Showing papers in "Breast Cancer Research and Treatment in 1997"
TL;DR: The purpose of this article is to present data on mortality in breast cancer in study and control groups of the Stockholm trial after 11 years of followup, to analyse which age groupbenefits most from screening, and whether mammographic screening can be successful in younger age groups.
Abstract: Results from several randomised mammography screening trials haveshown that it is possible to reduce mortalityin breast cancer by mammographic screening at leastfor women above 50 years of age. Thepurpose of this article is to present dataon mortality in breast cancer in study andcontrol groups of the Stockholm trial after 11years of followup, to analyse which age groupbenefits most from screening. In March 1981, 40,318women in Stockholm, aged 40 through 64 years,entered a randomized trial of breast cancer screeningby single view mammography alone, versus no interventionin a control group of 20 000 women.Two screening rounds were performed and the attendancerate was over 80% in the two rounds.During 1986 the control group was invited onceto screening. Totally 428 and 217 cases ofbreast cancer were diagnosed in the study andcontrol groups respectively. After a mean follow-up of11.4 years a nonsignificant mortality reduction of 26%was observed for the whole study group, witha relative risk (RR) of death in breastcancer of 0.74 (CI(confidence interval)=0.5–1.1). Forwomen aged 50–64 years a significant 38% mortalityreduction was observed with a RR of 0.62(CI=0.38–1.0). For women aged 40–49 yearsno effect on mortality was found, with aRR of death in breast cancer of 1.08(CI=0.54–2.17). The breakpoint for benefit inthis study seemed to be at 50 yearsof age when 5-year age groups were analysed,but this tendency is uncertain because of thelow statistical power in the analysis of theyounger age groups. Long screening intervals, the useof single-view mammography, and the fact that morethan 50% of the women in age group40–49 years were still below 50 years ofage when the study was closed, were allfacts that could have influenced the results inage group 40–49 years. Larger studies are neededto answer the question whether mammographic screening canbe successful in younger age groups.
210 citations
TL;DR: Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes.
Abstract: Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.
176 citations
TL;DR: By modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
Abstract: Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 μM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-xL or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
165 citations
TL;DR: It is demonstrated that, despite its lower calcemic activity in vivo, the vitamin D analog EB1089 induces effects that are indistinguishable from those of 1,25(OH)2D3 on cell number, cell cycle and indices of apoptosis in MCF-7 cells in vitro.
Abstract: 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, inhibits breast cancer cell growth both in vivo and in vitro. In addition to its anti-proliferative effects, 1,25(OH)2D3 induces morphological and biochemical markers of apoptosis in MCF-7 cells. In the studies reported here, we compared the effects of 1,25(OH)2D3 and EB1089, a low calcemic vitamin D analog, on cell cycle kinetics and apoptosis in MCF-7 cells. Both vitamin D compounds reduced viable MCF-7 cell number in a time and dose dependent manner, with EB1089 approximately 50 fold more potent than 1,25(OH)2D3. Flow cytometric analysis indicated that both agents induced cell cycle arrest in G0/G1 which was associated with accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein. MCF-7 cells treated with either 1,25(OH)2D3 or EB1089 for 48 h exhibited characteristics of apoptosis, including cytoplasmic condensation, pyknotic nuclei, condensed chromatin and DNA fragmentation. Cells treated with either agent exhibited up regulation of proteins associated with mammary gland regression (clusterin and cathepsin B) and down regulation of the anti-apoptotic protein bcl-2. These studies demonstrate that, despite its lower calcemic activity in vivo, the vitamin D analog EB1089 induces effects that are indistinguishable from those of 1,25(OH)2D3 on cell number, cell cycle and indices of apoptosis in MCF-7 cells in vitro. In addition, since both agents rapidly down regulate estrogen receptor, disruption of estrogen dependent signalling may play a role in the induction of apoptosis by vitamin D compounds in MCF-7 cells.
164 citations
TL;DR: Future studies on the anticancer potential of soy isoflavonoids should examine their interaction with other phytochemical components of soybeans and exploit newly developed animal models of breast cancer in which specific genes have been activated or inactivated.
