Karin van der Kooy

Bio: Karin van der Kooy is an academic researcher from Netherlands Cancer Institute. The author has contributed to research in topics: Breast cancer & Odds ratio. The author has an hindex of 3, co-authored 4 publications receiving 9516 citations.

Gene expression profiling predicts clinical outcome of breast cancer

Abstract: Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

Physical Activity and Breast Cancer Risk in Women Aged 20-54 Years

Abstract: Background/methods Although several studies have suggested that physical activity is associated with a decreased risk of breast cancer, such a decrease has not been found consistently, perhaps because physical activity was assessed in different ways and for restricted periods. Few studies have assessed the risk of breast cancer in relation to lifetime physical activity. We used data from a population-based, case-control study, including 918 case subjects (aged 20-54 years) and 918 age-matched population control subjects, to examine associations between breast cancer risk and physical activity at ages 10-12 years and 13-15 years, lifetime recreational activity, and title of longest held job. Results Women who were more active than their peers at ages 10-12 years had a lower risk of breast cancer (odds ratio [OR] = 0.68; 95% confidence interval [CI] = 0.49-0.94). Women who had ever engaged in recreational physical activity had a reduced risk of breast cancer compared with inactive women (OR = 0.70; 95% CI = 0.56-0.88). Neither very early recreational activity (before age 20 years) nor recent activity (last 5 years) was associated with a greater reduction in risk than recreational activity in the intermediate period. Furthermore, women who started recreational activities after age 20 years and women who started earlier and continued their activities throughout adult life experienced a similar reduction in risk. Lean women, i.e., women with a body mass index (weight in kg/[height in m](2)) less than 21. 8 kg/m(2), appeared to have a lower risk associated with recreational physical activity than women with a body mass index greater than 24.5 kg/m(2) (OR = 0.57 [95% CI = 0.40-0.82] and OR = 0. 92 [95% CI = 0.65-1.29], respectively). Conclusions Our findings support the hypothesis that recreational physical activity is associated with a decreased risk of breast cancer. Physical activity in early or recent life does not appear to be associated with additional beneficial effects.

p53 Protein Overexpression in Relation to Risk Factors for Breast Cancer

Abstract: To investigate whether breast tumors developing through a pathway with p53 protein overexpression (p53+) show different risk factor associations compared with breast tumors without p53 overexpression (p53-), the authors determined p53 overexpression in tissue sections of 528 patients with invasive breast cancer by using immunohistochemistry. These patients and 918 healthy controls aged 20-54 years participated in a Netherlands population-based case-control study on oral contraceptives in 1986-1989. A total of 142 tumors (27%) demonstrated clear p53 overexpression (p53+). Most risk factors did not show different associations with p53+ and p53- tumors. However, use of oral contraceptives for 9 or more years was associated with a 2.5-fold increase in the risk of p53+ tumors (95% confidence interval 1.4-4.4 ; test for trend with months of use, p = 0.01), whereas such use increased the risk of p53- tumors only 1.4-fold (95% confidence interval 0.9-2.1 ; test for trend, p = 0.06). Prolonged lactation (≥25 weeks) was associated with a 40% reduction in risk of p53+ tumors (odds ratio = 0.6 ; 95% confidence interval 0.3-1.0 ; test for trend with weeks of lactation, p = 0.09), whereas the risk of p53- tumors was not associated with lactation. The authors conclude that p53+ and p53- breast tumors are not associated with very distinct risk profiles but that the stronger associations of p53+ tumors with oral contraceptive use and lactation suggest differences in risks that deserve further investigation. If these findings can be confirmed and possible molecular mechanisms explored, this may help to elucidate the associations between these risk factors and breast cancer in general.

p53 and Neu (c-erbB-2) Overexpression in Relation to Risk Factors for Breast Cancer

Abstract: Different types of breast cancer, with and without protein overexpression of neu (c-erbB-2) or p53, were studied to determine whether there was an association with known risk factors for breast cancer. Neu and p53 protein expressions were evaluated by immunohistochemistry in primary breast tumor samples from a series of patients aged 20–54 years, who participated in a case-control study. Neu overexpression was shown in 117 out of 597 tumors (19.6%) and p53 overexpression in 142 out of 528 tumors (26.9%). Diagnosis at a young age (≤35 years) was found to be associated with p53 and neu overexpression. Age at first full-term pregnancy (≥29 years) was more strongly related to neu[+] than to neu[−] tumors. Other risk factors were not significantly associated for breast tumors categorized according to neu or p53 protein expression.

Comprehensive molecular portraits of human breast tumours

Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

Epithelial–mesenchymal transitions in tumour progression

Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer

Abstract: background The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor–positive tumors is poorly defined by clinical and histopathological measures. methods We tested whether the results of a reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancerrelated genes and 5 reference genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group (low, intermediate, or high) for each patient. results Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51, 22, and 27 percent, respectively. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low-risk, intermediate-risk, and high-risk groups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence interval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that in the high-risk group (P<0.001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P<0.001). The recurrence score was also predictive of overall survival (P<0.001) and could be used as a continuous function to predict distant recurrence in individual patients. conclusions The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor–positive breast cancer.

The fundamental role of epigenetic events in cancer

Abstract: Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.