Early ipsilateral breast tumor recurrences after breast conservation affect survival: an analysis of the National Cancer Institute randomized trial

PURPOSE: To evaluate the effect of an ipsilateral breast tumor recurrence (IBTR) after breast-conservation therapy (BCT) on survival. METHODS AND MATERIALS: One hundred twenty-one women were randomized to BCT. Patients with an IBTR were analyzed to determine survival. Analysis was performed with Kaplan-Meier estimates, log-rank tests, and time-dependent covariate Cox models. RESULTS: At a median follow-up of 18.4 years, 27 patients had an IBTR. The median survival time after IBTR was 13.1 years. The 5-year survival rate was 91.8% (95% confidence interval [CI], 81.5-100%). The 10-year survival rate was 54.3% (95% CI, 35.8-82.6%). According to a Cox model with time-dependent covariates, the hazard ratio or relative risk of dying for those with an IBTR at <5.3 years after BCT relative to patients without an IBTR after BCT is 1.47 (95% CI, 1.02-2.12%; p = 0.04). The hazard ratio for those who relapse after 5.3 years is 0.59 (95% CI, 0.22-1.61%; p = 0.31). Age at randomization, original tumor size, and the presence of positive regional nodes at initial presentation were not found to be associated with decreased survival. CONCLUSIONS: There seems to be a significant association of early IBTR after BCT with decreased survival. Local control should be maximized.     

Factors associated with local recurrence and cause-specific survival in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy or mastectomy

PURPOSE: We reviewed our institution's experience treating patients with ductal carcinoma in situ (DCIS) of the breast to determine risk factors for ipsilateral breast tumor recurrence (IBTR) and cause-specific survival (CSS) after breast-conserving therapy (BCT) or mastectomy. MATERIALS AND METHODS: Between 1981 and 1999, 410 cases of DCIS (405 patients) were treated at our institution; 367 were managed with breast-conserving surgery (54 with lumpectomy alone and 313 with adjuvant radiation therapy (RT) [median dose, 45 Gy]). Of these 313 patients, 298 received also a supplemental boost of RT to the lumpectomy cavity (median dose, 16 Gy). Forty-three patients underwent mastectomy; 2 (5%) received adjuvant RT to the chest wall. A true recurrence/marginal miss (TR/MM) IBTR was defined as failure within or adjacent to the tumor bed in patients undergoing BCT. Median follow-up for all patients was 7 years (mean: 6.1 years). RESULTS: Thirty patients (8.2%) experienced an IBTR after BCT (25 [8%] after RT, 5 [9.3%] after no RT), and 2 patients (4.7%) developed a chest wall recurrence after mastectomy. Of the 32 local failures, 20 (63%) were invasive (18/30 [60%] after BCT and 2/2 [100%] after mastectomy), and 37% were DCIS alone. Twenty-four (80%) of the IBTRs were classified as TR/MM. The 10-year freedom from local failure, CSS, and overall survival after BCT or mastectomy were 89% vs. 90% (p = 0.4), 98% vs. 100% (p = 0.7), and 89% vs. 100% (p = 0.3), respectively. Factors associated with IBTR on Cox multivariate analysis were younger age (p = 0.02, hazard ratio [HR] 1.06 per year), electron boost energy < or = 9 MeV (p = 0.03, HR 1.41), final margins < or = 2 mm (p = 0.007; HR, 3.65), and no breast radiation (p = 0.002, HR 5.56). On Cox univariate analysis for BCT patients, IBTR, TR/MM failures, and predominant nuclear Grade 3 were associated with an increased risk of distant metastases and a reduced CSS. CONCLUSIONS: After treatment for DCIS, 10-year rates of local control, CSS, and overall survival were similar after mastectomy and BCT. Young age (<45 years), close/positive margins (< or = 2 mm), no breast radiation, and lower electron boost energies (< or = 9 MeV) were associated with IBTR. Local failure and predominant nuclear Grade 3 were found to have a small (4%-12%) but statistically significantly negative impact on the rates of distant metastasis and CSS. These results suggest that optimizing local therapy (surgery and radiation) is crucial to improve local control and CSS in patients treated with DCIS.     

Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer: risk factors and impact on distant metastases

BACKGROUND: The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long-term follow-up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group. METHODS: Patients (N = 1901)with unilateral breast cancer < or = 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR. RESULTS: At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676-5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis. CONCLUSIONS: Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases.     

Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy

BACKGROUND: The current study identified determinants of systemic recurrence and disease-specific survival (DSS) in patients with early-stage breast carcinoma treated with breast-conserving surgery and radiation therapy (breast-conserving therapy, or BCT). METHODS: The study population consisted of 1,043 consecutive women with Stages I or II breast carcinoma who underwent BCT between 1970 and 1994. Clinical and pathologic characteristics evaluated included age, tumor size, tumor grade, estrogen and progesterone receptor status, surgical margins, axillary lymph node involvement, and use of adjuvant therapy. RESULTS: At a median follow-up time of 8.4 years, 127 patients (12%) had developed an ipsilateral breast tumor recurrence (IBTR), and 184 patients (18%) had developed a systemic recurrence. On multivariate logistic regression analysis, tumor size greater than 2 cm, positive lymph nodes, lack of adjuvant tamoxifen therapy, and positive margins (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.3; P = 0.034) were predictors of systemic recurrence. When IBTR was added into the model, adjuvant therapy and surgical margins were not independent predictors; however, IBTR was an independent predictor of systemic recurrence (IBTR vs. no IBTR; OR, 6.2; 95% CI, 3.1-12.3; P < 0.001). The 10 year DSS rate after BCT was 87%. On multivariate Cox proportional hazards model analysis, the following factors were independent predictors of poor DSS: tumor size greater than 2 cm (vs. < or = 2 cm; relative risk [RR], 2.3; 95% CI, 1.2-4.3; P = 0.010), negative progesterone receptor status (vs. positive; RR, 2.7; 95% CI, 1.4-5.1; P = 0.003), positive margins (vs. negative; RR, 3.9; 95% CI, 1.4-11.5; P = 0.011), and IBTR (vs. no IBTR; RR, 5.5; 95% CI, 2.8-11.0; P < 0.001). CONCLUSIONS: Positive surgical margins and IBTR are predictors of systemic recurrence and disease-specific survival after BCT. Aggressive local therapy is necessary to ensure adequate surgical margins and to minimize IBTR.     

When can a second conservative approach be considered for ipsilateral breast tumour recurrence?

BACKGROUND: Mastectomy is considered the treatment of choice in patients with ipsilateral breast tumour recurrence (IBTR) after breast-conserving surgery (BCS). PATIENTS AND METHODS: One hundred and sixty-one patients with invasive IBTR who underwent a second conservative approach were retrospectively evaluated in order to describe prognosis, determine predictive factors of outcome and select the subset of patients with the best local control. RESULTS: Fifty-seven patients (35.4%) relapsed after IBTR. Thirty-four patients (21.1%) had further in-breast recurrences and four patients (2.5%) had skin relapses. Five years cumulative incidence of local relapse was 31.4%. Twenty-four patients (17.8%, 5 years cumulative incidence) died during the follow-up. At the multivariate analysis, recurrent tumour size >2 cm was found to affect local-disease-free survival [hazard ratio (HR): 2.8, 95% confidence interval (CI) 1.2-6.2], whereas Ki-67 >or=20% and time to relapse 48 months, eight (12.8%, 5 years cumulative incidence) had further local relapses. CONCLUSIONS: Some patients with IBTR might receive a second BCS, especially when a good local control can be estimated (small recurrent tumour, late relapse), also taking into account patients' preference.     

