Gene expression profiling to predict the risk of locoregional recurrence in breast cancer: a pooled analysis.

The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.

Low complication rates are achievable after postmastectomy breast reconstruction and radiation therapy.

PURPOSE: To report our institution's experience of complications and cosmetic results among patients who underwent modified radical mastectomy followed by reconstruction and radiation therapy (RT). METHODS AND MATERIALS: Between 1987 and 2002, 85 patients with breast cancer underwent modified radical mastectomy, breast reconstruction, and postoperative RT. Reconstruction consisted of tissue expander/implant (TE/I) in 50 patients and an autologous transverse rectus abdominis myocutaneous (TRAM) flap in 35 patients. The primary end point of this study was the actuarial incidence of major and minor complications involving the reconstruction. Cosmesis was also assessed at each follow-up visit. RESULTS: The median follow-up from reconstruction was 28 months. The 5-year major complication rate was 0% in the TRAM group vs. 5% in the TE/I group (p = 0.21). The 5-year minor complication rate was 39% for the TRAM group vs. 14% for the TE/I group (p = 0.04). None (0%) of the TRAM complications required any corrective surgery, whereas 2 (33%) of the TE/I complications required implant removal. Of the TRAM patients with complications, 100% had superior cosmetic scores of excellent/good compared to only 17% of the TE/I patients who had complications (p = 0.003). Use of our custom-fashioned bolus resulted in a lower complication rate compared with standard bolus (p = 0.05). CONCLUSIONS: Patients treated with breast reconstruction and RT can experience a very low rate of major complications. We demonstrate no significant difference in the overall rate of major complications between TRAM and TE/I patients. Bolus can be safely used during postmastectomy RT with reconstruction, and we advocate the use of a custom wax bolus in the treatment of these patients. Postmastectomy RT should be considered in all eligible patients, even in the setting of reconstruction.

Recursive partitioning identifies patients at high and low risk for ipsilateral tumor recurrence after breast-conserving surgery and radiation.

PURPOSE: Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer. PATIENTS AND METHODS: Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years. RESULTS: Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P =.03). For patients

Quantifying radiation therapy-induced brain injury with whole-brain proton MR spectroscopy: initial observations.

PURPOSE: To quantify the extent of neuronal cell loss imparted to the brain by means of radiation therapy through the decline of the amino acid derivative N-acetylaspartate (NAA) by using proton (hydrogen 1) magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Proton MR spectroscopy in a clinical MR imager was used to ascertain the amount of whole-brain NAA before and immediately after whole-brain radiation therapy 3-4 weeks later. Eight patients (four women, four men; median age, 55 years; age range, 39-70 years) were studied. All subjects had lung cancer (non-small cell lung cancer [n = 5], small-cell lung cancer [n = 3]) and received either palliative or prophylactic whole-brain radiation therapy. Six of them also underwent a Mini-Mental Status Examination (MMSE) for correlation with the whole-brain NAA. Two-tailed Student t tests were used to evaluate the data. RESULTS: A significant (P = .042) average decline in whole-brain NAA of -0.91 mmol per person was observed in the cohort. No corresponding changes occurred in MMSE scores. There was no significant difference in whole-brain NAA decline between prophylactic and therapeutic whole-brain radiation therapy. CONCLUSION: Since whole-brain NAA loss was detected even when MMSE scores were unchanged, the former seems to be a more sensitive measure of radiation therapy injury than is the latter.

Second cancers after conservative surgery and radiation for stages I-II breast cancer: identifying a subset of women at increased risk.

