Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols

  • Wesley Greaves1,

    Affiliated with

    • Lianchun Xiao2,

      Affiliated with

      • Beatriz Sanchez-Espiridion1,

        Affiliated with

        • Kranthi Kunkalla1,

          Affiliated with

          • Kunal S Dave1,

            Affiliated with

            • Cynthia S Liang1,

              Affiliated with

              • Rajesh R Singh1,

                Affiliated with

                • Anas Younes3,

                  Affiliated with

                  • L Jeffrey Medeiros1 and

                    Affiliated with

                    • Francisco Vega1Email author

                      Affiliated with

                      Journal of Hematology & Oncology20125:47

                      DOI: 10.1186/1756-8722-5-47

                      Received: 21 June 2012

                      Accepted: 1 August 2012

                      Published: 7 August 2012

                      Abstract

                      Background

                      The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2.

                      Findings

                      We analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028).

                      Conclusions

                      Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.

                      Keywords

                      Classical Hodgkin lymphoma ABCC1 ATP binding cassettes Immunohistochemistry

                      Background

                      Classical Hodgkin lymphoma (CHL) is largely a curable disease using the widely accepted current standard first-line chemotherapy regimen of doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens, with or without consolidation radiotherapy [1]. However, approximately 20% of patients with CHL do not respond following first-line therapy, or relapse quickly, and require additional treatment with salvage chemotherapy with or without stem cell transplantation [1, 2]. A drawback to the currently used treatment modalities is their association with potentially life-threatening toxicities. In addition, patients cured of CHL have an increased lifetime relative risk of death from non CHL-related causes, presumably attributable, at least in part, to therapy [3]. Thus, investigators continue to actively pursue novel prognostic biomarkers and therapeutic options in CHL patients with the goals of maintaining or improving survival rates as well as minimizing adverse side effects in patients with favorable prognosis [2]. Recently, a number of biomarkers expressed by Hodgkin and Reed-Sternberg (HRS) cells as assessed in tissue samples have been proposed as being useful for predicting prognosis in CHL patients [4]. These molecules include matrix metalloproteinase 11 (MMP11), CD20, Bcl2, MAL, HLA class II and Ki67, as well as cells within the CHL microenvironment, such as tumor-associated macrophages or subsets of tumor-infiltrating lymphocytes, including FOXP3+ regulatory T cells (Tregs) and granzyme B + T/NK cells [510].

                      The development of chemotherapy resistance by cancer cells is multifactorial [11]. ATP binding cassette (ABC) transporters comprise a ubiquitous family of transmembrane proteins that play a physiologic role in the transport of substrates across cytoplasmic membranes. ABC transporters also play a role in multidrug resistance (MDR) in multiple tumor types by using ATP as an energy source to actively expel drug substrates from the tumor cell cytoplasm into the extracellular space [12]. Expression of ABC transporters has been shown to correlate with response to therapy and prognosis in several hematological malignancies including acute myeloid leukemia and diffuse large B-cell lymphoma [1315]. Although the clinical impact of ABC transporters in CHL has not been reported, several drugs used to treat CHL are known substrates of various ABC transporters [11, 16], including doxorubicin (a substrate for ABCB1, ABCC1, ABCC2, ABCC3, ABCG2), vinblastine (a substrate for ABCB1 and ABCC1) and vincristine (a substrate for ABCC1).

                      Steidl et al. recently showed overexpression of the ABC transporter, ABCC1 (also known as multidrug resistance protein 1 - MRP1) in the therapy-resistant CHL-derived cell line, KMH2 [17]. They further showed that increased sensitivity of KMH2 cells to Adriamycin® toxicity by siRNA silencing of ABCC1. Prompted by this finding, we assessed for expression of five ABC transporters, ABCG2, ABCB1, ABCC1, ABCC2, and ABCC3, in untreated CHL tumor specimens. We also investigated the potential prognostic value of expression of these ABC transporters in CHL.

