Liisa Pylkkänen

Invasive lobular carcinoma of the breast has better short- and long-term survival than invasive ductal carcinoma.

The outcome and prognostic factors of 217 women with invasive lobular carcinoma (ILC) and those of 1121 women with invasive ductal carcinoma (IDC) of the breast were compared. The patients were followed up for 10-43 years. Women with ILC had axillary nodal metastases less frequently than those with IDC (43% vs 53%, P = 0.02), although there was no difference in the primary tumour size between the groups. ILCs were more frequently of low grade, had lower mitotic counts and had less tumour necrosis. Furthermore, ILCs had lower S-phase fractions and were more often DNA diploid in flow cytometric analysis than IDCs (P < 0.0001 for all comparisons). The 5- and 30-year corrected survival rates of women with ILC were 78% and 50%, respectively, compared with 63% and 37% for women with IDC (P = 0.001). Small pT1NOMO ILCs (n = 41) had 100% 10-year and 83% 20-year corrected survival rates. In a multivariate analysis, a large primary tumour size, the presence of axillary nodal metastases, a high mitotic count and the presence of tumour necrosis all had an independent prognostic value in ILC. We conclude that ILC is associated with better survival than IDC.

Artificial Neural Networks Applied to Survival Prediction in Breast Cancer

In this study, we evaluated the accuracy of a neural network in predicting 5-, 10- and 15-year breast-cancer-specific survival. A series of 951 breast cancer patients was divided into a training set of 651 and a validation set of 300 patients. Eight variables were entered as input to the network: tumor size, axillary nodal status, histological type, mitotic count, nuclear pleomorphism, tubule formation, tumor necrosis and age. The area under the ROC curve (AUC) was used as a measure of accuracy of the prediction models in generating survival estimates for the patients in the independent validation set. The AUC values of the neural network models for 5-, 10- and 15-year breast-cancer-specific survival were 0.909, 0.886 and 0.883, respectively.The corresponding AUC values for logistic regression were 0.897, 0.862 and 0.858. Axillary lymph node status (N0 vs. N+) predicted 5-year survival with a specificity of 71% and a sensitivity of 77%. The sensitivity of the neural network model was 91% at this specificity level. The rate of false predictions at 5 years was 82/300 for nodal status and 40/300 for the neural network. When nodal status was excluded from the neural network model, the rate of false predictions increased only to 49/300 (AUC 0.877). An artificial neural network is very accurate in the 5-, 10- and 15-year breast-cancer-specific survival prediction. The consistently high accuracy over time and the good predictive performance of a network trained without information on nodal status demonstrate that neural networks can be important tools for cancer survival prediction.

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.

Prostatic dysplasia associated with increased expression of C-MYC in neonatally estrogenized mice

Neonatal estrogenization of the mouse with diethylstilbestrol (DES; 2 micrograms./pup/day for days 1 to 3) or 17 beta-estradiol (200 micrograms./pup/day for days 1 to 3) resulted in epithelial dysplasia in the posterior periurethral region of the prostate at the age of 1 year. The dysplastic lesions ranged from mild to severe and, in addition to emergence of nuclear anaplasia, the architectural pattern of the glands was disturbed. Prenatal estrogenization (100 micrograms./kg. of maternal body weight on days 13 and 15 of gestation) only resulted in mild epithelial hyperplasia and occasional dysplasia in the ventral lobe of the prostate, but not in the posterior periurethral region. When neonatally estrogenized mice were allowed to grow until the age of 18 months, the degree and extent of the dysplasia of the posterior periurethral region was increased, but no frank invasion or metastases could be demonstrated. Combined estrogen and androgen treatment of neonatally estrogenized mice for 3 months (between 9 and 12 months of age) augmented nuclear dysplasia, but no invasive growth was seen in this group, either. Mild epithelial dysplasia was found in the dorsolateral lobes and coagulating glands of similarly treated control animals. A relation between the activation of certain proto-oncogenes and the development of several cancers has been shown in humans and experimental animals. In the present study, Northern blot analysis of total RNAs showed that the levels of c-myc mRNA were increased in the ventral and dorsolateral lobes, coagulating glands and prostatic urethra of neoDES mice at the age of 9 months. However, it remains to be determined whether the increase in c-myc expression is involved in the development of hyperplastic and dysplastic changes in the prostate of neoDES mice.