PURPOSE: To assess the risk and patterns of second malignancy in a group of women treated with conservative surgery and radiation in a relatively contemporary manner for early-stage invasive breast cancer, and to identify a subgroup of these women at increased risk for a second cancer. METHODS AND MATERIALS: From 1978 to 1994, 1,253 women with unilateral Stage I-II breast cancer underwent wide excision, axillary dissection, and radiation. The median follow-up was 8.9 years, with 446 patients followed for >or= 10 years. The median age was 55 years. Sixty-eight percent had T1 tumors and 74% were axillary-node negative. Radiation was directed to the breast only in 78%. Adjuvant therapy consisted of chemotherapy in 19%, tamoxifen in 19%, and both in 8%. Factors analyzed for their association with the cumulative incidence of all second malignancies, contralateral breast cancer, and non-breast cancer malignancy were: age, menopausal status, race, family history, obesity, smoking, tumor size, location, histology, pathologic nodal status, region(s) treated with radiation, and the use and type of adjuvant therapy. RESULTS: One hundred seventy-six women developed a second malignancy (87 contralateral breast cancers at a median interval of 5.8 years, and 98 non-breast cancer malignancies at a median interval of 7.2 years). Nine women had both a contralateral breast cancer and non-breast cancer second malignancy. The 5- and 10-year cumulative incidences of a second malignancy were 5% and 16% for all cancers, 3% and 7% for contralateral breast cancer, 3% and 8%, for all second non-breast cancer malignancies, and 1% and 5%, respectively, for second non-breast cancer malignancies, excluding skin cancers. Patient age was a significant factor for contralateral breast cancer and non-breast cancer second malignancy. Young age was associated with an increased risk of contralateral breast cancer, while older age was associated with an increased the risk of a second non-breast cancer second malignancy. A positive family history increased the risk of contralateral breast cancer, but not non-breast cancer malignancies. The risk of a contralateral breast cancer increased as the number of affected relatives increased. Tamoxifen resulted in a nonsignificant decrease in contralateral breast cancer and an increase in non-breast cancer second malignancies. The 5-and 10-year cumulative incidences for leukemia and lung cancer were 0.08% and 0.2%, and 0.8% and 1%, respectively. There was no significant effect of chemotherapy or the regions treated with radiation on contralateral breast cancer or non-breast cancer second malignancy. The most common types of second non-breast cancer malignancies were skin cancers, followed by gynecologic malignancies (endometrial), and gastrointestinal malignancies (colorectal and pancreas). CONCLUSION: The 10-years cumulative incidence of a second cancer in this study was 16%. Young age and family history predicted for an increased risk of contralateral breast cancer, and older age predicted for an increased risk of non-breast cancer malignancy. The majority of patients treated with conservative surgery and radiation with or without adjuvant systemic therapy will not develop a second cancer. Long-term follow-up is important to document the risk and patterns of second cancer, and knowledge of this risk and the patterns will influence surveillance and prevention strategies.

Local recurrence of breast cancer in the stereotactic core needle biopsy site: case reports and review of the literature.

Early mammographic detection of nonpalpable breast lesions has led to the increasing use of stereotactic core biopsies for tissue diagnosis. Tumor seeding the needle tract is a theorectical concern; the incidence and clinical significance of this potential complication are unknown. We report three cases of subcutaneous breast cancer recurrence at the stereotactic biopsy site after definitive treatment of the primary breast tumor. Two cases were clinically evident and relevant; the third was detected in the preclinical, microscopic state. All three patients underwent multiple passes during stereotactic large-core biopsies (14 gauge needle) followed by modified radical mastectomy. Two patients developed a subcutaneous recurrence at the site of the previous biopsy 12 and 17 months later; one had excision of the skin and dermis at the time of mastectomy revealing tumor cells locally. In summary, clinically relevant recurrence from tumor cells seeding the needle tract is reported in two patients after definitive surgical therapy (without adjuvant radiation therapy). Often, the biopsy site is outside the boundaries of surgical resection. Since the core needle biopsy exit site represents a potential area of malignant seeding and subsequent tumor recurrence, we recommend excising the stereotactic core biopsy tract at the time of definitive surgical resection of the primary tumor.

Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation.