                      Design and methods

                      The overall clinical and pathologic features of the study group are summarized in Table 1. The group included 103 patients with CHL who were seen at our hospital and treated with standard front-line chemotherapy using ABVD (36 patients) or equivalent regimens including CVPP/ABDIC (cyclophosphamide, vinblastine, procarbazine, and prednisone/Adriamycin®, bleomycin, dacarbazine, lomustine and prednisone) (20 patients), MOPP/ABVD (mechlorethamine, vincristine, prednisone, procarbazine/Adriamycin®, bleomycin, vinblastine, dacarbazine) (3 patients) or NOVP (Novantrone®, vincristine, vinblastine, and prednisone) (44 patients) with and without radiotherapy. Additionally, 10 patients underwent allogeneic stem cell transplantation as salvage therapy. We analyzed for expression of five ABC transporters - ABCG2, ABCB1, ABCC1, ABCC2, and ABCC3 - in pre-treatment samples of CHL using (see Table 2). immunohistochemical methods and tissue microarrays (TMA). Seven TMAs were constructed using triplicate cores prepared from routinely processed paraffin-embedded tissue specimens as described previously [18]. Additionally, we were able to retrieve tissue blocks and use routine histologic sections to analyze ABCC1 and ABCG2 expression in 13 and 5 CHL tumors, respectively, that suffered tissue loss on the TMAs. This work was performed under an approved IRB protocol in our institution. For each marker, a tumor was considered positive when HRS cells were positive. For these proteins expression was all or none. In other words, in positive cases virtually all HRS cells were positive.
                      Table 1

                      Selected demographic and histologic features of 103 CHL patients

                      Parameter

                      n (%)

                      Gender

                       

                       Male

                      59 (57.3%)

                       Female

                      44 (42.7%)

                      Mean age

                      36 years (range: 13–85)

                      Age ≥ 45 years

                      28 (27%)

                      Ann Arbor Stage

                       

                       I

                      9 (8.7%)

                       II

                      48 (46.6%)

                       III

                      26 (25.2%)

                       IV

                      20 (19.4%)

                      IPS

                       

                       < 3

                      83 (80.6%)

                       ≥ 3

                      20 (19.4%)

                      Radiotherapy

                       

                       No

                      21 (22.6%)

                       Yes

                      72 (77.4%)

                      Chemotherapy

                       

                       ABVD

                      34 (33%)

                       ABVD + rituximab

                      2 (1.94%)

                       CVPP/ABDIC

                      20 (19.4%)

                       MOPP/ABVD

                      3 (2.9%)

                       NOVP

                      44 (42.7%)

                      CHL Histologic Subtype:

                       

                       Nodular sclerosis

                      75 (72.8%)

                       Mixed cellularity

                      22 (21.3%)

                       Lymphocyte rich

                      3 (2.9%)

                       Lymphocyte depleted

                      3 (2.9%)

                      Table 2

                      Antibodies used for immunohistochemistry

                      Antibody Common Name

                      Systematic Name

                      Clone

                      Manufacturer

                      Antibody Conc.

