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Background: The purpose of the current study was to evaluate the impact of radiotherapy (RT) among women aged ≥ 70 years with T1-2N0 estrogen receptor (ER)-negative breast cancer using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data., Methods: The study included 3432 women, 2850 of whom received and 582 of whom did not receive RT after breast-conserving surgery. Outcomes were estimated by the cumulative incidence method and compared with the Gray test. The Fine and Gray subdistribution hazard regression models were used to assess the impact of RT and other variables., Results: Women who received RT were more commonly aged <75 years (42% vs 16%), had T1 tumors (78% vs 65%), ductal carcinoma histology (91% vs 88%), a Charlson-Deyo Comorbidity Index of 0 (41% vs 25%), and had received chemotherapy (29% vs 12%). The 5-year cumulative incidence of mastectomy and breast cancer-specific death for patients who received versus those did not receive adjuvant RT was 4.9% and 8.3% versus 10.8% and 24.1%, respectively (P<.001). On multivariable analysis, the omission of RT was found to be an independent predictor of an increased risk of mastectomy (hazard ratio, 2.33; 95% confidence interval, 1.56-3.49). Among women aged ≥ 80 years or with T1N0 tumors, the mastectomy incidence with or without receipt of RT was 3.4% vs. 6.9%, and 5.3% vs 7.7%, respectively., Conclusions: The use of adjuvant RT after breast-conserving surgery in older women with T1-2N0 estrogen receptor-negative breast cancer is associated with a reduced incidence of future mastectomy and breast cancer death. The magnitude of benefit may be small for women aged ≥80 years or those with T1 tumors. Cancer 2016;122:3059-3068. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: The use of surgery and radiation therapy in treating ductal carcinoma in situ (DCIS) is directed by treatment guidelines and evidence from research. This study investigated recent patterns in DCIS treatment by demographic factors., Methods: Data for women diagnosed with DCIS between 1998 and 2011 (n = 416,232) in the National Cancer Data Base were assessed for trends in treatment patterns by age group, calendar year, ancestral/ethnic group, and geographic region. The likelihood of receiving specific treatment modalities was analyzed with multivariable logistic regression., Results: DCIS cases were most frequently treated with breast-conserving surgery (BCS) and adjuvant radiation (45.6%). After an initial rise, the use of adjuvant radiation after BCS plateaued at approximately 70% after 2007, with increasing utilization of mastectomy beyond 2005. In addition, there was an increasing trend in postmastectomy reconstruction over time, and women of African ancestry (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.72) and Hispanic women (OR, 0.83; 95% CI, 0.78-0.89) were less likely to undergo reconstruction in comparison with women of European ancestry. A similar trend was observed in contralateral risk-reducing mastectomy utilization, with women of European ancestry having a more rapid rise in the utilization of contralateral risk-reducing mastectomy in comparison with all other ancestral/ethnic groups., Conclusions: Recent trends demonstrate a plateau in radiation therapy administration after BCS along with increasing utilization of mastectomy, reconstruction, and contralateral risk-reducing mastectomy. There are substantial differences in treatment utilization according to ancestry/ethnicity and geographical region. Further studies examining patient-physician decision making surrounding DCIS treatment are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2810-2818. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: The benefit of adding radiation therapy after excision of ductal carcinoma in situ (DCIS) is widely debated. Randomized clinical trials are underpowered to delineate long-term outcomes after radiation., Methods: The authors of this report constructed a Markov decision model to simulate the clinical course of DCIS in a woman aged 60 years who received treatment with either of 2 breast-conserving strategies: excision alone or excision plus radiation therapy. Sensitivity analyses were used to study the influence of risk of local recurrence, likelihood of invasive disease at recurrence, surgical choice at recurrence, and patient age at diagnosis on treatment outcomes., Results: The addition of radiation therapy was associated with slight improvements in invasive disease-free and overall survival. However, radiation therapy decreased the chance of having both breasts intact over a patient's lifetime. Radiation therapy improved survival by 2.1 months for women who were diagnosed with DCIS at age 60 years but decreased the chance of having both breasts by 8.6% relative to excision alone. The differences in outcomes between the treatment strategies became smaller with increasing age at diagnosis. Sensitivity analyses revealed a greater benefit for radiation with an increased likelihood of invasive recurrence. The decrement in breast preservation with radiation therapy was mitigated by an increased likelihood of mastectomy at the time of recurrence or new breast cancer diagnosis., Conclusions: The current analysis quantified the benefits of radiation after excision of DCIS but also revealed that radiation therapy may increase the likelihood of eventual mastectomy. Therefore, the authors concluded that patient age and preferences should be considered when making the decision to add or forgo radiation for DCIS., (Copyright © 2011 American Cancer Society.)

