Gudrun Pohl

Clinical Role of Multidrug Resistance Protein 1 Expression in Chemotherapy Resistance in Early-Stage Breast Cancer: The Austrian Breast and Colorectal Cancer Study Group

PURPOSE The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.

Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy

Our purpose was to determine the expression of the drug resistance factors multidrug resistance protein (MRP1), lung resistance protein (LRP) and P-glycoprotein (Pgp) in breast carcinoma patients treated with preoperative chemotherapy. We have studied the expression of these proteins in breast carcinomas by immunohistochemistry both prior (n = 80) and after (n = 68) preoperative chemotherapy and compared their expression with response to preoperative chemotherapy. In paired samples prior and after chemotherapy expression of drug resistance factors was significantly lower in prechemotherapy samples as compared with postchemotherapy specimens. This was observed for MRP1 (62% vs. 88%, P < 0.001), LRP (65% vs. 97%, P < 0.001) and Pgp (55% vs. 100%, P < 0.001). Prechemotherapy expression of MRP1 was more frequently observed in patients with distant metastases than in those without (50% vs. 8%, P = 0.02). No associations were observed between LRP expression and clinical parameters. Pgp expression was more frequently detected in lobular carcinomas than in ductal carcinomas (93% vs. 46%, P = 0.001) and in patients with positive lymph nodes than in patients with negative lymph nodes (65% vs. 31%, P = 0.008) but was independent of other clinical parameters. No significant associations were found between the prechemotherapy or postchemotherapy expression of either of these three proteins and response to preoperative chemotherapy. However, prechemotherapy MRP1 expression was significantly associated with shorter progression-free survival of the patients (P = 0.02), whereas no such associations were observed for either LRP or Pgp. In conclusion, preoperative chemotherapy increases the expression of MRP1, LRP and Pgp. Response to chemotherapy is not associated with pre- or postchemotherapy expression levels of these drug resistance proteins but time to progression may be influenced by prechemotherapy MRP1 expression.

Expression of Cell Cycle Regulatory Proteins in Breast Carcinomas Before and After Preoperative Chemotherapy

Molecular markers predicting response to preoperative chemotherapy would be of major clinical relevance in breast cancer. Therefore, we studied the relationship between the expression of cell cycle regulatory proteins and clinical outcome in breast cancer patients receiving preoperative chemotherapy. Expression of p21Waf1, p27Kip1, p53, cyclin D3 and Ki-67 was determined in breast carcinomas by means of immunohistochemistry both prior and after preoperative chemotherapy. Expression data were compared with both clinical parameters and response to preoperative chemotherapy with either cyclophosphamide/methotrexate/5-fluorouracil (CMF, n = 29) or epirubicin/docetaxel (ED, n = 36). In paired samples before and after preoperative chemotherapy, the percentage of p21Waf1, p27Kip1, p53 and cyclin D3 positive nuclei of tumor cells in postchemotherapy specimens was significantly higher than the percentage in prechemotherapy samples but no change in Ki-67 expression was observed. High Ki-67 expression (p = 0.02), negative estrogen receptor status (p = 0.01) and negative progesterone receptor status (p = 0.04) were associated with complete pathologic response to chemotherapy, whereas the other markers did not predict response. In conclusion, expression levels of p21Waf1, p27Kip1, p53 and cyclin D3 significantly increased after preoperative chemotherapy in breast carcinomas but only high Ki-67 expression, negative estrogen receptor status and negative progesterone receptor status were associated with complete pathologic response to preoperative chemotherapy.

High p27Kip1 Expression Predicts Superior Relapse-Free and Overall Survival for Premenopausal Women With Early-Stage Breast Cancer Receiving Adjuvant Treatment With Tamoxifen Plus Goserelin

PURPOSE To determine the predictive value of p27Kip1 in premenopausal women with early-stage hormone receptor-positive breast cancer. PATIENTS AND METHODS We retrospectively examined tumor specimens from 512 patients with breast cancer who were enrolled onto Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5. In this trial, premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease were randomly assigned to receive either 5 years of tamoxifen plus 3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil. p27Kip1 expression was assessed by immunohistochemistry, and its association with clinical outcome was determined. Statistical analyses were performed to test for interaction between p27Kip1 status and treatment. RESULTS High p27Kip1 expression (nuclear p27Kip1 staining in >/= 50% of tumor cells) independently predicted superior relapse-free survival (RFS) and overall survival (OS) in both the total study population (RFS: relative risk [RR], 0.53; 95% CI, 0.34 to 0.82; P =.004; OS: RR, 0.29; 95% CI, 0.15 to 0.58; P <.001) and patients treated with combination endocrine therapy (RFS: RR, 0.32; 95% CI, 0.16 to 0.63; P =.001; OS: RR, 0.16; 95% CI, 0.05 to 0.53; P =.003). The interaction between p27Kip1 expression and treatment was statistically significant for RFS (P =.04) but not for OS (P =.27). CONCLUSION High p27Kip1 expression was an independent predictor of responsiveness to hormonal therapy and thus may be useful for the selection of premenopausal women with early-stage hormone receptor-positive breast cancer for adjuvant combination endocrine therapy.

