Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report.

BACKGROUND: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. RESULTS: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. CONCLUSION: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX.

BACKGROUND: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. PATIENTS AND METHODS: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. RESULTS: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. CONCLUSION: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy.

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer.

BACKGROUND: The International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. PATIENTS AND METHODS: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF→ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. RESULTS: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF→ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). CONCLUSIONS: For pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea.

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer.

BACKGROUND: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. PATIENTS AND METHODS: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). RESULTS: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. CONCLUSION: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Clinical use of selective estrogen receptor modulators and down regulators with the main focus on breast cancer.

Selective estrogen receptor modulators (SERMs) and selective estrogen down regulators (SERDs) act as estrogen receptor (ER) agonists or antagonist depending on the targeted tissue and the specific configuration of the used SERM or SERD. Effects on bone, endometrium and breast cancer are of interest. Endocrine treatments have been used in breast cancer since the end of the 19th century. In the second part of the last century different compound of SERMs and SERDs have been developed and we will discuss them mainly as used in the treatment and prevention of breast cancer. Tamoxifen is the widely investigated and most used representative of these drugs and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting and for prevention of the disease. Its role has been challenged in the last years by the introduction of third generation aromatase inhibitors that have proven a higher activity than tamoxifen and a different toxicity pattern. Several other SERMs have been investigated, but none of them was clearly superior to tamoxifen. The main interest in different SERMs has to be seen in the slightly different safety profile between the different compounds. SERDs act as pure estrogen antagonist. They have been used in the treatment of advanced breast cancers and their role in other settings still needs further investigation. The increased use of aromatase inhibitors as first line endocrine therapy raises new questions on the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies and the combination of endocrine therapies with new targeted therapies in hormone sensitive breast cancer remains a very important research issue. Polymorphisms in genes coding for tamoxifen metabolizing enzymes, as for instance, the CYP2D6 genotype, have the potential of becoming clinically useful predictive marker for tamoxifen response. With this meaningful newer knowledge it is possible that the place of tamoxifen in the treatment of breast cancer will be redefined in the future.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?

BACKGROUND: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly. METHODS: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. RESULTS: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. CONCLUSIONS: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.

Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer.

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.

Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference. International Breast Cancer Study Group.

PURPOSE: Adjuvant cytotoxics prolong disease-free survival (DFS) and overall survival (OS) in patients with operable breast cancer. The first reported effective adjuvant combination regimen consisted of oral cyclophosphamide on days 1 to 14 with intravenous methotrexate and fluorouracil on days 1 and 8, repeated every 28 days (classical CMF). These drugs have since been extensively used with or without endocrine therapies and/or other cytotoxic agents. Although doses and schedules have varied widely, the combination of these three drugs is generically referred to as CMF. RESULTS: Reducing the dose and/or altering the schedule of CMF have compromised its efficacy in metastatic breast cancer. Reduction below standard dose of a similar regimen also gave inferior results in the adjuvant setting. CONCLUSION: Details of dose and schedule may therefore explain part of the heterogeneity of results observed with CMF. Particular controversy surrounds the contribution of CMF in postmenopausal women who are also receiving tamoxifen (TAM). However, the trials that demonstrated a significant benefit for the addition of CMF to TAM, even in postmenopausal women with estrogen receptor-positive tumors, used classical CMF. Therefore, adherence to the classical dose and schedule is recommended when CMF is used in adjuvant therapy.

Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer.

PURPOSE: To evaluate the impact of subsequent pregnancy on the prognosis of patients with early breast cancer. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Quality-of-life scores predict outcome in metastatic but not early breast cancer. International Breast Cancer Study Group.