Background: Although postmastectomy radiation therapy (PMRT) improves survival for patients with high-risk breast cancer, previous literature suggested that it is underused. The impact of recent clinical guidelines on PMRT use is unknown. Accordingly, the authors used the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort to determine whether the use of PMRT has increased in response to evidence-based guidelines., Methods: In total, 38,322 women aged ≥66 years who underwent mastectomy for invasive breast cancer between 1992 and 2005 were identified. Time trends in the receipt of PMRT for low-risk (T1/T2 N0), intermediate-risk (T1/T2 N1), and high-risk (T3/T4 and/or N2/N3) patients were characterized. Multivariate logistic regression identified risk factors for PMRT omission., Results: The receipt of PMRT by patients with high-risk breast cancer increased from 36.5% (95% confidence interval, 26%-46.9%) to 57.7% (95% confidence interval, 46.9%-68.4%) between 1996 and 1998 with the publication of landmark clinical trials. However no further increase in PMRT use was observed between 1999 and 2005 despite publication of multiple guidelines endorsing its use; during this period, only 54.8% (2729 of 4978) of high-risk patients received PMRT. Within this high-risk group, patients with smaller tumors or less advanced lymph node disease were at risk for PMRT omission., Conclusions: After an initial increase in PMRT use in response to clinical trials, the use of PMRT did not increase further in response to guideline publication, and nearly 50% of patients with high-risk breast cancer still do not receive PMRT. Additional research is needed to determine how clinical guidelines can be used to bridge the gap between level I evidence and clinical practice., (Copyright © 2011 American Cancer Society.)

Background: Recent data from Eastern Cooperative Oncology Group (ECOG) Study 5194 (E5194) prospectively defined a low-risk subset of ductal carcinoma in situ (DCIS) patients where radiation therapy was omitted after lumpectomy alone. The purpose of the study was to determine the ipsilateral breast tumor recurrence (IBTR) in DCIS patients who met the criteria of E5194 treated with lumpectomy and adjuvant whole breast radiation therapy (RT)., Methods: A total of 263 patients with DCIS were treated between 1980 and 2009 who met the enrollment criteria for E5194: 1) low to intermediate grade (LIG) with size >0.3 cm but <2.5 cm and margins >3 mm (n = 196), or 2) high grade (HG), size <1 cm and margins >3 mm (n = 67). All patients were treated with lumpectomy and whole breast RT with a boost to a median total tumor bed dose of 6400 cGy. Standard statistical analyses were performed with SAS (v. 9.2)., Results: The average follow-up time was 6.9 years. The 5-year and 7-year IBTR for the LIG cohort in this study was 1.5% and 4.4% compared with 6.1% and 10.5% in E5194, respectively. The 5-year and 7-year IBTR for the HG cohort was 2.0% and 2.0% in this study compared with 15.3% and 18% in E5194, respectively., Conclusions: Adjuvant whole breast radiation therapy reduced the rate of local recurrence by more than 70% in patients with DCIS who met the criteria of E5194 (6.1% to 1.5% in the LIG cohort and 15.3% to 2% in the HG cohort). Additional follow-up is necessary given that 70% of IBTRs occurred after 5 years., (Copyright © 2010 American Cancer Society.)

Background: The purpose of this study was to determine the ipsilateral breast tumor recurrence (IBTR) in ductal carcinoma in situ (DCIS) patients treated in the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial who met the criteria for E5194 treated with local excision and adjuvant accelerated partial breast irradiation (APBI)., Methods: A total of 194 patients with DCIS were treated between 2002 and 2004 in the Mammosite registry trial; of these, 70 patients met the enrollment criteria for E5194: 1) low to intermediate grade (LIG)-pathological size >0.3 but <2.5 cm and margins ≥3 mm (n = 41) or 2) high grade (HG)-pathological size <1 cm and margins ≥3 mm (n = 29). All patients were treated with lumpectomy followed by adjuvant APBI using MammoSite. Median follow-up was 52.7 months (range, 0-88.4). SAS (version 8.2) was used for statistical analysis., Results: In the LIG cohort, the 5-year IBTR was 0%, compared with 6.1% at 5 years in E5194. In the HG cohort, the 5-year IBTR was 5.3%, compared with 15.3% at 5 years in E5194. The overall 5-year IBTR was 2%, and there were no cases of elsewhere or regional failures in the entire cohort. The 5-year contralateral breast event rate was 0% and 5.6% in LIG and HG patients, respectively (compared with 3.5% and 4.2%, respectively, in E5194)., Conclusions: This study found that patients who met the criteria of E5194 treated with APBI had extremely low rates of recurrence (0% vs 6.1% in the LIG cohort and 5.3% vs 15.3% in the HG cohort)., (Copyright © 2010 American Cancer Society.)