Abstract: Genistein (5,7,4′-trihydroxyisoflavone), one of two major isoflavonoids in soy, has anti-proliferative effects on mitogen-stimulated cell growth of human breast cancer cells in culture and is a candidate for use in the prevention of breast cancer. Soy protein preparations containing isoflavonoid conjugates have chemopreventive activity in carcinogen-induced rat models of breast cancer. Recent experiments in these models with purified genistein have revealed that the timing of the exposure of rats to this isoflavonoid is critical. Rats treated neonatally or prepuberally with genistein have a longer latency before the appearance of 7,12-dimethylbenz[a]anthracene-induced mammary tumors and a marked reduction in tumor number. The mechanism of genistein's preventive action is in part dependent on its estrogenic activity, which causes a more rapid differentiation of the cells of the mammary gland, analogous to the effects of an early pregnancy. Rats administered genistein after 35 days of age have smaller alterations in breast cancer risk, with a maximum reduction in mammary tumor number of 27%. In ovariectomized nude mice, dietary genistein increases cell proliferation of human breast cancer MCF-7 cell xenografts compared with a control diet. This estrogen-like effect of genistein is not observed in non-ovariectomized rats. Future studies on the anticancer potential of soy isoflavonoids should examine their interaction with other phytochemical components of soybeans and exploit newly developed animal models of breast cancer in which specific genes have been activated or inactivated.
161 citations
TL;DR: This model has a number of important implications for the clinicaluses of tamoxifen in the prevention and treatment of breast cancer and suggests anumber of novel approaches to the treatment ofadvanced breast cancer.
Abstract: Transforming Growth Factor-beta (TGF beta) is the most potent known inhibitor of the progression of normal mammary epithelial cells through the cell cycle. During the early stages of breast cancer development, the transformed epithelial cells appear to still be sensitive to TGF beta-mediated growth arrest, and TGF beta can act as an anti-tumor promoter. In contrast, advanced breast cancers are mostly refractory to TGF beta-mediated growth inhibition and produce large amounts of TGF beta, which may enhance tumor cell invasion and metastasis by its effects on extracellular matrix. We postulate that this seemingly paradoxical switch in the responsiveness of tumor cells to TGF beta during progression is the consequence of the activation of the latent TGF beta that is produced and deposited into the tumor microenvironment, thereby driving the clonal expansion of TGF beta-resistant tumor cells. While tumor cells themselves may activate TGF beta, recent observations suggest that environmental tumor promoters or carcinogens, such as ionizing radiation, can cause stromal fibroblasts to activate TGF beta by epigenetic mechanisms. As the biological effects of the anti-estrogen tamoxifen may well be mediated by TGF beta, this model has a number of important implications for the clinical uses of tamoxifen in the prevention and treatment of breast cancer. In addition, it suggests a number of novel approaches to the treatment of advanced breast cancer.
152 citations
TL;DR: It is suggested that monounsaturated and polyunsaturated fats, as well as soy foods, might reduce the risk of premenopausal bilateral breast cancer.
Abstract: We investigated associations between diet and premenopausal bilateral breast cancer in a familial matched case-control study. We studied 140 cases from population-based registries in Los Angeles County (California) and Connecticut, and from the major hospitals in the southern parts of the Province of Quebec. Unaffected sisters of the cases served as matched controls (222 total). Dietary intake were assessed with a food frequency questionnaire. Total fat, monounsaturated fat, polyunsaturated fat, oleic acid, and linoleic acid intake was inversely associated with premenopausal bilateral breast cancer risk. Consumption of carbohydrates (and sweetened beverages) was associated with an increased risk. We observed no associations for dietary fiber, antioxidants, or major food groupings, but we did observe inverse associations for intake of low fat dairy products and tofu. These findings suggest that monounsaturated and polyunsaturated fats, as well as soy foods, might reduce the risk of premenopausal bilateral breast cancer.
137 citations
TL;DR: Available data on the role of DIA support its importance as a favorable prognostic factor for early breast cancer patients, however, due to the possible biases of this type of evaluation, this result should be interpreted with caution.
Abstract: Background: The role of amenorrhea induced by chemotherapyin premenopausal women with early breast cancer isvery controversial. Analyses by various authors of theeffect of drug-induced amenorrhea (DIA) on treatment outcomehave yielded conflicting results. In order to gaininsight into the role of DIA, we reviewedall published data addressing the issue of DIAas a prognostic factor. Methods: Computerised and manualsearches were conducted of relevant studies published from1966 to 1995. Results: Thirteen studies involving 3929patients were selected. In two papers, the prognosticrole of DIA was analysed in three andtwo different groups of patients, respectively. Overall, 16groups of patients were evaluated. With 12 groups,a higher disease free survival was observed inpatients developing DIA compared to those who didnot. This difference was statistically significant in eightgroups. Data on overall survival, reported in onlyfive studies, indicated that it was always improvedin patients who became amenorrheic. Conclusions: Available dataon the role of DIA support its importanceas a favorable prognostic factor for early breastcancer patients. However, due to the possible biasesof this type of evaluation, this result shouldbe interpreted with caution.
