To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local ...treatment, and patterns of recurrence.
Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types.
Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01).
ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.
The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ...ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, “old-fashioned” treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.
To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT).
Prognostic ...factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT.
No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001).
Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.
Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer ...Study Group Trial VII.
Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years.
Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio HR, 1.00; 95% confidence interval CI, 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received.
CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.
To evaluate the impact of subsequent pregnancy on the prognosis of patients with early breast cancer.
One hundred eight patients who became pregnant after diagnosis of early-stage breast cancer were ...identified in institutions participating in International Breast Cancer Study Group (IBCSG) studies. Fourteen had relapse of breast cancer before their first subsequent pregnancy. The remaining 94 patients (including eight who relapsed during pregnancy) formed the study group reported here. A comparison group of 188 was obtained by randomly selecting two patients, matched for nodal status, tumor size, age, and year of diagnosis from the IBCSG database, who were free of relapse for at least as long as the time between breast cancer diagnosis and completion of pregnancy for each pregnant patient. Survival comparison used Cox proportional hazards regression models.
Overall 5- and 10-year survival percentages (+/- SE) measured from the diagnosis of early-stage breast cancer among the 94 study group patients were 92% +/- 3% and 86% +/- 4%, respectively. For the matched comparison group survival was 85% +/- 3% at 5 years and 74% +/- 4% at 10 years (risk ratio, 0.44; 95% confidence interval, 0.21 to 0.96; P =.04).
Subsequent pregnancy does not adversely affect the prognosis of early-stage breast cancer. The superior survival seen in this and other controlled series may merely reflect a healthy patient selection bias, but is also consistent with an antitumor effect of the pregnancy.
Cancer presenting at the medial site of the breast may have a worse prognosis compared with tumors located in external quadrants. For medial tumors, axillary lymph node staging may not accurately ...reflect the metastatic potential of the disease.
Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years.
A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS).
Tumor site has a significant prognostic utility, especially for axillary lymph node-negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.
Increasing numbers of older women are affected by early breast cancer, because of prolonged life expectancy and the increasing incidence of breast cancer with age. The role of adjuvant therapy for ...this population is still a matter of debate. We reviewed the long-term outcome of a mature trial comparing endocrine treatment versus no adjuvant therapy in older women with node-positive breast cancer.
From 1978 to 1981, 349 women 66 to 80 years of age with pathologically involved lymph nodes after total mastectomy and axillary clearance were randomly assigned to receive 12 months of adjuvant tamoxifen plus low-dose prednisone (p+T) or no adjuvant therapy. Three hundred twenty patients were eligible.
At 21 years' median follow-up, 1 year of p+T significantly prolonged disease-free survival (DFS; P =.003) and overall survival (P =.05; 15-year DFS, 10% +/- 3% v 19% +/- 3%; hazard ratio, 0.71; 95% CI, 0.58 to 0.86). When comparing competing causes of failure (breast cancer recurrence and deaths before breast cancer recurrence), p+T was far superior in controlling breast cancer recurrence (P =.0003), but the improvement was seen mainly in soft tissue sites. Conversely, patients in the p+T group were more likely to die before a breast cancer recurrence (P =.03).
This trial demonstrates that significant treatment benefits continue to be observed in older patients treated for 1 year with p+T. Despite issues relating to competing causes of failure, older breast cancer patients can benefit from treatment and should be considered for trials of adjuvant systemic therapy.
To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with ...bisphosphonates.
We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10. 7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence.
For the entire population with operable disease, the cumulative incidence of bone metastases at any time was 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years).
Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue.
We investigated tumor- and patient-related features that might influence the response to perioperative chemotherapy (PeCT) compared with no adjuvant therapy for patients with node-negative breast ...cancer.
A total of 1,275 patients were randomized to either no adjuvant treatment (427 patients) or PeCT (848 patients). The following variables thought to have prognostic significance were evaluated: grade, tumor size, estrogen (ER) and progesterone receptor (PgR) content (absent; low, 1 to 9 fmol/mg cytosol protein; or positive, > or = 10 fmol/mg cytosol protein), c-erbB-2 overexpression, menopausal status, and age. Cox proportional hazards regression models were used to assess the relative influence of these factors to predict the effect of PeCT on disease-free survival (DFS). Median follow-up was 13.5 years.
The 10-year DFS percentage for 692 premenopausal patients did not significantly differ between the PeCT and no-adjuvant-treatment groups: 61% and 59%, respectively (relative risk RR, 0.95; 95% confidence interval CI, 0.75 to 1.20; P = .70). No predictive factors were identified. For 583 postmenopausal patients, 10-year DFS percentages for the groups were 63% and 58%, respectively (RR, 0.75; 95% CI, 0.58 to 0.93; P = .03). The absence of expression of ER, PgR, or both ER and PgR was the most important factor predicting improved outcome with PeCT among postmenopausal patients. The 10-year DFS percentages were 85% and 53% for the steroid hormone receptor-absent cohort of treated and untreated patients, respectively (RR, 0.18; 95% CI, 0.06 to 0.49; P = .0009).
The role of PeCT should be explored for patients whose primary tumors do not express steroid hormone receptors, because it is likely that early initiation of treatment is exclusively relevant for such patients.
We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive ...lymph nodes (LN1-3+).
We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years.
In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy.
Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.
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