BACKGROUND: Lobular carcinoma in situ (LCIS) is a known risk factor for the development of invasive breast carcinoma. However, little is known regarding the impact of LCIS in association with an invasive carcinoma on the risk of an ipsilateral breast tumor recurrence (IBTR) in patients who are treated with conservative surgery (CS) and radiation therapy (RT). The purpose of this study was to examine the influence of LCIS on the local recurrence rate in patients with early stage breast carcinoma after breast-conserving therapy. METHODS: Between 1979 and 1995, 1274 patients with Stage I or Stage II invasive breast carcinoma were treated with CS and RT. The median follow-up time was 6.3 years. RESULTS: LCIS was present in 65 of 1274 patients (5%) in the study population. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1125 patients; 2%). Ipsilateral breast tumor recurrence (IBTR) occurred in 57 of 1209 patients (5%) without LCIS compared with 10 of 65 patients (15%) with LCIS (P = 0.001). The 10-year cumulative incidence rate of IBTR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003). In both groups, the majority of recurrences were invasive. The 10-year cumulative incidence rate of IBTR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46). Subsets of patients in which the presence of LCIS was associated with an increased risk of breast recurrence included tumor size < 2 cm (T1), age < 50 years, invasive ductal carcinoma, negative lymph node status, and the absence of any adjuvant systemic treatment (chemotherapy or hormonal therapy) (P < 0.001). LCIS margin status, invasive lobular carcinoma histology, T2 tumor size, and positive axillary lymph nodes were not associated with an increased risk of breast recurrence in these women. CONCLUSIONS: The authors conclude that the presence of LCIS significantly increases the risk of an ipsilateral breast tumor recurrence in certain subsets of patients who are treated with breast-conserving therapy. The risk of local recurrence appears to be modified by the use of tamoxifen. Further studies are needed to address this issue.

Local recurrence after mastectomy or breast-conserving surgery and radiation.

Approximately 10% to 15% of patients with stage I/II invasive breast cancer will develop a clinically isolated local recurrence. The standard management of an ipsilateral breast tumor recurrence following breast-conserving surgery and radiation is salvage mastectomy, while local excision and radiation are optimal treatment of a chest wall recurrence following initial mastectomy. Although there are few data regarding the efficacy of systemic therapy after isolated local relapse, chemotherapy and/or hormonal therapy should be considered for most patients because of the high risk of subsequent distant relapse. However, local relapse does not always herald distant metastases. A prolonged interval between initial treatment and local recurrence is the most important prognostic factor for subsequent outcome, and when combined with other favorable characteristics, can predict 5-year survival rates of 70% or higher.

Accuracy of the extent of axillary nodal positivity related to primary tumor size, number of involved nodes, and number of nodes examined.

PURPOSE: While a number of studies have evaluated the minimum number of axillary nodes that need to be examined to accurately determine nodal positivity or negativity, there is little information on the number of nodes which must be examined to determine the extent of nodal positivity. This study attempts to determine for patients with 1-3 positive nodes the probability that the number of positive nodes reported is the true number of positive nodes as well as the probability that 4 or more nodes could be positive based on primary tumor size and number of nodes examined. MATERIALS AND METHODS: From 1979 to 1998, 1652 women with Stages I-II invasive breast cancer underwent an axillary dissection as part of their breast conservation therapy and had more than 10 lymph nodes examined. The mean and median number of nodes identified in the dissection was 19 and 17 (range, 11-75). The median age was 55 years. A total of 1155 women had T1 tumors and 497 had T2 tumors. Of the 459 node-positive women, 72% had 1-3 positive nodes, 18% had 4-9 positive nodes, and 10% had 10 or more positive nodes. A mathematical model based on tumor size and number of nodes examined was created using the hypergeometric distribution and Bayes Theorem. The resulting model was used to estimate the accuracy of the reported number of positive nodes and the probability of 4 or more positive nodes based on various observed sampling combinations. RESULTS: For patients with T1 tumors and 1, 2, or 3 positive nodes, the minimum number of nodes examined needed for a 90% probability of accuracy is 19, 20, and 20. For T2 tumors and 1, 2, or 3 positive nodes, a minimum of 20 nodes is required. The probability of 4 or more positive nodes increases as tumor size and the number of reported positive nodes increase and as the number of examined nodes decreases. For a 10% or less probability of 4 or more positive nodes, a patient with a T1 tumor and 1, 2, or 3 observed positive nodes would require a minimum of 8, 15, and 20 nodes removed. For a T2 tumor and 1, 2, or 3 observed positive nodes, the corresponding numbers are 10, 16, and 20. CONCLUSION: The accuracy of the extent of axillary nodal positivity is influenced by the number of observed positive nodes, tumor size, and the number of nodes examined. Underestimation of the number of positive nodes will result in errors in the assessment of an individual's risk for locoregional recurrence, distant disease, and breast cancer death and will adversely impact on treatment recommendations. This model provides the clinician with a means for assessing the accuracy of the number of positive nodes reported in patients with 1-3 positive nodes.

Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer.

PURPOSE: To compare outcome for ipsilateral breast tumor recurrence (IBTR), or regional node recurrence, initial and subsequent distant metastases, and overall and cause-specific survival in women treated with conservative surgery and radiation based on whether or not radiation was targeted to the internal mammary nodes (IMN). METHODS AND MATERIALS: From 1979-1994, 1383 women with Stage I-II breast cancer underwent wide excision, axillary node dissection with >/=10 nodes removed, and radiation. Median follow-up was 6 years; median age was 55 years. A total of 114 women had radiation targeted to the IMN with deep tangents and 1269 did not. Women who received IMN treatment were more often axillary node-positive (40% vs. 25%, p = 0. 002), had central or inner quadrant tumors (61% vs. 40%, p = 0.001), and had T2 tumors (47% vs. 31%, p = 0.001). All axillary node-positive women received adjuvant chemotherapy and/or tamoxifen. For axillary node-negative women, 13% of the IMN treatment group received adjuvant systemic therapy compared to 37% of the no treatment group (p = 0.001). Radiation was directed to the breast only in 97% of the axillary node-negative women who had IMN treatment and 99% of the no IMN treatment group. For axillary node-positive women, 98% of the IMN-treated group had radiation to the breast and supraclavicular nodes +/- a posterior axillary field compared to 77% of the no IMN treatment group (p = 0.001). There were no significant differences between the two groups for median age, menopausal status, histology, final surgical margin, estrogen and progesterone receptor status, or the number of positive nodes. RESULTS: There were no significant differences in the 5- and 10-year cumulative incidence of an IBTR, regional node recurrence, initial or total distant metastases for the two groups. Similarly 5- and 10-year actuarial overall and cause-specific survival were not significantly different. However, subset analysis revealed a statistically significant increase in initial (29% vs. 15% at 10 yr, p = 0.002) and total (30% vs. 17% at 10 yr, p = 0.01) distant metastases and a significant decrease in cause-specific survival (76% vs. 89% at 10 yr, p = 0.02) for postmenopausal women who received IMN treatment. These findings could not be attributed to differences in the use of systemic therapy or the number of positive nodes. Axillary node-positive patients did not experience a significant decrease in initial (36% vs. 22% at 10 yr, p = 0.21) or total distant metastases (37% vs. 28% at 10 yr, p = 0.62) or a significant improvement in cause-specific survival (72% vs. 76% at 10 yr, p = 0.76) with IMN treatment regardless of whether the tumor was lateral or medial/central in location. IMN treatment was not associated with an increase in non-breast cancer deaths during this period of observation. CONCLUSIONS: This retrospective series was unable to identify a significant benefit for IMN irradiation in terms of distant metastases or cause-specific survival for the entire patient population, and in particular, for patients with positive axillary nodes and medially located lesions. The results of the proposed or ongoing prospective randomized trials will further address this controversial issue.

Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist?

PURPOSE: The elective treatment of internal mammary lymph nodes (++IMNs) in breast cancer is controversial. Previous randomized trials have not shown a benefit to the extended radical mastectomy or elective IMN irradiation overall, but a survival benefit has been suggested by some for subgroups of patients with medial tumors and positive axillary lymph nodes. The advent of effective systemic chemotherapy and potential for serious cardiac morbidity have also been factors leading to the decreased use of IMN irradiation during the past decade. The recent publishing of positive trials testing postmastectomy radiation that had included regional IMN irradiation has renewed interest in their elective treatment. The purpose of this study is to critically review historical and new data regarding IMNs in breast cancer. METHODS AND MATERIALS: The historical incidence of occult IMN positivity in operable breast cancer is reviewed, and the new information provided by sentinel lymph node studies also discussed. The results of published randomized prospective trials testing the value of elective IMN dissection and/or radiation are analyzed. The data regarding patterns of failure following elective IMN treatment is studied to determine its impact on local-regional control, distant metastases, and survival. A conclusion is drawn regarding the merits of elective IMN treatment based on this review of the literature. RESULTS: Although controversial, the existing data from prospective, randomized trials of IMN treatment do not seem to support their elective dissection or irradiation. While it has not been shown to contribute to a survival benefit, the IMN irradiation increases the risk of cardiac toxicity that has effaced the value of radiation of the chest wall in reducing breast cancer deaths in previous randomized studies and meta-analyses. Sentinel lymph node mapping provides an opportunity to further evaluate the IMN chain in early stage breast cancer. Biopsy of "hot" nodes may be considered in the future to select patients who are most likely to benefit from additional regional therapy to these nodes. CONCLUSIONS: Irradiation of the IMN chain in conjunction with the chest wall and supraclavicular region should be considered only for those with pathologically proven IMNs with the goal of improving tumor regional control.

Microinvasive breast carcinoma: clinicopathologic analysis of a single institution experience.

BACKGROUND: Microinvasive breast carcinoma (MIC) has a good prognosis but specific definitions have varied in the past, making the clinical significance of MIC a subject of debate. METHODS: Microscopic slides of 59 cases of breast carcinoma originally diagnosed as MIC were reviewed retrospectively. Histologic parameters were correlated with clinical findings and outcome to define diagnostic criteria better. RESULTS: On review, the 59 cases were recategorized as follows: pure DCIS (N = 16), DCIS with foci equivocal for microinvasion (N = 7), DCIS with > or =1 focus of microinvasion (N = 11), T1 invasive carcinomas with > or =90% DCIS (N = 18), and T1 tumors with <90% DCIS (N = 7). The MIC cases in the current study averaged 3 separate foci of early infiltration outside the basement membrane, each one not >1.0 mm. The mean follow-up was 95 months. Six patients (10%) had only local recurrence: 1 case each in patients with equivocal microinvasion, microinvasion, and T1 tumors with <90% DCIS and 3 cases among the patients with T1 tumors with > or = 90% DCIS. Four patients, all with T1 tumors with > or =90% DCIS, had distant failure (7%). In the MIC group, only one patient developed a local recurrence after breast conservation. No patient had axillary lymph node metastasis. For the entire series, factors associated with local recurrence were younger age, breast conservation versus mastectomy, and close surgical margins. The only factor associated with distant failure was the size of the DCIS component. Seven patients with T1 tumors with > or =90% DCIS experienced local or distant failure and 5 of these (71%) developed progressive disease or died of disease. All other patients who developed a recurrence were disease free at last follow-up. In a retrospective series, poorer outcome in carcinomas with > or =90% DCIS may be related to the greater likelihood of missed larger areas of invasive carcinoma. Therefore, meticulous and extensive sampling of these carcinomas is required. CONCLUSIONS: MIC as defined has a good prognosis. It has a different biology than T1 invasive carcinoma with > or =90% DCIS, which may progress and cause death. Large tumors with multiple foci of microinvasion may have metastatic potential.

Ipsilateral breast tumor recurrence following breast-conserving surgery for early-stage invasive cancer.

Ipsilateral breast tumor recurrence (IBTR) following conservative surgery and radiation for early stage invasive cancer occurs in approximately 15% of all patients at 10 years and is diminished with surgical excisions which achieve negative margins. Treatment strategies of breast-conserving surgery with or without radiation that result in IBTR rates of 30 40% will impact negatively on survival and the magnitude of this effect will be influenced by the predominant pattern of local failure as well as initial and subsequent distant metastases. Optimal local control in early-stage invasive breast cancer is important to minimize the risk of a salvage mastectomy and maximize the potential for long-term survival.

Postmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation.

PURPOSE: To compare the pretreatment characteristics and outcome of postmenopausal women with stage I-II breast cancer treated with conservative surgery and radiation who had a history of hormone replacement therapy (HRT) with those who had never received HRT. MATERIALS AND METHODS: From 1979 to 1993, 485 postmenopausal women underwent excisional biopsy, axillary dissection, and radiation for stage I-II breast cancer. The median follow-up was 5.9 years. One hundred forty-one patients reported a history of HRT. The median length of use was 5 years. Three hundred forty-four patients reported no history of HRT. RESULTS: Statistically significant differences between the two groups were observed for median age (HRT 60 years v no HRT 64 years; P =.0009), median weight (HRT 142 lbs v no HRT 152 lbs; P =.004), clinical tumor size < or = 2 cm (HRT 77% v no HRT 66%; P =.02), and the use of re-excision (HRT 62% v no HRT 49%; P =.01). The method of detection by mammogram only (HRT 52% v no HRT 42%; P =.06) was of borderline statistical significance. The HRT patients had a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence (8% v 2%; P =.02), a statistically significant decreased cumulative incidence of distant metastases (HRT 6% v no HRT 17%; P =.01), and a borderline statistically significant improvement in cause-specific survival at 10 years (HRT 92% v no HRT 86%; P =.07). Postmenopausal women with a history of HRT did not have an increased risk of contralateral breast cancer or second non-breast cancer malignancy. CONCLUSION: This study failed to identify an adverse effect of HRT on breast cancer mortality in patients with stage I-II disease treated with conservative surgery and radiation.

Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group.

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

Patients with early stage invasive cancer with close or positive margins treated with conservative surgery and radiation have an increased risk of breast recurrence that is delayed by adjuvant systemic therapy.

PURPOSE: The association between a positive resection margin and the risk of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation is controversial. The width of the resection margin that minimizes the risk of IBTR is unknown. While adjuvant systemic therapy may decrease the risk of an IBTR in all patients, its impact on patients with positive or close margins is largely unknown. This study examines the interaction between margin status, margin width, and adjuvant systemic therapy on the 5- and 10-year risk of IBTR after conservative surgery and radiation. METHODS AND MATERIALS: A series of 1,262 patients with clinical Stage I or II breast cancer were treated by breast-conserving surgery, axillary node dissection, and radiation between March 1979 and December 1992. The median follow-up was 6.3 years (range 0.1-15.6). The median age was 55 years (range 24-89). Clinical size was T1 in 66% and T2 in 34%. Seventy-three percent of patients were node-negative. Only 5 % of patients had tumors that were EIC-positive. Forty-one percent had a single excision, and 59% had a reexcision. The final margins were negative in 77%, positive in 12%, and close (< or = 2 mm) in 11%. The median total dose to the tumor bed was 60 Gy with negative margins, 64 Gy with close margins, and 66 Gy with positive margins. Chemotherapy +/- tamoxifen was used in 28%, tamoxifen alone in 20%, and no adjuvant systemic therapy in 52%. RESULTS: The 5-year cumulative incidence (CI) of IBTR was not significantly different between patients with negative (4%), positive (5%), or close (7%) margins. However, by 10 years, a significant difference in IBTR became apparent (negative 7%, positive 12%, close 14%, p = 0.04). There was no significant difference in IBTR when a close or positive margin was involved by invasive tumor or DCIS. Reexcision diminished the IBTR rate to 7% at 10 years if the final margin was negative; however, the highest risk was observed in patients with persistently positive (13%) or close (21%) (p = 0.02) margins. The median interval to failure was 3.7 years after no adjuvant systemic therapy, 5.0 years after chemotherapy +/- tamoxifen, and 6.7 years after tamoxifen alone. This delay to IBTR was observed in patients with close or positive margins, with little impact on the time to failure in patients with negative margins. The 5-year CI of IBTR in patients with close or positive margins was 1% with adjuvant systemic therapy and 13% with no adjuvant therapy. However, by 10 years, the CI of IBTR was similar (18% vs. 14%) due to more late failures in the patients who received adjuvant systemic therapy. CONCLUSION: A negative margin (> 2 mm) identifies patients with a very low risk of IBTR (7% at 10 years) after conservative surgery and radiation. Patients with a close margin (< or = 2 mm) are at an equal or greater risk of IBTR as with a positive margin, especially following a reexcision. A margin involved by DCIS or invasive tumor has the same increased risk of IBTR. A reexcision of an initially close or positive margin that results in a negative final margin reduces the risk of IBTR to that of an initially negative margin. A close or positive margin is associated with an increased risk of IBTR even in patients who are EIC-negative or receiving higher boost doses of radiation. The median time to IBTR is delayed; however, the CI is not significantly decreased by adjuvant systemic therapy in patients with close or positive margins-the 5 year results in these patients underestimate their ultimate risk of recurrence.

