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Immunohistochemical Analysis of P-Glycoprotein Expression in Breast Cancer: Clinical Correlations*

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Immunohistochemical Analysis of P-Glycoprotein Expression in Breast Cancer: Clinical Correlations* ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 25, No. 1 Copyright © 1995, Institute for Clinical Science, Inc. Immunohistochemical Analysis of P-glycoprotein Expression in Breast Cancer: Clinical Correlations* DAVID A. DECKER, M.D.,t LAURA W. MORRIS, B.S.,$ ALLAN J. LEVINE, M.D.,§ JANE E. PETTINGA, M.D . , 11 JENNIPHER L. GRUDZIEN, B.S.,f and DANIEL H. FARKAS, Ph.D.** Departments of Medicine,t Anatomic Pathology,t and Clinical Pathology,§ William Beaumont Hospital, Royal Oak, MI 48073 and Department of Biology, Oakland University,l! Rochester, MI 48309 and Department of Surgery, William Beaumont Hospital-Troy,U Troy, MI 48098 and Bio-Oncology Laboratory,** Pontiac, MI 48057 ABSTRACT Paraffin-embedded, formalin-fixed tissue (PEFFT) specimens from a subset of breast cancer patients were analyzed by immunohistochemistry to determine whether or not the presence of P-glycoprotein identified che­ motherapy resistance. Two antibodies, C219 (monoclonal) and Abl (poly­ clonal), demonstrated appropriate immunostaining. Retrospectively and prospectively, P-glycoprotein expression was determined from PEFFT of 20 breast cancer biopsies (19 patients with locally advanced or metastatic disease). Immunohistochemical staining was graded for number of positive cells (NO to N4) and intensity (10 to 13). The immunostaining N and I of both antibodies were similar. There was no correlation between N, (P = 0.13) or I, (P = 0.67) and chemotherapy response or between N, (P = 0.63) or I, (P = 0.89) and survival. Five patients had residual cancer at repeat biopsy after systemic chemotherapy for locally advanced disease. These specimens had similar N and I as the primary cancer. This assay accurately identifies P-glycoprotein expression in PEFFT and revealed no correlation between expression and chemotherapy response or survival. * Send reprint requests to David A. Decker, M.D., Cancer Care Associates, P.C., 3535 West 13 Mile Road, Suite 707, Royal Oak, MI 48073. 52 0091-7370/95/0100-0052 $01.20 © Institute for Clinical Science, Inc. IMMUNOHISTOCHEMICAL ANALYSIS OF P-GLYCOPROTEIN IN BREAST CANCER 53 Introduction tion. Clinical protocols to address these issues are being developed and reported. Intrinsic or acquired resistance to These investigations include intensive breast cancer chemotherapy remains a chemotherapy with either bone marrow major obstacle. A common factor in non­ autografting/stem cell harvesting or hema­ responsiveness is multidrug resistance topoietic growth factors and utilization of (MDR) . 1,2 In humans, two closely related chemosensitization agents that can inhibit MDR genes have been identified, MDR1 the outward transport function of P-glyco- and MDR2. Only MDR1 has been linked protein, e.g., verapamil, cyclosporin, quini- to the multidrug resistance phenotype, dine, or tamoxifen.8,9,10,11,12,13 encoding a highly homologous integral An immunohistochemical assay for transmembrane protein, Mdrl (P-glyco- MDR expression in paraffin-embedded, protein ) . 3,4 The P-glycoprotein (P for per­ formalin-fixed tissue (PEFFT) is meability) has a molecular weight of reported and its application to identify a 170,000 daltons and consists of a hydro- subset of breast cancer patients resistant phobic region with six transmembrane to chemotherapy is attempted. domains arranged in pairs, and a hydro­ philic cytoplasmic region containing Material and Methods potential nucleotide binding sites.5 This glycoprotein functions as an energy dependent outward transport pump that Antibodies to P-glycoprotein that could decreases intracellular drug accumula­ be used in PEFFT were validated. Eight (xm thick tissues sections were affixed to tion .3 ,4 Laboratory tumors expressing the MDR phenotype are resistant to a broad glass microscope slides. Tissue sections range of antineoplastic agents derived were deparaffinized with xylenes and from natural products, e.g., the vinca rehydrated through descending saline alkaloids (vincristine, vinblastine), (phosphate buffered saline, PBS). Tissue anthracyclines (doxorubicin, daunorubi- sections were incubated 30 minutes at cin), and podophyllotoxins (VP-16). Fur­ room temperature in PBS containing 5 thermore, resistance to other classes of percent non-immune serum to block non­ antineoplastic agents, the antimetabolite specific binding. Antibody dilution was trimetrexate and the synthetic dihydroxy- made using PBS containing 1 percent anthracenedione derivative mitox- normal serum. All incubations with per­ antrone, may also be mediated by this formed in a humidified chamber to pre­ vent evaporation. Monoclonal antibodies m echanism .6,7 Identification of MDR1 expression C219 (lOjxg/section) and C494 (5jxg/ holds the promise of being be a predictor section) were used in conjunction with for clinical drug resistance. Patients with Target Unmasking Fluid* as per the manu­ tumors expressing MDR1 should be poor facturers recommended protocol. Other candidates for therapy with vinca alka­ primary antibodies were polyclonal loids, anthracyclines, or podophyllotox­ M drl,t diluted 1:1000, and monoclonal ins. These individuals may be better anti-epithelial membrane antigen,t candidates for either no chemotherapy, diluted 1:5. All primary antibody incuba­ high-dose chemotherapy to increase intracellular concentration, therapy with antineoplastic agents whose resistance is * Signet Laboratories, Inc., Dedham, MA 02026. t Abl, Oncogene Science, Inc., Uniondale, NY not mediated by MDR, or protocols 11554. designed to inhibit P-glycoprotein func­ t Biomeda, Foster City, CA 94401. 54 DECKER, MORRIS, LEVINE, PETTINGA, GRUDZIEN, AND FARKAS tions were 2 hours at room temperature. A series of 19 patients treated at Biotinylated secondary antibodies,§ William Beaumont Hospital, Royal Oak diluted 1:500, were incubated 30 min­ and Troy, Michigan, was studied. utes at room temperature. Colorimetric Patients were identified either retrospec­ detection was made using Vectastain tively or prospectively from a single ABC-Alkaline phosphatase and Substrate medial oncology practice between Octo­ Kits (#SK5200).§ Endogenous alkaline ber 1988 and followed until date of death phosphatase was blocked by the addition or if still alive on April 1, 1993. Patients of Levamisole11 diluted 0.25mG/mL to the were selected if they had a biopsied substrate solution. breast cancer available in archival paraf­ Replicated sections assayed without fin measurable cancer, and received che­ the addition of primary antibody were motherapy within two months of the included to evaluate non-specific bind­ biopsy. Primary breast cancers (T2—T4b) ing from secondary antibodies and kits. were assayed in 11 patients (table I). Two Normal human kidney control sections of these (cases 8 and 14) also had meta­ were included in each assay to monitor static cancer at the time of presentation substrate incubation times and antibody (Ml). Five patients with locally advanced performance. Sections were counter­ cancer (T4b) had a diagnostic biopsy with stained with Nuclear Fast Red, dehy­ Mdrl assay followed by two to six cycles drated with alcohol, cleared with xylenes of chemotherapy and then a repeat post and mounted with Permount. A normal chemotherapy biopsy or mastectomy human tissue survey was conducted to with Mdrl assay. One patient (case 12) determine whether or not these antibod­ had a locally advanced breast cancer ies would stain PEFFT in a similar pat­ treated with chemotherapy followed by a tern to that described for similar frozen negative mastectomy specimen. She tissue specimens. C494 demonstrated experienced a chest wall recurrence poor staining on human control kidney (case 19) about one year later (Ml) and and was therefore not utilized further. again recovered chemotherapy for the The polyclonal rabbit antibody and C219 recurrent disease. Nine biopsies were both demonstrated an immunostaining from metastatic disease; either chest wall pattern on PEFFT similar to frozen speci­ or lymph node recurrence. mens. There was immunostaining on the Patients received only systemic che­ apical surface of both small and large motherapy except one who received con­ intestine, parietal cells of the stomach, current chemotherapy with mitox- Kulchitsky cells in the bowel, proximal antrone, fluorouracil, leucovorin (NFL), renal tubular cells, bile canalicular cells, and tamoxifen (case 8 ). All p atien ts hepatocytes, and adrenal cortex. Staining received at least two cycles of chemo­ was observed on the plasma membrane therapy. Response criteria were deter­ and/or cytoplasmic Golgi. Tissues mined clinically in a standard manner by expected to be negative were indeed physical exam and/or radiograms: com­ negative. The polyclonal antibody plete response (CR), partial response resulted in better resolution with more (PR), 50 percent regression from the maxi­ uniform staining at a much lower dilution mum diameter of all the initial tumors, than C219. stable disease (STAB), no change, and progression (PROG). Survival was calcu­ lated from the date of biopsy to death or if still alive on April 1, 1993. The following § Vector Laboratories, Burlingame, CA 94010. 11 Sigma Chemical Company, St. Louis, MO chemotherapy programs were used: NFL 63178. (mitoxantrone, fluorouracil, leucovorin), IMMUNOHISTOCHEMICAL ANALYSIS OF P-GLYCOPROTEIN IN BREAST CANCER 55 TABLE I Patients, Stage, Chemotherapy, Expression of P-glycoprotein, Response, and Survival Case Stage3 Chemotherapy1’ Expression of P-giycoproteinF Response11 Survival Mdr V Mdr 19 Mdr P (Ab 1) (C219) (Ab 1) 1 T2N0M0 CDF NO 10
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