Adjuvant treatment for early breast cancer: the Ludwig breast cancer studies

The Ludwig Breast Cancer Study Group conducted four concomitant trials involving adjuvant chemotherapy and endocrine therapy. In Ludwig I, adjuvant combination chemotherapy was used with or without prednisone to treat premenopausal and perimenopausal women with metastases in 1-3 axillary lymph nodes. The impact of adding low-dose, continuous prednisone (7.5 mg/day) to an adjuvant, chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was investigated in a randomized trial of 491 premenopausal and perimenopausal patients with operable breast cancer and metastases in 1-3 axillary lymph nodes. As a consequence of lower hematologic toxicity, a significantly higher dose of CMF could be administered with added prednisone (P less than 0.0001). However, at the 4-year median follow-up, no significant improvement was observed in disease-free survival (DFS) (73% vs. 77%; P = 0.35) or overall survival (OS) (both 86%; P = 0.73). Induced amenorrhea was associated with a longer DFS for younger patients, those who received lower CMF doses, and those with tumors that were estrogen receptor (ER) positive. In Ludwig III, adjuvant therapy was administered to younger postmenopausal women in a study of chemotherapy plus endocrine therapy versus endocrine therapy alone versus mastectomy alone. In this randomized trial of 463 postmenopausal women 65 years of age or younger with axillary node metastases, treatment with the combination of CMF plus low-dose prednisone and tamoxifen (CMFp + T), was compared to endocrine therapy alone (p + T) or to no further treatment after total mastectomy and axillary clearance. At a median follow-up of 4 years, the DFS was 61% for the CMFp + T group, compared with 48% for the p + T group (P = 0.01) and 31% for the observation group (P less than 0.0001). The 4-year OS rates were not statistically different (76%, 67%, and 68%, respectively; P = 0.30). Treatment with CMFp + T reduced local, regional, and distant metastases and was equally effective in improving DFS in patients with ER-positive or ER-negative tumors. In Ludwig II, chemotherapy was given with or without oophorectomy in premenopausal and perimenopausal patients with metastases in 4 or more axillary nodes.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of adjuvant prednisone combined with CMF on patterns of relapse and occurrence of second malignancies in patients with breast cancer

BACKGROUND:: The addition of low-dose prednisone (p) to the adjuvant regimenof cyclophosphamide, methotrexate, 5-fluorouracil (CMF) allowedpatients to receive a larger dose of cytotoxics when comparedwith those on CMF alone. However, disease-free survival andoverall survival were similar for the two groups. To test thehypothesis that low-dose prednisone might influence the efficacyof the cytotoxic regimen used, the toxicity profiles of thetwo treatment regimens and the patterns of treatment failure(relapse, second malignancy, or death) were examined. PATIENTS AND METHODS:: 491 premenopausal and perimenopausal patients with one to threepositive axillary lymph nodes included in International (Ludwig)Breast Cancer Study Group (IBCSG) trial I from 1978 to 1981and randomized to receive CMFp or CMFp were analyzed for differencesin long-term outcome and toxic events. The 250 patients assignedto CMF and prednisone received on the average 12% more cytotoxicdrugs than those who received CMF alone. RESULTS:: The 13-year DFS for the CMFp group was 49% as compared to 52%for CMF alone, and the respective OS percents were 59% and 65%.Several toxic effects such as leukopenia, alopecia, mucositisand induced amenorrhea were reported at a similar incidencein the two treatment groups. Using cumulative incidence methodologyfor competing risks, we detected a statistically significantincrease in first relapse in the skeleton for the CMFp groupat 13 years follow-up with a relative risk (RR) of 2.06 [confidenceinterval (CI), 1.23 to 3.46; P = 0.004]. Patients with largertumors in the CMFp regimen were especially subject to this increasewith a RR for failure in the skeleton of 3.32 (95% CI, 1.57to 7.02; P = 0.0005). CMFp-treated patients also had a largerproportion of second malignancies (not breast cancer), withRR of 3.34(95% CI, 0.91 to 12.31; P = 0.09). CONCLUSIONS:: Low-dose continuous prednisone added to adjuvant CMF chemotherapyenabled the use of higher doses of cytotoxics. This increaseddose had no beneficial effect on treatment outcome, but wasassociated with an increased risk for bone relapses and a small,not statistically significant increased incidence of secondmalignancies. The effects of steroids, which are widely usedas antiemetics (oral or pulse injection) together with cytotoxics,should be investigated to identify their influence upon treatmentoutcome. adjuvant therapy, breast cancer, CMF, patterns of relapse, prednisone, secondary neoplasm     

