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.     

乳腺癌乳房切除术后局部区域复发的研究现况

 乳腺癌在乳房切除术后出现局部区域复发（LRR）,虽是疾病进展的一个信号,但LRR不同于远处转移。其中部分患者经积极治疗后仍预后较好,尤其是孤立的LRR患者;复发间隔、复发位点和复发灶数目等对LRR患者预后有较大影响;对适合的LRR患者,手术切除和内分泌治疗的价值已被证实,化疗的价值仍有待进一步研究。     

Second non-breast primary cancer following adjuvant therapy for early breast cancer: A report from the International Breast Cancer Study Group

The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of the first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for 5 years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of 8 years and endocrine therapy (toremifene or tamoxifen) versus chemo-endocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular, the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemo-endocrine therapy compared with endocrine therapy.     

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study

Introduction

Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T→C polymorphism.

Methods

Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses.

Results

We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A ₂/A ₂ genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A ₁/A ₁ (wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions.

Conclusion

We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene-environment interactions.     

HER2-positive breast cancer: update on Breast Cancer International Research Group trials

HER2 gene amplification occurs in approximately 20% of primary breast cancers and is associated with a poor prognosis. Recently, trastuzumab, a humanized murine monoclonal antibody directed against the extracellular domain of HER2, was introduced for the treatment of patients with HER2-overexpressing advanced breast cancer. Trastuzumab has activity as both a single agent and in combination with chemotherapy. However, trastuzumab in conjunction with anthracyclines produces an unacceptably high rate of cardiac toxicity, which has prompted the search for alternative regimens. Docetaxel and the platinum salts are logical candidates to be combined with trastuzumab since these agents exhibit potent synergy with the antibody in preclinical experiments. Furthermore, the available phase II clinical data using the TCH (docetaxel/platinum/trastuzumab) regimen suggest this combination has significant activity. The Breast Cancer International Research Group (BCIRG) 006 trial is a 3-arm adjuvant study comparing doxorubicin/cyclophosphamide followed by docetaxel, the same regimen with trastuzumab administered with docetaxel (TH), and TCH in 3150 women with node-positive or high-risk node-negative, HER2-positive breast cancer. BCIRG 007 compares TH and TCH as first-line therapy in patients with HER2-positive metastatic breast cancer. In both trials, entry is restricted to patients whose tumors are positive for HER2 gene amplification as determined by fluorescence in situ hybridization. The data from these trials, in addition to the results from other ongoing randomized studies, will help define the optimal way to utilize trastuzumab in the management of patients with HER2-positive breast cancer.     

Impact of aggregate of risk factors for isolated locoregional failure in breast cancer patients treated with mastectomy without radiotherapy

Background

The impact of aggregate of risk factors on isolated locoregional failure after mastectomy without radiotherapy was assessed.

Methods

We reviewed 1091 patients who had stage I–III unilateral breast cancer and received mastectomy between 1990 and 2002.

Results

Median follow-up time was 67 (1–175) months. On multivariate analysis, four or more positive axillary lymph nodes (AXLN ≥4), pT4, primary tumor larger than 5 cm (T >5 cm), severe lymphatic invasion (ly2–3), and negative hormone receptor status (HR negative) were the statistically significant risk factors (hazard ratios 5.78, 2.31, 2.47, 2.99, and 3.40, respectively). The 8-year isolated locoregional failure-free rates of patients with single risk factor were 88% for AXLN ≥4, 93% for pT4, 93% for T >5 cm, 98% for ly2–3, and 97% for HR negative. Considering impact on isolated locoregional failure, AXLN ≥4 was termed the major risk factor and other factors were termed minor risk factors. The 8-year isolated locoregional failure-free rates were 98% for patients with only 0–1 minor risk factors (low-risk group), 86% for patients with the major risk factor alone or with only 2–4 minor risk factors (intermediate-risk group), 72% for patients with the major risk factor plus 1–2 minor risk factors (high-risk group), and 28% for patients with the major risk factor plus 3–4 minor risk factors (very high-risk group).

