title: Breast cancer after curative chemotherapy in non-Hodgkin's lymphoma: examination of the role of drug resistance and retrospective comparison to the outcome of de novo breast cancer.
abstract: We examined the outcome of patients who developed breast cancer after curative chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to the outcome of a retrospectively selected matched-pair group of patients with de novo breast cancer, and evaluated the role of drug resistance-related protein (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented with breast cancer (BC) in complete remission after CHOP for NHL. The median age was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6 courses of CHOP, and were in complete remission. These patients were compared to a matched-pair group of de novo BC patients selected from our database over the same time period. Breast cancer tissue was stained by immunohistochemistry for drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in 12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10 stage IV and were treated with conventional chemotherapy regimens. All progressed early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and soft tissue (n=5), and received second-line chemotherapy with mitomycin-C + vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01). Time from NHL to breast cancer development was 19 (14-27) months in patients with positive drug resistance proteins (group A), and 37 (26-56) months in patients with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with stage IIIA/B disease, there was no difference between the examined and control matched-pair group in median TTP, but there was in overall survival (OS) (23 vs 36 months, p=0.029). In advanced disease, there were more responders in the control vs the examined group (p=0.07). Patients in the control matched-pair group had more prolonged OS when compared to group A patients who developed BC in <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing shortly after a complete response in NHL, is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of drug resistance mechanisms concerning MDR, MRP and LRP indicates that most of these patients have BC that overexpress these proteins leading to the suggestion that these mechanisms might be a part of the aggressive disease phenotype and partially explain the poor outcome.
authors.affiliation: Department of Pathophysiology, Laikon General Hospital, Athens University School of Medicine, 11527 Athens, Greece. tsavari1@otenet.gr
authors.forename: N
authors.initials: N
authors.lastname: Tsavaris
authors.forename: C
authors.initials: C
authors.lastname: Kosmas
authors.forename: H
authors.initials: H
authors.lastname: Zorzos
authors.forename: A
authors.initials: A
authors.lastname: Lazaris
authors.forename: M
authors.initials: M
authors.lastname: Vadiaka
authors.forename: A
authors.initials: A
authors.lastname: Dimitrakopoulos
authors.forename: M P
authors.initials: MP
authors.lastname: Siakantaris
authors.forename: S
authors.initials: S
authors.lastname: Rokana
authors.forename: E
authors.initials: E
authors.lastname: Papalambros
authors.forename: G A
authors.initials: GA
authors.lastname: Pangalis
authors.forename: P
authors.initials: P
authors.lastname: Davaris
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000378:metabolism; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007120:Immunochemistry; D008228:Lymphoma, Non-Hodgkin / Q000150:complications* / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000378:metabolism; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface / Q000032:analysis / Q000378:metabolism; D012189:Retrospective Studies; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003520:Cyclophosphamide; D004317:Doxorubicin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011241:Prednisone; D017027:Protein Tyrosine Phosphatases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface; D014750:Vincristine; C516841:PTPRA protein, human