ER阳性乳癌病人全身辅助治疗的研究

目的研究雌激素受体阳性(ER+)乳癌病人接受不同全身辅助治疗的预后,以期指导病人的治疗。方法387例ER+乳癌病人分成三组辅助内分泌治疗组(178例)绝经后(绝经前病人先切除卵巢)病人服用三苯氧胺(TAM)5年。辅助化疗组(154例)主要化疗方案有CMFVP;CMF;CF;FVC等。联合治疗组(55例)化疗+TAM,其中绝经前病人未切除卵巢。采用生命表的方法观察三组病人的5年无病生存率(DFS)和总生存率(OS)。结果在不同年龄、不同月经状态、不同局部肿瘤T期及不同转移淋巴结数目的病人中,都显示出辅助内分泌治疗的5年无病生存率和总生存率明显好于辅助化疗者,差异有显著意义。在转移淋巴结≥10个组内,虽然仍是内分泌治疗结果好于化疗组,但未显示统计学意义。联合治疗的病人,在各个亚组分析中,都不优于辅助内分泌治疗。结论ER及绝经状态应作为决定取舍辅助内分泌治疗的主要依据,对于ER阳性乳癌病人,术后内分泌治疗为最合适。     

A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer

The sequential doxorubicin --> CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF x 6 cycles (CMF); (b) doxorubicin x 4 cycles followed by CMF x 6 cycles (A --> CMF); (c) CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (CMF --> GT); and (d) doxorubicin x 4 cycles followed by CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (A --> CMF --> GT). The study used a 2 x 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A --> CMF or arms a+c vs b+d) and (2) the effect of adding GT after chemotherapy (arms a+b vs c+d). At a median follow-up of 72 months, A --> CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR)=0.740 (95% confidence interval (CI): 0.556-0.986; P=0.040) and produced a nonsignificant improvement of overall survival (OS) (HR=0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR=0.74; 95% CI: 0.555-0.987; P=0.040), with a nonsignificant improvement of OS (HR=0.84; 95% CI: 0.54-1.32). A --> CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients.     

Conservative surgery and irradiation (QUART) in the treatment of 243 stage I-II breast cancer patients.

From 1980 to 1987, 243 evaluable patients with pT1, pT2 (less than 3 centimeters in diameter), N0, M0, invasive breast cancer were treated with "quadrantectomy" with axillary dissection followed by electron beam radiation therapy (QUART) at the St. Bortolo Hospital, Vicenza. Stage II patients received adjuvant chemotherapy (CMF) if preperimenopausal or hormonotherapy (tamoxifen) if postmenopausal. The median follow-up was 54 months (26 to 116 months). The 4.5-year overall survival (OS) and disease-free survival (DFS) were respectively 91% and 85%; the 10-year actuarially estimated OS and DFS was 77%. Thirty-three patients relapsed, 11 of whom had local recurrence, and 23 developed distant metastases. A significantly longer OS and DFS were observed in stage I versus stage II (p = 0.0008) and in pT1 versus pT2 (p = 0.001) tumors. No difference was found regarding menopausal status and histotype. The local control of disease was very high (95.5%), with a significantly higher local recurrence rate in premenopausal women compared to postmenopausal (10/117 versus 1/126; p = 0.009). Tumor size did not influence the frequency of local recurrence. No major complications occurred but a significantly higher rate of reversible radiation-pneumonitis occurred in patients treated with higher energies of electrons (17 to 20 MeV) compared with lower (6 to 13 MeV) (33/177 versus 7/66; p less than 0.05). Cosmetic results were judged as excellent in 20%, satisfactory in 68%, unsatisfactory in 6% and not evaluable in 6% of cases. We conclude first, that small pT2 breast carcinomas may also be safely treated with QUART, second, that the electron beam is a radiotherapeutic technique able to produce a good cosmetic result and to assure a satisfactory local control and, finally, that the use of tamoxifen in postmenopausal stage II breast carcinomas is safe and easy to combine with radiotherapy in the conservative management of early breast cancer due to the lower toxic effects, compared to those observed in premenopausal women treated with chemotherapy.     

Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188).

PURPOSE: Chemotherapy, tamoxifen, and ovarian ablation/suppression (OA/OS) are effective adjuvant approaches for premenopausal, steroid hormone receptor-positive breast cancer. The value of combined therapy has not been clearly established. PATIENTS AND METHODS: Premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer (1,503 eligible patients) were randomly assigned to six cycles of cyclophosphamide, doxorubicin, and fluorouracil (CAF), CAF followed by 5 years of monthly goserelin (CAF-Z), or CAF followed by 5 years of monthly goserelin and daily tamoxifen (CAF-ZT). The primary end points were time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) for CAF-Z versus CAF, and CAF-ZT versus CAF-Z. RESULTS: With a median follow-up of 9.6 years, the addition of tamoxifen to CAF-Z improved TTR and DFS but not OS. There was no overall advantage for addition of goserelin to CAF. CONCLUSION: Addition of tamoxifen to CAF-Z improves outcome for premenopausal node-positive, receptor-positive breast cancer. The role of OA/OS alone or with other endocrine agents should be studied more intensely.     

绝经前和围绝经期妇女乳腺癌的内分泌治疗进展

在绝经前和围绝经期乳腺癌患者中,无论其淋巴结状态如何,卵巢去势辅助治疗均有利于患者的无病生存率及总生存率的改善。药物性卵巢去势与手术或放疗卵巢去势疗效相当,可有效地取代传统去势方法。对于激素敏感(ER/PR阳性)的患者,药物性卵巢去势与CMF化疗方案等效,且与三苯氧胺联用可进一步提高疗效。已有大规模前瞻性临床随机研究证据表明在常规的辅助治疗后加用药物性卵巢去势可以进一步改善预后。     

Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.     

Postoperative chemotherapy and chemohormonal therapy in women with node-positive breast cancer

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)     

The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients

We analysed the incidence of amenorrhoea and its associationwith outcome in a cohort of 1127 premenopausal women with breastcancer randomized to International Trial V (formerly LudwigV). For 552 patients without axillary lymph node involvement,one course of perioperative cytotoxic drugs was compared withno-adjuvant chemotherapy. For 575 patients with node-positivedisease, a single course of cytotoxic chemotherapy was comparedwith a prolonged treatment (6 or 7 courses). Amenorrhoea wasdefined as having no menstrual bleeding for a 3-month intervalwithin the first 9 months after surgery. Amenorrhoea was observedin21% of the 199 patients with node-negative breast cancer whoreceived no adjuvant therapy, 31% of the 353 node-negative patientswho had a single course of cytotoxic therapy, 31% of the 188patients with node-positive disease who had the same short-durationtherapy, and 68% of the 387 node-positive patients who had aprolonged adjuvant therapy. Amenorrhoea was associated withan increased disease-free survival (DFS) only in the patientswith prolonged cytotoxic therapy: 4-year DFS % (± s.e.)was 68% ± 3% vs. 61% ± 5% for the amenorrhoeaand the no-amenorrhoea groups, respectively, (p = 0.05). Incontrast, the comparison between prolonged therapy and one singlecourse among node-positive patients showed a much larger treatmenteffect (4-year DFS 66% vs. 38%, p < 0.0001). We concludethat although cytotoxics-induced amenorrhoea is associated witha better outcome, it is unlikely that this form of endocrinemanipulation is the main mechanism of response to adjuvant systemicchemotherapy. breast cancer, adjuvant chemotherapy, endocrine mechanism, cytotoxics-induced amenorrhoea, oophorectomy, perioperative therapy, node-negative, node-positive, premenopausal     

Adjuvant hormone treatment and chemotherapy in postmenopausal women with operable breast cancer: a retrospective analysis.

