Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.

BACKGROUND: Four previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation. METHODS: In the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35-70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928. FINDINGS: Between April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16.0 years (IQR 14.1-17.6), 601 breast cancers have been reported (251 [7.0%] in 3579 patients in the tamoxifen group vs 350 [9.8%] in 3575 women in the placebo group; hazard ratio [HR] 0.71 [95% CI 0.60-0.83], p<0.0001). The risk of developing breast cancer was similar between years 0-10 (226 [6.3%] in 3575 women in the placebo group vs 163 [4.6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001) and after 10 years (124 [3.8%] in 3295 women vs 88 [2.6%] in 3343, respectively; HR 0.69 [0.53-0.91], p=0.009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0.66 [95% CI 0.54-0.81], p<0.0001) and ductal carcinoma in situ (0.65 [0.43-1.00], p=0.05), but no effect was noted for invasive oestrogen receptor-negative breast cancer (HR 1.05 [95% CI 0.71-1.57], p=0.8). INTERPRETATION: These results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention. FUNDING: Cancer Research UK (UK) and the National Health and Medical Research Council (Australia).

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development.

Bone morphogenetic proteins (BMPs) are extracellular signaling molecules that belong to the transforming growth factor ß (TGFß) superfamily and are known to regulate cell proliferation, differentiation and motility, especially during development. BMP4 has an indispensable role in vertebrate development while limited information on BMP4 expression and function exists in adult tissues. Nevertheless, its contribution to cancer development and progression has gained increasing interest in recent years. Functional studies, especially in breast cancer, have implicated BMP4 both in inhibition of cell proliferation and in promotion of cell migration and invasion. To gain an insight into the function of BMP4 in normal and cancer tissues, BMP4 protein expression levels were analyzed by immunohistochemistry in 34 different normal organs/tissues, 34 different tumor types and finally in 486 breast cancer samples where possible associations between BMP4 and clinicopathological parameters were statistically evaluated. In over 20% of normal and malignant tissues, BMP4 was expressed at high level. Strong expression was observed particularly in some normal epithelial cells, such as bladder and stomach, and in squamous cell carcinomas. In breast cancer, strong BMP4 expression was detected in 25% of patients, and was associated with low proliferation index and increased frequency of tumor recurrence. Taken together, BMP4 is expressed in a subset of normal adult tissues and is likely to contribute to tissue homeostasis. However, in tumors, BMP4 expression levels vary considerably, implying diverse roles in different tumor types. This role is biphasic in breast cancer as BMP4 expression is linked to reduced proliferation and increased recurrence, thus corroborating our previous in-vitro functional data.

A double-blind placebo-controlled study to evaluate endometrial safety and gynaecological symptoms in women treated for up to 5 years with tamoxifen or placebo - a substudy for IBIS I Breast Cancer Prevention Trial.

AIMS OF THE STUDY: This prospective study was performed to investigate the effects of 5-year's use of tamoxifen in preventive setting on endometrium and gynaecological symptoms. MATERIAL AND METHODS: Altogether 96 women were treated either with tamoxifen (TAM, n=45) or placebo (PLA, n=51) for up to 5 years in a randomised, double-blind IBIS I breast cancer prevention trial, clinically followed-up for an additional year and for the occurrence of malignancies at least 9 years between 2/1995 and 7/2009 in Finland. The gynaecological follow-up with trans-vaginal ultrasound and endometrial biopsies were performed at baseline, at 2.5 and 5 years and at the 6 years follow-up visit. RESULTS: Women in the TAM group discontinued the treatment significantly more often (44% versus 22%; p=0.017) and earlier (at 15 versus 30 months; p=0.044), than those in the PLA group. In postmenopausal women the median endometrial thickness was significantly increased at five years in the TAM group (median 4.3 versus 2.0mm, p=0.011), but there was no difference between the groups at one year after the treatment. There were also statistically significantly more referrals to hospitals due to gynaecological findings in the TAM group (risk rates (RR) 3.15; 95% confidence intervals (CI) 1.12-10.10), but no differences in hysterectomy rates or other serious adverse event rates were observed. CONCLUSIONS: The discontinuation rate in the TAM group was high, and the discontinuations also occurred early. Even though there were significantly more non-serious gynaecological events during the TAM treatment, routine gynaecological follow-up cannot be recommended.

Evaluation of frequency of clinical symptoms and signs within six months prior to death in patients with advanced solid cancers.

