, grade 3 or higher hematological toxicity was observed in 9 patients, and febrile neutropenia developed in 3 patients with FEC100. In arm B, grade 3 or higher hematological toxicity was observed in 7 patients, but febrile neutropenia was not noted in any patients. Grade 3 or higher non-hematological toxicity was observed with FEC100 in 2 patients each in the two arms. Grade 1 or 2 edema developed in 11 patients with DOC100 in the two arms. Conclusions: In both arm A and B, adverse events associated with FEC100 were frequently observed but spontaneously recovered, or adequate management was possible by supportive therapy. Adverse events associated with DOC100 were mild. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early stage breast cancer. However, DOC100 followed by FEC100 may be more tolerable and effective. No significant financial relationships to disclose.

scholarly journals Inclusion of Platinum Agents in Neoadjuvant Chemotherapy Regimens for Triple-Negative Breast Cancer Patients: Development of GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Recommendation by the Italian Association of Medical Oncology (AIOM)

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1137 ◽  
Author(s):  
Maria Vittoria Dieci ◽  
Lucia Del Mastro ◽  
Michela Cinquini ◽  
Filippo Montemurro ◽  
Laura Biganzoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Medical Oncology ◽  
Serious Adverse Events ◽  
Assessment Development ◽  
Grade 3

In the absence of identified therapeutic targets, chemotherapy is the main systemic treatment option for triple-negative breast cancer (TNBC). The achievement of a pathological complete response (pCR) after neoadjuvant chemotherapy leads to good outcome, whereas patients not achieving a pCR are at high risk of relapse. Various trials have evaluated the inclusion of platinum in neoadjuvant chemotherapy regimens for TNBC, leading to non-univocal results. The panel of the Italian Association of Medical Oncology (AIOM) Guidelines on Breast Cancer developed a clinical recommendation on the addition of platinum to anthracycline/taxane-based neoadjuvant chemotherapy for TNBC by using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology and the Evidence to Decision framework (EtD). Five studies were eligible. The panel identified the following outcomes of benefit: pCR (critical), disease/event-free survival (DFS/EFS, critical), and overall survival (OS, critical). The panel identified febrile neutropenia (critical), serious adverse events (critical), anemia grade 3–4 (important), thrombocytopenia grade 3–4 (important) as outcomes of harms. The probability of pCR was higher in the platinum-based chemotherapy group versus control group (RR = 1.45, 95%CI 1.28–1.64); however, no impact on long-term outcome was observed. Neoadjuvant treatment regimens containing platinum resulted in a non-significant increase in the risk of febrile neutropenia and in a significant increase in the risk serious adverse events, G3–G4 anemia and G3–G4 thrombocytopenia: 11.3% versus 0.8%, RR = 15.66 (95%CI 6.38–38.44). The panel judged uncertain/favorable the benefit/harms balance. The panel’s final recommendation was conditional in favor of the inclusion of platinum in anthracycline/taxane-based neoadjuvant regimens for TNBC.

Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (DPYD) genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3028-3028
Author(s):  
Theodore John Wigle ◽  
Brandi Povitz ◽  
Wendy Teft ◽  
Robin Legan ◽  
John Gordon Lenehan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Prospective Cohort ◽  
Primary Outcome ◽  
Dihydropyrimidine Dehydrogenase ◽  
Care Providers ◽  
Wild Type ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact

3028 Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to demonstrate the feasibility of implementing a hospital-wide pretreatment DPYD testing service based on the CPIC 2013 guideline on fluoropyrimidines and DPYD. Methods: We enrolled participants prior to planned fluoropyrimidine treatment as well as those who had experienced adverse events (AEs) after initiation of therapy, from December 1, 2013 to November 30, 2018. The patients tested pretreatment were analyzed as a prospective cohort to assess AEs within 90 days of fluoropyrimidine initiation and associated hospital cost. The primary outcome was the rate of severe global fluoropyrimidine-related toxicity in the pretreatment cohort (grade≥3, CTCAE v.4.0.3). Results: Of 1362 patients genotyped for DPYD within the study period 1041 were enrolled pretreatment and included in the primary analysis. The median age was 65 years (19-90), 57% male, 51% 5-FU, and 49% capecitabine. Dose reductions were recommended for 21 DPYD variant carriers who were detected pretreatment. There was no significant difference in the primary outcome between DPYD variant (29%) and wild type (18%) patients (Fisher’s exact test p = 0.25). Costs associated with ER visits and hospitalizations at our tertiary care centre were $1,268 (89-8,562) (Median (IQR)) and $2,961 (341-13,567) for DPYD variant (n = 4) and wild-type (n = 99) patients respectively. Post-AE genotyping (n = 70) found five DPYD variant patients; all experienced grade≥3 toxicity, costs were $15,825 (10,962-25,310), and one poor metabolizer died due to complications. Targeted next generation exome sequencing of DPYD wild-type patients who experienced severe AEs identified five potentially deleterious genetic variants in ABC efflux transporters. Conclusions: Pretreatment DPYD genotype guided dosing of fluorouracil and capecitabine is feasible and benefits patients, health care providers, and hospitals. Our data supports adoption of pretreatment DPYD genotyping as a standard of care.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

2005 ◽  
Vol 23 (23) ◽  
pp. 5314-5322 ◽  
Author(s):  
Stephen Chan ◽  
Max E. Scheulen ◽  
Stephen Johnston ◽  
Klaus Mross ◽  
Fatima Cardoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Dose Level ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Febrile neutropenia incidence and hematological toxicity with the FEC100-docetaxel regimen in the treatment of early-stage breast cancer