Two hundred consecutive postmenopausal women with operable breast cancer and metastatic axillary nodes were treated during the period January - December 1981 with adjuvant chemotherapy (CMF) or hormonal treatment (tamoxifen). The distribution of receptor status (estrogen or progesterone), number of axillary metastatic nodes (less than = 3 or greater than 3), surgical treatment and size of the primary tumor were homogeneous in both groups. Receptor status and number of axillary lymph nodes were correlated with adjuvant treatment efficacy. Ten-year disease-free survival (DFS) was higher in the TAM-treated (72%) than in the CMF-treated group (52%) (p less than 0.01). In patients with less than = 3 axillary metastatic nodes, those treated with TAM had a higher DFS rate than those treated with CMF (75% vs 59%, p less than 0.01). There was no difference in DFS between CMF-and TAM-treated groups within the greater than 3 metastatic lymph node patients. In ER + primary tumors, DFS was higher in the subset treated with TAM (62%) than with CMF (51%) (p less than 0.05), whereas no difference in DFS was observed in ER- patients between the two treatment groups. Considering the TAM group, DFS was better (p less than 0.01) for ER+ cases than for ER- cases only at 5 years of observation. In the CMF group, DFS was not influenced by ER status. PgR content did not affect DFS in either adjuvant treatment group.     

Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer.

PURPOSE: Studies evaluating the relationship of HER-2/neu breast tumor status and response to adjuvant endocrine therapy have reached conflicting conclusions about resistance of HER-2/neu-positive tumors to this treatment. We studied 282 patients participating in a randomized controlled trial of adjuvant oophorectomy and tamoxifen or observation who had estrogen receptor-positive tumors and whose tumors were evaluated for HER-2/neu overexpression by immunohistochemistry. PATIENTS AND METHODS: Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier disease-free and overall survival estimate methods were used. RESULTS: HER-2/neu overexpression was a negative prognostic factor for overall survival. In univariate analyses, in HER-2/neu-positive patients, the hazard ratio (HR) for disease-free survival (DFS) with adjuvant endocrine therapy was 0.37 (95% confidence interval [CI], 0.26 to 0.89); for HER-2/neu-negative patients, the corresponding HR for DFS was 0.48 (95% CI, 0.31 to 0.71). The overall survival (OS) data were HR=0.26 (95% CI, 0.07 to 0.92) and HR=0.68 (95% CI, 0.32 to 1.42) for HER-2/neu-positive and HER-2/neu-negative patients, respectively. In multivariate models, the P values for tests of interaction of HER-2/neu status and response to adjuvant endocrine therapy were 0.18 and 0.07 for DFS and OS, respectively. Kaplan-Meier DFS and OS curves and 3-year DFS estimates were consistent in showing greater benefit to the HER-2/neu-positive subgroup given adjuvant treatment. CONCLUSION: HER-2/neu overexpression does not adversely and may favorably influence response to adjuvant oophorectomy and tamoxifen treatment in patients with estrogen receptor-positive tumors.     

Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis

The use of adjuvant chemotherapy for postmenopausal patients with early breast cancer remains controversial because the potential benefits in terms of prolongation of disease-free survival (DFS) and overall survival (OS) must be balanced against the toxicity of treatment. Following mastectomy, 463 evaluable postmenopausal women with node-positive breast cancer were randomized to receive either chemoendocrine therapy for 1 year, or endocrine therapy alone for 1 year, or no adjuvant therapy (Ludwig Trial III). At 7-years median follow-up, OS was longer for the chemoendocrine-treated patients compared with controls (P = .04) and compared with the adjuvant endocrine therapy-alone group (P = .08). In order to balance this therapeutic advantage against the toxic effects of treatment, OS time was divided into time with toxicity (TOX), time without symptoms and toxicity (TWiST), and time after systemic relapse (REL). TOX and REL were weighted by coefficients of utility relative to TWiST and the results added to give a period of quality-adjusted survival (Q-TWiST). Benefits measured by Q-TWiST generally favored chemoendocrine therapy. For example, if TOX and REL were both given utility coefficients of 0.5 relative to 1.0 for TWiST, then by 7 years the average Q-TWiST for chemoendocrine therapy was 6.7 months longer than for no-adjuvant therapy (P = .05) and 4.1 months longer than for endocrine therapy alone (P = .20). Quality-adjusted survival analysis is recommended in assessing costs and benefits of toxic adjuvant therapy. In this example, it supports the use of chemoendocrine therapy in postmenopausal node-positive patients for a wide range of relative values assigned to periods with symptoms and toxicity.     

Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93.

BACKGROUND: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome. PATIENTS AND METHODS: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years. RESULTS: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years. CONCLUSIONS: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.     

Salvage treatment of patients suffering relapse after adjuvant CMF chemotherapy

The efficacy of salvage treatments in 243 patients with operable breast cancer and positive axillary nodes who failed during or after adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and fluorouracil) was analyzed. Results were compared with those achieved in 100 patients who had relapses after radical mastectomy alone (control group). Salvage treatments consisted primarily of endocrine therapy (castration in premenopausal patients and tamoxifen in postmenopausal women) and chemotherapy (CMF or Adriamycin [doxorubicin] regimens). In 20 patients, however, first salvage treatment consisted of local therapy only (i.e., radiation therapy with or without surgery). In women previously treated with adjuvant CMF, complete plus partial remissions after first salvage treatment were 37% with a median duration of 17 months. In the control group, the response rate was 43% with a median duration of 16 months. The findings also indicated that drug-induced amenorrhea did not lower the objective response to salvage castration. In patients failing with a disease-free interval in excess of 12 months from end of adjuvant CMF, retreatment with the same combination was able to induce remission in 52% of the patients. Current data, derived from prospective controlled studies, confirm that, despite relatively high remission rates, all forms of salvage treatment failed to provide, in unselected cases, long-term control of relapsed breast cancer. Most important, prior adjuvant chemotherapy with CMF did not adversely affect results compared to concomitant controls.     

Relapse of breast cancer after adjuvant treatment in premenopausal and perimenopausal women: patterns and prognoses

Eight hundred eighteen premenopausal or perimenopausal breast cancer patients with axillary node metastases were treated with adjuvant chemotherapy (CMF) with or without endocrine treatment (prednisone, oophorectomy) in two concurrent prospective trials. Three hundred fifty-two (43%) had recurrent disease at a median follow-up time of 6 years. The 2-year survival percentages from time of first relapse were 16% for patients with initial metastases in visceral or multiple sites (including bone and soft tissue), 41% for those with regional metastases or skeletal relapse alone and 70% for patients with isolated local recurrence or contralateral breast cancer. The features that most influenced prognosis within the categories defined by site of first relapse were disease-free interval (less than 24 months v greater than or equal to 24 months), and estrogen receptor content in the primary tumor. These features had clinical importance (identifying patients with at least a 50% 2-year survival percentage) only in those patients with local, contralateral breast, regional, or bony disease alone. The treatment of individual patients after relapse must be directed toward optimized palliation. The results of this study are important for defining groups of patients who relapse after CMF for whom the subsequent therapeutic approach might be differentiated (eg, experimental treatments for dire prognosis, accent on minimal side effect treatment for intermediate prognosis, and investigation of adjuvant systemic therapy for isolated local recurrence).     

A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma.

