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Kaija Holli

Publications and source records attributed to Kaija Holli.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer.

Biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germ line mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations, two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared with 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) associated previously with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial [P = 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI) 1.5-103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9, 95% CI 0.9-56.4), compared with 1/1107 in controls, suggesting an apparent yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer-associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.

Ataxia Telangiectasia↗
PubMed2006

Generalisability of survival estimates for patients with breast cancer--a comparison across two population-based series.

The purpose of the study was to analyse the generalisability and geographic transportability of survival estimates produced by commonly used prognostic factors. We compared the influence of tumour size, histologic grade, axillary nodal status, oestrogen and progesterone receptor contents, age at diagnosis and two prognostication schemes (the Nottingham Prognostic Index and St. Gallen criteria) in two nationwide cohorts of patients diagnosed with breast cancer in 1991-2, the FinProg (n=2923, Finland) and the SEER series (n=43,249, the United States (US)). Eight-year estimates of breast cancer-specific (84% versus 80%), relative (86% versus 83%), and overall (70% versus 69%) survival were slightly more favourable in the SEER than in the FinProg series, respectively. Despite differences in demographic variables and the frequency of use of adjuvant therapies and mammography screening between the series, the prognostic factors examined produced close to overlapping survival curves with similar shapes. The results suggest that quantitative survival estimates based on frequently used prognostic factors and prognostication schemes are generalisable and transportable between large, unselected cohorts of breast cancer patients.

Adult↗
PubMed2006

Population-based mammography screening results in substantial savings in treatment costs for fatal breast cancer.

AIMS: The aim was to assess the effect of population-based mammography screening on treatment costs for fatal breast cancer in Turku, Finland. MATERIALS AND METHODS: The study included 556 women with invasive breast cancer, diagnosed at the age of 40-74 years in 1987-1993: 427 in the screened group (screen-detected or interval cancer) and 129 in the unscreened group (not yet invited or refused screening). Both groups were followed up for 8 years from diagnosis. RESULTS: In the unscreened group, 32 (25%) patients died of breast cancer versus 49 (12%) in the screened group (p < 0.001). The non-discounted mean treatment costs were 2.8-fold for those dying of breast cancer compared to survivors: 26,222 euros versus 9,434 euros; the difference between means was 16,788 euros (95% CI 14,915-18,660) (p<0.001). The mean costs for fatal cases were high, irrespective of the way cancer was detected: 23,800 euros in the unscreened group versus 27,803 euros in the screened group; the difference between means was -4,003 euros (-10,810 to 2802) (p=0.245). In the unscreened group, patients with fatal breast cancer accounted for 41% (0.76/1.87 million euros) of the total treatment costs versus 29% (1.36/4.76 million euros) in the screened group. It was estimated that about one third of costs for fatal breast cancer were avoided through mammography screening, accounting for 72-81% of the estimated total treatment cost savings achieved by screening. About 31-35% of the screening costs for 1987 to 1993 were offset by savings in treatment costs. CONCLUSIONS: Treatment costs for fatal breast cancer are high. Mammography screening results in substantial treatment cost savings, in which reduction of fatal disease is the key element.

Adult↗
PubMed2006

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.

BARD1 (BRCA1-associated RING-domain 1) is a tumor suppressor whose protein product interacts with BRCA1, and in which rare somatic and germline mutations have been reported in breast, uterine, and endometrial cancers. We aimed to evaluate whether there are BARD1 genetic variants that contribute to breast cancer risk by screening the gene for germline alterations in 45 Finnish familial breast cancer patients and in seven patients with both breast and ovarian cancer. Two of the missense alterations identified (Cys557Ser and Val507Met) were recently suggested to associate with an increased breast cancer risk. We also analyzed these variants in large and independent series of familial and unselected breast cancer patients and healthy controls. No clearly deleterious mutations were detected in the initial mutation screening. No association of the Cys557Ser and breast cancer risk was observed as the variant was found altogether in 1.4% (16/1181) of familial and 2.2% (34/1565) of unselected breast cancer patients, and in 2.5% (27/1083) of healthy controls. The frequency of the Val-allele of the Val507Met variant was modestly higher among breast cancer patients than among healthy controls, although the difference did not reach statistical significance. No statistically significant association of the Cys557Ser or Val507Met variants with any clinicopathologic parameters was observed. These results suggest that the contribution of the BARD1 germline variants to breast cancer predisposition is very limited, and that neither Cys557Ser nor Val507Met have an effect on familial breast cancer susceptibility.

Breast Neoplasms↗
PubMed2006

Radiological pulmonary findings after breast cancer irradiation: A prospective study.