MRP Expression in Acute Myeloid Leukemia

To determine the clinical significance of the multidrug resistance protein (MRP) in patients with de novo AML, we have studied MRP expression of leukemic cells at diagnosis and its association with clinical outcome in 127 patients. MRP expression was determined by immunocytochemistry by means of monoclonal antibodies QCRL-l/QCRL-3. MRP expression was low, intermediate and high in 30%, 46% and 24% of the patients, respectively. MRP expression was independent of age and sex of the patients, white blood cell count, FAB subtype, serum lactate dehydrogenase levels and karyotype aberrations. MRP expression had no impact on response to induction chemotherapy. The complete remission rates were 75%, 70% and 64% for patients with low, intermediate and high expression, respectively. Patients with intermediate or high MRP expression showed a trend toward shorter overall survival (p=0.09) as compared to patients with low MRP expression. MRP does not predict for response to induction chemotherapy but intermediate or high MRP expression might be associated with shorter overall survival of the patients.

Expression of resistance markers to methotrexate predicts clinical improvement in patients with rheumatoid arthritis

Background: Methotrexate is transported into the cell by the reduced folate carrier (RFC) and out of the cell by members of the multidrug resistance protein family (MRP). Transport proteins may affect the therapeutic efficacy of this drug in patients with rheumatoid arthritis. Objective: To investigate the potential benefit of the presence of RFC and the absence of functional MRP for the efficacy of methotrexate treatment. Methods: The study involved 163 patients (116 female, 47 male; mean age 59.5 years) on methotrexate (mean weekly dose 12.2 mg). RFC was determined using reverse transcriptase polymerase chain reaction, and MRP function by flow cytometry, using a calcein acetoxymethylesther/probenecid assay. Clinical response to methotrexate was evaluated by the EULAR response criteria and the ACR 20% improvement criteria. The clinical data were obtained at the beginning of methotrexate treatment and at the time of blood sampling during ongoing therapy. Patients were divided into four groups according to the presence (+) or absence (−) of RFC and functional (f) MRP. Results: fMRP+/RFC+ and fMRP−/RFC− patients more often had good EULAR response rates (60%, p = 0.014, and 53%, p = 0.035, respectively) in comparison with the fMRP−/RFC+ group (29%); fMRP+/RFC− patients had a low frequency of good disease activity responses. Conclusions: Absence of fMRP plus presence of RFC did not prove to be related to beneficial effects of methotrexate, but the lack or the presence of both fMRP and RFC led to a significantly better therapeutic outcome. Determination of these markers may predict responsiveness to methotrexate.

Supportive treatment for anemic cancer patients.

SummaryAnemia in cancer patients is frequent but often underestimated. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with cancer. Presently, trials investigate whether treatment of anemic cancer patients with erythropoietin impacts on outcome of chemo- and/or radiotherapy and on overall survival. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients. Supportive treatment of anemic cancer patients presenting anemia-related symptoms should be performed to reduce symptoms in cancer patients and optimize outcome to anticancer therapy.ZusammenfassungViele Krebspatienten leiden zusätzlich an Anämie, doch häufig wird der negative Einfluss der Anamie-assoziierten Symptome unterschätzt. Durch diese Symptome wird die Lebensqualität der Patienten erheblich gemindert. Auch die Prognose und das Therapieansprechen können durch das Vorliegen einer Anämie verschlechtert werden. Therapiemaßnahmen inkludieren die Applikation von hämatopoetischen Wachstumsfaktoren sowie die Transfusion von Blutkonserven. Blutkonserven führen in der Regel zu einer raschen Besserung der Anämiesymptomatik, die leider oft nur kurzfristig anhält. Die Applikation von Epoietin oder Darbepoietin alfa führt zu einem Anstieg des Hämoglobins, einem verminderten Transfusionsbedarf sowie einer Verbesserung der Lebensqualität. Derzeit wird im Rahmen klinischer Studien evaluiert, ob durch die Behandlung anämischer Patienten mit Erythropoietin das Ansprechen auf Chemo- und/oder Strahlentherapie sowie die Überlebenszeit beeinflusst wird. Hämatoonkologen sollten sich der Tatsache bewusst sein, dass Anämie bei Krebspatienten ein behandlungsbedürftiges Symptom ist, und ihren Patienten daher adäquate Therapiemaßnahmen anbieten. Das supportive Behandlungskonzept der Anämie bei Krebspatienten sollte dazu beitragen, Anämie-assoziierte Symptome zu verringern und ein optimales Ansprechen auf die zytotoxische Therapie zu erlangen.