Predictors of systemic recurrence and disease-specific survival after ipsilateral breast tumor recurrence

BACKGROUND: In patients with breast carcinoma, ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) is an independent predictor of systemic recurrence and disease-specific survival (DSS). However, only a subgroup of patients with IBTR develop systemic recurrences. Therefore, the management of isolated IBTR remains controversial. The objective of the current study was to identify determinants of systemic recurrence and DSS after IBTR. METHODS: The medical records of 120 women who underwent BCT for Stage 0-III breast carcinoma between 1971 and 1996 and who subsequently developed isolated IBTR were reviewed. Clinicopathologic factors were studied using univariate and multivariate analyses for their association with DSS and the development of systemic recurrence after IBTR. RESULTS: The median time to IBTR was 59 months. At a median follow-up of 80 months after IBTR, 45 patients (37.5%) had a systemic recurrence. Initial lymph node status was the strongest predictor of systemic recurrence according to the a univariate analysis (P = 0.001). Other significant factors included lymphovascular invasion (LVI) in the primary tumor, time to IBTR < or = 48 months, clinical and pathologic IBTR tumor size > 1 cm, LVI in the recurrent tumor, and skin involvement at IBTR. In a multivariate logistic regression analysis, initially positive lymph node status (relative risk [RR], 5.3; 95% confidence interval [95% CI], 1.4-20.1; P = 0.015) and skin involvement at IBTR (RR, 15.1; 95% CI, 1.5-153.8; P = 0.022) remained independent predictors of systemic recurrence. The 5-year and 10-year DSS rates after IBTR were 78% and 68%, respectively. In a multivariate Cox proportional hazards model analysis, only LVI in the recurrent tumor was found to be an independent predictor of DSS (RR, 4.6; 95% CI, 1.5-14.1; P = 0.008). CONCLUSIONS: Patients who initially had lymph node-positive disease or skin involvement or LVI at IBTR represented especially high-risk groups that warranted consideration for aggressive, systemic treatment and novel, targeted therapies after IBTR. Determinants of prognosis after IBTR should be taken into account when evaluating the need for further systemic therapy and designing risk-stratified clinical trials.     

Influence of education level on breast cancer risk and survival in Sweden between 1990 and 2004

On account of limited recent data regarding the role of education in breast cancer risk and prognosis, we conducted this study to assess the association between education level and in situ and invasive breast cancer risk and invasive breast cancer survival, using the 2006 update of the Swedish Family-Cancer Database. Cox's proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) adjusted for age, time-period, parity, age at first birth, county of residence, and family history of breast cancer. Compared to women completing less than 9 years of education, university graduates were more likely to be diagnosed with in situ (HR = 1.44, 95% CI: 1.28-1.63) and invasive (HR = 1.28, 95% CI: 1.20-1.36) breast cancer, and the lack of homogeneity between these two HRs was statistically significant, p = 0.007. Further stratification revealed that the lack of homogeneity was greatest for breast cancers diagnosed before age 50. Compared to women completing less than 9 years of education, university graduates were associated with the highest survival following a breast cancer diagnosis (lowest fatality hazard ratio), HR = 0.68, 95% CI: 0.61-0.75. Further research is warranted to elucidate possible behaviors or characteristics associated with education that could explain the differences in incidence and survival, such as compliance with cancer screening.     

The prognosis of patients with local recurrence more than five years after breast conservation therapy for invasive breast carcinoma.

AIMS: The increasing use of breast-conserving therapy (BCT) and the rising incidence and improved prognosis of early breast are causing a substantial increase in the absolute number of patients with a late local recurrence following BCT. This study examined the characteristics and the prognosis of patients with a local recurrence occurring more than 5 years after BCT. METHODS: In the period 1982-1997, 3280 patients with invasive breast cancer underwent breast-conserving therapy in one of the eight community hospitals in the South-eastern part of The Netherlands. Of these patients, 98 developed a local recurrence in the breast more than 5 years after BCT. RESULTS: Eighty-five of the 98 recurrences were invasive, 12 were purely in situ and for one patient this information was not available. The 5 years distant recurrence-free survival rate of 85 patients with a late invasive local recurrence was 68% (95% confidence interval [CI], 56-80) and significantly better than the rate of 41% (95% CI, 33-48) in an existing cohort of 173 patients with invasive recurrence within 5 years after BCT (p=0.007). Local excision of the recurrence was followed by a significantly lower local control rate than salvage mastectomy (50 vs 89%; p=0.004). CONCLUSION: The prognosis of patients with a local recurrence more than 5 years after BCT is significantly better than of patients with local recurrence within 5 years after BCT.     