                      Normal Tissue Control

                      ABCG2

                      MXR, BCRP, ABC-P

                      Mouse monoclonal BXP-21

                      Santa Cruz Biotechnology Inc. Santa Cruz, CA

                      1:40

                      Placenta

                      MDR1

                      ABCB1, PGP

                      Mouse monoclonal G-1

                      Santa Cruz Biotechnology Inc. Santa Cruz, CA

                      1:100

                      Liver

                      MRP1

                      ABCC1

                      Mouse monoclonal QCRL-1

                      Santa Cruz Biotechnology Inc. Santa Cruz, CA

                      1:50

                      Stomach

                      MRP2

                      ABCC2

                      Mouse monoclonal M2 III-6

                      Abcam Inc. Cambridge MA

                      1:50

                      Liver

                      MRP3

                      ABCC3

                      Mouse monoclonal DTX1

                      Abcam Inc. Cambridge MA

                      1:50

                      Liver

                      Fisher’s exact test was used to evaluate the association of clinical response with categorical variables. The Kaplan-Meier method and log rank test were used for survival analysis. The following variables were evaluated in univariate analysis: disease stage (IV vs. I/II/III), chemotherapy (ABVD, CVP or NOVP), radiation therapy (yes and no), bone marrow metastasis (positive and negative), serum albumin (< and > 40 g/L), WBC (< and ≥ 15,000 per mm3), hemoglobin (< or > 105 g/L), lymphocytes (< and ≥ 600 per mm3 or < and ≥ 8% of WBC), gender, International Prognostic Score (IPS) (< and ≥ 3), and age (< and ≥ 45 years). Multivariate Cox proportional hazards models including variables with p value < 0.15 in univariate analysis were fitted to evaluate the association of survival with demographic and clinical factors. Variables with p values < 0.05 were considered statistically significant. S plus software 8.04 (TIBCO software Inc., Palo Alto, CA) and SAS software (SAS Institute Inc., Cary, NC) were used for statistical analysis.

                      Results and discussion

                      We tested for expression of five ABC transporters in untreated tumor specimens of CHL. These transporters use as substrates chemotherapeutic agents commonly used to treat CHL patients including Adriamycin®, vincristine, vinblastine, and mitoxantrone, among others [11]. ABCG2 and ABCC1 were expressed by HRS cells in a subset of CHL tumors (Figure 1). Sixteen of 82 (19.5%) CHL were positive for ABCC1 and 25 of 77 (32.5%) CHL were positive for ABCG2 (a subset of tissue cores was variably lost on the TMAs). Both ABCC1 and ABCG2 showed cytoplasmic expression in all HRS cells (Figures 1C and F). There was no substantial difference in the intensity of expression of ABCC1 or ABCG2 by HRS cells. Variable, non-specific staining for ABCC1 and ABCG2 was also observed inconsistently in a small subset of background inflammatory cells, including plasma cells, lymphocytes, eosinophils and histiocytes, in both HRS-positive and HRS-negative cases. There was no expression of ABCB1, ABCC2 and ABCC3 by HRS cells in any case analyzed (Figures 2B, D and E). Consistent expression of both ABCC1 and ABCG2 in endothelial cells was used as an internal positive control for immunohistochemical staining (see Figures 2B and D).
                      http://static-content.springer.com/image/art%3A10.1186%2F1756-8722-5-47/MediaObjects/13045_2012_Article_249_Fig1_HTML.jpg
                      Figure 1

                      Immunohistochemical expression of ABC proteins in positive controls and CHL tumors. A. ABCC1 is expressed by gastric glands (positive control). B. CHL with negative expression of ABCC1 by HRS cells; scattered histiocytes are weakly positive. C. CHL with HRS cells positive for cytoplasmic expression of ABCC1. D. Placenta with ABCG2 expression in trophoblastic cells (positive control). E. CHL with HRS cells negative for ABCG2; endothelial cells and scattered inflammatory cells are positive. F. CHL with HRS cells positive for cytoplasmic expression of ABCG2.

                      http://static-content.springer.com/image/art%3A10.1186%2F1756-8722-5-47/MediaObjects/13045_2012_Article_249_Fig2_HTML.jpg
                      Figure 2

                      Immunohistochemical expression of ABC proteins in positive controls and call tumors. A. Canalicular staining pattern of MDR1 in liver (positive control). B. MDR1 is not expressed in the HRS cells of CHL (white arrows); endothelial cells are positive (black arrow). C. Canalicular staining pattern of ABCC2 in liver (positive control). D. HRS cells are negative for ABCC2; endothelial cells and scattered lymphocytes are positive. E. Hepatocytes show cytoplasmic expression of ABCC3 (positive control). F. HRS cells are negative for ABCC3.