Background: Boost radiotherapy (RT) improves outcomes for patients with invasive breast cancer, but whether this is applicable to patients with pure ductal carcinoma in situ (DCIS) is unclear. This study examined outcomes from whole breast RT, with or without a boost, and the impact of different dose-fractionation schedules in a population-based cohort of women with pure DCIS treated with breast-conserving surgery (BCS)., Methods: Data was analyzed for 957 subjects diagnosed between 1985 and 1999. RT use was analyzed over time. Ten-year Kaplan-Meier local control (LC), breast cancer specific survival (BCSS), and overall survival (OS) were compared using the log-rank test. Cox regression modeling of LC was performed., Results: Median follow-up was 9.3 years. Of the patient cohort 475 (50%) had no RT (NoRT) after BCS, 338 (35%) had RT without a partial breast boost (RTNoB), and 144 (15%) had RT with boost (RT + B). Subjects with risk factors of local recurrence were more likely to receive RT. Subjects receiving adjuvant RT had a trend toward improved LC (15-year LC: NoRT 87%; RTNoB 94%; RT + B 91%; P = .065). Multivariable analysis showed that RT with or without a boost was significantly associated with improved LC (HR, 0.29 and 0.38, respectively, compared with NoRT, P = .025), with no difference associated with a boost or different dose-fractionation schedules., Conclusions: Adjuvant RT improves local control in patients with DCIS treated with BCS. Hypofractionation is as effective as standard fractionation schedules. Boost RT was not associated with improved LC compared with whole breast RT alone. Cancer 2011. © 2010 American Cancer Society., (Copyright © 2010 American Cancer Society.)

Background: The study aimed to identify factors associated with less-than-optimal radiotherapy (RT) and its impact on disease-free survival in women aged 66+ years diagnosed with stage I breast cancer or ductal carcinoma in situ (DCIS)., Methods: The subjects were women diagnosed from 1991 to 1999 in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database who underwent breast-conserving surgery and RT within 12 months postdiagnosis. The authors conducted descriptive and multivariate survival analyses, and considered age, race, poverty, marital status, comorbidity indices, rural/urban, radiation oncologist density, comedo necrosis histology (DCIS only), chemotherapy receipt (stage I only), and RT completion (3+ weeks of treatment) and delay (8+ weeks postsurgery without chemotherapy; 4+ weeks postchemotherapy)., Results: Of 7791 subjects, 16% experienced RT delay, and 3% had incomplete RT. Subjects with stage I disease who were more likely to delay RT were of black race (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.17-2.08), whereas women in areas of high radiation oncologist density were less likely to delay (OR, 0.73; 95% CI, 0.66-0.81). Those living in high poverty areas were less likely to complete RT (P < .03), as were those undergoing chemotherapy (OR, 1.82; 95% CI, 1.15-2.88). Stage I breast cancer patients with delayed RT were more likely to experience a subsequent breast event (OR, 1.14; 95% CI, 1.00-1.30), and those with incomplete RT had a higher rate of overall mortality (OR, 1.32; 95% CI, 1.06-1.63). Factors associated with lower subsequent breast events included older age, lower poverty, and being married. RT delays of 12+ weeks (or 8+ weeks postchemotherapy) had a strongly negative impact on subsequent events (OR, 3.94; 95% CI, 2.51-6.17 for DCIS; OR, 2.77; 95% CI, 1.84-2.59 for stage I)., Conclusions: RT should be facilitated to ensure completion and timeliness, especially for early invasive breast cancer patients., ((c) 2008 American Cancer Society)

Background: A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer., Methods: Twenty-five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m(2)/day, Days 1-5) and vinorelbine (6-mg/m(2) bolus on Day 1 and 6 mg/m(2)/day continuous infusion on Days 1-5) chemotherapy combined with concurrent 30-gray fractionated external-beam radiotherapy. Chemotherapy was given at 3-week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases., Results: Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression-free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3-4 events were noted in 5 (20%) patients, and there were no toxic deaths., Conclusions: Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated.