Service screening mammography reduces breast cancer mortality among elderly women in Turku

Objectives: The aim of this study was to assess the effects of service screening mammography on breast carcinoma incidence and refined mortality among women aged 55–69 at entry in three cities employing different screening policies. Methods: Since 1987, the city of Turku, Finland, has provided service screening mammography for women aged 55–69 at entry (in 1987), and Tampere provided screening for women aged 55–59 at entry, whereas Helsinki did not screen any of these age groups. The incidence of breast carcinoma during the screening period 1987–97 in women born in 1918–32 (1918–22, 1923–27, 1928–32) was compared with incidence during the pre-screening period 1976–86 in women born in 1907–21 (1907–11, 1912–16, 1917–21) in each city. The follow-up for mortality was four years longer. Results: Breast carcinoma incidence was 31–38% higher in the screening period in all three cities irrespective of screening. In breast carcinoma mortality, no significant changes were seen in Helsinki or Tampere. In Turku, a 36% mortality reduction (relative risk [RR] 0.64; 95% confidence interval [CI] 0.47–0.88; P=0.007) in the whole study population and a 47% reduction in women aged 65–69 at entry (RR 0.53; 95% CI 0.28–0.99; P=0.047) were seen. Conclusions: The incidence of breast carcinoma increased in all study cities irrespective of screening. The comprehensive screening programme in Turku including women aged 55–69 at entry was associated with a significant reduction in breast carcinoma mortality. The pronounced decrease in mortality in the oldest age group (65–69 years at entry) also indicated that women of this age group greatly benefit from mammography screening.

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 β (TGFβ) 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.

Animal models for the preneoplastic lesions of the prostate.

OBJECTIVES Reliable and adequate animal models are required, not only for investigation of etiology, pathogenesis, and treatment of prostate cancer, but also for chemoprevention of prostatic carcinogenesis. METHODS Animal models for the study of premalignant changes in the prostate are reviewed in the paper, with specific reference to the neonatally estrogenized mouse model. RESULTS Neonatal treatment of newborn Han:NMRI mice with synthetic non-steroidal estrogen, diethylstilbestrol (DES; 2 micrograms/pup on days 1-3 after birth) promoted hyperplastic and dysplastic changes in the periurethral region of the prostate at the age of 9-18 months. Dietary soy partially inhibited the development of prostatic dysplasia in these neonatally estrogenized animals, which may be due to phytoestrogens contained in soy-rich food. CONCLUSION Prostatic cancer and its possible precursors develop spontaneously, or can be induced by different chemical and hormonal manipulations in certain animal species and strains. Neonatal estrogenization of the mouse results in prostatic dysplasia, which can be partially prevented by dietary soy. There are morphological similarities between human prostatic intraepithelial neoplasia (PIN) and dysplastic changes in rodent prostates, but more data is needed before these dysplastic lesions can be considered equivalent to human PIN.

Histopathological evidence for an association of inflammation with ductal pin‐like lesions but not with ductal adenocarcinoma in the prostate of the noble rat

Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)‐like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis.

Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans.

Lignans and their in vivo metabolites, especially enterolactone (ENL), have attracted substantial interest as potential chemopreventive agents for prostate cancer. Preclinical and clinical interventions performed with lignan-rich flaxseed that use surrogate biomarkers as endpoints suggest that lignans may attenuate prostate carcinogenesis in individuals with increased risk or with diagnosed cancer. No unequivocal prostate cancer risk reduction has been found for lignans in epidemiological studies, suggesting that lignan concentrations found in populations consuming a regular non-supplemented diet are not chemopreventive in prostate cancer. Presumably, the main obstacles in assessing the efficacy of food lignans is limited knowledge of the serum and tissue lignan concentrations required for the putative prevention. Further clinical studies performed with the purified compounds are required to substantiate a health claim.

Long-term survival in node-positive breast cancer treated by locoregional therapy alone.

To investigate the long-term survival rate of node-positive (pN+) breast cancer treated by locoregional therapy alone, we made an attempt to identify all such patients followed up for at least 15 years after treatment in a defined geographical area (city of Turku, Southwestern Finland) and time period (1945-79) using the files of the local hospitals and the Finnish Cancer Registry. The clinical and autopsy records and histological slides of 1172 women diagnosed with breast cancer in the city were reviewed. From this cohort we identified 339 women with unilateral node-positive breast cancer treated with locoregional therapy without systemic adjuvant therapy. The relative survival rate of the cohort compared with the general female population matched for age and year of follow-up was calculated. The 15- and 30-year survival rates corrected for known intercurrent deaths were 26% (95% CI, 21-31%) and 21% (16-26%) respectively, and the relative survival rates 23% and 21% respectively. None of the patients with pN2 disease survived for 15 years, whereas the 30-year corrected survival rate in pN1 disease was 24% (18-30%). Women with pT1N1M0 cancer had as high as 59% (43-75%) 15-year survival rate corrected for intercurrent deaths. A trend for improving survival was found by the decade of diagnosis. The results indicate that a considerable proportion of women with pN1 breast carcinoma treated with locoregional therapy alone become 30-year survivors and are probably cured. Adequate locoregional treatment is mandatory in the care of node-positive breast cancer.