The Salzburg concept of intraoperative radiotherapy for breast cancer: results and considerations

Aim of this study is to show that ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery can be reduced by proper surgery and modern radiotherapy techniques. Three hundred and seventy eight women with stage I or II breast cancer had breast conserving surgery and received 51-56.1 Gy of postoperative radiation to the whole breast in 1.7 Gy fractions, but patients received different boost strategies. Group 1 (n = 188) received electron boost radiation of 12 Gy subsequent to the irradiation to the whole breast, group 2 (n = 190) received intraoperative electron boost radiation of 9 Gy directly to the tumor bed, followed by whole breast irradiation. After a median follow up period of 81.0 months in group 1 and a median follow up period of 51.1 months in group 2, 12 IBTRs (6.4%) could be observed in group 1 and no IBTR could be observed in group 2 (0.0%). The 5-year actuarial rates of IBTR were 4.3% (95% CI, 1.9-8.3%) and 0.0% (95% CI, 0.0-1.9%), respectively (p = 0.0018). The 5-year actuarial rates of distant recurrence were 8.6% (95% CI, 4.9-13.5%) and 4.2% (95% CI, 1.8-8.2%), respectively (p = 0.08). The 5 year disease-free survival rates were 90.9% (95% CI, 85.8-94.7%) in group 1 and 95.8% (95% CI, 91.8-98.2%) in group 2 (p = 0.064). Immediate IORT-boost and whole breast irradiation yields excellent local control at 5 years, and was associated with a statistically significant decreased rate of IBTR compared with a similar cohort of patients treated with whole breast irradiation and conventional electron boost.     

The impact of lobular carcinoma in situ in association with invasive breast cancer on the rate of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy

PURPOSE: The significance of lobular carcinoma in situ (LCIS) associated with invasive breast cancer in patients undergoing breast-conserving therapy (BCT) remains controversial. We examined the impact of the presence and extent of LCIS associated with invasive breast cancer on clinical outcome in BCT patients. METHODS AND MATERIALS: From 1980 to 1996, 607 cases of invasive breast cancer were treated with BCT. All slides were reviewed by a single pathologist. Positive margin was defined as presence of invasive carcinoma/ductal carcinoma in situ at the inked margin. Multiple clinical, pathologic, and treatment-related variables were analyzed for their association with ipsilateral breast tumor recurrence (IBTR) and true recurrence/marginal miss (TR/MM). Median follow-up was 8.7 years. RESULTS: Fifty-six patients (9%) had LCIS in association with invasive cancer. On univariate analysis, positive final margin, positive/no reexcision, smaller maximum specimen dimension, and the presence of LCIS predicted for IBTR. The 10-year IBTR rate was 14% for cases with LCIS vs. 7% without LCIS (p=0.04). On multivariate analysis, positive margin (p<0.01), positive/no reexcision (p=0.04), and presence of LCIS (p=0.02) remained independently associated with IBTR; positive margin (p<0.01) and LCIS (p=0.04) were also associated with TR/MM failure. When examining only cases with negative final margins, the presence of LCIS remained associated with higher IBTR and TR/MM rates (p<0.01). CONCLUSION: The presence of LCIS was independently associated with higher rate of IBTR and TR/MM after BCT for invasive breast cancer. LCIS may have significant premalignant potential and progress to an invasive IBTR at the site of index lesion. The adequacy of excision of LCIS associated with invasive carcinoma should be considered in patients undergoing BCT.     