Background: In this retrospective study, the authors hypothesized that magnetic resonance imaging (MRI) would alter partial breast irradiation (PBI) eligibility by identifying cancers outside the PBI volume compared with mammography alone., Methods: Since 2002, MRI was used nonselectively at the authors' institution for the staging of patients with nonmetastatic breast cancer. Of 450 consecutive patients with invasive breast cancer, 110 patients who were eligible for PBI were identified by using criteria outlined by National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Oncology Group trial 0413 based on mammography, ultrasonography, and initial pathology. In that trial, patients were randomized (stage I/II invasive cancers that measured

Background: The role of postmastectomy radiotherapy (PMRT) for lymph node-negative locally advanced breast carcinoma (T3N0M0) after modified radical mastectomy (MRM) with regard to improvement in survival remains an area of controversy., Methods: The 1973-2004 National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database was examined for patients with T3N0M0 ductal, lobular, or mixed ductal and lobular carcinoma of the breast who underwent MRM, treated from 1988-2003. Patients who were men, who had positive lymph nodes, who survived < or =6 months, for whom breast cancer was not the first malignancy, who had nonbeam radiation, intraoperative or preoperative radiation were excluded. The average treatment effect of PMRT on mortality was estimated with a propensity score case-matched analysis., Results: In all, 1777 patients were identified; 568 (32%) patients received PMRT. Median tumor size was 6.3 cm. The median number of lymph nodes examined was 14 (range, 1-49). Propensity score matched case-control analysis showed no improvement in overall survival with the delivery of PMRT in this group. Older patients, patients with ER- disease (compared with ER+), and patients with high-grade tumors (compared with well differentiated) had increased mortality., Conclusions: The use of PMRT for T3N0M0 breast carcinoma after MRM is not associated with an increase in overall survival. It was not possible to analyze local control in this study given the limitations of the SEER database. The impact of potential improvement in local control as it relates to overall survival should be the subject of further investigation., ((Copyright) 2008 American Cancer Society.)

Background: Hypothyroidism is a potential complication after radiation therapy (RT) when treatment fields include the thyroid. The authors assessed risk of hypothyroidism in breast cancer patients who were receiving RT to a supraclavicular field, which typically includes a portion of thyroid., Methods: The authors identified 38,255 women (aged>65) without history of hypothyroidism from the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort diagnosed with stage 0-III breast cancer from 1992-2002 and 111,944 cancer-free controls. The authors compared hypothyroidism incidence among irradiated patients with 4+positive lymph nodes (4+LN, surrogate for supraclavicular RT) and no positive nodes (0 LN, surrogate for no supraclavicular RT), nonirradiated patients, and controls. Proportional hazards models tested associations of LN, RT, and breast cancer status with hypothyroidism., Results: The 5-year incidence of hypothyroidism was identical (14%) in irradiated patients with 4+LN, 0 LN, and nonirradiated patients (P=.52). After adjusting for sociodemographic and clinical characteristics, hypothyroidism risk was not increased in irradiated patients with 4+LN versus 0 LN (hazard ratio(HR)=1.04; 95% confidence interval (CI), 0.89-1.23). However, all patients, regardless of RT status, were more likely to be diagnosed with hypothyroidism compared with cancer-free controls (HR=1.21; 95% CI, 1.17-1.25)., Conclusions: Development of hypothyroidism is fairly common in older breast cancer survivors. Although supraclavicular irradiation does not appear to amplify risks, further studies on the role of routine thyroid function monitoring in all breast cancer patients regardless of treatment status may be warranted, given the excess risks compared with the general population., (Copyright (c) 2008 American Cancer Society.)