Conclusions

Aggregate of risk factors increased the risk of isolated locoregional failure significantly. Patients with the major risk factor plus one or more minor risk factors seemed to be candidates for postmastectomy radiotherapy.     

Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer: results from International Breast Cancer Study Group trials

BACKGROUND: Others have reported ocular toxicity after adjuvant chemoendocrine therapy, but this study looked at ocular toxicity in similarly treated patients from large randomized clinical trials. METHODS: Information was retrieved on incidence and timing of ocular toxicity from the International Breast Cancer Study Group (IBCSG) database of 4948 eligible patients randomized to receive tamoxifen or toremifene alone or in combination with chemotherapy (either concurrently or sequentially). Case reports of patients with ocular toxicity were evaluated to determine whether ocular toxicity occurred during chemotherapy and/or hormonal therapy. Additional information was obtained from participating institutions for patients in whom ocular toxicity occurred after chemotherapy but during administration of tamoxifen or toremifene. RESULTS: Ocular toxicity was reported in 538 of 4948 (10.9%) patients during adjuvant treatment, mainly during chemotherapy. Forty-five of 4948 (0.9%) patients had ocular toxicity during hormone therapy alone, but only 30 (0.6%) patients had ocular toxicity reported either without receiving any chemotherapy or beyond 3 months after completing chemotherapy and, thus, possibly related to tamoxifen or toremifene. In 3 cases, retinal alterations, without typical aspects of tamoxifen toxicity, were reported; 4 patients had cataract (2 bilateral), 12 impaired visual acuity, 10 ocular irritation, 1 optical neuritis, and the rest had other symptoms. CONCLUSION: Ocular toxicity during adjuvant therapy is a common side effect mainly represented by irritative symptoms due to chemotherapy. By contrast, ocular toxicity during hormonal therapy is rare and does not appear to justify a regular program of ocular examination. However, patients should be informed of this rare side effect so that they may seek prompt ophthalmic evaluation for ocular complaints.     

Vitamin supplement use and risk for breast cancer: the Shanghai Breast Cancer Study

Objective The influence of vitamin supplements on breast cancer risk is unclear and the interactive effects of dietary and supplemental sources are unknown. This study investigated (1) the association between self-reported vitamin supplement use (multivitamin, A, B, C, and E) and breast cancer and (2) the combined effect of vitamin supplements in relation to dietary vitamin intakes on breast cancer risk. Methods The Shanghai Breast Cancer Study was a population-based case-control study conducted in Shanghai in 1996-1998 (Phase I) and 2002-2004 (Phase II). Participants were aged 25-64 (Phase I) and 20-70 years (Phase II). The analyses included 3,454 incident breast cancer cases and 3,474 controls. Unconditional logistic regression models were used to determine adjusted odds ratios (ORs) for breast cancer risk associated with vitamin supplement use. Results Overall, breast cancer risk was not related to any vitamin supplement intake. However, a 20% reduction in breast cancer risk was observed with vitamin E supplement use among women with low-dietary vitamin E intake (OR = 0.8; 95% confidence interval (CI), 0.6-1.0). A non-significant 20% risk reduction was observed among vitamin B supplement users with low B dietary intake (OR = 0.8; 95% CI, 0.6-1.1). Frequent use of a vitamin B supplement was adversely associated with breast cancer risk among those with high dietary vitamin B intake (OR = 1.4; 95% CI: 0.9-2.1; P for interaction = 0.07). Conclusions This study suggests that vitamins E and B supplements may confer protection against breast cancer among women who have low dietary intake of those vitamins.     

MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study

In addition to tumor invasion and angiogenesis, matrix metalloproteinase (MMP)9 also contributes to carcinogenesis and tumor growth. Genetic variation that may influence MMP9 expression was evaluated among participants of the Shanghai Breast Cancer Genetics Study (SBCGS) for associations with breast cancer susceptibility. In stage 1, 11 MMP9 single nucleotide polymorphisms (SNPs) were genotyped by the Affymetrix Targeted Genotyping System and/or the Affymetrix Genome-Wide Human SNP Array 6.0 among 4,227 SBCGS participants. One SNP was further genotyped using the Sequenom iPLEX MassARRAY platform among an additional 6,270 SBCGS participants. Associations with breast cancer risk were evaluated by odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models that included adjustment for age, education, and genotyping stage when appropriate. In Stage 1, rare allele homozygotes for a promoter SNP (rs3918241) or a non-synonymous SNP (rs2274756, R668Q) tended to occur more frequently among breast cancer cases (P value = 0.116 and 0.056, respectively). Given their high linkage disequilibrium (D′ = 1.0, r ² = 0.97), one (rs3918241) was selected for additional analysis. An association with breast cancer risk was not supported by additional Stage 2 genotyping. In combined analysis, no elevated risk of breast cancer among homozygotes was found (OR: 1.2, 95% CI: 0.8–1.8). Common genetic variation in MMP9 was not found to be significantly associated with breast cancer susceptibility among participants of the Shanghai Breast Cancer Genetics Study.     

Breast reconstruction after mastectomy for cancer

Mastectomy is a mutilating but today unavoidable surgical procedure, that could be indicated as primary treatment of breast cancer, as prophylactic therapy in well selected high-risk patients, and in the management of treatment failure after breast-conserving therapy. Breast reconstruction is a sure, safe, well-proved and aesthetically satisfactory alternative without untoward oncological consequences, that should be offered to all patients subjected to mastectomy, regardless of disease stage or salvage mastectomy status. It should be offered through a meticulous, honest, timeless and complete discussion, with an open and respectful attitude toward the final decision of the patients: breast reconstruction is not for every patient.     

Clinical trial update: International Breast Cancer Study Group

The International Breast Cancer Study Group (IBCSG) has been conducting large, phase III clinical trials since 1978. Prior to 1986, these activities were carried out under the name of Ludwig Breast Cancer Study Group. Seven trials of adjuvant therapies are currently open for patient accrual, five of which are described in this report. The IBCSG has been a leader in the field of tailored treatment approaches for specific subpopulations of patients with breast cancer, believing that what is best for the majority may not be best for a defined minority.     

Adjuvant systemic therapy for breast cancer in the elderly: competing causes of mortality. International Breast Cancer Study Group

Between 1978 and 1981 we conducted a trial in which adjuvant endocrine therapy consisting of tamoxifen (T = 20 mg/d) and low-dose prednisone (p = 7.5 mg/d) for the duration of one year (p + T), was compared with no adjuvant therapy (observation) in 320 women with operable breast cancer aged 66 to 80 years (median age, 70 years). All patients had axillary lymph node metastases after at least a total mastectomy and axillary clearance. At 96 months median follow-up, 9.1% of the patients died without apparent relapse from cancer. An additional 1.9% had a second malignant neoplastic disease (not breast cancer). The 8-year disease-free survival (DFS) percentages (+/- SE) for the p + T and the observation groups were 36% (+/- 4%), and 22% (+/- 3%), (P = .004). The 8-year overall survival percentages were 49% (+/- 4%) and 42% (+/- 4%), respectively (P = .43). We conclude that despite a large proportion of deaths without relapse of breast cancer, a significant advantage for the p + T group in terms of DFS was demonstrated. We hypothesize that an endocrine therapy of longer duration might have an overall survival benefit in a population of elderly patients.     