Indications and limits of breast conserving treatment

In Japan, 41% of surgeries for breast cancer were breast conserving treatment (BCT) in 2000. The indications for BCT in the guidelines of the Japanese Breast Cancer Society (1999) are as follows: (1) tumor size is 3 cm or less, (2) image diagnosis indicates no sign of extensive intraductal spread, (3) cases with multiple tumor are excluded, (4) radiation therapy is possible, (5) the patient wants to receive BCT. The pathological negative margin is favorable in BCT; however, we estimate based on our study that only about 30% of all breast cancers can be completely resected by partial mastectomy. To extend the indications for BCT, the roles of postoperative radiotherapy, endocrine therapy and preoperative chemotherapy will be important. Patients with ipsilateral breast tumor recurrence (IBTR) have increased risk of distant metastases, and the presence of IBTR is an important predictive factor for distant metastases. When we discuss the indications and limits of BCT, we have to take the rate of IBTR into careful consideration.     

The safety of breast-conserving therapy in patients with breast cancer aged < or = 40 years

BACKGROUND: The objectives of this study were to study the probability of local control after breast-conserving therapy (BCT) in a large population of patients with early-stage breast cancer aged < or = 40 years and to determine which factors had prognostic value. METHODS: All patients (n = 758) aged < or = 40 years with clinical stage I or II breast cancer who underwent BCT in general hospitals in the southern part of the Netherlands between 1988 and 2002 were selected for the current analysis. BCT included local excision of the tumor followed by irradiation of the breast. Of 758 patients, 329 patients (43%) received adjuvant systemic treatment, and 36 patients (5%) underwent a microscopically incomplete excision. The median follow-up was 8.5 years. RESULTS: During follow-up, 95 patients developed a local recurrence without evidence of distant disease at the time the recurrence was diagnosed. Contralateral breast cancer was diagnosed in 59 patients. The 5- and 10-year actuarial local recurrence rates were 9.0% (95% confidence interval [95% CI], 6.6-11.4%) and 17.9% (95% CI, 14.1-21.7%), respectively. In a multivariate analysis, adjuvant systemic treatment reduced the risk of local recurrence (hazards ratio [HR], 0.47; 95% CI, 0.28-0.78) and contralateral breast cancer (HR, 0.46; 95% CI, 0.24-0.87) by >50%. CONCLUSIONS: The risk of local recurrence in young patients who underwent BCT was reduced strongly by using adjuvant systemic treatment. This finding may provide an argument if favor of advising the use of systemic treatment for all patients aged < or = 40 years who undergo BCT.     

Prognostic influence of BCL2 expression in breast cancer

Although BCL2 has occasionally been suggested as a candidate prognostic factor for breast cancer, it is still not accepted as a prognostic factor. We attempted to validate the role of BCL2 as a prognostic factor of breast cancer. Data on 7,230 primary breast cancer patients from the Seoul National University Hospital Breast Care Center were analyzed. Three current prognostic models, including the St. Gallen model, the Nottingham prognostic index (NPI) model and the TNM model, were used for analysis of the prognostic influence of BCL2. The positive BCL2 group showed more favorable features with regard to clinicopathologic parameters than the BCL2 negative group and a strong correlation was observed between BCL2 and the hormonal receptor. The positive BCL2 group showed better prognosis in overall survival and disease free survival (log-rank test, both p < 0.001), even in all subgroups, than the BCL2 negative group. BCL2 was a significant prognostic factor in both univariate (hazard ratio [HR], 0.361; 95% confidence interval (CI), 0.306-0.426; p < 0.001) and multivariate analyses (HR, 0.417; 95% CI, 0.417-0.705; p < 0.001). BCL2 had a strong influence on the established prognostic models, including the St. Gallen model, the NPI model and the TNM model. BCL2 was a powerful independent prognostic factor for breast cancer and had a strong influence on the current prognostic models. Favorable clinicopathologic features and a strong correlation with the hormonal receptor are suggested as the causes of superior survival in patients with BCL2 positive breast cancer.     

Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer--comparison between Adjuvant!, St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial

BACKGROUND: Defining risk categories in breast cancer is of considerable clinical significance. We have developed a novel risk classification algorithm and compared its prognostic utility to the Web-based tool Adjuvant! and to the St Gallen risk classification. PATIENTS AND METHODS: After a median follow-up of 10 years, we retrospectively analyzed 410 consecutive node-negative breast cancer patients who had not received adjuvant systemic therapy. High risk was defined by any of the following criteria: (i) age <35 years, (ii) grade 3, (iii) human epithelial growth factor receptor-2 positivity, (iv) vascular invasion, (v) progesterone receptor negativity, (vi) grade 2 tumors >2 cm. All patients were also characterized using Adjuvant! and the St Gallen 2007 risk categories. We analyzed disease-free survival (DFS) and overall survival (OS). RESULTS: The Node-Negative-Breast Cancer-3 (NNBC-3) algorithm enlarged the low-risk group to 37% as compared with Adjuvant! (17%) and St Gallen (18%), respectively. In multivariate analysis, both Adjuvant! [P = 0.027, hazard ratio (HR) 3.81, 96% confidence interval (CI) 1.16-12.47] and the NNBC-3 risk classification (P = 0.049, HR 1.95, 95% CI 1.00-3.81) significantly predicted OS, but only the NNBC-3 algorithm retained its prognostic significance in multivariate analysis for DFS (P < 0.0005). CONCLUSION: The novel NNBC-3 risk algorithm is the only clinicopathological risk classification algorithm significantly predicting DFS as well as OS.     

Ipsilateral breast tumor recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06.

Ipsilateral breast tumor recurrence (IBTR) occurred in 42 of 488 (9%) pathologically evaluable patients enrolled in NSABP protocol B-06 with a mean potential follow-up of 103 months (range 68-161 months) following treatment for Stage I and II invasive breast cancer by lumpectomy and local breast irradiation (LXRT). IBTR were observed at or close to the same quadrant as the index cancers and their histologic types and nuclear grades were similar if not identical in 95 and 93%, respectively. This information confirms our earlier findings which indicated that multicentricity is of little or no clinical significance in the treatment of breast cancer by LXRT; breast cancers rarely if ever change their biologic potential once clinically detected; and lastly, most if not all IBTR represent residual cancer. Cox regression analyses revealed only a patient age less than 35 years to be significantly related to IBTR. No relationship between IBTR and so-called extensive intraductal component (EIC) or 31 other pathologic features of the index cancers was found. Overall survival was significantly related to nodal status (P = 0.01), nuclear grade (P = less than 0.001) histologic tumor type (P = 0.01) and IBTR (P = less than 0.001). This latter was considered as an indicator rather than instigator of distant disease and reduced survival since the latter is no different in patients treated by LXRT, lumpectomy alone after which IBTR is much more frequent, or mastectomy, which precludes its expression. We conclude that there are as yet no viable markers which would contraindicate treating patients with breast cancer by LXRT.     

Twenty-five year results of the national cancer institute randomized breast conservation trial