PURPOSE: We compared the prognostic value of quality-of-life (QL) scores in the adjuvant setting and after relapse in two randomized trials of the International Breast Cancer Study Group. PATIENTS AND METHODS: More than 2,000 premenopausal and postmenopausal patients with node-positive breast cancer who were participating in randomized trials that compared adjuvant therapies completed QL assessments for physical well-being, mood, appetite, and coping at study entry and at months 3 and 18 if they remained relapse-free and, in case of relapse, at 1 month and at 6 months after relapse. Cox regression models were used to test the relationship between QL scores and disease-free survival (DFS), in the adjuvant setting, or overall survival, in the case of postrelapse QL measurement. All models were stratified by language/country group and included other factors related to QL and/or outcome. RESULTS: DFS was not significantly predicted by QL scores at baseline or month 18, or by changes in QL score between baseline and months 3 or 18. In contrast, after relapse, QL scores were predictive for subsequent overall survival. One month after relapse, better mood (P =.04) in premenopausal patients and better appetite (P =.005) in postmenopausal patients were associated with longer survival. Six months after relapse, better physical well-being (P =.03) and appetite (P =.03) in premenopausal patients and better physical well-being (P <.0001), mood (P =.002), appetite (P =.0001), and coping (P =.0001) in postmenopausal patients predicted longer survival. CONCLUSION: Any prognostic significance of QL scores in the adjuvant setting is minimal or obscured by chemotherapy effects, but there is strong prognostic significance of QL scores after disease relapse. The contrast suggests that patient perception of the severity of underlying illness may determine reported QL scores.

Defining clinical benefit in postmenopausal patients with breast cancer under second-line endocrine treatment: does quality of life matter?

PURPOSE: In endocrine therapy trials in advanced breast cancer, patients with response (complete response/partial response [CR/PR]) and patients with stable disease for at least 6 months (SD(6m)) have shown similar survival and therefore are often defined as a population with clinical benefit (patients with CR/PR or SD(6m)). We evaluated the impact of response and/or clinical benefit on quality of life (QL) in postmenopausal patients under second-line endocrine treatment after failure of tamoxifen. PATIENTS AND METHODS: One hundred twenty-eight of 177 eligible patients of a randomized trial (Swiss Group for Clinical Cancer Research 20/90) receiving either formestane (250 mg intramuscularly biweekly) or megestrol acetate (160 mg orally daily) were analyzed. The baseline characteristics (with the exception of site of metastases) were balanced among patients with CR/PR, SD(6m), and progressive disease (PD). Patients completed QL indicators at baseline and at 1, 3, 5, 7, 9, and 11 months. Responders were separately compared with nonresponders (patients with SD(6m) or PD) and with patients with SD(6m), and patients with clinical benefit were compared with patients with PD by analysis of covariance with adjustment for baseline scores. RESULTS: Overall, 88% (557 of 634) of expected QL forms were received. In the comparison of responders versus patients with both SD(6m) and PD, responders indicated better physical well-being (P =. 004) and mood (P =.02) at month 3. Compared only with patients with SD(6m), responders showed no significant difference in baseline QL and time to treatment failure (328.5 v 340 days). While under treatment, responders reported significantly better physical well-being (months 3 to 11), mood (months 5 to 11), coping (months 5 to 9), and appetite (months 7 to 11) and less dizziness (month 9) than patients with SD(6m). The changes between baseline and months 5 and 7, respectively, indicated improvement in responders but heterogeneous patterns in patients with SD(6m). CONCLUSION: Although the CR/PR and SD(6m) groups had similar times to treatment failure, patients with CR/PR reported better QL, suggesting more beneficial response to second-line endocrine treatment. Patients' subjective perspective should be taken into account in this mainly palliative setting. Future trials should be designed so that the CR/PR and SD(6m) groups are investigated separately.

Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group.