This retrospective study documented the frequency of the clinical symptoms and signs that increase in advanced cancer patients as they move toward death in order to create a sum score and correlate it with survival. Of 572 adult patients who were treated in four selected hospitals and who died in 1998 and 1999, data at six, three, and one month(s) prior to death was available for 257. The results showed that the number of symptoms and certain clinical findings accelerated toward death, increasing the sum score. Younger patients obtained higher sum scores at one month prior to death than did elderly ones (p=0.014); this suggests that elderly patients die at a point where they show less worsening in their clinical condition than do younger patients. The score was independent of cancer type or gender. The results of this analysis provide data for further development of a clinical tool to predict long-term survival in palliative care settings.

Effect of surgeon's caseload on the quality of surgery and breast cancer recurrence.

The aim of this study was to evaluate the effects of the caseloads of individual surgeons on breast cancer primary care and outcome. The extent of primary breast cancer and axillary surgery and the appearance of local recurrences were evaluated for 1377 women operated in Pirkanmaa region between 1.1.1997 and 31.12.2001 and followed- up at least until 31.12.2008 or death. Caseloads of each surgeon were divided into three categories: over 550, 100-200 and under 60. Breast conserving surgery was performed more often by surgeons with the highest (OR 1.32) and the middle (OR 1.54) caseload volumes compared to those with the lowest volumes (p = 0.018). Surgeons with the lowest caseloads also dissected fewer lymph nodes (mean 9.4 versus 11.2 in the highest and 10.9 in the middle caseload volumes; p ≤ 0.001). There were no differences in recurrences between the groups during the mean follow-up time of 8.9 years.

Long-term prognosis of breast cancer detected by mammography screening or other methods.

INTRODUCTION: Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods. METHODS: Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed. RESULTS: Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed. CONCLUSIONS: Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up.

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

INTRODUCTION: Some 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Breast 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.

RAD51C is a susceptibility gene for ovarian cancer.

A homozygous mutation in the RAD51C gene was recently found to cause Fanconi anemia-like disorder. Furthermore, six heterozygous deleterious RAD51C mutations were detected in German breast and ovarian cancer families. We screened 277 Finnish familial breast or ovarian cancer patients for RAD51C and identified two recurrent deleterious mutations (c.93delG and c.837+1G>A). These mutations were further genotyped in 491 familial breast cancer patients, 409 unselected ovarian cancer patients and two series of unselected breast cancer cases (884 from Helsinki and 686 from Tampere) and population controls (1279 and 807, respectively). The mutation frequency among all breast cancer cases was not different from the controls (4 out of 2239, 0.2% versus population controls 2 out of 2086, 0.1%, P= 0.7). In the Helsinki series, each mutation was found in four cases with personal or family history of ovarian cancer. No mutations were found among cases with familial breast cancer only, four out of the eight carriers did not have family history of breast cancer. The mutations associated with an increased risk of familial breast and ovarian cancer (OR: 13.59, 95% CI 1.89-97.6, P= 0.026 compared with controls), but especially with familial ovarian cancer in the absence of breast cancer (OR: 213, 95% CI 25.6-1769, P= 0.0002) and also with unselected ovarian cancer (OR: 6.31, 95% CI 1.15-34.6, P= 0.033), with a significantly higher mutation rate among the familial cases (two out of eight, 25%) than the unselected ovarian cancer cases (4 out of 409, 1%) (OR: 33.8, 95% CI 5.15-221, P= 0.005). These results suggest RAD51C as the first moderate-to-high risk susceptibility gene for ovarian cancer.

Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer.

BACKGROUND: The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer. METHODS: Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein. RESULTS: 1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor. CONCLUSIONS: Running high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.

Variation in 'standard care' for breast cancer across Europe: a EUROCARE-3 high resolution study.