Breast conservation therapy (BCT) consisting of lumpectomy and postoperative radiation has become an accepted alternative to mastectomy (MRM) for the treatment of early stage breast cancer. We currently report the 25 year outcomes of a single institution, prospective, randomized clinical trial at the National Cancer Institute. 237 women with pathologically confirmed invasive breast tumors 5 cm or less were accrued between 1979 and 1987 and randomized to receive either BCT or MRM. Overall survival was the primary endpoint. Patients with node positive disease were included and treated with doxorubicin and cyclophosphamide. Both arms received axillary dissection. BCT patients had radiation to the whole breast followed by a boost. At a median follow-up of 25.7 years, overall survival was 43.8% for the MRM group and 37.9% for BCT (P = 0.38). Although the cumulative incidence of a disease-free survival event was higher in BCT patients (29.0% MRM vs. 56.4% BCT, P = 0.0017), the additional treatment failures were primarily isolated ipsilateral breast tumor recurrences (IBTR's) requiring salvage mastectomy. 22.3% of BCT patients experienced an IBTR. Distant disease and second cancers were similar in both arms. After 25 years, long term survival between BCT and MRM continues to be similar in patients treated for early stage breast cancer. Patients receiving BCT may be at risk for additional treatment-related morbidity, which may occur as a late event. Further studies are required to delineate patients at higher risk for these events, and prolonged follow up should be encouraged after treatment for all women.     

Improving local control with breast-conserving therapy: a 27-year single-institution experience

BACKGROUND: The risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) is associated with treatment and tumor-related variables, such as surgical margin status and the use of systemic therapy, and these variables have changed over time. Correspondingly, the authors of the current study hypothesized that the contemporary multidisciplinary management of breast carcinoma would lead to an improvement in IBTR rates after BCT. METHODS: Between 1970 and 1996, 1355 patients with pathologic Stage I-II invasive breast carcinoma underwent BCT (breast-conserving surgery and adjuvant radiation therapy) at The University of Texas M. D. Anderson Cancer Center. Contemporary methods of analyzing surgical margins were in routine use by 1994. To analyze the effect of this variable and others, patient and tumor characteristics and IBTR rates in patients treated during 1994-1996 were compared with those in patients treated from 1970 to 1993. RESULTS: Characteristics were similar in patients treated during 1994-1996 (n = 381) and those treated before 1994 (n = 974) except for patients aged >50 years (63.3% vs. 51.7%, P < 0.001), and patients who had a family history of breast carcinoma (37.9% vs. 30.8%, P = 0.017). Patients treated after 1994 were less likely to have positive or unknown margins (2.9 % vs. 24.1 %, P = 0.0001), more likely to receive chemotherapy (40.5% vs. 26%, P < 0.001), and more likely to receive hormonal therapy (33.3% vs. 19.4%, P < 0.001), but less likely to receive radiation boosts to the primary tumor bed (59.8% vs. 89%, P < 0.001). The 5-year cumulative IBTR rate was significantly lower among patients treated in 1994-1996 than among patients treated before 1994 (1.3% vs. 5.7%, P = 0.001) largely because of the drop in IBTR rates among patients aged < or = 50 years (1.4 % vs. 9.1 %, P = 0.0001). On multivariate analysis, age > 50 (hazards ratio [HR] = 0.401; P = 0.0001), presence of negative surgical margins (HR = 0.574; P = 0.017), and use of adjuvant hormonal therapy (HR = 0.402; P = 0.05) were independent predictors of improved 5-year IBTR-free survival. On subgroup analysis, use of chemotherapy was associated with increased IBTR-free survival among women aged < or = 50 years (HR = 0.383; P = 0.001). Although 5-year cumulative IBTR rates were lower among women aged > 50 years than among younger women before 1994 (2.6 % vs. 9.1%, P < 0.0001), no such difference was found in the group treated in 1994-1996 (1.2 % for age > 50 yrs vs. 1.4 % for < or = 50 yrs, P = 0.999). CONCLUSIONS: The IBTR rate after BCT appears to be declining, especially among patients < 50 years of age. However, long-term follow-up is necessary to confirm this finding. This finding may reflect changes in surgical approaches and pathologic evaluation as well as an increased use of systemic therapy. The current low incidence of IBTR with multidisciplinary management of breast carcinoma may result in more patients choosing BCT over mastectomy.     