PURPOSE: The aim of this study was to determine whether serum matrix metalloproteinase (MMP) -2 and MMP-9 levels could predict overall and disease-free survival in primary node-positive breast cancer. EXPERIMENTAL DESIGN: MMP-2 and MMP-9 levels were quantitatively measured in serum after surgery from 133 patients with primary node-positive breast cancer using enzyme-linked immunoassays. All of the patients received adjuvant therapy, postmenopausal endocrine treatment (tamoxifen or toremifen for 3 years) and premenopausal six cycles of CMF chemotherapy. The follow-up time for all of the patients was 5 years. RESULTS: Overall survival (OS) and disease-free survival (DFS) rates were better among patients with low MMP-2 levels than in patients with high levels (OS, 91% versus 75%, P = 0.020; DFS, 82% versus 58%, P = 0.005). The appearance of bone and visceral metastases was also significantly lower in patients with low serum MMP-2 levels (bone metastases, 10% versus 23%, P = 0.050; visceral metastases, 12% versus 34%, P = 0.018). The prognostic value of MMP-2 levels was most pronounced among a subgroup of estrogen receptor-positive patients (OS, 96% versus 78%, P = 0.052; DFS, 85% versus 58%, P = 0.014), whereas no significant difference was found among estrogen receptor-negative patients (OS, 73% versus 69%, P = 0.25; DFS, 73% versus 63%, P = 0.32). In multivariate analysis, MMP-2 level together with nodal status (NS), progesterone receptor (PgR), and tumor size (T) remained independent predictors for DFS (NS, P = 0.002; PgR, P = 0.004; T, P = 0.023; MMP2, P = 0.039) and OS (NS, P = 0.0002; PgR, P = 0.004; T, P = 0.004; MMP2, P = 0.032). MMP-9 levels did not correlate with survival. CONCLUSIONS: The results suggest that serum postoperative MMP-2 level is a predictor of DFS and OS, and could help to stratify breast cancer patients with primary node-positive disease into low- and high-risk groups.     

Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed. The patients were treated with lumpectomy and axillary dissection followed by external beam radiotherapy to the residual breast. High-risk patients (n = 94), as well as 31 low-risk patients, received additional radiation to the regional lymph nodes. Adjuvant systemic treatment was given to all high-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m2) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia, and dyspigmentation which were scored on a 4-point categorical scale after median 6.6 years. The observations were analyzed in multivariate logistic regression analysis which included potential risk factors on outcome related to systemic treatment, surgery, radiation technique, tumor, and patient characteristics. In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However, univariate analysis showed that tamoxifen was significantly associated with breast fibrosis (p < 0.004), as was radiation to the regional lymph nodes (p < 0.0001). A strong interaction between axillary irradiation and tamoxifen treatment occurred since 26 of 27 high-risk postmenopausal patients had received both tamoxifen and axillary irradiation. In multivariate regression analysis, axillary irradiation independently predicted moderate/severe breast fibrosis with a relative risk of 5.0 (2.0-12.5) and 9.6 (3.3-27.7) in premenopausal and postmenopausal patients, respectively. To circumvent the strong interaction between tamoxifen treatment and axillary irradiation, a subsequent analysis omitting axillary treatment from the multivariate regression showed a significant effect of both tamoxifen and CMF on the occurrence of breast fibrosis with relative risks of 5.3 (CI 1.8-15.8) and 4.4 (1.8-10.3), respectively. Adjuvant systemic treatment with CMF given sequentially to radiotherapy independently predicted an adverse cosmetic outcome as well as increased skin telangiectasia after breast conserving treatment. Due to a strong interaction between tamoxifen administration and radiation to the regional lymph nodes, the effect of tamoxifen on the development of fibrosis could not be fully discerned in this study. Axillary irradiation increased the incidence of moderate to severe breast fibrosis in both premenopausal and postmenopausal patients.     

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

BackgroundThe 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 methodsFrom 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.ResultsFor 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).ConclusionsFor 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.     

Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93.

BACKGROUND: Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years. PATIENTS AND METHODS: 1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy. RESULTS: Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three). CONCLUSIONS: Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer.