Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML)

The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.

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Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-04-0795 ◽

2004 ◽

Vol 10 (23) ◽

pp. 7896-7902 ◽

Cited By ~ 118

Author(s):

Zineb Benderra ◽

Anne-Marie Faussat ◽

Lydia Sayada ◽

Jean-Yves Perrot ◽

Driss Chaoui ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Cancer Resistance ◽

P Glycoprotein ◽

Myeloid Leukemias ◽

Resistance Protein ◽

Acute Myeloid

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Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999

Blood ◽

10.1182/blood-2010-04-277269 ◽

2010 ◽

Vol 116 (20) ◽

pp. 4077-4085 ◽

Cited By ~ 120

Author(s):

Larry D. Cripe ◽

Hajime Uno ◽

Elisabeth M. Paietta ◽

Mark R. Litzow ◽

Rhett P. Ketterling ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Remission Rate ◽

Eastern Cooperative Oncology Group ◽

Cancer Resistance ◽

Oncology Group ◽

P Glycoprotein ◽

Resistance Protein ◽

Acute Myeloid

AbstractZosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp–mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp+ patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930.

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Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia

Blood ◽

10.1182/blood.v99.10.3763 ◽

2002 ◽

Vol 99 (10) ◽

pp. 3763-3770 ◽

Cited By ~ 78

Author(s):

Dorina M. van der Kolk ◽

Edo Vellenga ◽

George L. Scheffer ◽

Michael Müller ◽

Susan E. Bates ◽

...

Keyword(s):

Myeloid Leukemia ◽

Breast Cancer Resistance Protein ◽

De Novo ◽

Refractory Disease ◽

Cancer Resistance ◽

Resistance Protein ◽

Fumitremorgin C ◽

Acute Myeloid ◽

Expression And Activity ◽

Refractory Aml

Overexpression of the breast cancer resistance protein (BCRP) efflux pump in human cancer cell lines results in resistance to a variety of cytostatic agents. The aim of this study was to analyze BCRP protein expression and activity in acute myeloid leukemia (AML) samples and to determine whether it is up-regulated due to clonal selection at relapse/refractory disease. BCRP protein expression was measured flow cytometrically with the monoclonal antibodies BXP-34 and BXP-21 in 20 paired samples of de novo and relapsed/refractory AML. BXP-34/immunoglobulin G1 ratios were observed of 1.6 ± 0.5 (mean ± SD, range 0.8-2.7) and BXP-21/immunoglobulin G2a ratios of 4.9 ± 3.0 (range 1.1-14.5) in the patient samples versus 9.8 ± 6.8 and 6.5 ± 2.4, respectively, in the MCF-7 cell line. BCRP activity was determined flow cytometrically by measuring mitoxantrone accumulation in absence and presence of the inhibitor fumitremorgin C. Mitoxantrone accumulation, expressed as mean fluorescence intensity (MFI), varied between 44 and 761 MFI (227 ± 146 MFI) and correlated inversely with BCRP expression (r = −0.58, P < .001). Addition of fumitremorgin C showed a small increase in mitoxantrone accumulation (11 ± 29 MFI, n = 40) apart from the effect of PSC833 and MK-571. No consistent up-regulation of BCRP expression or activity was observed at relapse/refractory disease; some cases showed an increase and other cases a decrease at relapse. Relatively high BCRP expression correlated with immature immunophenotype, as determined by expression of the surface marker CD34 (r = 0.54, P = .001). In conclusion, this study shows that BCRP protein is expressed at low but variable levels in AML, especially in immature CD34+cells. BCRP was not consistently up-regulated in relapsed/refractory AML.

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