The lung resistance protein (LRP) predicts poor outcome in acute myeloid leukemia.

To determine the clinical significance of the lung resistance protein (LRP) in acute myeloid leukemia (AML), we have studied LRP expression of leukemic blasts and its association with clinical outcome in patients with de novo AML. LRP expression of leukemic blasts was determined by immunocytochemistry by means of monoclonal antibody LRP-56. LRP expression at diagnosis was detected in 31 out of 86 (36%) patients and correlated with white blood cell count (p = 0.01). The complete remission rate of induction chemotherapy was 72% for all treated patients (n = 82). The complete remission rate was 81% for patients without LRP expression but only 55% for patients with LRP expression (p = 0.01). Overall survival and disease-free survival were estimated according to Kaplan-Meier in 82 and 59 patients, respectively. At a median follow-up of 16 months, median overall survival was 17 months for LRP-negative patients but only 8 months for LRP-positive patients (p = 0.006). Disease-free survival was 9 months for LRP-negative patients and 6 months for LRP-positive patients (p = 0.078). Thus LRP predicts for poor outcome indicating that the LRP gene is a clinically relevant drug resistance gene in AML.

Pathophysiology and diagnosis of dyspnea in patients with advanced cancer

ZusammenfassungDie Prävalenz von Dyspnoe bei Tumorpatienten im fortgeschrittenen Stadium bewegt sich von 19 % bis 64 %. Um Dyspnoe bei Tumorpatienten adäquat zu behandeln, ist es notwendig, die genauen Mechanismen der Dyspnoe zu kennen. Auch die genaue Diagnosestellung kann wesentliches zur Therapieentscheidung beitragen. Klinisch sollten daher alle zu Grunde liegenden Möglichkeiten für Dyspnoe bei Tumorpatienten abgeklärt werden. Detailliertes Wissen über die mannigfaltigen Ursachen von Dyspnoe ist zwingend notwendig. Anamneseerhebung, physikalische Untersuchung und andere ausgewählte Untersuchungen sollten rasch durchgeführt werden, um schnell zu einer therapeutischen Entscheidung kommen zu können. Das Abschätzen der Quantität und der Qualität der Dyspnoe können ebenfalls dazu beitragen, die Bedürfnisse der Patienten so schnell wie möglich zu erfassen.SummaryThe reported prevalence of dyspnea in patients with various cancers ranges from 19% to 64%. For optimal clinical management of dyspnea in cancer patients, accurate diagnosis of the underlying cause and thorough understanding of the pathomechanisms of dyspnea seems mandatory. The clinical approach to a patient with advanced cancer and dyspnea should include adequate history taking, physical examination, and selected diagnostic investigations. These should be performed immediately to enable quick treatment decisions. In addition, self assessment of the intensity of dyspnea by the patient may help to assess patients needs as soon as possible.

Response to Fortunat and Röggla

cer patients” [1] we indicate that presently there is insufficient evidence to claim that erythropoietin improves survival in cancer patients. As stated in our article there was suggestive evidence from few trials that survival may be improved, whereas two other recently conducted trials indicated the contrary. Due to these inconsistent results, the three major manufacturers of erythropoietic agents recently reviewed all their data on file. This database comprises more than several thousand patients enrolled into prospective randomized trials. None of the three independent analyses revealed a difference in survival between the EPO treatment and control patients [2]. Erythropoietins increase hemoglobin, reduce transfusion need and improve physical exercise capacity and overall quality of life. The only side effect of importance is a 30 % increase in thrombotic events [3]. This is preferentially found in patients with solid tumors if erythropoietin treatment is started at high baseline hemoglobin levels. In hematological malignancies no increase in thrombotic events was noted. In summary, the overwhelming evidence of data on erythropoietin treatment in anemic patients with cancer indicates that there is a slight increase of thromboembolic complications and a large amount of data substantiating the benefit of erythropoietin treatment, in particular an increase of hemoglobin level, the reduction in transfusion need, improvement in exercise capacity and overall quality of life.