Adjuvant Therapy for Early Breast Cancer: A Time to Refine
19 Nov 1997-Journal of the National Cancer Institute (Oxford University Press)-Vol. 89, Iss: 22, pp 1652-1654
TL;DR: Adjuvant endocrine therapy and chemotherapy are now being used extensively to treat primary breast cancer and are probably beginning to have an impact on national mortality data in the U.K. as discussed by the authors.
Abstract: Adjuvant endocrine therapy and chemotherapy are now being used extensively to treat primary breast cancer and are probably beginning to have an impact on national mortality data in the U.K. (1,2). The main difficulty at present is identifying those patients who may require such treatment. The widespread use and evaluation of adjuvant combination chemotherapy started in 1976 after Bonadonna et al. (3) reported the results of an innovative trial using cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy for the treatment of patients with axillary lymph node-positive primary breast cancer. Their results showed that such treatment could substantially reduce the risk of relapse. Many trials have since confirmed these initial results, and, in 1985, an overview metaanalysis of these trials (4) showed a statistically significant reduction in mortality for women under the age of 50 years who were given adjuvant combination chemotherapy. Similarly, early trials of endocrine therapy using ovarian ablation had shown reductions in the rates of relapse (5,6) and were followed in 1977 by the start of the NATO (Nolvadex Adjuvant Trial Organization) trial of adjuvant tamoxifen, which subsequently showed that tamoxifen given for 2 years after mastectomy reduced the risk of relapse and death (7). Since then, other trials have shown similar results, and the 1985 overview (4) confirmed that there was a significant reduction in mortality in women aged 50 years or older who received adjuvant tamoxifen. Following these results, a National Institutes of Health consensus conference in 1985 (8) recommended that adjuvant combination chemotherapy should become standard care for premenopausal women with positive axillary lymph nodes, whereas tamoxifen should be used as the standard treatment of choice for postmenopausal women with estrogen receptor (ER)-positive tumors. Adjuvant therapy was not recommended for any other categories of patients. Subsequently, a repeat overview metaanalysis in Oxford in 1990 (9), comprising many more clinical trials, indicated that tamoxifen could be of benefit for most patients with primary breast cancer and that there was also a significant survival benefit for patients with negative axillary lymph nodes who received adjuvant combination chemotherapy. The magnitude of this survival benefit for chemotherapy appeared to be small, with an absolute odds reduction in mortality of only about 4% at 10 years for patients with negative axillary lymph nodes. However, Slevin et al. (10) have noted that most patients with breast cancer would accept severe toxicity from treatment in order to achieve as little as a 1% improvement in survival. The toxicity from adjuvant chemotherapy is generally mild and seldom life threatening; therefore, a 4% reduction in mortality at 10 years is likely to be considered an attractive option by most patients with axillary lymph node-negative primary breast cancer. In 1982, the National Surgical Adjuvant Breast and Bowel Project (NSABP) commenced a clinical trial (B-14) in which adjuvant tamoxifen was given to patients with lymph nodenegative, ER-positive primary breast cancers. Analysis in 1989 (11) showed that there was a significant reduction in relapse rates, although the survival benefit did not reach statistical significance. The investigators concluded that, although the prognosis for these patients on tamoxifen was good, additional benefit might be achieved by the addition of combination chemotherapy. Therefore, they started a new trial, NSABP B-20, which compared tamoxifen alone with tamoxifen plus CMF (or MF) chemotherapy in patients with axillary lymph nodenegative, ER-positive primary breast cancer. The results from this trial, reported in this issue of the Journal (12), show that the addition of chemotherapy to tamoxifen caused a further improvement in disease-free survival of about 5% and an additional improvement in survival of about 3%—strikingly similar to the results from the 1990 overview (9), which indirectly compared tamoxifen alone with tamoxifen plus polychemotherapy. Furthermore, no easily discernible group (age, menopausal status, and primary tumor size) could be identified that did not gain benefit. This beneficial effect of adding chemotherapy to tamoxifen in patients with axillary lymph node-negative primary breast cancer is in keeping with the 1990 overview metaanalysis data (9), which indicated that the absolute benefit for adjuvant chemotherapy was similar for patients with lymph node-negative or lymph node-positive breast cancer. This finding is not surprising, since axillary lymph node status has never been shown to be predictive of sensitivity to adjuvant chemotherapy. There is no biologic basis to suppose that axillary lymph node involvement should indicate chemosensitivity, and there are reasons to suppose that less extensive disease might be more likely to respond to chemotherapy. The principal conclusion from the NSABP B-20 trial, together with the data from the overview meta-analysis, is that
Citations
More filters
TL;DR: Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls, and these differences did not seem to be caused by significant differences in mood disturbance between the two groups.