Background: There still is debate as to whether breast carcinoma patients with isolated supraclavicular recurrence should be considered to be patients with disseminated disease or patients for whom aggressive treatment with curative intent is justified., Methods: In the period 1984-1994, 4669 patients with invasive breast carcinoma underwent axillary dissection in 1 of 8 community hospitals in the southeastern part of the Netherlands. During follow-up, 42 patients with isolated supraclavicular recurrence, without other sites of distant disease, were identified., Results: The median interval between treatment of the primary tumor and diagnosis of the supraclavicular recurrence was 2.5 years (range, 0.2-11.5 years). Radiotherapy was administered to 25 patients (60%), 5 of whom also underwent surgery and 16 of whom also received chemotherapy or hormonal therapy. Eleven patients received hormonal therapy only, and four received chemotherapy only. One patient received surgical treatment only, and one patient remained untreated. Complete remission was achieved in 35 patients (83%), but a second supraclavicular recurrence occurred in 12 (34% of patients who achieved complete remission). Overall, 6 patients (14%) were alive without evidence of disease after a follow-up period of 4.4-8.3 years. The 5-year actuarial overall survival and distant disease-free survival rates, based on the date of diagnosis of supraclavicular recurrence, were 38% (95% confidence interval [CI], 23-53%) and 22% (95% CI, 8-35%), respectively. The distant disease-free survival rate was somewhat better for the 25 patients who underwent radiotherapy as part of the treatment for supraclavicular recurrence than it was for the 17 patients who did not receive radiotherapy (P = 0.06); the difference became more pronounced after the exclusion of 8 patients who had received axillary and supraclavicular radiotherapy as part of treatment for the primary tumor (P = 0.002)., Conclusions: Although complete remission can be obtained in most patients with isolated supraclavicular recurrence, the prognosis for these patients is poor. Involved field radiotherapy appears to play an important role in the treatment of supraclavicular recurrence and may improve the distant recurrence-free survival rate., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11469)

Background: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of radiation therapy directed at the tumor bed., Methods: From 1982 to 1994, 498 women with 509 Stage I/II breast carcinomas with a median follow-up of 121 months were treated. Final margin status (FMS) categories were defined as greater than 5 mm, greater than 2-5 mm, greater than 0-2 mm, and positive. For margins less than or equal to 2 mm or indeterminate, reexcisions were performed if feasible. All patients received whole breast irradiation to 50.0-50.4 Gy. Final tumor bed boosts as a function of FMS were as follows: no residual on reexcision, no boost performed; FMS greater than 5 mm, boost of 10 Gy; FMS greater than 2-5 mm, boost of 14 Gy; FMS greater than 0-2 mm or positive, boost of 20 Gy. Cases were analyzed for local failure with respect to histology, age, tumor size, excision volume, reexcision, and total dose., Results: FMS was positive, greater than 0-2 mm, greater than 2-5 mm, and greater than 5 mm, and no residual tumor on reexcision in 21%, 20%, 17%, 14%, and 28% of cases, respectively. At 12 years, Kaplan-Meier local failure rates were 17% for FMS positive, 9% for FMS greater than 0-2 mm, 5% for FMS greater than 2-5 mm, 0% for FMS greater than 5 mm, and 6% for specimens without evidence of residuum on reexcision (P = 0.009). Patients 45 years old and younger had a 12-year local failure rate of 15% whereas patients older than 45 years had a 12-year local failure rate of 6% (P = 0.01). On multivariate analysis, young age (P = 0.03) predicted increased local failure rate, whereas margins that were less than or equal to 2 mm or positive predicted late (> 5 years) but not early (< or = 5 years) recurrence (P = 0.003)., Conclusions: Graded tumor bed dose escalation in response to FMS results in very low rates of local failure over the first 5 years for all FMS categories. However, tumors with close/positive margins have significantly increased local failure rates after 5 years of follow-up even with increased radiation boost dose. In addition, graded tumor bed dose escalation does not fully overcome the adverse influence of young age., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.10981)

Background: Tumor characteristics are strong predictors of survival among women with breast carcinoma, yet the variability in prognosis among women presenting with similar stages suggests other factors may also play an important role. We examine the prognostic significance of etiologic risk factors for breast carcinoma to determine whether factors that influence the development of breast carcinoma also affect the course of the disease among a prospective cohort of young women with bilateral breast carcinoma., Methods: The 369 U.S. women included in this study were from the Cancer and Steroid Hormone Study who were diagnosed with an invasive first primary breast carcinoma between 1980 and 1982 and a second primary breast carcinoma before 1999. Cox proportional hazards models were used to evaluate factors known and suspected to be associated with breast carcinoma and with survival, based on reporting at the time of the first primary., Results: One hundred sixty women died during the 16-18-year follow-up period. The adjusted 1, 5, 10, and 15-year survival rates following diagnosis of second primary breast carcinoma were 94%, 70%, 55%, and 49%, respectively. Survival rates werepoorest among the youngest women, those diagnosed with a second primary within 5 years of their first, poor African American women, women with either primary diagnosed at a later stage, those with less than 12 years of school, single women, and those with major weight gain between age 18 and adulthood., Conclusions: This study provided little evidence that important etiologic factors for breast carcinoma predict mortality following diagnosis of a second primary breast carcinoma., (Copyright 2002 American Cancer Society.)