134 citations
TL;DR: These studies provide new insight and impetus in defining a role for c-Myc in breast tumorigenesis and may point toward novel targets for breast cancer therapy.
Abstract: The proto-oncogene c-myc is commonly amplified and overexpressed in human breast tumors, and the tumorigenic potential of c-myc overexpression in mammary tissue has been confirmed by both in vitro and in vivo models of breast cancer. However, the mechanisms by which Myc promotes tumorigenesis are not well understood. Recent evidence indicates that Myc can promote cell proliferation as well as cell death via apoptosis. These studies provide new insight and impetus in defining a role for c-Myc in breast tumorigenesis and may point toward novel targets for breast cancer therapy.
128 citations
TL;DR: Preoperative evaluation of serum tumor necrosis factor alpha concentrations maybe a valuable parameter for reflecting the severity of staging for invasive breast cancer, and predicting the significant, higher serum concentration of tumor necrosisfactor alpha.
Abstract: Background: The outcome of breast cancer is usuallydetermined by multiple factors. Serum tumor necrosis factoralpha concentration has been found to be increasedin the circulation of patients with malignancy. Thisstudy was designed with the aim to investigateany correlation between the serum tumor necrosis factoralpha and the clinicopathological fetures and furthermore evaluatethe prognostic significance of serum tumor necrosis factoralpha concentration in breast cancer. Methods: Forty consecutivepatients with invasive breast cancer undergoing modified radicalmastectomy were prospectively included and evaluated. Venous bloodsamples were collected before the surgery. Sera wereobtained by centrifugation, and stored at − 70°C until assayed. The control group consisted 30healthy, age-matched subjects. Serum concentrations of tumor necrosisfactor alpha were measured by the quantitative sandwichenzyme immunoassay technique. The data on tumor size,age, estrogen receptor status, lymph node status andTNM staging were reviewed and recorded.Results: The mean value of serum tumor necrosis factor alphain patients with invasive breast cancer was 1.47± 0.58 pg/ml and that of the controlgroup was 0.98 ± 0.37 pg/ml, and thedifference was significant (P < 0.01). With univariableanalysis, patients with maximum tumor size of 5cm or larger (P=0.03), more advancedTNM staging (P < 0.01); and more advancedlymph node status (P < 0.01) were shownto have significantly higher serum concentrations of tumornecrosis factor alpha. However, with multivariable analysis, TNMstaging appeared as the only independent factor (P< 0.01) predicting the significant, higher serum concentrationsof tumor necrosis factor alpha. Conclusion: Preoperative evaluationof serum tumor necrosis factor alpha concentrations maybe a valuable parameter for reflecting the severityof staging for invasive breast cancer.
126 citations
TL;DR: Although there is an overall significant association between greater MRI enhancement amplitude and vessel density, MRI gadolinium enhancement of breast lesions is not an accurate predictor of vessel density.
Abstract: Purpose. To determine whether dynamic magnetic resonance (MR) imagingenhancement parameters are associated with vessel density of malignant andbenign breast lesions. Materials and methods. Forty-five patients with 48breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo(SPGR) MR imaging followed by excisional biopsy and Factor VIII staining andvessel density measurement in the lesions. Results. The vessel densitieswere not significantly different in 25 malignant breast lesions as comparedto 23 benign breast lesions. Among all 48 lesions, greater MR enhancementshowed an association with increased vessel density. Seventy-four percent ofall lesions with MRI enhancement amplitude greater or equal to three timespost-precontrast ratio had vessel densities greater than the median of 172as compared to 34% of lesions with enhancement amplitude less thanthree times, p = 0.02. The rate and washout of MR enhancement showedno significant association with vessel density. Conclusion. Although thereis an overall significant association between greater MRI enhancementamplitude and vessel density, MRI gadolinium enhancement of breast lesionsis not an accurate predictor of vessel density.
TL;DR: Several mechanisms of action may account for the antitumor activities of monoterpenes, which act through multiple mechanisms in the chemoprevention of mammary and other cancers.
Abstract: A number of dietary monoterpenes have chemopreventive activity against rat mammary cancer. For example, d-limonene, which comprises over 90% of orange peel oil, has chemopreventive activity against rodent mammary cancer during the initiation phase as well as the promotion/progression phase. Similarly, the monoterpenoids carveol, uroterpenol, and sobrerol have chemopreventive activity against mammary cancer when fed during the initiation phase. d-limonene and perillyl alcohol, a more potent analog of limonene, also have chemotherapeutic activity against rodent mammary and pancreatic tumors. As a result, their cancer chemotherapeutic activities are under evaluation in Phase I clinical trials. Several mechanisms of action may account for the antitumor activities of monoterpenes. The blocking chemopreventive effects of limonene and other monoterpenes during the initiation phase of mammary carcinogenesis are due to the induction of Phase II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification. The post-initiation phase chemopreventive and chemotherapeutic activities of monoterpenes may be due to the induction of tumor cell apoptosis, tumor redifferentiation, and/or inhibition of the post-translational isoprenylation of cell growth-regulating proteins. Thus, monoterpenes act through multiple mechanisms in the chemoprevention of mammary and other cancers.