2012 ◽  
Vol 99 (7-8) ◽  
pp. E75-E80 ◽  
Author(s):  
Sophie Cousin ◽  
émilie Le Rhun ◽  
Audrey Mailliez ◽  
Charles Fournier ◽  
Jacques Bonneterre
Keyword(s):  
Breast Cancer ◽  
Febrile Neutropenia ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Hematological Toxicity

scholarly journals Efficacy of combination-chemotherapy with pirarubicin, ifosfamide, and etoposide for soft tissue sarcoma: a single-institution retrospective analysis

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Shiro Saito ◽  
Hisaki Aiba ◽  
Satoshi Yamada ◽  
Hideki Okamoto ◽  
Katsuhiro Hayashi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Adverse Events ◽  
Combination Chemotherapy ◽  
Progressive Disease ◽  
Treatment Phase ◽  
Hematological Toxicity ◽  
Single Institution ◽  
Grade 3

Abstract Background The standard chemotherapy regimens for soft tissue sarcoma are doxorubicin-based. This retrospective study aimed to assess the efficacy and safety of pirarubicin, ifosfamide, and etoposide combination therapy for patients with this disease. Methods Between 2008 and 2017, 25 patients with soft tissue sarcoma were treated with pirarubicin (30 mg/m2, 2 days), ifosfamide (2 g/m2, 5 days), and etoposide (100 mg/m2, 3 days) every 3 weeks. The primary endpoint was overall response, and the secondary endpoint was adverse events of this regimen. Results Responses to this regimen according to RECIST criteria were partial response (n = 9, 36%), stable disease (n = 9, 36%) and progressive disease (n = 7, 28%). During the treatment phase, frequent grade 3 or worse adverse events were hematological toxicities including white blood cell decreases (96%), febrile neutropenia (68%), anemia (68%), and platelet count decreases (48%). No long-term adverse events were reported during the study period. Conclusion This regimen was comparable to previously published doxorubicin-based combination chemotherapy in terms of response rate. Although there were no long-lasting adverse events, based on our results, severe hematological toxicity should be considered.

Ifosfamide and mitoxantrone as first-line chemotherapy for metastatic breast cancer.

1993 ◽  
Vol 11 (3) ◽  
pp. 461-466 ◽  
Author(s):  
J E Perez ◽  
M Machiavelli ◽  
B A Leone ◽  
A Romero ◽  
M G Rabinovich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Complete Response ◽  
Severe Toxicity ◽  
First Line ◽  
Metastatic Breast Carcinoma ◽  
Time To Treatment Failure ◽  
Grade 3 ◽  
Line Chemotherapy

PURPOSE A phase II trial was performed to evaluate the efficacy and toxicity of a combination of ifosfamide (IFX) and mitoxantrone (MXN) as first-line chemotherapy for metastatic breast carcinoma. PATIENTS AND METHODS Between January 1990 and August 1991, 48 patients with metastatic breast cancer were entered onto the study. Therapy consisted of IFX 2 g/m2 given as a 1-hour intravenous (IV) infusion on days 1 to 3; mesna 400 mg/m2 as an IV bolus immediately before and 4 hours after IFX administration and 2,000 mg orally 8 hours after IFX administration on days 1 to 3; and MXN 12 mg/m2 as an i.v. bolus on day 3. Cycles were repeated every 21 days until progressive disease (PD) or severe toxicity developed. RESULTS One patient was considered not assessable for response. Objective regression (OR) was observed in 28 of 47 patients (60%; 95% confidence interval, 46% to 74%). Six patients (13%) had a complete response (CR) and 22 (47%) had a partial response (PR). The median time to treatment failure for the whole group was 9 months (range, 1 to 28); median survival was 19 months (range, 2 to 28). There were no treatment-related deaths. The limiting toxicity was myelosuppression. Leukopenia occurred in 37 patients (77%) and was grade 3 or 4 in 19 patients (40%). Nausea and vomiting were observed in 38 patients (80%), mucositis in 16 patients (33%), and grade 2 hematuria in two patients (4%). Eight patients (16%) developed mild neurotoxicity. CONCLUSION The combination of IFX plus MXN is an active regimen against metastatic breast cancer with moderate toxicity that deserves further evaluation.

scholarly journals Salvage radiotherapy for second oligo-recurrence in patients with breast cancer

2017 ◽  
Vol 59 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Mari Miyata ◽  
Takayuki Ohguri ◽  
Katsuya Yahara ◽  
Shinsaku Yamaguchi ◽  
Hajime Imada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Objective Response ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Late Toxicity ◽  
Distant Metastases ◽  
Salvage Radiotherapy ◽  
Severe Toxicity ◽  
Term Survival ◽  
Grade 3

Abstract A new concept designated ‘oligo-recurrence (OR)’ has been proposed, which indicates one to several distant metastases/recurrences in one or more organs, which can be treated with local therapy, after the primary site of the cancer has been controlled. The purpose of this study was to assess the efficacy and toxicity of salvage radiotherapy (RT) for the second OR of breast cancer. The second OR was defined as once-salvaged patients with OR who had a second failure that was also detected as the state of OR. Twenty-one patients with second OR were treated with salvage RT and were retrospectively analyzed. The sites of the second OR were locoregional recurrence in 7 patients and distant metastasis in 14 patients. Salvage RT was performed at a median total dose of 60 Gy. Nineteen (90%) patients had an objective response. The median overall survival and progression-free survival (PFS) times were 41 and 24 months after salvage RT for the second OR, respectively. The 3-year local (in-field) control (LC) rates were 93%. The toxicities were mild; acute toxicities ≥Grade 3 were seen in one patient with Grade 3 dermatitis, and no late toxicity ≥Grade 2 was observed. In conclusion, salvage RT for the second OR was able to achieve a better LC rate and longer PFS time without inducing severe toxicity, and therefore may be a potentially effective modality for inducing long-term survival in select patients.

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