Background: To distinguish true local recurrences (TR) from new primary tumors (NP) and to assess whether this distinction has prognostic value in patients who develop ipsilateral breast tumor recurrences (IBTR) after breast-conserving surgery and radiotherapy., Methods: Between 1970 and 1994, 1339 patients underwent breast-conserving surgery at The University of Texas M. D. Anderson Cancer Center for ductal carcinoma in situ or invasive carcinoma. Of these patients, 139 (10.4%) had an IBTR as the first site of failure. For the 126 patients with clinical data available for retrospective review, we classified the IBTR as a TR if it was located within 3 cm of the primary tumor bed and was of the same histologic subtype. All other IBTRs were designated NP., Results: Of the 126 patients, 48 (38%) patients were classified as NP and 78 (62%) as TR. Mean time to disease recurrence was 7.3 years for NP versus 5.6 years for TR (P = 0.0669). The patients with NP had improved 10-year rates of overall survival (NP 77% vs. TR 46%, P = 0.0002), cause-specific survival (NP 83% vs. TR 49%, P = 0.0001), and distant disease-free survival (NP 77% vs. TR 26%, P < 0.0001). Patients with NP more often developed contralateral breast carcinoma (10-year rate: NP 29% vs. TR 8%, P = 0.0043), but were less likely to develop a second local recurrence after salvage treatment of the first IBTR (NP 2% vs. TR 18%, P = 0.008)., Conclusions: Patients with NP had significantly better survival rates than those with TR, but were more likely to develop contralateral breast carcinoma. Distinguishing new breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies. This is because patients with new carcinomas had significantly lower rates of metastasis than those with local disease recurrence, but were more likely to develop contralateral breast carcinomas., (Copyright 2002 American Cancer Society.)

Background: The objective of the current study was to evaluate the effectiveness and morbidity of primary axillary radiotherapy in breast-conserving therapy for postmenopausal, clinically axillary lymph node negative patients with early stage breast carcinoma., Methods: Between 1983-1997, 105 patients with clinically negative axillary lymph nodes and breast carcinoma were treated with wide local excision followed by radiotherapy to the breast, and axillary and supraclavicular lymph node areas. Adjuvant treatment with tamoxifen was given to 75 patients. The median follow-up of patients still alive was 41 months (range, 8-137 months). Fifty-five patients with no evidence of disease at last follow-up were examined prospectively with respect to late functional damage., Results: The mean age of the patients was 64 years. Three patients developed a local recurrence. No isolated axillary lymph node recurrence was observed. In two patients, axillary recurrence was accompanied by distant metastases. The 5-year disease free interval and the overall survival were 82% (standard error [SE], 6%) and 83% (SE, 6%), respectively. In five patients, arm edema was reported and impaired shoulder function was reported in seven patients. Prospectively scored, arm edema was reported subjectively by the patient in 4% and objectively measured in 11% of cases. Impaired shoulder function was reported subjectively in 35% and objectively measured in 17% of cases. No brachial plexus neuropathy was noted., Conclusions: Primary axillary radiotherapy for postmenopausal women with clinically lymph node negative, early stage breast carcinoma was found to result in low axillary lymph node recurrence rates with only limited late complications. Therefore, primary axillary radiotherapy should be considered as axillary treatment in selected patients as an alternative to axillary lymph node dissection., (Copyright 2000 American Cancer Society.)

Background: When found in an otherwise benign biopsy, lobular carcinoma in situ (LCIS) has been associated with an increased risk of development of a subsequent invasive breast carcinoma. However, the association between LCIS and the risk of subsequent local recurrence in patients with infiltrating carcinoma treated with conservative surgery and radiation therapy has received relatively little attention., Methods: Between 1968 and 1986, 1625 patients with clinical Stage I-II invasive breast carcinoma were treated at the Joint Center for Radiation Therapy at Harvard Medical School with breast-conserving surgery (CS) and radiation therapy (RT) to a total dose to the primary site of > or =60 grays. Analysis was limited to 1181 patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, or infiltrating carcinoma with mixed ductal and lobular features who, on review of their histologic slides, had sufficient normal tissue adjacent to the tumor to evaluate for the presence of LCIS and also had a minimum potential follow-up time of 8 years. The median follow-up time was 161 months., Results: One hundred thirty-seven patients (12%) had LCIS either within the tumor or in the macroscopically normal adjacent tissue. The 8-year crude risk of recurrence was not significantly increased for patients with LCIS associated with invasive ductal, invasive lobular, or mixed ductal and lobular carcinoma. Among the 119 patients with associated LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%, compared with 12% for the 1062 patients without associated LCIS. For the 70 patients with moderate or marked LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%. The extent of LCIS did not affect the risk of recurrence. The risks of contralateral disease and of distant failure were similarly not affected by the presence or extent of LCIS., Conclusions: Breast-conserving therapy involving limited surgery and radiation therapy is an appropriate method of treating patients with invasive breast carcinoma with or without associated LCIS. Neither the presence nor the extent of LCIS should influence management decisions regarding patients with invasive breast carcinoma. [See editorial counterpoint and reply to counterpoint on pages 978-81 and 982-3, this issue.], (Copyright 2000 American Cancer Society.)

