Estrogen receptor, Progesterone receptor, HER2 status and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial (original) (raw)
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JNCI Journal of the National Cancer Institute, 1996
Background: Postsurgical treatment with tamoxifen has been shown to improve overall survival among patients with early stage breast cancer. However, the optimal duration of tamoxifen treatment remains controversial. Purpose: A multicenter, randomized trial was initiated in Sweden in the early 1980s to compare 2 years with 5 years of adjuvant tamoxifen in the treatment of postmenopausal women younger than 75 years of age who had early stage, axillary lymph node-negative or -positive, invasive disease. Methods: The trial was planned and organized by the Swedish Breast Cancer Group, and it involved five regional breast cancer study organizations (South Sweden, South-East Sweden, Stockholm, Uppsala-Orebro, and North Sweden). During the period from 1983 through 1991, a total of 3887 patients were entered in the trial; 3545 (91%) women remained alive and recurrence free at 2 years and could thus contribute meaningful information to the 2-year (n = 1801) versus 5year (n = 1744) comparison. Primary surgery consisted of either modified radical mastectomy or breast-conserving surgery. Radiation therapy was indicated for patients with lymph node-positive disease and was generally offered to all women who were treated with breast-conserving surgery. Only 89 (2.5%) of the 3545 women who were recurrence free at 2 years received adjuvant chemotherapy concurrently with tamoxifen. Twenty-milligram daily doses of tamoxifen were used at two centers, and 40-mg daily doses were used at the remaining three centers. Estrogen receptor status of the tumor was known for 2987 women (77% of the entered patients). Primary end points in the trial were eventfree survival (local-regional recurrence, distant metastasis, contralateral breast cancer, or death) and overall survival. Survival curves were estimated by use of the life-table method. The Cox proportional hazards model was used to make comparisons between the 2-and 5-year treatment groups. Results: Patients assigned to receive 5 years of tamoxifen, compared with 2 years of tamoxifen, experienced statistically significant improvements in event-free survival (relative hazard = 0.82; 95% confidence interval [CI] = 0.71-0.96) and overall survival (relative hazard = 0.82; 95% CI = 0.69-0.99). These findings translate into an 18% relative reduction in both first events (95% CI = 4%-29%) and mortality (95% CI = 1%-31%) with the longer treatment. Overall survival at 10 years was estimated to be 80% among patients in the 5-year tamoxifen group who were alive and recurrence free at 2 years, compared with 74% among corresponding patients in the 2-year treatment group. The benefit associated with the longer treatment extended to women with lymph node-positive as well as lymph nodenegative disease, but it appeared to be restricted to women whose tumors were classified as estrogen receptor positive. Conclusion: Five years of adjuvant tamoxifen is more beneficial than 2 years in the treatment of postmenopausal women with estrogen receptor-positive, early stage, invasive breast cancer. [J Natl Cancer Inst 1996;88:1543-9]
Journal of Clinical Pathology, 2005
Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment. Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer. Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression. Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly. Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
Breast Cancer Research and Treatment, 1995
370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 rag/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.
Cancer prevention research (Philadelphia, Pa.), 2017
The randomized, double-blinded Royal Marsden Tamoxifen Breast Cancer Prevention Trial in healthy high-risk women started in 1986 and is still blinded. Eligible participants (n = 2,471) were randomly assigned to tamoxifen (20 mg/d) or placebo for 8 years. Analysis in 2006 showed a 30% risk reduction of estrogen receptor (ER)-positive invasive breast cancer mostly in the posttreatment period. Biomarker analysis in this population may identify any subgroup-specific preventive effects tamoxifen. After a median follow-up of 18.4 years, 242 patients had developed invasive cancer, 134 on placebo and 108 on tamoxifen. From these, 180 tissue blocks were available and ER, progesterone receptor (PgR), Ki67, HER2, and EGFR were immunohistochemically analyzed. A 32% reduction in ER(+) and PgR(+) invasive cancers resulted after 8 years of treatment. Quantitative levels of ER and PgR were lower in the tamoxifen-treated group, significantly so for ER (P = 0.001). These lower ER levels were restrict...