On a population-based sample of 13,500 European breast cancer patients mostly diagnosed in 1996-1998 and archived by 26 cancer registries, we used logistic regression to estimate odds of conservative surgery plus radiotherapy (BCS+RT) versus other surgery, in T1N0M0 cases by country, adjusted for age and tumour size. We also examined: BCS+RT in relation to total national expenditure on health (TNEH); chemotherapy use in N+ patients; tamoxifen use in oestrogen-positive patients; and whether 10 nodes were examined in lymphadenectomies. Stage, diagnostic examinations and treatments were obtained from clinical records. T1N0M0 cases were 33.0% of the total. 55.0% of T1N0M0 received BCS+RT, range 9.0% (Estonia) to 78.0% (France). Compared to France, odds of BCS+RT were lower in all other countries, even after adjusting for covariates. Women of 70-99 years had 67% lower odds of BCS+RT than women of 15-39 years. BCS+RT was 20% in low TNEH, 58% in medium TNEH, and 64% in high TNEH countries. Chemotherapy was given to 63.0% of N+ and 90.7% of premenopausal N+ (15-49 years), with marked variation by country, mainly in post-menopause (50-99 years). Hormonal therapy was given to 55.5% of oestrogen-positive cases, 44.6% at 15-49 years and 58.8% at 50-99 years; with marked variation across countries especially in premenopause. The variation in breast cancer care across Europe prior to the development of European guidelines was striking; older women received BCS+RT much less than younger women; and adherence to 'standard care' varied even among countries with medium/high TNEH, suggesting sub-optimal resource allocation.

Radiotherapy after segmental resection of breast cancer with favorable prognostic features: 12-year follow-up results of a randomized trial.

PURPOSE: Postoperative breast irradiation is considered standard after breast-preserving surgery for cancer. We evaluated the efficacy of radiation therapy in the prevention of local recurrence in a patient population that had small-size breast cancer with features that suggested low biologic aggressiveness. PATIENTS AND METHODS: Women (n = 264) older than 40 years who were treated by breast resection with > or = 1 cm of tumor-free margin and axillary nodal dissection were randomly assigned to receive or not to receive breast irradiation (cumulative dose, 50 Gy) after surgery. The tumor was required to be < or = 20 mm, node negative, progesterone receptor positive, well to moderately well differentiated and unifocal, and of low cell proliferation rate (ie, S phase fraction < or = 7% or nuclear Ki-67 expression < 10%) and had to lack an extensive intraductal component. The median follow-up time was 12.1 years after random assignment. RESULTS: Sixteen (11.6%) and 34 (27.2%) cancers recurred locally in the radiotherapy and the control arms, respectively (P = .0013). Time to local recurrence was longer in the radiotherapy arm (hazard ratio [HR], 0.36; 95% CI, 0.20 to 0.65; P = .00071). Twenty-one patients assigned to radiotherapy and 26 assigned to control died during the follow-up. There were no differences in overall survival time (HR, 0.63; 95% CI, 0.35 to 1.12; P = .11), distant disease-free survival (P = .94), or breast cancer-specific survival (P = .56) between the radiation therapy and control groups. CONCLUSION: Radiation therapy after breast resection reduces the frequency of ipsilateral breast recurrences, even among women with small-size breast cancers that have favorable histologic features and that are resected with at least a 1-cm margin. Postoperative radiotherapy did not significantly improve survival.

Lower recurrence risk through mammographic screening reduces breast cancer treatment costs.

Mammographic screening is associated with a reduced risk of breast cancer recurrence. The objective of the study was to evaluate treatment costs due to breast cancer recurrence in relation to patients' use of mammographic screening, consecutively collected in a defined population. The study included 418 women exposed to screening and 109 women unexposed to screening diagnosed with stage I-III breast cancer. During the first eight years after primary diagnosis, 19% (N=80) of the exposed women and 33% (N=36) of the unexposed women developed recurrent disease, P=0.002. In the exposed group, 41% of the 8-year treatment costs were for the treatment of patients who developed recurrent disease, compared with 52% in the unexposed group, P=0.039. Among the relapsed patients, the mean post-recurrence costs were EUR14,950, accounting for 65% of their total 8-year costs. The mean post-recurrence costs were comparable for both exposure groups irrespective of the detection method.

Comparison of cancer registry and clinical data as predictors for breast cancer survival.

BACKGROUND: In spite of the increasing amount of clinically relevant information for survival from breast cancer, the amount of data recorded in a population-based cancer registry is limited and the registry-based survival predictions are routinely made without clinical details. OBJECTIVE: To find out how important is the role of screening and clinical tumor characteristics in addition to cancer registry information in describing the breast cancer survival. METHODS: A representative clinical database on 483 breast cancer patients diagnosed during 1996-1997 in Tampere University Hospital Area was linked with Finnish Cancer Registry data and a survival model including the available registry variables was compared to models including screen-detection information and clinical tumor characteristics also. RESULTS AND CONCLUSION: Estimates of registry stage and age act as surrogates for clinical variables and mammography-detection. The surrogacy was found to be almost complete indicating that clinical variables are not necessarily needed when making breast cancer mortality predictions based on a population-based cancer registry. In cases with dissimilar staging cancer registry stage gave a better picture of the breast cancer survival than the clinical stage.

