Vesa Kataja

A common coding variant in CASP8 is associated with breast cancer risk

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 −202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9–15 studies, comprising 11,391–18,290 cases and 14,753–22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85–0.94) and 0.74 (95% c.i.: 0.62–0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; Ptrend = 1.1 × 10−7) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02–1.13) and 1.16 (95% c.i.: 1.08–1.25), respectively; Ptrend = 2.8 × 10−5). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.NOTE: In the version of this article initially published, there was an error that affected the calculations of the odds ratios, confidence intervals, between-study heterogeneity, trend test and test for association for SNP ICAM5 V301I in Table 1 (ICAM5 V301I); genotype counts in Supplementary Table 2 (ICAM5; ICR_FBCS and Kuopio studies) and minor allele frequencies, trend test and odds ratios for heterozygotes and rare homozygotes in Supplementary Table 3 (ICAM5; ICR_FBCS and Kuopio studies). The errors in Table 1 have been corrected in the PDF version of the article. The errors in supplementary information have been corrected online.

Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial

BACKGROUND We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). PATIENTS AND METHODS A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models. RESULTS Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC; for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77; 95% confidence interval (CI) 0.61-0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS P interaction = 0.025). CONCLUSIONS Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.

A recurrent mutation in PALB2 in Finnish cancer families

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2–PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.

Fluorouracil, Epirubicin, and Cyclophosphamide With Either Docetaxel or Vinorelbine, With or Without Trastuzumab, As Adjuvant Treatments of Breast Cancer: Final Results of the FinHer Trial

PURPOSE Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive cancer are unknown. PATIENTS AND METHODS One thousand ten women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment. RESULTS Women assigned to docetaxel had better distant disease-free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure. CONCLUSION Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.

Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis

Purpose: In the present study, we investigated the expression and prognostic value of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer as well as their relation to transcription factor activator protein (AP)-2 and HER2 oncogene. The role of invasion and metastasis-promoting MMPs and their potential regulators, AP-2 and HER2, is currently still unclear in breast cancer. Experimental Design: MMP-2 and MMP-9 expressions were analyzed immunohistochemically in a large prospective series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital (Kuopio, Finland). The relation of MMP-2 and MMP-9 expressions to AP-2, HER2, clinicopathological data, and survival was investigated. Results: Both MMP-2 and MMP-9 were expressed in the cytoplasm of malignant and stromal cells. High expression of MMPs in carcinoma cells was related to small tumors (T1, stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of MMP-2 and MMP-9 in carcinoma cells, but not in stromal cells, was related to high AP-2 expression. Positive stromal MMP-2 expression was associated with HER2 overexpression in the whole patient group and in the node-negative patient subgroup. Positive stromal MMP-9 expression was related to HER2 overexpression in estrogen receptor (ER)-positive disease. In the univariate survival analysis, positive stromal MMP-9 predicted shorter recurrence-free survival (RFS; P = 0.0389) and breast cancer-related survival (BCRS; P = 0.0081) in ER+ disease, especially in the subgroup of ER+ tumors of ≤2 cm in diameter (T1; P = 0.0031 for RFS, and P = 0.0089 for BCRS). High MMP-9 expression in cancer cells predicted longer RFS (P = 0.0351) in the whole patient group. In the multivariate analysis of the whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells (P = 0.0248), HER2 overexpression (P = 0.0001), and advanced-stage disease (P = 0.0002). Shorter BCRS was predicted by advanced-stage disease (P < 0.0001). Conclusions: Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2. Positive stromal MMP-9 expression predicts poor survival in the hormone-responsive small tumors, whereas MMP-9 expression in carcinoma cells favors survival. Evaluation of MMP-9 expression seems to add valuable information on breast cancer prognosis.

A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

NAD(P)H:quinone oxidoreductase 1 NQO1 * 2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1*2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 × 10−6) and in p53-aberrant tumors (P = 6.15 × 10−5). Survival after metastasis was reduced among NQO1*2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1*2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.

Safety and Efficacy Results of a Randomized Trial Comparing Adjuvant Toremifene and Tamoxifen in Postmenopausal Patients With Node-Positive Breast Cancer

PURPOSE In this multicenter trial, toremifene 40 mg/d was compared with tamoxifen 20 mg/d, both given orally for 3 years to postmenopausal, axillary node-positive women after breast surgery. PATIENTS AND METHODS The first 899 patients (toremifene, n = 459; tamoxifen, n = 440) of the total of 1,480 patients accrued to the trial were included in this scheduled safety analysis. The mean follow-up time was 3.4 years. RESULTS The two treatment groups were well balanced with respect to patient and disease characteristics. The subjective side-effect profile was similar in both treatment groups. Slightly more vascular complications (deep vein thromboses, cerebrovascular events, and pulmonary embolisms) were seen among tamoxifen-treated patients (5.9%) as compared with toremifene-treated patients (3.5%) (P: =.11), whereas bone fractures (P: =.09) and vaginal leukorrhea (P: =.05) were more common in the toremifene group. The number of subsequent second cancers was similar. The breast cancer recurrence rate was 23.1% (n = 106) in the toremifene group and 26.1% (n = 115) in the tamoxifen group (P: =.31). When only patients with estrogen receptor (ER)-positive cancer were considered (n = 556), the risk for breast cancer recurrence was nonsignificantly lower among the toremifene-treated women, with a hazards ratio of 0.74 (90% confidence interval, 0.52 to 1.04; P: =.14). The mean time to breast cancer recurrence and overall survival were similar in both groups. CONCLUSION The side-effect profile of toremifene resembles that of tamoxifen. The efficacy of toremifene seems to be no less than that of tamoxifen. The trend for fewer breast cancer recurrences in the ER-positive subgroup is encouraging, but a longer follow-up is needed to confirm this.

Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study

IntroductionSome molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site.MethodsWe identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes.ResultsA total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR.ConclusionsBreast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.

5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy—A randomised study

166 patients receiving moderately emetogenic chemotherapy were entered into a randomised prospective study in which the efficacy of single dose ondansetron 8 mg, tropisetron 5 mg and granisetron 3 mg in the prophylaxis of acute vomiting was evaluated. 130 patients were evaluable for analysis. During the 24 h following the start of chemotherapy complete control of vomiting was achieved in 80% [95% confidence interval (CI) 73.1; 86.9] of patients receiving granisetron compared with 75% (95% CI 67.1; 82.1) of those on tropisetron and 69% (95% CI 60.5; 76.5) on ondansetron. The patients experienced significantly fewer failures with granisetron (6.2%, 95% CI 2.1; 10.3) than with either ondansetron (14.6%, 95% CI 8.5; 20.6) or tropisetron (13.8%, 95% CI 7.9; 19.7). When asked, 34 (26%) patients out of 130 expressed no preference, 54 (42%) preferred granisetron, 22 (17%) preferred ondansetron and 20 (15%) preferred tropisetron. All the 5-HT3 receptor antagonists were highly effective in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy. The observed differences in the control of emesis, although statistically significant, may not have clinical significance.