Postmastectomy radiation in patients with one to three positive axillary nodes receiving adjuvant chemotherapy: An unresolved issue.

The rationale for postmastectomy radiation is based on the prevention of locoregional recurrence in the chest wall, regional lymphatics, or both. The randomized trials of postmastectomy radiation in patients with one to three positive nodes receiving adjuvant chemotherapy have shown a proportional reduction in locoregional recurrence rates of two thirds. The absolute benefit, however, varies with the magnitude of the risk in patients who do not receive radiation. The survival benefit from radiation is best explained by the prevention of an isolated locoregional recurrence, which could serve as a source of fatal distant metastases and parallels the difference in the total incidence of distant metastases. The current dilemma is to identify patients with one to three positive nodes who have had an adequate axillary dissection and remain at substantial risk for a locoregional recurrence despite adjuvant chemotherapy. The routine use of postmastectomy radiation in all axillary node-positive patients requires further evaluation.

Lung and heart dose volume analyses with CT simulator in radiation treatment of breast cancer.

PURPOSE: Radiation pneumonitis and cardiac effects are directly related to the irradiated lung and heart volumes in the treatment fields. The central lung distance (CLD) from a tangential breast radiograph is shown to be a significant indicator of ipsilateral irradiated lung volume. Retrospective analysis of the pattern of dose volume of lung and heart with actual volume data from a CT simulator in the treatment of breast cancer is presented with respect to CLD. METHODS AND MATERIALS: The heart and lung volumes in the tangential treatment fields were analyzed in 108 consecutive cases (52 left and 56 right breast) referred for CT simulation. All patients in this study were immobilized and placed on an inclined breast board in actual treatment setup. Both arms were stretched over head to avoid collision with the scanner aperture. Radiopaque marks were placed on the medial and lateral borders of the tangential fields. All patients were scanned in spiral mode with slice width and thickness of 3 mm each, respectively. The lung and heart structures as well as irradiated areas were delineated on each slice and respective volumes were accurately measured. The treatment beam parameters were recorded and the digitally reconstructed radiographs (DRRs) were generated for the measurement of the CLD and analysis. RESULTS: Using CT data the mean volume and standard deviation of left and right lungs were 1307.7+/-297.7 cm3 and 1529.6+/-298.5 cm3, respectively. The magnitude of irradiated volume in left and right lung is nearly equal for the same CLD that produces different percent irradiated volumes (PIV). The left and right PIV lungs are 8.3+/-4.7% and 6.6+/-3.7%, respectively. The PIV data have shown to correlate with CLD with second- and third-degree polynomials; however, in this study a simple straight line regression is used to provide better confidence than the higher order polynomials. The regression lines for the left and right breasts are very different based on actual CT data. The slopes of regression lines for the left and right lung are 0.6%/mm and 0.5%/mm, respectively which is statistically different with thep value of 0.01. A maximum heart PIV of >3.0% is observed in 80% of the patients. The heart PIV is inversely correlated with gantry angle and weakly correlated with CLD. CONCLUSIONS: The CT-simulator provides accurate volumetric information of the heart and lungs in the treatment fields. The lung PIV is directly correlated to the CLD (0.6%/mm and 0.5%/mm for the left and right lungs). Left and right lungs have different volumes and hence, different regression lines are recommended. An additional 12% lung volume could be irradiated in the supraclavicular field. Heart volume is not correlated with the CLD. The heart PIV is associated to the beam angle. Heart volume may not be accurately visualized in a tangential radiograph; however, this can be easily seen in a DRR with contour delineation and can be minimized with proper beam parameters iteratively with a virtual simulator. Lung and heart PIV along with dose volume histograms (DVH) are essential in reducing pulmonary and cardiac complications.