                      We sought to determine if there was an association between expression of either ABCC1 or ABCG2 and clinical endpoints, such as response to treatment (refractory disease vs non-refractory disease), overall survival (OS), and failure free survival (FFS). Admittedly, the numbers are relatively small hampering this analysis. In this study FFS was defined as lack of disease progression, recurrence or death. Refractory disease was defined as patients with only a partial response to therapy, or recurrence within the first 18 months of initial therapy [19, 20]. The log rank test showed that ABCC1 expression was marginally associated with FFS: 19 of 66 ABCC1 negative patients and 7 of the ABCC1 positive patients experienced treatment failure. The estimated 5-year FFS probabilities were 80.7% (95% CI:71.4% -91.2%) for ABCC1 negative group and 68.8% (95% CI:49.4%-95.7%) for the ABCC1 positive group, respectively (p = 0.06, Figure 3). Multivariate analysis after adjusting for the effects of age, hemoglobin level, and albumin level suggested that ABCC1 expression was an independent prognostic marker for FFS. Patients with ABCC1 expression had a higher risk of treatment failure than patients without ABCC1 expression (HR = 2.88, 95% CI: 1.18-7.01, p = 0.02, Table 3). Fisher’s exact test suggested that ABCC1 expression was also associated with initial response to treatment (primary refractory vs non-primary refractory). Six of 16 patients (37.5%) with ABCC1 expression versus 6 of 66 patients (9.1%) without ABCC1 expression were primary refractory (p = 0.01). This finding supports the results of Steidl and colleagues in the KMH2 cell line [17] and suggests that expression of ABCC1 may contribute to primary drug resistance in CHL. Three of 16 patients with ABCC1 positive tumors and 11 of 66 patients with ABCC1 negative tumors died, no significant difference was detected in OS between the ABCC1 positive and negative groups (p = 0.74). ABCC1 expression was not significantly associated with other clinical parameters (Table 4). Fisher’s exact test was also used to compare the patient characteristics between ABCC1 known and ABCC1 unknown groups (Additional file 1: Table S1). More patients 45 years of age or older had ABCC1 measurements (17/28, 60.7%) (p value =0.0036). A majority of patients who received CVPP treatment had ABCC1 measurements (18/20, 90%) (p value = 0.049). No other significant difference was detected.
                      http://static-content.springer.com/image/art%3A10.1186%2F1756-8722-5-47/MediaObjects/13045_2012_Article_249_Fig3_HTML.jpg
                      Figure 3

                      ABCC1 expression was marginally associated with failure-free survival (p = 0.06).

                      Table 3

                      Multivariate analysis to evaluate the association between FFS and ABCC1

                        

                      HR (95% CI)

                      P value

                      ABCC1

                      Positive vs. negative

                      2.84 (1.12, 7.19)

                      0.028

                      Albumin

                      <4 vs. > 4

                      1.59 (0.70, 3.63)

                      0.27

                      Age

                      > = 45 vs. <45

                      2.14 (1.53, 0.13)

                      0.13

                      * Please note: HB (<10.5 vs. > 10.5) was included in the model as a stratification factor since the proportional hazards assumption for it was not held.

                      Table 4

                      Fisher’s exact test to evaluate the association between ABCC1 and other clinical factors

                      Covariate

                      Score

                      ABCC1 Negative

                      ABCC1 Positive

                      Fisher's ExactTest (2-Tail)

                      ABCG2

                      Negative

                      39 (79.6%)

                      10 (20.4%)

                      .5227

                      Positive

                      22 (88%)

                      3 (12%)

                      Chemotherapy

                      ABVD (R-ABVD & MOPP/ABVD)

                      20 (76.9%)

                      6 (23.1%)

                      .8762

                      CVPP/ABDIC

                      15 (83.3%)

                      3 (16.7%)

                      NOVP

                      31 (81.6%)

                      7 (18.4%)

                      Radiotherapy

                      No

                      17 (89.5%)

                      2 (10.5%)

                      .3329

                      Yes

                      45 (77.6%)

                      13 (22.4%)

                      Bone marrow disease

                      No

                      62 (79.5%)

                      16 (20.5%)

                      1.000

                      Yes

                      3 (100%)

                      0 (0%)

                      Stage IV disease

                      No

                      53 (80.3%)

                      13 (19.7%)

                      1.000

                      Yes

                      13 (81.3%)

                      3 (18.8%)

                      Hemoglobin

                      ≥105 g/l

                      58 (79.5%)

                      15 (20.5%)

                      .6811

                      < 105 g/l

                      8 (88.9%)

                      1 (11.1%)

                      Albumin

                      ≥ 40 g/l

                      35 (79.5%)

