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Biomedical subjects

K Holli

Publications and source records attributed to K Holli.

At least 19 recordsLinked to original sources
PubMed2001

Omission of histologic grading from clinical decision making may result in overuse of adjuvant therapies in breast cancer: results from a nationwide study.

PURPOSE: To investigate the influence of routinely performed histologic grading on breast cancer outcome prediction and patient selection for adjuvant therapy. PATIENTS AND METHODS: The analysis is based on a cohort of 2,842 women diagnosed with breast cancer and comprising 91% of all breast cancers diagnosed in five defined geographical regions in Finland in 1991 through 1992. Data on clinicopathologic factors and follow-up were collected from hospital case records and national registries. Histologic grade assessed at diagnosis and other clinicopathologic data were available for 1,554 operable unilateral invasive carcinomas. The relative value of grade with respect to competing prognostic factors was estimated with the Cox proportional hazards model and logistic regression. Interactions and nonlinearity of factors were accounted for by using an artificial neural network. RESULTS: Histologic grade was correlated strongly with survival in the entire series and in all subgroups studied. Women with well-differentiated node-negative cancer had a 97% 5-year distant disease-free survival rate as compared with 78% for women with poorly differentiated cancer. Grade was an independent prognostic factor in multivariate models and increased the predictive accuracy of a neural network model. Inclusion of grade data in a Cox multivariate model based on tumor size and hormone receptor status in node-negative cancer increased the proportion of patients with 5% or less risk for distant recurrence at 5 years from 15% to 54%. CONCLUSION: Even when assessed by pathologists who have no special training in breast cancer pathology, histologic grade has substantial and independent prognostic value in breast cancer. Omission of grading from clinical decision making may result in considerable overuse of adjuvant therapies.

Adult↗
PubMed2001

Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population.

To date, two major familial breast cancer predisposition genes, BRCA1 and BRCA2, have been identified with hundreds of germ-line mutations, accounting for 5--10% of all breast cancer and 40--60% of all inherited breast cancer. Unexpectedly elevated incidence of breast cancer, especially in the older age classes, was observed in a Western Finnish region representing a relatively homogeneous population. This study was designed to test the hypothesis that there are inherited BRCA1 or BRCA2 mutations, which confer variable and/or age-dependent penetrance on carriers. Expecting a founder effect, we searched for geographical clustering of breast cancer cases and searched for associations between the affected phenotype and shared genomic segments in the BRCA1 and BRCA2 genomic regions. Our haplotype association study did not reveal any founder effects for either BRCA1 or BRCA2. However, there were two mutations prevalent in this geographical area with minor founder effects, BRCA2 T8555G and 999del5. This is one of the few geographically ascertained, population-based studies that indicate an overall frequency of BRCA1 and BRCA2 mutations at about 2--3% in all breast cancer cases. The geographical clustering of breast cancer cases was not explained by BRCA1 or BRCA2 genes.

Age of Onset↗
PubMed2001

c-erbB-2 positivity is a factor for poor prognosis in breast cancer and poor response to hormonal or chemotherapy treatment in advanced disease.

The aim of this work was to evaluate the prognostic and predictive values of c-erbB-2 in breast cancer. 650 patients were enrolled. The amplification/overexpression of c-erbB-2 from fresh frozen or paraffin-embedded breast tumour tissue samples was analysed by polymerase chain reaction (PCR) technique (75%), immunohistochemically (17%) or by Southern blot analysis (8%). 126 patients (19%) were positive for c-erbB-2. 148 patients developed metastatic disease, but only 35 were positive for c-erbB-2. Positivity for c-erbB-2 was significantly associated with node positivity, large tumour size, high grade of malignancy, low receptor status, postmenopausal status, and with a shorter overall survival. In multivariate regression analysis, only tumour size and nodal involvement were risk factors for poor survival when analysed separately together with c-erbB-2 and receptor status. Metastatic patients with c-erbB-2 positivity had a significantly shorter survival and disease-free survival (DFS) than the c-erbB-2-negative patients. 29 advanced patients with c-erbB-2 positivity showed a poor response rate to hormonal, non-anthracycline-based and anthracycline-based therapies. Positivity for the c-erbB-2 is a poor prognostic factor in breast cancer, but it also emerges as predictive of the response to hormonal or chemotherapy treatment once the disease has recurred.

Antineoplastic Agents, Hormonal↗
PubMed2001

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.

Breast Neoplasms↗
PubMed2001

Lumpectomy with or without postoperative radiotherapy for breast cancer with favourable prognostic features: results of a randomized study.