The presence of proliferative breast disease with atypia does not significantly influence outcome in early-stage invasive breast cancer treated with conservative surgery and radiation.

PURPOSE: To evaluate the influence of the benign background breast-tissue change of atypical hyperplasia (AH) on outcome in patients with early-stage invasive breast cancer treated with conservative surgery and radiation. MATERIALS AND METHODS: Four hundred and sixty women with Stage I--II breast cancer treated with conservative surgery and radiation from 1982-1994 had pathologic assessment of their background adjacent benign breast tissue. The median follow-up was 5.6 years (range 0.1-15). The median age was 55 years (range 24-88). Of these, 23% had positive axillary nodes; 25% received adjuvant chemotherapy (CMF or CAF) with (9%) or without (17%) tamoxifen. Of the total, 24% received adjuvant tamoxifen alone. The patients were divided into 2 groups: 131 patients with atypical hyperplasia (ductal, 99 patients; lobular, 20 pts; and type not specified, 12 pts), and 329 patients with no proliferative changes or proliferative changes without atypia. RESULT: A statistically significant difference was observed between the 2 groups for method of detection, primary tumor size, presence of lobular carcinoma in situ (LCIS), pathologic nodal status, region(s) treated with radiation, and type of adjuvant therapy. Patients with atypical hyperplasia (AH) had smaller primary tumors (T1 80% vs. 70%) more often detected solely by mammography (51% vs. 36%) with negative axillary nodes (87% vs. 73%) and radiation treatment to the breast only (93% vs. 78%). LCIS was observed in 9% of the patients with AH and 3% of those without AH. Patients with AH more often received tamoxifen alone (32% vs. 21%), rather than chemotherapy (15% vs. 29%). There were no statistically significant differences between the 2 groups for race, age, menopausal status, family history, histology, histologic subtype DCIS when present, the presence or absence of an extensive intraductal component, final margin status, estrogen or progesterone receptor status, use of re-excision, or total radiation dose to the primary. The 5- and 10-year actuarial ipsilateral breast tumor recurrence rates were 2% and 12% for patients with AH and 4% and 8% for those without AH (p=0.44). Younger women or those with a positive family history of breast cancer with AH did not have an increased rate of breast failure when compared to similar patients without AH. There were no significant differences in the 5- and 10-year actuarial rates of distant metastases (AH 5- and 10-year 7% and 7%, no AH 5- and 10-year 8% and 16%,p=0.31), regional node recurrence (AH 1% and 1%, no AH 1% and 1%,p=0.71), contralateral breast cancer (AH 3% and 3%, no AH 3% and 8%,p=0.71), overall survival (AH 95% and 86%, no AH 95% and 89%, p=0.79), or cause-specific survival (AH 98% and 95%, no AH 96% and 91%,p=0.27). Subset analysis for ipsilateral breast tumor recurrence, distant metastases, overall, and cause-specific survival for T1 vs. T2 tumors and path node-negative vs. path node-positive patients revealed no significant differences between the 2 groups. CONCLUSION: AH was not associated with an increased risk of ipsilateral breast tumor recurrence or contralateral breast cancer in this study of patients with invasive breast cancer treated with conservative surgery and radiation. Therefore, the presence of proliferative changes with atypia in background benign breast tissue should not be a contraindication to breast-conservation therapy.