TL;DR: An enhanced inhibitory effect on cell proliferation with the combination of Tamoxifen and the antibody compared to that seen by either agent alone is found.
Abstract: HER-2/neu overexpression has been associated with poor prognosis in human breast cancer. Many of these cancers are also ER-positive. A logical therapeutic approach for patients who are ER-positive and overexpress HER-2/neu may be to block both the ER and the HER-2/neu pathways. In our study, we used both the MTT tetrazolium dye assay and 3H-thymidine incorporation to measure the effects of the anti-estrogen Tamoxifen or the 4D5 anti-HER-2/neu antibody alone or in combination on the growth of BT474 human breast cancer cells which express ER and overexpress HER-2/neu. We found an enhanced inhibitory effect on cell proliferation with the combination of Tamoxifen and the antibody compared to that seen by either agent alone. This simultaneous interruption of both the ER and the HER-2/neu pathways may be relevant in the clinical treatment of patients who are both ER-positive and overexpress HER-2/neu.
TL;DR: Analysis of relapse data from untreated early stage breast cancer patients with 16–20 yearfollow-up shows that the frequency of relapse has a double peaked distribution, and model simulations predict that patients who relapse inthe second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy isnormally administered.
Abstract: Recent analysis of relapse data from 1173 untreatedearly stage breast cancer patients with 16–20 yearfollow-up shows that the frequency of relapse hasa double peaked distribution. There is a sharppeak at 18 months, a nadir at 50months and a broad peak at 60 months.Patients with larger tumors more frequently relapse inthe first peak while those with smaller tumorsrelapse equally in both peaks.No existing theory of tumor growth predicts thiseffect. To help understand this phenomenon, a modelof metastatic growth has been proposed consisting ofthree distinct phases: a single cell, an avasculargrowth, and a vascularized lesion. Computer simulation ofthis model shows that the second relapse peakcan be explained by a steady stochastic progressionfrom one phase to the next phase. However,to account for the first relapse peak, asudden perturbation of that development at the timeof surgery is necessary.Model simulations predict that patients who relapse inthe second peak would have micrometastases in statesof relatively low chemosensitivity when adjuvant therapy isnormally administered. The simulation predicts that 15% ofT1, 39% of T2, and 51% of T3staged patients benefit from adjuvant chemotherapy, partially offsettingthe advantage of early detection. This suggests thatearly detection and adjuvant chemotherapy may not besymbiotic strategies. New therapies are needed to benefitpatients who would relapse in the second peak.
TL;DR: Reduced risk of premenopausal breast cancer was associated with high energy expenditure in physical activity during teenage, although the trend was not statistically significant.
Abstract: To further clarify risk factors for breast cancerin Japanese women, a self-administered questionnaire was completedby 157 cases with histologically confirmed breast cancerfrom 1989 to 1993 and by 369 ageand residential area matched controls in Gifu, Japan.Conditional logistic regression model was used to assessthe relations. Multivariate analyses showed that breast cancerrisk decreased with body mass index for premenopausalwomen (RR=0.45; 95% CI=0.22–0.92for BMI ≥ 23 vs. < 21 (kg/m2)),but the risk increased with body mass indexfor postmenopausal women (RR=1.98; 95% CI= 0.86–4.55 for BMI ≥ 24 vs. <21.5 (kg/m2)). The risk increased with a smallnumber of births in pre- and post-menopausal women(1.83; 1.11–2.99 and 6.06; 2.40–15.3 for 1–2 birthsand nulliparity, respectively, vs. ≥ 3 births). Ex-or current smoking increased the risk of breastcancer (2.31; 1.19–4.49). Reduced risk of premenopausal breastcancer was associated with high energy expenditure inphysical activity during teenage, although the trend wasnot statistically significant.
TL;DR: A multivariate statistical analysis including the variables with which both proteins were associated will reveal any possible independent prognostic value of PCNA andHSP70 immunostaining in local, ductal invasive breast cancerNOS.