The aim of this trial was to study the value of adding post-operative radiotherapy to lumpectomy in a subgroup of breast cancer patients with favourable patient-, tumour-, and treatment-related prognostic features. 152 women aged over 40 with unifocal breast cancer seen in preoperative mammography were randomly assigned to lumpectomy alone (no-XRT group) or to lumpectomy followed by radiotherapy to the ipsilateral breast (50 Gy given within 5 weeks, XRT group). All cancers were required to be invasive node-negative, smaller than 2 cm in diameter and well or moderately differentiated, to contain no extensive intraductal component, to be progesterone receptor-positive, DNA diploid, have S-phase fraction </=7 and be excised with at least 1 cm margin. During a mean follow-up time of 6.7 years, 13 (18.1%) cancers recurred locally in the no-XRT and 6 (7.5%) in the XRT group (P = 0.03). There was no difference between the groups in the ultimate breast preservation rate (95.0% vs. 94.4% in XRT and no-XRT, respectively, P = 0.88), distant metastasis-free survival (P = 0.36), or 5-year cancer-specific survival (97.1% in XRT and 98.6 in no-XRT). Radiation therapy given after lumpectomy reduces the frequency of ipsilateral breast recurrences even in women with small breast cancer with several favourable clinical and biological features. However, the breast preservation rate may not increase due to more frequent use of salvage mastectomies in patients treated with postoperative radiotherapy.

Adult↗
PubMed2000

Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group.

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.

Antineoplastic Agents, Hormonal↗
PubMed2000

Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.

Aged↗
PubMed2000

Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer.

The role of estrogen (ER) and progesterone receptors (PR) in breast cancer is well established. Identification of the second human estrogen receptor, the estrogen receptor beta (ERbeta), prompted us to evaluate its role in breast cancer. We studied the expression of ERbeta by immunohistochemistry and mRNA in situ hybridization in 92 primary breast cancers and studied its association with ERalpha, PR, and various other clinicopathological factors. Sixty percent of tumors were defined as ERbeta-positive (nuclear staining in >20% of the cancer cells). Normal ductal epithelium and 5 of 7 intraductal cancers were also found to express ERbeta. Three-fourths of the ERalpha- and PR-positive tumors were positive for ERbeta, whereas ERalpha and PR were positive in 87% and 67% of ERbeta-positive tumors, respectively. ERbeta was associated with negative axillary node status (P < 0.0001), low grade (P = 0.0003), low S-phase fraction (P = 0.0003), and premenopausal status (P = 0.04). In conclusion, the coexpression of ERbeta with ERalpha and PR as well as its association with the other indicators of low biological aggressiveness of breast cancer suggest that ERbeta-positive tumors are likely to respond to hormonal therapy. The independent predictive value of ERbeta remains to be established.

Adult↗
PubMed2000

Information and communication in the context of a clinical trial.

The aim of this study was to determine the communicative needs of the patients in the context of being invited to participate in a clinical trial. A questionnaire was sent to 299 patients with breast cancer randomised in a trial of adjuvant therapy. It was returned by 261 (87%) of them. Ninety-one per cent (231/255) of the patients regarded the information provided as easy or quite easy to understand. However, the method of treatment allocation was unclear to most patients: 51% (128/251) thought that the doctor had chosen the treatment while only 23% (57/251) knew that they had been randomised. Younger and better educated patients had a better understanding. For 55% (125/226) of the patients written information had been helpful in decision making. This correlated highly with the education of the patient. Sixty-eight per cent (174/255) of the patients thought that they had enough time for decision-making. Less educated patients and older patients had needed more time. Eighty-seven per cent (218/251) were happy with their decision to participate. While most patients are satisfied with the information received, there is a poor understanding of how treatment is allocated. Information should be modified for older and less-educated patients. The needs of the patients when offered participation in a clinical trial are clear information, enough time to consider the options and psychological support.

Adult↗
PubMed2000

Toremifene. where do we stand?

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.

Antineoplastic Agents, Hormonal↗
PubMed2000

Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer.

Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15-20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40 mg toremifene or 20 mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40 mg toremifene and 20 mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.

Age Factors↗
PubMed2000

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.

Adult↗
PubMed1999

Quality control in health care: an experiment in radiotherapy planning for breast cancer patients after mastectomy.