Penetrance analysis of the PALB2 c.1592delT founder mutation.

PURPOSE: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer. EXPERIMENTAL DESIGN: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history. RESULTS: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years. CONCLUSIONS: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.

Molecular subtypes of breast cancers detected in mammography screening and outside of screening.

PURPOSE: The frequency and significance of gene expression profile-derived molecular subtypes of breast cancers found in mammography screening are unknown. EXPERIMENTAL DESIGN: We identified breast cancers diagnosed in women of any age living in defined geographic regions in Finland in 1991 to 1992 and collected clinical and pathologic data. Surrogates for the molecular subtypes were determined for 247 cancers found in organized mammography screening and 989 cancers detected outside of screening using immunohistochemistry or in situ hybridization. Molecular subtypes were defined as luminal A [estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-], luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, cytokeratin 5+, and/or HER1+), HER2+/ER- (ER-, PR-, and HER2+), and unclassified. The median follow-up time was 9.4 years. RESULTS: The luminal type A was common (73.7%) and the HER2+/ER- type is rare (5.7%) in screen-detected cancer, and only 16% were HER2 positive. Women with cancer diagnosed in screening at ages 50 to 69 years had similar molecular subtype distribution as women whose cancer was found outside of screening at age >69 years. In a multivariate model, cancer detection at screening independently predicted favorable distant disease-free survival when the molecular subtype was included as a covariate in addition to age, histologic grade, and cancer size. Women with small (pT(1)N(0)M(0)) HER2-positive cancer had similar outcome regardless of the method of detection. CONCLUSIONS: Molecular subtype distribution of screen-detected breast cancer differs from that of cancers found outside of screening and accounts in part for the better outcome of screen-detected cancer.

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 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 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.

ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer.

Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P=0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.

Early detection of skin cancer as public health policy: comparison of campaign and routine activity.

OBJECTIVE: The objective of this study was to evaluate the early detection of skin cancer, with emphasis on comparison of campaign (short high-intensity periods) and routine (continuous low-intensity) activity. METHODS: The study population consisted of 5903 campaign and 4284 routine attenders visiting a nurse at the Pirkanmaa Cancer Society between January 1, 1991, and December 31, 2000. Skin cancers were identified from the Finnish Cancer Registry. The performance of the program was evaluated in terms of sensitivity, specificity, positive and negative predictive values. RESULTS: A single lesion was more frequently examined during campaigns whereas a partial or total body were examined less frequently (p<0.001). Attenders received referral for removal of a lesion more frequently in routine activity (52% vs. 20% p<0.001), regardless of extent of the examination. The cumulative incidence of skin cancer within 24 months was 3.2% for routine and 1.6% for campaign attenders (p<0.001). Sensitivity was higher (82% vs. 59%, p<0.001), while specificity was lower (49% vs. 79%, p<0.001) for routine activity. CONCLUSIONS: Even though neither approach appears optimal, scheduled appointments with adequate time allocation per subject provided a lower threshold for detection and a higher yield of skin cancers compared to high-intensity campaigns.

A short communication course for physicians improves the quality of patient information in a clinical trial.

We investigated whether a short course in communication skills for physicians would improve the quality of informed consent in a randomized clinical adjuvant trial on breast cancer. In this prospective, case-controlled intervention study, physicians and research nurses who introduced the cancer treatment trial to patients at three of the participating hospitals first attended a one-day communication skills course. The quality of informed consent was then evaluated by addressing a standardized questionnaire, QuIC, to trial patients at the three intervention hospitals and at control hospitals. Response rate was 90.0% (n = 288). Of the patients treated by the intervention group, 73% were very satisfied with the information received compared with 56% of those of the control group (p = 0.003). The patients of the intervention group considered the time given for making their decision sufficient more often than those of the controls (98% vs. 90%, p = 0.004). The patients of the intervention group recalled more often than those of the controls that the physician had also offered other therapeutic options than the trial treatment (91% vs. 97%, p = 0.032). They also understood the main aim of the study better than the patients of the controls (89% vs. 78%, p = 0.030). In conclusion, a short communication skills course for the trial physicians and nurses improved the quality of informed consent and patient satisfaction in the trial.