Abstract: A series of 80 female patients undergoing surgery for primary breast ductal infiltrating carcinoma not otherwise specified (NOS) was immunohistochemically studied in order to verify any relationships between Proliferating Cell Nuclear Antigen (PCNA) immunostaining, Heat Shock Protein 70 (HSP70) immunoreactivity, and several clinicopathological predictors. Positive PCNA scores (> 20% of strongly immunopositive malignant nuclei) were observed in neoplastic cells' nuclei in 13 tumors (16.25%) and were intimately associated with axillary nodal involvement (p = 0.0131), relatively high tumor grades (p = 0.0016), increased tumor size (p = 0.0312), and low or negative levels of estrogen receptors (p = 0.0323). HSP70 positive immunoexpression in malignant cells' cytoplasm (percentage of HSP70 immunoreactive cells > 10%) was detected in 33 samples (41.25%). It correlated significantly with presence of axillary lymph nodal metastases (p = 0.0033) and rather poor tumor differentiation (p = 0.0014), whereas an association of borderline statistical significance emerged between HSP70 immunoreactivity and high progesterone receptor status (p = 0.0637). PCNA positive immunostaining demonstrates the tumors' proliferative fraction and might be used as an indicator of increased malignant potential in breast cancer since it was associated with four adverse prognosticators. HSP70 immunodetection is a probable marker of the biological stress experienced by breast cancer cells, since it was related to relatively high tumor grades. Since both proteins may potentially predict disease outcome, their prognostic significance must be validated by direct relation to survival. A multivariate statistical analysis including the variables with which both proteins were associated will reveal any possible independent prognostic value of PCNA and HSP70 immunostaining in local, ductal invasive breast cancer NOS.
TL;DR: The results suggest that the threshold of E2 required to induce PgR expression in normal human breastepithelial cells is lower than that needed to induce proliferation and that the majority of proliferating breast cells do not express the PGR.
Abstract: High serum concentrations of estradiol (E2) equivalent tothose observed in the luteal phase of the menstrual cycle stimulate bothepithelial cell proliferation and progesterone receptor (PgR) expression innormal human breast tissue xenografted into athymic nude mice. We reporthere the results of further investigations designed to determine whether theinduction of PgR expression and proliferation require differentE2 concentrations and whether proliferating cells expressedthe PgR. In untreated normal breast xenografts, the PgR was virtuallyundetectable and proliferation was at basal levels. Progesterone (Pg)treatment alone had no effect compared to no treatment. Treatment withE2 at follicular phase serum concentrations maximallyincreased PgR expression but was without effect on proliferation. However,treatment with E2 at luteal phase serum concentrations, aloneor in combination with Pg, significantly increased both the PgR content andthe proliferation of the breast epithelium. These experimentally deriveddata reflected the observations made on normal breast tissue at surgicalbiopsy where PgR content was similar in both halves of the menstrual cycle,whereas proliferation was significantly higher in the luteal phase. Finally,using double labelling techniques, it was demonstrated that proliferatingepithelial cells rarely expressed PgR in normal breast tissue obtained atsurgical biopsy. These results suggest that the threshold ofE2 required to induce PgR expression in normal human breastepithelial cells is lower than that required to induce proliferation andthat the majority of proliferating breast cells do not express the PgR.
TL;DR: TOR60 and TAM40 show equivalent clinical efficacy and tolerability in postmenopausal women with advanced estrogen receptor (ER) positive or ERunknown breast cancer and the higher dose of toremifene slightly but not statistically significantly improves response rate and timeto progression.
Abstract: Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.
TL;DR: Endpoints for both in situ and excision assays are described, including approaches for determining cell kill, tumor growth delay, survival, and other estimates of activity.
Abstract: Considerable effort has been placed into the identification of new antineoplastic agents to treat breast cancer and other malignant diseases. The basic approaches, in terms of model selection, endpoints, and data analysis, have changed in the previous few decades. This article deals with many of the issues associated with designing in vivo studies to investigate the activity of experimental and established compounds and their potential interactions. Endpoints for both in situ and excision assays are described, including approaches for determining cell kill, tumor growth delay, survival, and other estimates of activity. Suggestions for approaches that may limit the number of animals also are included, as are possible alternatives for death as an experimental endpoint. Other concerns, such routes for drug administration, drug dosage, and preliminary assessments of toxicity also are addressed. Statistical considerations are only briefly discussed, since these are addressed in detail in the accompanying article by Hanfelt (Hanfelt JJ, Breast Cancer Res Treat 46:279-302, 1997). The approaches suggested within this article are presented to draw attention to many of the key issues in experimental design and are not intended to exclude other approaches.