Abstract: PURPOSE: Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls. PATIENTS AND METHODS: The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C). RESULTS: Univariate analysis showed statistically significant differences (P = .009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P = .046) when controlling for age, educ...
555 citations
Journal Article•
TL;DR: It is concluded that several components of the uPA system are potential predictors of RFS and OS in patients with primary invasive breast cancer and may benefit from targeted therapies that are currently being developed.
Abstract: The antigen levels of components of the urokinase-type plasminogen activator (uPA) system of plasminogen activation are correlated with prognosis in several types of cancers, including breast cancer. In the present study involving 2780 patients with primary invasive breast cancer, we have evaluated the prognostic importance of the four major components of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1 and PAI-2]. The antigen levels were determined by ELISA in cytosols prepared from primary breast tumors. The levels of the four factors significantly correlated with each other; the Spearman rank correlation coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to 0.59 (between uPA and PAI-1). The median duration of follow-up of patients still alive was 88 months. In the multivariate analyses for relapse-free survival (RFS) and overall survival (OS), we defined a basic model including age, menopausal status, tumor size and grade, lymph node status, adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1, and PAI-2 were considered as categorical variables, each with two cut points that were established by isotonic regression analysis. Compared with tumors with low levels, those with intermediate and high levels showed a relative hazard rate (RHR) and 95% confidence interval (95% CI) of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and 2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS in all patients. Compared with tumors with high PAI-2 levels, those with intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30 (1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were obtained in the multivariate analysis for OS in all patients. Furthermore, uPA and PAI-1 were independent predictive factors of a poor RFS and OS in node-negative and node-positive patients. PAI-2 also added to the multivariate models for RFS in node-negative and node-positive patients, and in the analysis for OS in node-negative patients. uPAR did not further contribute to any of the multivariate models. A prognostic score was calculated based on the estimates from the final multivariate model for RFS. Using this score, the difference between the highest and lowest 10% risk groups was 66% in the analysis for RFS at 10 years and 61% in the analysis for OS. Moreover, separate prognostic scores were calculated for node-negative and node-positive patients. In the 10% highest risk groups, the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at 10 years for node-negative and node-positive patients, respectively. These proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest risk groups of relapse. We conclude that several components of the uPA system are potential predictors of RFS and OS in patients with primary invasive breast cancer. Knowledge of these factors could be helpful to assess the individual risk of patients, to select various types of adjuvant treatment and to identify patients who may benefit from targeted therapies that are currently being developed.
414 citations
TL;DR: The Ki‐67 nuclear antigen may be considered as an alternative to mitotic counts in grading schemes and as a single parameter that can be used in fine‐needle aspirates and small biopsies.
Abstract: BACKGROUND
The number of mitoses and, thus, the proliferative capacity of a tumor is one of the most crucial variables for tumor grading. The Ki-67 nuclear antigen may be considered as an alternative to mitotic counts in grading schemes and as a single parameter that can be used in fine-needle aspirates and small biopsies.
METHODS
Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was performed on 434 breast carcinoma specimens from the International Breast Cancer Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were used to replace the mitotic counts component in the Nottingham grade (NHG) to produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single parameter.