Background: Although in recent years there has been a dramatic increase in both the incidence of ductal carcinoma in situ (DCIS) and breast-conserving therapy for patients who have this disease, the optimal treatment for these patients remains controversial. Most data regarding outcomes have come from small, retrospective studies, with little data published from prospective, randomized studies. This study investigates the effects of age, postoperative breast irradiation, and other factors on local relapse free survival after breast-conserving surgery for women with DCIS in a large, single-institution series., Methods: A review was performed of all patients with DCIS who underwent breast-conserving surgery at Memorial Sloan-Kettering Cancer Center from 1978 through 1990. Of the 171 cases identified, data on follow-up and radiation therapy were available for 157. All available pathology slides (132 of 157) were rereviewed to determine histologic subtype, nuclear grade, presence of necrosis, and microscopic tumor size. Sixty-five patients (41%) received postoperative radiation therapy; selection criteria evolved over the time period. The median follow-up was 74 months., Results: Factors that were significantly (P< or =0.05) associated with a lower recurrence rate were older age, noncomedo subtype, lower nuclear grade, negative margins, and postoperative radiation therapy. The 6-year actuarial recurrence rate was 9.6% for patients who received postoperative radiation therapy and 20.7% for patients who had excision only (P = 0.05). Comparison of patients of ages > or =70, 40-69, and <40 years revealed a significantly lower risk of recurrence with increasing age. Actuarial 6-year local relapse rates were 10.8%, 14.0%, and 47.2%, respectively (P = 0.047). A benefit from radiation therapy was suggested for each age group. There was no statistically significant correlation between age group and any histologic factor examined. In multivariate analysis, only margin status was statistically significant (P = 0.05)., Conclusions: In addition to margin status, pathologic factors, and the use of radiation therapy, age is another factor that should be considered in assessing the risk of local recurrence after breast-conserving surgery for patients with DCIS., (Copyright 1999 American Cancer Society.)

Background: Although histologic grade has previously been described as a predictor of distant failure, it is uncertain whether histologic grade should be used to decide which patients should undergo axillary lymph node dissection and whether grade should be considered as a selection factor for breast-conserving therapy., Methods: The authors retrospectively analyzed data from 1081 patients with American Joint Committee on Cancer Stage I or II infiltrating ductal carcinoma treated with breast-conserving therapy at the Joint Center for Radiation Therapy between 1970 and 1986. All patients had pathology slides reviewed by one of two study pathologists. Using the Elston modification of the Bloom-Richardson grading system, patients were divided by histologic grade into 3 groups (219 with Grade I, 482 with Grade II, and 380 with Grade III). The median follow-up time for 716 survivors was 134 months. The incidence of various pathologic features was examined with respect to histologic grade. In addition, the 10-year crude rates of failure (by first site) were examined as they related to grade. A polychotomous logistic regression model was used to determine the effect of grade on local and distant failure., Results: High grade tumors tended to be larger, to exhibit more mononuclear cellular reaction and necrosis, and were more likely to be estrogen receptor negative. Patients with high grade tumors were also younger than those with lower grade tumors. The incidence of an extensive intraductal component and lymphatic vessel invasion did not vary significantly by histologic grade. The incidence of pathologic lymph node metastases also did not vary by grade, even when stratified by tumor size. In both univariable and multivariable analyses, the 10-year crude rate of local recurrence was not related to histologic grade (P = 0.44). Distant recurrence rates, however, were significantly higher as grade increased (p = 0.002)., Conclusions: Higher histologic grade predicted an increased incidence of distant recurrence, but not a greater likelihood of axillary lymph node metastases or local recurrence after breast-conserving therapy. The authors conclude that grade should not be used to make decisions regarding local management.

Background: There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process., Methods: The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point., Results: There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years., Conclusions: DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy.