TL;DR: In this article, the authors evaluated prognostic factors for dissemination and survival in patients with local or regional recurrence of breast cancer and defined subgroups of patients at different risk of developing metastases in specific anatomical sites.
Abstract: Purposes: The study evaluates prognostic factors for dissemination and survival in patients with local or regional recurrence of breast cancer. Furthermore, the aim was to define subgroups of patients at different risk of developing metastases in specific anatomical sites. Patients and methods: The study included 140 patients with isolated local or regional node recurrence, who entered a prospective study for staging of patients with first recurrence of breast cancer in the period 1983–85. The primary treatment was a simple mastectomy; node positive patients received adjuvant radiotherapy and chemotherapy or tamoxifen.If possible, the locoregional recurrence was treated with surgery and/or radiotherapy, otherwise by systemic therapy. Results: Median follow up was 10.4 years; 78 patients developed distant metastases (soft tissue, 32%; bone, 45%; viscera 40%). Median time to dissemination was 4.4 years, and the ten year dissemination rate was 72%. Median time to dissemination was 3.7 years for patients with recurrence in the regional nodes compared to 6.5 years for patients with chest wall recurrence only, p = 0.05. No specific time sequence (temporal pattern) was observed in the anatomical distribution of metastases, and the anatomical site of recurrence could not be predicted by any of the prognostic factors. At follow up, 93 patients had died. The median survival was 5.6 years and 30% were alive after 10 years. Forty-three of the 99 patients who received local therapy only did not develop metastases. Fifteen of these patients died without evidence of metastatic disease while 28 patients were still alive without distant recurrence after a median follow up time of 9.3 years (range, 6.5–11.9 years). Level of LDH and the number of positive regional nodes (NPOS) at primary diagnosis were significant independent prognostic factors for survival after recurrence. Conclusions: Approximately one third of the patients receiving local treatment only, were alive and without distant metastases up to ten years after locoregional recurrence, indicating that there is a subset of patients which may be long term survivors after local treatment only (surgery or radiotherapy). The duration of survival can be estimated by LDH and NPOS, but the model needs validation in a separate data set before clinical use.
TL;DR: The analysis confirmed the prognostic role of age at surgery, histology, and primary tumor site, in that young patients withtumors of lobular histology or located at inner/centralmammary quadrants were at greater risk of developing CBC.
Abstract: The purpose of the present study was to assess prognostic factor for metachronous contralateral recurrence of breast cancer (CBC). Two factors were of particular interest, namely estrogen (ER) and progesterone (PgR) receptors assayed with the biochemical method in primary tumor tissue. Information was obtained from a prospective clinical database for 1763 axillary node-negative women who had received curative surgery, mostly of the conservative type, and followed-up for a median of 82 months. The analysis was performed based on both a standard (linear) Cox model and an artificial neural network (ANN) extension of this model proposed by Faraggi and Simon. Furthermore, to assess the prognostic importance of the factors considered, model predictive ability was computed. In agreement with already published studies, the results of our analysis confirmed the prognostic role of age at surgery, histology, and primary tumor site, in that young patients (< or = 45 years) with tumors of lobular histology or located at inner/central mammary quadrants were at greater risk of developing CBC. ER and PgR were also shown to have a prognostic role. Their effect, however, was not simple in relation to the presence of interactions between ER and age, and between PgR and histology. In fact, ER appeared to play a protective role in young patients, whereas the opposite was true in older women. Higher levels of PgR implied a greater hazard of CBC occurrence in infiltrating duct carcinoma or tumors with an associated extensive intraductal component, and a lower hazard in infiltrating lobular carcinoma or other histotypes. In spite of the above findings, the predictive value of both the standard and ANN Cox models was relatively low, thus suggesting an intrinsic limitation of the prognostic variables considered, rather than their suboptimal modeling. Research for better prognostic variables should therefore continue.
TL;DR: The change in the joint distribution of the four risk factors accounted for less than 40% of the increase observed from 1959–60 to 1983–87, suggesting the effects of otherpowerful risk factors.
Abstract: The incidence rate of breast cancer in Japan rose more than two-fold from 1959-60 to 1983-87. To assess to what extent this increase can be explained by changes in the prevalence of four major risk factors of breast cancer (i.e. age at menarche, age at first birth, age at menopause, and parity), we estimated the probability of developing breast cancer based on the joint distribution and relative risks of these four risk factors. The age-specific incidence rate during 1959-60 reported by the Miyagi Prefectural Cancer Registry was used to estimate the baseline hazard rate for women without the four risk factors in the same age group. Assuming that the baseline hazard rate is constant during all periods, we calculated the expected incidence rates during the periods of 1959-60, 1962-64, 1968-71, 1973-77, 1978-81, and 1983-87 for each age group. Large discrepancies were noted between the observed and expected incidence rates during 1983-87 in all age groups. The change in the joint distribution of the four risk factors accounted for less than 40% of the increase observed from 1959-60 to 1983-87, suggesting the effects of other powerful risk factors.
