title: Identification of intermediate risk breast cancer patients with 1-3 positive lymph nodes and excellent survival after tamoxifen as only systemic adjuvant therapy by use of markers of proliferation and apoptosis.
abstract: BACKGROUND
  According to current guidelines, patients with primary breast cancer and 1-3 lymph node metastases will in general be offered adjuvant chemotherapy.
  
  
  OBJECTIVE
  Our objective was to investigate the relationship between markers of proliferation and apoptosis with survival for patients subjected to adjuvant tamoxifen solely.
  
  
  METHODS
  Tumour cytosol samples from 409 consecutive patients with operable oestrogen receptor positive BC, stage I-III and treated with tamoxifen for 2 or 5 years were assessed for levels of caspase-cleaved cytokeratin-18 (ccCK18), an indicator of apoptosis, by use of an ELISA assay. Data on S-phase fraction (SPF) were available for 370 patients. Survival analyses were performed according to levels of ccCK18 and SPF separately, as well as combined.
  
  
  RESULTS
  A wide range of ccCK18 protein levels was found, median 9.97, range 0.0-87.3 pg/μgDNA. Increasing SPFs were significantly associated with a lower distant recurrence-free survival (DRFS) (p = 0.025) and breast cancer survival (BCS) (p = 0.046). In the group with low SPF (below mean), low amounts of ccCK/18 correlated with a shorter DRFS (p = 0.0028) and BCS (p = 0.0027). A Proliferation Index (PI); a quotient of ccCK18/SPF was constructed. Low PI (high ccCK18/SPF ratios) were significantly correlated with an improved survival both when analysed as continuous variables; DRFS (p = 0.021), BCS (p = 0.038) and when divided into quartiles; DRFS (p < 0.001) and BCS (p = 0.0012). A similar correlation was found in patients with 1-3 lymph node metastases; DRFS (p = 0.089) and BCS (p = 0.019). A Cox's proportional hazard model including age, tumour size, lymph node status, PgR and ccCK18/SPF was used for multivariate analysis. High ccCK18/SPF ratios correlated with improved survival; DRFS (HR = 0.47 (0.22-0.98), p = 0.043), and BCS (HR = 0.39 (0.16-1.00), p = 0.049), respectively.
  
  
  CONCLUSIONS
  By use of a proliferation index based on markers of proliferation and apoptosis, a group of patients with 1-3 lymph node metastases with good outcome following adjuvant tamoxifen was identified; this group could possibly be spared adjuvant chemotherapy.
authors: Department of Oncology, Sahlgrenska Academy and University Hospital, Gothenburg, Sweden; Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address: barbro.linderholm@ki.se.
authors: B K
authors: BK
authors: Linderholm
authors: S
authors: S
authors: Linder
authors: L-G
authors: LG
authors: Arnesson
authors: O
authors: O
authors: Stål
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D004273:DNA, Neoplasm / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000032:analysis* / Q000378:metabolism; D008207:Lymphatic Metastasis; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016196:S Phase; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D053538:Keratin-18; D013629:Tamoxifen; D020169:Caspases
keywords: Apoptosis; Intermediate risk breast cancer; Proliferation; Survival; Tamoxifen