PURPOSE: The importance of evaluating and improving quality in clinical practice is now generally acknowledged. In this study we estimated different sources of variation in radiotherapy planning for breast cancer patients after mastectomy and sought to test the applicability of a reproducibility and repeatability (R&R) study in a clinical context. METHODS: Eleven radiation oncologists planned radiotherapy three times for three different kinds of breast cancer patients without knowing they were handling the same patient three times. Variation was divided into different components: physicians as operators, patients as parts, and repeated measurements as trials. Variation due to difference across trials (repeatability), that across the physicians (reproducibility), and that across the patients (variability) were estimated, as well as interactions between physicians and patients. Calculation was based on the sum of squares, and analysis was supported by various graphical presentations such as range charts and box plots. RESULTS: Some parts of the planning process were characterized by higher and different kinds of variation than the others. Interphysician variation (i.e., reproducibility) was not high but there were some clearly outlying physicians. The highest variation was in repeatability (= intraphysician variation). The major part of the variation was, however, that from patient to patient: 33% of the total in Parameter 1 and 85% of the total in Parameter 2. CONCLUSIONS: R&R studies are applicable and are needed to evaluate and improve quality in clinical practice. This kind of analysis provides opportunities to establish which kinds of patients require particularly careful attention, which points in the process are most critical for variation, which are the most difficult aspects for each physician and call for more careful description in documents, and which physicians need further training.

Analysis of Variance↗
PubMed1999

The visibility of cancer on earlier mammograms in a population-based screening programme.

The aim of this study was to examine how frequently the later-round screen-detected and interval breast cancers were visible in earlier screening mammograms by retrospective review and to compare their radiological and clinicopathological features with those diagnosed by primary screening. In a population-based mammography screening programme 63,731 women aged 50-59 years were invited and 56,158 examinations were carried out in the period 1987-1992 in the Tampere area in Finland. A total of 276 breast cancers were detected, of which 131 were diagnosed on later screening rounds or were interval cancers. A retrospective review of previous screening mammograms was carried out in 130 cases by the radiologist who diagnosed the breast cancer and thus knew the exact location of the tumour, no blinded review was carried out. 43 (33%) cancers were visible, 84 (65%) were not visible and 3 (2%) not included on the mammogram in a retrospective review. Later round screen-detected cancers were statistically significantly more often visible in earlier screening mammograms (43%) than interval cancers (19%) (P = 0.002). Tumours missed by screening mammography but which were visible on retrospective review were often histologically well-differentiated and were more often diagnosed in the subsequent screening round than by clinical diagnosis as interval cancers. If all retrospectively visible interval cancers had been diagnosed by screening 19% (10/54) of the interval cancers could have been avoided. If all retrospectively visible cancers had been diagnosed at the time of false-negative screening or assessment 65% (84/130) of all patients would have benefitted from an earlier diagnosis compared with the actual figure of 31% (41/130).

Breast Neoplasms↗
PubMed1999

Smoking and survival from lung cancer.

The role of smoking in the etiology of lung cancer is well known but less is known about whether smoking also affects the pathological process. In the present analysis 290 lung cancer patients were divided into three equal-sized groups according to lifetime cigarette consumption (heavy, moderate, light/none). The age of the patient, histology, TNM and S-phase fraction of the tumor were confirmed as prognostic factors. The association between smoking and these factors was evaluated. There was a significant difference in histological type of tumor; adenocarcinomas were more common than other types among light smokers. Tumor size, nodal status and occurrence of distant metastases did not differ significantly between the smoking groups. Heavy smokers had a greater frequency of aneuploid tumors and the S-phase fraction was higher among these patients but neither of these differences was statistically significant. Survival analysis indicated no statistically significant association between survival and lifetime total cigarette consumption. Apart from histological type, smoking is not materially associated with clinical and biological prognostic factors, nor does smoking materially affect the survival of lung cancer patients. Our study material was relatively small and therefore not of sufficient power to detect small effects.

Aged↗
PubMed1999

Hereditary breast cancer.

Information on genetics is in process of exponential growth, with a corresponding recognition that most medical information, screening and diagnostic tests, and disease processes have a genetic component. Hereditary breast cancer is a good example, showing the complexity of cancer genetics in a clinical context. The contribution of family history to the risk of developing breast cancer has been appreciated for some time. Breast cancer was believed to be a result of multiple genetic and environmental factors. Today it is known that single genes are also responsible for breast cancer and some of these genes (BRCA1 and BRCA2) can be identified by genetic testing. Genetic information on breast cancer is, however, still limited and although the tests that are now available can be beneficial, they also carry some risks and limitations.

BRCA2 Protein↗