TL;DR: In this article, the authors investigated the effect of the circulating Her-2 gene product (NEU) on the risk of recurrence in node-positive breast cancer patients, using 120 fmol/ml as a cut-off level, and found that NEU was an independent prognosticfactor for predicting disease-free survival but not for overall survival.
Abstract: This retrospective case control study investigated the therametricvalue of the circulating c-erbB-2 gene product (Her-2,NEU) as (1) an eligibility criterion for highdoses of chemotherapy and (2) response to standardadjuvant chemotherapy in node-positive breast cancer patients. Preoperativec-erbB-2 levels were measured in 211 locally advanced(> 3 nodes positive), pre- and perimenopausal breastcancer patients to determine if circulating levels ofthe gene product can assist in the determinationof appropriate therapeutic options.152 of 211 breast cancer patients received post-operativelya combination chemotherapy including the anthracycline analog mitoxantrone,while 59 patients were treated with conventional CMFtherapy. Using 120 fmol/ml as a cut-off level,elevated c-erbB-2 values were found in 26 (12.3%)patients with locally advanced breast cancer. In univariateanalysis significant survival differences were detected when c-erbB-2‘positive’ patients were compared with c-erbB-2 ‘negative’ patients.However, no significant survival differences were detected, whenc-erbB-2 ‘positive’ patients were compared according to regimenof adjuvant treatment.In multivariate analysis c-erbB-2 was an independent prognosticfactor for predicting disease-free survival, but not foroverall survival. High levels of c-erbB-2 were associatedwith low estrogen and progesterone receptor concentrations ofthe tumor cytosol. There was no correlation betweenelevated c-erbB-2 values and age, tumor size ordegree of nodal involvement. c-erbB-2 was a betterpredictor of risk of recurrence than extent ofnodal involvement or hormone receptor status.
TL;DR: Four BRCA2 hereditary breast cancer families manifested significant excesses of ‘tubular-lobular group’ (TLG) invasive carcinomas and lobular carcinoma in situ/atypical lobular hyperplasia in comparison to BRCa1-HBC cases.
Abstract: Four BRCA2 hereditary breast cancer (HBC) families manifested significant excesses of ‘tubular-lobular group’ (TLG) invasive carcinomas and lobular carcinoma in situ/atypical lobular hyperplasia in comparison to BRCA1-HBC cases.
TL;DR: The efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.
Abstract: We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% ± 12% and for mortality 6% ± 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.
TL;DR: In this paper, the presence in bone marrow of cells which react with monoclonal antibodies against tumor-associated antigens has been proposed over the last few years as a new prognostic factor in breast cancer patients.
Abstract: Background: The presence in bone marrow of cells which react with monoclonal antibodies against tumor-associated antigens has been proposed over the last few years as a new prognostic factor in breast cancer patients. Patients and methods: Bone marrow aspirates were obtained from 109 stage I and II breast cancer patients during or 2–4 weeks after primary surgery. The samples were processed for leukocyte separation on a Ficoll-Hypaque gradient and then used to prepare cytospin slides for immunocytochemical analysis. The slides were stained with a pool of monoclonal antibodies (MoAbs) which recognize tumor associated antigens, using the alkaline phosphatase anti-alkaline phosphatase method. The median follow-up was 36 months (range 15–62); 22 patients relapsed and 7 died. Results: Thirty-four of the 109 patients (31.1%) had MoAb positive bone marrow cells. The bone marrow was positive in 28/74 (37.9%) patients who had the aspirate taken during surgery and in 6/35 (17.1%) who had it taken after surgery (p = 0.055). No association was found between bone marrow positivity and tumour size, nodal status, menopausal status, estrogen receptor positivity or the proliferative index. No association was found between bone marrow and prognosis: the log-rank test was 0.291 (p > 0.5) for OS and 0.023 for DFS; the hazard ratio (positive vs negative) was 1.51 for OS (95% CI: 0.33–6.86) and 0.93 for DFS (95% CI: 0.35–2.45). Conclusions: In our series, bone marrow positivity did not correlate with prognostic parameters or prognosis. Of interest is the relative excess of positivity when the bone marrow was obtained during surgery.
TL;DR: There was a significant trend in increasing E2 level with increasing height after taking account of age and body mass index (BMI), and trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy.