Patient subsets with T1-T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy

PURPOSE: To identify patient subsets with T1-T2N0 breast cancer at high risk of locoregional recurrence (LRR) who may warrant consideration for postmastectomy radiotherapy. METHODS AND MATERIALS: Data were analyzed for 1505 women referred between 1989 and 1999 with pathologic T1-T2N0M0 breast cancer treated with mastectomy with clear margins and no adjuvant radiotherapy. Logistic regression analysis was performed to identify statistically significant factors associated with LRR. Recursive partitioning was used to develop a classification tree model for LRR given the prognostic variables. RESULTS: The median follow-up was 7.0 years. The 10-year Kaplan-Meier LRR rate was 7.8%. On logistic regression analysis, the statistically significant factors predicting LRR were histologic grade (p <0.0001), lymphovascular invasion (LVI) (p <0.0001), T stage (p = 0.05), and systemic therapy use (p = 0.01). In the recursive partitioning model, the first split in the classification tree was histologic grade. For 972 patients without high-grade histologic features, the 10-year Kaplan-Meier LRR rate was 5.5%. For 533 patients with Grade 3 disease (LRR rate 12.1%), the concomitant presence of LVI was associated with a LRR rate of 21.2% (n = 126). In patients with Grade 3 disease without LVI, T2 tumors conferred a LRR rate of 13.4% (n = 194), which increased to 23.2% for patients who did not receive systemic therapy (n = 63). CONCLUSION: Women with pT1-T2N0 breast cancer experienced a LRR risk of approximately 20% in the presence of Grade 3 disease with LVI or Grade 3 disease, T2 tumors, and no systemic therapy. These subsets of node-negative patients warrant consideration of for postmastectomy radiotherapy.     

Cancer risk after radiotherapy for breast cancer

Among women with breast cancer, we compared the relative and absolute rates of subsequent cancers in 1541 women treated with radiotherapy (RT) to 4570 women not so treated (NRT), using all registered in the Swiss Vaud Cancer Registry in the period between 1978 and 1998, and followed up to December 2002. Standardised incidence ratios (SIRs) and the corresponding 95% confidence intervals (CIs) were based on age- and calendar year-specific incidence rates in the Vaud general population. There were 11 lung cancers in RT (SIR = 1.40; 95% CI: 0.70-2.51) and 17 in NRT women (SIR = 0.76; 95% CI: 0.44-1.22), 72 contralateral breast cancers in RT (SIR = 1.85; 95% CI: 1.45-2.33) and 150 in NRT women (SIR = 1.38; 95% CI: 1.16-1.61), and 90 other neoplasms in RT (SIR = 1.37; 95% CI: 1.10-1.68) and 224 in NRT women (SIR = 1.05; 95% CI: 0.91-1.19). Overall, there were 173 second neoplasms in RT women (SIR = 1.54, 95% CI: 1.32-1.78) and 391 among NRT women (SIR = 1.13, 95% CI: 1.02-1.25). The estimates were significantly heterogeneous. After 15 years, 20% of RT cases vs 16% of NRT cases had developed a second neoplasm. The appreciable excess risk of subsequent neoplasms after RT for breast cancer must be weighed against the approximately 5% reduction of breast cancer mortality at 15 years after RT.     

Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study

The incidence of breast cancer among women in Shanghai, a traditionally low-risk population, has increased substantially over the past 20 years. To evaluate the association of menstrual and reproductive factors with breast cancer risk and the influence of these factors on the temporal trend of breast cancer incidence, we analyzed data from the Shanghai Breast Cancer Study, a population-based case-control study of breast cancer recently completed among Chinese women in urban Shanghai. In-person interviews were completed for 1,459 women newly diagnosed with breast cancer between ages 25 and 64 and for 1,556 controls frequency-matched to cases by age. Unconditional logistic regression was employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) related to menstrual and reproductive factors. Earlier menarcheal age, nulliparity, and later age at first live birth were associated with increased risk of breast cancer among both pre- and post-menopausal women, while never having breast-fed and later age at menopause were associated with elevated risk only among post-menopausal women. Among controls, 32% of younger women (40 years) reported starting menarche at age of 13 or younger, and this factor contributed to 44% of cases diagnosed among younger women and 26% to 28% of cases in older women. Older age at first live birth or at menopause explained a considerable portion of cases diagnosed in older, but not younger, women. Our study suggests that the changes in menstrual and reproductive patterns among women in Shanghai have contributed to the recent increase in breast cancer incidence, particularly among younger women.