                      9 (20.5%)

                      1.000

                      < 40 g/l

                      23 (82.1%)

                      5 (17.9%)

                      WBC

                      <15,000 per mm3

                      62 (79.5%)

                      16 (20.5%)

                      .5814

                      ≥15,000 per mm3

                      4 (100%)

                      0 (0%)

                      Lymphocytes

                      < 600 per mm3

                      52 (80%)

                      13 (20%)

                      1.000

                      ≥ 600 per mm3

                      11 (78.6%)

                      3 (21.4%)

                      Age ≥45

                      < 45 years

                      51 (78.5%)

                      14 (21.5%)

                      .5028

                      ≥ 45 years

                      15 (88.2%)

                      2 (11.8%)

                      Sex

                      Female

                      26 (76.5%)

                      8 (23.5%)

                      .5731

                      Male

                      40 (83.3%)

                      8 (16.7%)

                      IPS

                      <3

                      51 (77.3%)

                      15 (22.7%)

                      .2811

                       

                      ≥3

                      14 (93.3%)

                      1 (6.7%)

                       

                      Expression of ABCG2 by HRS cells was not significantly associated with OS, FFS or initial response to treatment. The lack of association of ABCG2 expression with treatment refractoriness, in contrast to ABCC1, is not fully explained, and relatively little is known about the differential substrate profiles of these two proteins. However, some authors have shown that certain drugs that are poor ABCC1 substrates, such as mitoxantrone (a type 2 topoisomerase inhibitor), are associated with overexpression of ABCG2 in vitro[11, 21], and such differences may have played a role in the discordant impact of these two proteins on therapy resistance in this patient cohort.

                      Conclusions

                      In summary, ABCC1 and ABCG2 are expressed by HRS cells in a subset of CHL tumors. Univariate and multivariate analyses showed that expression of ABCC1 by HRS cells is associated with an increased risk of tumor progression, treatment resistance or death in CHL patients. Our findings corroborate those published by Steidl and colleagues [17] in the KMH2 cell line and provide evidence that expression of ABCC1 may be useful as an indicator of poorer FFS or failure to respond to therapy in CHL patients who are treated with standard regimens. Additionally, ABCC1 may serve as a potential target for therapeutic intervention by increasing susceptibility to chemotherapy.

                      Abbreviations

                      CHL: 

                      Classical Hodgkin lymphoma

                      ABVD: 

                      Adriamycin, bleomycin, vinblastine, and dacarbazine

                      HRS: 

                      Hodgkin Reed-Sternberg cells

                      MMP11: 

                      Matrix metalloproteinase 11

                      ABC: 

                      ATP binding cassette

                      MDR: 

                      Multidrug resistance

                      CVPP: 

                      Cyclophosphamide, vinblastine, procarbazine, and prednisone

                      NOVP: 

                      Novantrone, vincristine, vinblastine, and prednisone

                      TMA: 

                      Tissue microarrays

                      WBC: 

                      White blood count

                      IPS: 

                      International prognostic index

                      FFS: 

                      Failure free survival

                      OS: 

                      Overall survival.

                      Declarations

                      Acknowledgements

                      This work was supported by funds from the K08 Physician-Scientist Award 1 K08 CA143151-01 (NIH) (to FV) SPORE Lymphoma grant UT M.D. Anderson Cancer Center Lymphoma SPORE 1P50CA136411-01A1 (to FV). A subset of patient samples were provided with assistance from the Biospecimens Core of the Lymphoma SPORE.

                      *Dr Beatriz Sanchez-Espiridion collaborated in this work as a visiting scientist supported by the Department of Pathology, M.D. Anderson España and by Centro Nacional de Investigationes Oncologicas (CNIO), Madrid (Spain).

                      Authors’ Affiliations

                      (1)
                      Department of Hematopathology, Unit 72, The University of Texas MD Anderson Cancer Center
                      (2)
                      Biostatistics, The University of Texas MD Anderson Cancer Center
                      (3)
                      Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center

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                      © Greaves et al.; licensee BioMed Central Ltd. 2012

                      This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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