Abstract: We measured serum levels of estradiol (E2), sex hormone-binding globulin SHBG), progesterone, and dehydroepiandrosterone sulfate (DHEAS) in 61 postmenopausal women drawn from female residents in a community in Japan to evaluate the relationships between these hormone levels and potential breast cancer risk factors. The information on reproductive history, body size, alcohol use, and physical activity was obtained by means of a self-administered questionnaire. There was a significant trend in increasing E2 level with increasing height after taking account of age and body mass index (BMI) (p for trend = 0.04). BMI was inversely associated with SHBG level after controlling age (p for trend = 0.01). Decreasing progesterone with increasing BMI was observed after controlling age and history of hysterectomy (P = 0.05). Alcohol consumption was positively associated with E2 level and there was a strong linear trend after controlling for age, height, and BMI (p for trend = 0.001). Trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy (p for trend = 0.01). Reproductive factors as well as physical activity were not related to any of the hormone levels.
TL;DR: RT-PCR data indicate that the PRL gene is expressed in the majority of both normal and neoplastic breast tissue samples, as well as all of the mammary cell lines, and suggests that PRL transcripts in breast tissues and mammarycell lines may undergo alternative splicing.
Abstract: Prolactin (PRL) has been implicated in the development of mammary cancer in rodents and humans. Although PRL and its mRNA have been detected in breast tissues and some mammary cell lines, the role of PRL as an autocrine/paracrine growth factor within the breast is not clear. A second, more distal, promoter has recently been identified in the human PRL gene. We have used reverse transcription-polymerase chain reaction (RT-PCR) to determine whether the distal or the proximal promoter directs expression of the PRL gene in normal and neoplastic breast tissues and in mammary cell lines. Total RNA was isolated from 10 normal and 20 neoplastic breast tissue samples and from 8 mammary cell lines; MDA-MB-231, SK-BR-3, T-47D, MCF10, MCF10T2, and 3 MCF7 derivatives. The RNA was reverse transcribed to cDNA using random hexamers as primers. PCR amplification of the cDNAs was performed, using a variety of PRL-specific primer pairs, and the DNA products were subjected to agarose gel electrophoresis and Southern blotting. The resulting data indicate that the PRL gene is expressed in the majority of both normal and neoplastic breast tissue samples, as well as all of the mammary cell lines. PRL-specific PCR products corresponding to transcripts that originated from the distal promoter were observed in a subset of the normal and neoplastic breast tissue samples and mammary cell lines. Together these data indicate that PRL transcripts in human breast tissues and human mammary cell lines originate, at least in part, from the distal PRL promoter. In addition, data are presented which suggest that PRL transcripts in breast tissues and mammary cell lines may undergo alternative splicing.
TL;DR: In 4 women with adenocarcinoma metastasis in an axillary lymph node consistent with breast cancer and without a primary tumor, MRI of the breast should be added to clinical examination and mammography before defining it as an occult primary and planning therapy.
Abstract: In 4 women with adenocarcinoma metastasis in anaxillary lymph node and no primary tumor found,we investigated whether Magnetic Resonance Imaging (MRI) ofthe breast could detect a clinically and mammographicallyoccult breast tumor. MRI detected an enhancing lesionin 3 women and an enhancing double lesionin one patient. MRI directed ultrasound guided fineneedle aspiration cytology confirmed the 5 breast carcinomasin the 4 women. In women with metastasis in an axillary lymphnode consistent with breast cancer and without aprimary tumor, MRI of the breast should beadded to clinical examination and mammography before definingit as an occult primary and planning therapy.
TL;DR: This study provided little support for the hypothesisthat risk factors for breast cancer are related to survival, and use of oral contraceptives was not correlated with survival.
Abstract: Several risk factors for the etiology of breastcancer have also been correlated with the prognosisof breast cancer. However, the published studies haveyielded conflicting results. Women under 71 years of age with stageI, II, or III breast cancer were eligiblefor inclusion in a clinical study. 866 patientswith breast cancer entered the study, of whom463 had positive lymph nodes. Survival was analysed using Cox's proportional hazards model.Age at menarche, parity, age at menopause andfamily history were not consistently related to survival.Young age at first full-term pregnancy was relatedto decreased survival (adjusted relative risk (RR): 1.69,95% confidence intervals (95% CI): 1.04–2.68), but itcannot be excluded that this result was dueto chance alone. Use of oral contraceptives wasnot correlated with survival (RR: 1.10, 95% CI:0.80–1.51) nor was family history (RR: 0.93, 95%CI: 0.66–1.30). This study provided little support for the hypothesisthat risk factors for breast cancer are relatedto survival.