The aim of this study was to evaluate radiation-induced pulmonary abnormalities of breast cancer patients. Altogether 202 consecutive patients receiving postoperative radiotherapy entered the study. Plain chest radiographs taken at entry and 3, 6 and 12 months after radiotherapy were evaluated according to modified Arriagada classification. In addition, pulmonary symptoms were recorded. Supplementary high-resolution computed tomography (HRCT) was employed in a subgroup of patients (n?=?15). Plain radiographs were interpreted by a radiologist, and uncertain findings were re-evaluated by a radiologist together with a radiation oncologist. Grade 2 pneumonitis was the most common abnormality. The proportion of patients yielding a grade 2 finding was 22.5%, 28.1%, and 16.0% at three, six, and twelve months, respectively. There were 2 normal findings in HRCTscans, and 8 in plain radiographs of the same patients. Radiological lung abnormalities are common after radiotherapy, but they are usually reversible, and their significance for the patient's well-being is minor. No correlation between symptoms and lung or pleural reactions was seen.

Breast Neoplasms↗
PubMed2005

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy.

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.

Adult↗
PubMed2005

Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients.

The CHEK2 kinase is a tumor suppressor whose activation in response to DNA double-strand breaks contributes to cell cycle arrest or apoptosis. The c.1100delC mutation is associated with familial breast cancer, and tumors from mutation carriers show reduced or absent CHEK2 protein expression. We have here studied CHEK2 protein expression by immunohistochemistry on a tissue microarray of 611 unselected breast tumors and also evaluated the tumor characteristics among 1,297 unselected breast cancer patients defined for the c.1100delC germ line mutation status (2.5% carrier frequency). CHEK2 protein expression was reduced in 21.1% of the unselected breast cancers studied. Tumors with reduced CHEK2 expression had more often larger primary tumor size (pT3-4; nominal significance p = 0.002) compared to tumors with normal staining. A similar trend for larger tumor size was seen among the 37 breast tumors from c.1100delC germ line mutation carriers. Tumors from c.1100delC mutation carriers were of higher grade than those of noncarriers (nominal significance p = 0.02). The c.1100delC germ line mutation also associated strongly with bilateral breast cancer. No significant correlation was seen between CHEK2 status and hormone receptor status, histology, lymph node status, or overall survival.

Breast Neoplasms↗
PubMed2005

Mammographic screening reduces risk of breast carcinoma recurrence.

BACKGROUND: The current report is a long-term evaluation of breast carcinoma recurrence, factors predicting recurrence, and postrecurrence prognosis in relation to patients' use of service screening, which has been provided in Turku, Finland, since 1987 for women ages 40-74 years. METHODS: The current study included 527 invasive breast carcinomas: 418 in the screening group (which included screen-detected and interval malignancies) and 109 in the nonscreening group (which included breast carcinomas detected before initial screening and those detected in patients who chose not to undergo screening). These breast carcinomas were diagnosed among women ages 40-74 years between 1987 and 1993, with follow-up extending until the end of 2001. RESULTS: In the screening group, the risk of recurrence was only approximately half of the corresponding risk in the nonscreening group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.39-0.83; P = 0.003). Five years after the primary diagnosis, 16% of patients in the screening group and 28% of patients in the nonscreening group (P = 0.001) had experienced recurrence; 10 years after diagnosis, the corresponding rates were 21% and 34%, respectively (P = 0.001). Postrecurrence prognosis was comparable for both detection groups (HR, 1.17; 95% CI, 0.70-1.94; P = 0.551), with approximately half of all patients dying of disease 5 years after recurrence. Detection of breast carcinoma via a method other than mammographic screening was associated with a high risk of recurrence on univariate analysis. On Cox multivariate analysis, risk factors for recurrence included lobular histologic type (HR, 2.23; 95% CI, 1.44-3.48; P < 0.001), poor histologic grade (HR, 2.02; 95% CI, 1.20-3.39; P = 0.008), and large tumor size (HR, 1.60; 95% CI, 1.07-2.37; P = 0.021). CONCLUSIONS: Long-term data from a population-based program demonstrated that mammographic screening reduced patients' risk of breast carcinoma recurrence. Specifically, the risk for patients with screen-detected disease was only approximately half of the risk for patients with non-screen-detected disease. Nonetheless, postrecurrence prognosis was comparable for patients in both detection groups.

Adult↗
PubMed2005

Search for large genomic alterations of the BRCA1 gene in a Finnish population.