PURPOSE: The proper time to commence adjuvant chemotherapy after primary surgery for breast cancer is unknown. An analysis of the International (Ludwig) Breast Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested that early initiation of adjuvant chemotherapy might improve outcome for premenopausal, node-positive patients whose tumors did not express any estrogen receptor (ER). PATIENTS AND METHODS: We investigated the relationship between early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788 premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The disease-free survival for 599 patients (84 with ER-absent tumors) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for 1,189 patients (142 with ER-absent tumors) who started chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years. RESULTS: Among patients with ER-absent tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group (226 patients; hazard ratio [HR], 0. 49; 95% confidence interval [CI], 0.33 to 0.72; P =.0003). This difference remained statistically significant in a Cox multiple regression analysis controlling for study group, number of positive nodes, tumor size, age, vessel invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P =.019). Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P =.40). CONCLUSION: In premenopausal patients with ER-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. Further confirmatory studies are required before any widespread modification of current clinical practice. In premenopausal patients with tumors expressing some ER, gains from early initiation are unlikely to be clinically significant.

Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII.

PURPOSE: To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies. PATIENTS AND METHODS: The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months' duration and/or tamoxifen. Median follow-up is 12 to 15.5 years. RESULTS: In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women. CONCLUSION: LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.

Identifying breast cancer patients at high risk for bone metastases.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Prognostic importance of thymidylate synthase expression in early breast cancer.

PURPOSE: To assess the prognostic importance of thymidylate synthase (TS) expression in breast tumors of patients with early-stage breast cancer, and to determine whether the benefit of chemotherapy (CT) is associated with TS expression. PATIENTS AND METHODS: The level of TS expression was evaluated in 210 node-negative and 278 node-positive patients enrolled onto Trial V of the International Breast Cancer Study Group ([IBCSG] formerly the Ludwig Breast Cancer Study Group) with a median follow-up time of 8.5 years. TS expression was assessed using the immunohistochemical method with the monoclonal antibody TS 106 on paraffin-embedded tissue specimens. RESULTS: High TS expression was associated with a significantly worse prognosis in node-positive but not in node-negative breast cancer patients. Twenty-seven percent of node-positive patients with high TS expression were disease-free at 10 years, compared with 44% of node-positive patients with low TS expression (P = .03). Forty-one percent of patients with node-positive high-TS-expressing tumors were alive after 10 years, compared with 49% of those with low TS expression (P = .06). The association between TS and disease-free survival (DFS) and overall survival (OS) was independent of other prognostic factors such as tumor size, tumor grade, nodal status, vessel invasion, estrogen receptor (ER)/ progestin receptor (PR) status, c-erb B-2, or Ki-67 expression. In node-positive patients, six cycles of standard adjuvant cyclophosphamide, methotrexate, and fluorouracil ([5-FU] CMF) CT improved DFS and OS compared with one cycle of perioperative CMF therapy. The magnitude of this benefit was greatest in patients whose tumors had high TS expression (P < .01 for DFS; P < .01 for OS). Node-negative patients demonstrated no difference in outcome to CT based on TS expression; however, the power to detect differences was limited by the small number of events in this group. CONCLUSION: In early-stage breast cancer, high TS expression is associated with a significantly worse prognosis in node-positive patients. Node-positive patients with high TS levels demonstrate the most significant improvement in DFS and OS when treated with six cycles of conventional adjuvant CMF therapy.

Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adjuvant therapy for very young women with breast cancer: need for tailored treatments.

Breast cancer rarely occurs in women below the age of 35 years. Data from various sources indicate that diagnosis at such an age is associated with a dire prognosis mainly because of a more aggressive presentation. Although the effect of chemotherapy for premenopausal patients is substantial, recent evidence on 2233 patients suggested that very young women with endocrine-responsive tumors had a statistically significantly higher risk of relapse than older premenopausal patients with such tumors. In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine nonresponsive. Information from studies on 7631 patients who were treated with chemotherapy alone in trials of three major U.S. cooperative groups showed a similar interaction between the effect of age and steroid hormone receptor status of the primary tumor. Better treatments for very young patients are required and may involve ovarian function suppression in addition to other endocrine agents in patients with endocrine responsive tumors and a more precise investigation of chemotherapy and its timing, duration, and intensity in those with endocrine nonresponsive tumors. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues, which further complicate the phase of treatment decision making. The development of more effective therapies for younger patients requires tailored treatment investigations and cannot rely on information predominantly contributed from older premenopausal women.