Breast conservation for ductal carcinoma in situ: Results at an Australian institution with evidence to recommend prospective assessment of the utility of a lumpectomy boost

Aim: We reviewed outcomes for ductal carcinoma in situ (DCIS) of the breast at our institution to assess risk factors for ipsilateral breast tumour recurrence (IBTR) after breast conservation (BCT). Methods: Records were reviewed of all patients who presented with biopsy‐confirmed DCIS of the breast prior to 1 January 2004. Variables analyzed included patient age, tumour size, grade, resection margins, comedonecrosis, surgery, tamoxifen, whole breast radiotherapy dose and addition of a boost. We also attempted to validate the University of Southern California/Van Nuys prognostic index (USC/VNPI). Results: One hundred and thirty patients had DCIS: four were excluded from analysis and another 10 had mastectomies. A total of 116 patients had BCT and this group comprised the study population. Median follow‐up was 7.7 years (1.6–12.4) and median age was 58 years. Five‐ and 10‐year overall survivals were 98% (93.5–99.6 95% CI) and 89% (74–95 95% CI). Five‐ and 10‐year breast failure‐free survivals were 96% (90–98 95% CI) and 93% (85–97 95% CI). Young age was the only significant factor associated with IBTR (P = 0.018). Patients with a high USC/VNPI score were also significant for increased IBTR (P = 0.04), but this effect disappeared when age was omitted from the index. There was a trend towards an increased risk of IBTR with a lower whole breast dose of less than 50 Gy (P = 0.18). A boost was not associated with reduced IBTR. The 10‐year IBTR for patients under 55 who received adjuvant radiotherapy to a whole breast dose of <50 Gy but no tamoxifen was 25%. Conclusion: Overall BCT local control and survival outcomes are excellent. There is a suggestion that younger patients should be treated with a whole breast dose equivalent to 50 Gy in 25 daily fractions regardless of a boost. However, this requires confirmation in a randomized phase III trial and therefore the currently active Trans‐Tasman Radiation Oncology Group randomized controlled trial 07.01 should be supported by the breast cancer treating community.     

Mammographic density and estrogen receptor status of breast cancer.

BACKGROUND: The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)-positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.METHODS: We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.RESULTS: Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).CONCLUSION: Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.     

The use of molecular assays to establish definitively the clonality of ipsilateral breast tumor recurrences and patterns of in-breast failure in patients with early-stage breast cancer treated with breast-conserving therapy

BACKGROUND: Results from numerous trials have indicated that breast-conserving therapy (BCT) produces outcomes equivalent to those produced by mastectomy in terms of both locoregional control and survival. However, conservative treatment has resulted in the dilemma of how best to address recurrences when they appear in a breast treated previously with radiation therapy. Attempts have been made to characterize ipsilateral breast tumor recurrences (IBTRs) as either true recurrences of the treated malignancy or new primary carcinomas, because cancers that represent new primary tumors may be associated with a more favorable prognosis compared with cancers that represent true recurrences. METHODS: The authors studied the clonality of IBTRs relative to the initial invasive carcinomas by using a polymerase chain reaction loss-of-heterozygosity molecular comparison assay in 29 patients who received breast-conserving therapy (BCT). RESULTS: Twenty-two IBTRs (76%) were related clonally to the initial carcinoma, and 7 IBTRs (24%) were clonally different. Clonally related IBTRs were more frequently higher grade (72.2% vs 14.3%; P = .009) and developed sooner after initial treatment (mean time to IBTR, 4.04 years in clonally related IBTRs vs 9.25 years in clonally different IBTRs; P = .002). Six patients subsequently developed distant metastases, and 5 of those patients (83.3%) had clonally related IBTRs. Clinical IBTR classification and molecular clonality assay results differed in 30% of all patients. The proportion of IBTRs that were related clonally at 5 years, 10 years, and 15 years after BCT were 93%, 67%, and 33%, respectively. CONCLUSIONS: Clinical classifications of IBTRs were unreliable methods for determining clonality in many patients. Molecular clonality assays provided a reliable means of identifying patients who may benefit from aggressive systemic therapy at the time of IBTR and also provided a more accurate assessment of the efficacy of various forms of local therapy.