Mutations in the BRCA1 and BRCA2 genes are known to predispose to breast cancer. In Finland, however, only 21% of all breast cancer families have mutations in these genes. Recent studies have shown that large genomic alterations of BRCA1 are common in many countries. Because such alterations will be missed in conventional mutation screening strategies, we decided to screen Finnish breast and ovarian cancer families for genomic alterations by using a multiplex polymerase chain reaction method. The most characteristic features of BRCA1-related breast cancer were used to select patients, namely (1) both breast and ovarian cancer in the family (48 patients), (2) four or more breast cancers in family (22 patients), or (3) young age (< or =40 years) of onset (58 patients). A total of 128 patients were included in the study. All exons of BRCA1 were analyzed but no alterations were found. This study excludes the frequent occurrence of large genomic alterations in the BRCA1 gene in Finland. Here, again, Finland differs from other countries with a mixed population structure. Our results are in agreement with the common hypothesis that there are still unknown breast cancer susceptibility gene(s) that are responsible for breast cancer predisposition.

Adult↗
PubMed2005

Resource savings in the single reading of plain radiographs by oncologist only in cancer patient follow-up: a randomized study.

The aim of this study was to estimate the need for a radiologist's clinical report in the interpretation of plain radiographs in cancer patient follow-up. Consecutive new cancer patients receiving primary treatment were randomized between two arms with different diagnostic modes: a double-reading arm (an oncologist and then a radiologist independently interpreted plain radiographs) and a single-reading arm (radiographs interpreted by an oncologist only; if necessary a radiologist's clinical report was obtained on separate request). Altogether 869 eligible patients participated. No differences were found in the total number of plain radiographs between the two arms. The number of radiologists was 20 and there were 28 oncologists. A separate clinical report was requested from a radiologist in 44% of all plain radiographs in the single-reading arm. This saving of radiologists' work (56%) took place without detriment, as the indicators of earliness of diagnosis were the same in both arms. The role of the radiologist should be more in consultation than in routine interpretation during follow-up.

Aged↗
PubMed2004

Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene.

PURPOSE: Long-term use of tamoxifen is associated with a two- to threefold increased risk of endometrial cancer in postmenopausal women. Toremifene is another triphenylethylene antiestrogen, which is as effective as tamoxifen in postmenopausal breast cancer. Thus far, its use has not been associated with an increased risk of endometrial cancer. K-ras codon 12 mutations seem to be important in endometrial carcinogenesis, and these mutations have been found in endometrial samples of patients on tamoxifen. The present study was undertaken to investigate if there is any difference in the frequency of endometrial K-ras mutations among patients treated with tamoxifen or toremifene. METHODS: Endometrial samples were taken from 23 postmenopausal breast cancer patients (tamoxifen, n = 11; toremifene, n = 12) before and after 36 months of treatment. DNA was isolated from formalin-fixed paraffin-embedded samples using a routine proteinase K digestion protocol. K-ras mutations in codon 12 were screened using real-time PCR and melting curve analysis in LightCycler equipment. Wild-type PNA oligomer was used to increase the sensitivity of the assay. RESULTS: All baseline samples contained wild-type K-ras, while 10/23 (43%) of the follow-up samples carried a codon 12 mutation. Mutations were identified in 3 of the 11 in the tamoxifen group and in 7 of the 12 in the toremifene group. Seven were transitions (G-->A), and three were transversions (two G-->T, one G-->C). One of the mutations in the toremifene group was associated with a polypoid endometrium. All the other mutations were found in an atrophic (n = 6) or proliferative (n = 3) endometrium. CONCLUSIONS: Both tamoxifen and toremifene induce endometrial K-ras codon 12 mutations. The significance of this finding to endometrial carcinogenesis remains to be elucidated.

Antineoplastic Agents, Hormonal↗
PubMed2004

CHEK2 variant I157T may be associated with increased breast cancer risk.

Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population-based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68-1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild-type CHEK2 co-expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.

Breast Neoplasms↗
PubMed2004

Risk for distant recurrence of breast cancer detected by mammography screening or other methods.