RESULTS
In both the lymph node positive subgroup and the lymph node negative subgroup, the NKG and Ki-67 group was correlated significantly with Bloom–Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph node negative cohort and estrogen receptor status, progesterone receptor status, and c-erbB-2 expression in the lymph node positive cohort also were correlated significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB-2 expression in the lymph node positive cohort only. NKG was similar to BRG and NHG when it was evaluated for prognostic significance. Patients with higher categoric Ki-67 percentages had worse overall and disease free survival in all groups except for the untreated, lymph node negative group.
CONCLUSIONS
Ki-67 detection represents a valuable tool and is a good objective substitute for mitotic counts when used in a grading system. When it is used alone, Ki-67 detection provides valuable information, although it is necessary to combine this with other parameters in the study of core biopsies and fine-needle aspirates. Cancer 2003;97:1321–31. © 2003 American Cancer Society.
DOI 10.1002/cncr.11188
200 citations
TL;DR: The hypothesis that tumour high PTA levels is associated with a worse outcome is supported, as determined by univariate analysis.
Abstract: In a previous report we suggested that the estimation of prothymosin α (PTA) levels in primary breast tumours might be used to identify breast cancer patients at high risk for distant metastasis (Dominguez F et al (1993) Eur J Cancer29A: 893–897). Here the role of tumour PTA levels as predictor was investigated with respect to both disease-free survival (DFS) and survival. Tumours were obtained from a series of 210 consecutive female patients with ductal carcinoma who underwent surgery at the Hospital Xeral de Galicia (Santiago de Compostela, Spain). Characteristics including PTA tumour levels, number of positive axillary nodes, patient's age at surgery and tumour histological grade were significantly associated with DFS and survival, as determined by univariate analysis. Patients with tumours with low or moderate PTA levels demonstrated a statistically decreased rate of tumour recurrence and a statistically significant increased overall survival in comparison with those whose tumours had high PTA levels. Patient's relative risk of dying was 2.1 times greater for tumours with high PTA levels than for those tumours with low or moderate PTA levels. In conclusion, these data support the hypothesis that tumour high PTA levels is associated with a worse outcome. © 2000 Cancer Research Campaign
65 citations
TL;DR: Indole-3-carbinol (I3C), a naturally occurring compound of Brassica vegetables, has promising anticancer properties and activates an anti-proliferative pathway that induces a G1 cell cycle arrest of human breast cancer cells by stimulating expression of the interferon gamma receptor 1 (IFNgammaR1).
Abstract: Indole-3-carbinol (I3C), a naturally occurring compound of Brassica vegetables, has promising anticancer properties and activates an anti-proliferative pathway that induces a G1 cell cycle arrest of human breast cancer cells. A microarray analysis of I3C treated versus untreated MCF-7 breast cancer cells revealed that I3C increased expression of the interferon gamma receptor 1 (IFNgammaR1). Western blot and RT-PCR analysis demonstrated that I3C strongly and rapidly stimulated IFNgammaR1 gene expression. Transfection of a series of 5' deletion constructs of the IFNgammaR1 reporter plasmids revealed that I3C significantly stimulates the promoter activity of the IFNgammaR1 and uncovered an I3C-responsive region between -540 and -240 bp of the IFNgammaR1 promoter. I3C stimulation of the IFNgammaR1 expression suggests that indole treatment should enhance IFNgamma responsiveness in breast cancer cells. A combination of I3C and IFNgamma synergistically activated STAT1 proteins by increasing phosphorylation at the Tyr-701 site. In addition, I3C and IFNgamma together more effectively induced a G1 cell cycle arrest and stimulated expression of the p21(Waf1/Cip1) cell cycle inhibitor, compared with the effects of either agent alone. Our results suggest that one mechanism by which I3C mediates these anticancer effects is by stimulating expression of the IFNgammaR1 and augmenting the IFNgamma response in MCF-7 human breast cancer cells.