International Journal of Radiation Oncology*Biology*Physics, 1996
To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Re-excision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of re-excision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p = 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5-year actuarial breast recurrence rate (21 vs. 4%; p = 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all patients or pathologic node-negative patients. Pathologically node-positive patients had a significant decrease in distant metastasis (35 vs. 11%; p = 0.02). There were no significant differences in cause-specific survival for patients receiving tamoxifen when compared to observation (95% no tamoxifen vs. 89% tamoxifen; p = 0.24). Similar findings were noted for pathologically node-negative patients. However, axillary node-positive patients receiving tamoxifen had an improvement in 5-year actuarial cause-specific survival (90% tamoxifen vs. 70% no tamoxifen; p = 0.10). Cosmesis (physician assessment) was good to excellent in 85% of the tamoxifen patients compared to 88% of the patients who did not receive tamoxifen. The addition of tamoxifen to conservative surgery and radiation in women with Stage I-II breast cancer and estrogen receptor positive tumors resulted in a modest but not statistically significant decrease in the 5-year actuarial risk of a breast recurrence. Tamoxifen significantly decreased the 5-year actuarial risk of distant metastasis in axillary node-positive patients and there was a trend towards improvement in cause-specific survival that was not statistically significant. Tamoxifen did not decrease the 5-year actuarial rate of distant metastasis in axillary node negative, patients and in this group, there was no improvement in cause-specific survival. Tamoxifen did not have an adverse effect on cosmesis or complications.
The Stockholm trial on adjuvant tamoxifen in early breast cancer
Breast Cancer Research and Treatment, 1987
The paper presents interim results of an on-going randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no endocrine adjuvant therapy in postmenopausal women with early breast cancer. A total of 1407 patients were included in the study between November 1976 through June 1984. Estrogen receptor (ER) data were available on 1184 patients (84 %). The median follow-up was 53 months. Adjuvant tamoxifen increased the recurrence-free interval (P<0.01) but had no significant effect on overall survival. Treatment failures were reduced by 25% (P<0.01) and deaths by 7% (P>0.05). Tamoxifen mainly decreased the frequency of loco-regional recurrence whereas distant metastases were less affected. The treatment effect was independent of tumor stage but was significantly related to the estrogen receptor (ER) content of the primary tumor. Tamoxifen appeared ineffective among ER negative patients, and the greatest effect was seen among those with high levels of ER. The results indicate that the main mechanism of action of adjuvant tamoxifen is similar to that suggested in advanced disease, i.e. an interaction with the estrogen receptor.
Breast Cancer Research and Treatment, 2002
There is now an emerging body of evidence that shows there is a relationship between the survival of breast cancer patients and the expression level of steroid receptors. The aim of this study was to determine the relationship existing between estrogen receptors (ER) and progesterone receptors (PR) cytosolic content and the prognosis of postmenopausal breast cancer women under tamoxifen therapy. Two hundred and nineteen postmenopausal patients, without neoadjuvant chemotherapy and treated postoperatively with tamoxifen for at least 2 years, were followed up in our Cancer Center. We used flexible regression modeling and log likelihood methods for determining optimum cut-off values for steroid receptors, which allows the separation of patients into significantly different categories in term of survival. For PR, 3 categories were defined (category 1: PR < 10, category 2: 10 ≤ PR < 60 and category 3: PR ≥60 fmol/mg P). Univariate analysis at 8 years indicated that significant differences in eventfree survival (EFS) were found for tumor size (T) (p = 0.005), lymph node status (N) (p = 0.003), histological Scarff, Bloom and Richardson grade (p = 0.003), ER values divided into 5 categories (p = 0.02) and PR values divided into 3 categories (p = 1 · 10 −5 ). Eight-year EFS rate for the 3 PR categories, adjusted for N, were 39, 66 and 81%, respectively. Multivariate Cox analysis indicated that only T, N and PR values were significant variables for EFS. Patients with PR values ≥60 present significantly greater EFS rates than patients with PR < 60 (p < 0.001). Our results show that the PR level in ER positive postmenopausal women is a strong prognostic marker in postmenopausal breast cancer women under tamoxifen therapy.