CONTEXT: Selection of systemic adjuvant therapies for women diagnosed as having breast cancer is based on risk estimations for cancer recurrence. In such estimations, tumors detected by mammography screening are considered to be associated with a similar risk of recurrence as tumors of similar size found by other methods. OBJECTIVE: To compare the risk of recurrence and survival among women with cancerous tumors detected by mammography screening compared with other methods (outside of screening). DESIGN, SETTING, AND PATIENTS: Retrospective study comparing clinical, histopathological, and biological features of cancerous tumors detected by mammography screening compared with tumors detected outside of screening. Women diagnosed as having breast cancer in 1991 or 1992 were identified from the Finnish Cancer Registry (n = 2842). The median follow-up time was 9.5 years. Cancer biological variables were analyzed from tumor tissue microarrays using immunohistochemistry or in situ hybridization and included ERBB2, TP53, and MK167 expression and ERBB2 amplification data. MAIN OUTCOME MEASURES: Univariate and multivariate analyses of potential risk factors for distant recurrence of breast cancer and 10-year survival. RESULTS: Of the 1983 women with unilateral invasive breast cancer, data on tumor diameter were available for 1918 women. Women with cancerous tumors detected by mammography screening had better estimated 10-year distant disease-free survival than women with tumors found outside of screening (tumor size of < or =10 mm [n = 386] 92% vs 85% [P =.04]; 11-20 mm [n = 808] 88% vs 76% [P<.001]; 21-30 mm [n = 409] 86% vs 63% [P =.008]; >30 mm [n = 315] 68% vs 50% [P =.12], respectively). In a Cox multivariate model that included cancer biological factors, the relative hazard ratio for distant recurrence among women with tumors detected outside of screening (HR, 1.90; 95% confidence interval, 1.15-3.11) was significantly higher than among women with tumors detected by mammography screening (P =.01). Breast cancer diagnosis by mammography screening was an independent prognostic variable reducing the relative HR for distant recurrence. This effect was equal to or greater than the effect of 1-cm decrease in tumor diameter (HR, 1.20; 95% confidence interval, 1.10-1.31). CONCLUSIONS: Cancerous tumors detected by mammography screening are associated with a better prognosis than tumors of similar size found outside of screening. The risk of distant metastases is overestimated for women diagnosed as having cancer by mammography screening unless the method of detection is taken into account in risk estimations.

Adult↗
PubMed2004

Double-reading of plain radiographs--no benefit with regard to earliness of diagnosis of cancer recurrence: a randomised follow-up study.

The aim of this study was to estimate the effect of the radiologist's interpretation of plain radiographs on the earliness of diagnosis of cancer recurrences. Data consisted of patients who had undergone primary treatment and were resident in the Tampere University Hospital Area in Finland during 1991-1997. Consecutive patients were randomised in a double-reading arm (an oncologist and a radiologist independently interpreting radiographs), and in a single-reading arm (interpretation by an oncologist only; if necessary, a radiologist's clinical report was obtained following a separate request). The time of diagnosis of recurrence and death were estimated by the cumulative probabilities of actuarial method with the Wilcoxon (Gehan) test. There were 869 eligible participants, mostly breast cancer patients (n = 516). In total, 227 recurrences were diagnosed, and of these 55 on plain radiographs, which is 24.2% of the total number of recurrences. There was no statistically significant difference between the arms in the number of recurrences (P = 0.85) or in the time of detecting the recurrence (P = 0.64). Altogether, 225 (25.9%) died from cancer and 38 (4.4%) from other causes. There was no statistically significant difference (P = 0.34) in survival between the two arms during the follow-up to 5 years. Double-reading of plain radiographs does not offer any extra benefit for the detection of recurrences or for patient's survival compared with single-reading.

Adult↗
PubMed2003

Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study.

PURPOSE: To assess the relative importance of 10 prognostic factors in pT1N0M0 breast cancer (< or =2 cm in diameter, node negative). EXPERIMENTAL DESIGN: Women diagnosed with breast cancer in Finland from 1991 to 1992 were identified from the files of the Finnish Cancer Registry, and individual clinicopathological data were collected from the hospital case records of women living in five regions comprising about one-half of the Finnish population. Of the women with minimum required information available (n = 2842), 852 had unilateral pT(1)N(0)M(0) cancer. The median follow-up time was 9.5 years, and only 5% had received systemic adjuvant therapy. Estrogen receptor (ER), progesterone receptor, erbB2, p53, and Ki-67 expression was determined from tumor tissue microarrays using immunohistochemistry, and the erbB2 (HER-2) amplification status was determined using chromogenic in situ hybridization. RESULTS: Primary tumor size < or =5 mm and histological grade 1 were associated with 100 and 95% (95% confidence interval, 92-98%) 9-year distant disease-free survival, respectively, whereas strong erbB2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk. ER and progesterone receptor values obtained from the hospital case records or tumor microarrays showed weaker association with outcome than the erbB2 status. Small (< or =10 mm) erbB2-negative cancers were associated with >90% 9-year distant disease-free survival, irrespective of histological grade. CONCLUSIONS: Prognosis of pT(1)N(0)M(0) breast cancer is generally well defined by the histological grade and primary tumor size. The erbB2 status was superior to ER as a prognostic factor in these tumors.

Adult↗
PubMed2002

A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.

CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63; P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0002), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women.

Breast Neoplasms↗