33 citations
References
More filters
TL;DR: Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation and was attained with a low incidence of clinically appreciable toxic effects.
Abstract: We conducted a randomized, double-blind, placebo-controlled trial of postoperative therapy with tamoxifen (10 mg twice a day) in 2644 patients with breast cancer, histologically negative axillary nodes, and estrogen-receptor-positive (greater than or equal to 10 fmol) tumors. No survival advantage was observed during four years of follow-up (92 percent for placebo vs. 93 percent for tamoxifen; P = 0.3). There was a significant prolongation of disease-free survival among women treated with tamoxifen, as compared with those receiving placebo (83 percent vs. 77 percent; P less than 0.00001). This advantage was observed in both the patients less than or equal to 49 years old (P = 0.0005) and those greater than or equal to 50 (P = 0.0008), particularly in the former, among whom the rate of treatment failure was reduced by 44 percent. Multivariate analysis indicated that all subgroups of patients benefited. Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation. The benefit was attained with a low incidence of clinically appreciable toxic effects. The magnitude of the improvement obtained does not preclude the need for future trials in which patients given tamoxifen could serve as the control group in an evaluation of potentially better therapies. Tamoxifen treatment is justified in patients who meet the eligibility criteria of the present study and who refuse to participate in those trials. Since patients with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not eligible for this study, no information is available to indicate that such patients should receive tamoxifen.
1,421 citations
TL;DR: It is indicated that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival and that the results obtained at five years accurately predict the outcome at 10 years.
Abstract: In 1971 we began a randomized trial to compare alternative local and regional treatments of breast cancer, all of which employ breast removal. Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months. There were no significant differences among three groups of patients with clinically negative axillary nodes, with respect to disease-free survival, distant-disease--free survival, or overall survival (about 57 per cent) at 10 years. The patients were treated by radical mastectomy, total ("simple") mastectomy without axillary dissection but with regional irradiation, or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive. Similarly, no differences were observed between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation. Survival at 10 years was about 38 per cent in both groups. Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival. The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years. We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer.
1,278 citations
TL;DR: Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage, and the effect of this therapy on survival and possible long-term side effects remain unknown.
Abstract: Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment failure occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P <10–6), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher percent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of this therapy on survival and possible long-term side effects remain unknown. (N Engl J Med 294:405–410, 1976)
1,251 citations
TL;DR: In a worldwide collaboration, information was sought and centrally checked on mortality and recurrence for each woman in any randomised trial that began before 1985 of any aspect of systemic adjuvant therapy for early breast cancer.
994 citations
Journal Article•
TL;DR: This overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality, and showed that combination chemotherapy was significantly more effective than single-agent therapy.
Abstract: We sought information worldwide on mortality according to assigned treatment in all randomized trials that began before 1985 of adjuvant tamoxifen or cytotoxic therapy for early breast cancer (with or without regional lymph-node involvement). Coverage was reasonably complete for most countries. In 28 trials of tamoxifen nearly 4000 of 16,513 women had died, and in 40 chemotherapy trials slightly more than 4000 of 13,442 women had died. The 8106 deaths were approximately evenly distributed over years 1, 2, 3, 4, and 5+ of follow-up, with little useful information beyond year 5. Systematic overviews of the results of these trials demonstrated reductions in mortality due to treatment that were significant when tamoxifen was compared with no tamoxifen (P less than 0.0001), any chemotherapy with no chemotherapy (P = 0.003), and polychemotherapy with single-agent chemotherapy (P = 0.001). In tamoxifen trials, there was a clear reduction in mortality only among women 50 or older, for whom assignment to tamoxifen reduced the annual odds of death during the first five years by about one fifth. In chemotherapy trials there was a clear reduction only among women under 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first five years by about one quarter. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy, but suggested that administration of chemotherapy for 8 to 24 months may offer no survival advantage over administration of the same chemotherapy for 4 to 6 months. Because it involved several thousand women, this overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality.
850 citations