Background: Breast conservation is now established treatment for patients with small breast cancers. The authors reviewed a large series of patients with long term follow-up who underwent conservative treatment. Clinical and pathologic factors were analyzed to identify patients at an increased risk of relapse in the breast (local relapse) or development of a contralateral tumor., Methods: Seven hundred fifty-seven patients with unilateral invasive breast cancer (T0-2, N0-1, M0) were treated conservatively (wide local excision and radiotherapy) at the Institut Gustave-Roussy between 1970 and 1982. The median follow-up was 9 years. The risk of local relapse or development of a contralateral tumor (as first event) was studied by univariate analysis for the main clinical, pathologic, and treatment factors. Those found to be significant were entered into a Cox proportional regression analysis., Results: Fifty-one patients relapsed in the treated breast (actuarial local relapse rates at 5 and 10 years were 5% and 8%, respectively) and 34 in the contralateral breast (actuarial contralateral tumor rates at 5 and 10 years were 3% and 6%, respectively). Multivariate analysis of the risk factors for local relapse showed that only age younger than 40 years (P < 0.02) or inadequate surgical excisioin (P < 0.02) were significant. No particular risk factors for contralateral tumor development were identified., Conclusions: Overall, for most patients, the risk of local relapse or of developing a contralateral tumor was low. A small number of young patients with inadequately excised tumors are at higher risk of local relapse, need more meticulous surgery, and may merit higher dose radiotherapy.

Background: Patients with inflammatory breast cancer have a high risk of developing a local recurrence and/or distant metastases. Treatment with combined chemotherapy and locoregional radiotherapy contributes to a decrease in both risks. This study presents treatment results and evaluates the pattern of failure when an alternating chemoradiotherapy schedule is used., Methods: One hundred twenty-five patients with nonmetastatic inflammatory breast cancer were treated with an alternating schedule of radiotherapy and chemotherapy. All women recruited were younger than 70 years of age and had a T4d, histologically proven infiltrating carcinoma with N0 to N2 axillary disease. The protocol consisted of three cycles of induction chemotherapy with doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil followed by three series of locoregional radiotherapy, delivering a total dose of 65-75 Gy to the breast tumor. Five additional cycles of chemotherapy with 5-fluorouracil/doxorubicin/cyclophosphamide were to be administered in between the first two and after the third radiotherapy course. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy., Results: Toxicity was moderate and this strategy proved feasible although most of the patients only received six instead of the eight planned cycles of chemotherapy. Eighty-two percent of the patients achieved a complete response at the end of the treatment. The cumulative 5-year local failure and distant metastasis rates were 27% and 53%, respectively. Assuming competing events, local failures, contralateral recurrences, and distant metastases were the first site of failure in 18%, 5%, and 38% of patients, respectively. The 5-year overall and disease free survival rates were 50% and 38%, respectively. The main prognostic factor was tumor size., Conclusions: Alternating high doses of radiotherapy and chemotherapy is a feasible treatment schedule and permits breast conservation. Disease free survival is comparable to that of recently published series. As the main causes of failure are distant metastases, higher dose chemotherapy should be evaluated, in an attempt to further improve overall survival.

Background: One thousand seventy patients treated conservatively for Stages I and II breast cancer between the years 1982 and 1994 were reviewed. The median follow-up was 40 months with a maximum follow-up of 152 months., Methods: All patients had a wide local excision and lower lymph axillary node dissection followed by radiation therapy. The entire breast received an external beam dose of 4500 cGy at 180 cGy/5 days/week. An additional boost dose of 2000 cGy to the tumor bed was given at the time of lumpectomy (perioperative) with an Ir-192 implant or with electron beam therapy after the external beam therapy., Results: The 5- and 10-year disease specific survival results were 97 and 90%, respectively for Stage I and 87 and 69% for patients with Stage II disease. The 5- and 10-year local control rates were 93 and 85% for Stage I and 92 and 87% for Stage II, respectively. The risk factors for local failure were premenopausal status and estrogen receptor-negative status at the univariate level but at the multivariate level the premenopausal and margins status were significant., Conclusion: These 10-year results were at least equivalent to reported series of similarly staged patients treated by mastectomy. This should encourage more surgeons to offer conservative treatment as an alternative to mastectomy to patients with Stage I and II breast cancer.

Background: Controversy exists concerning the natural history of ductal carcinoma in situ (DCIS) of the breast, including its pathologic expression and treatment. This controversy has been fostered largely by the retrospective nature and limited sample sizes of extant studies., Method: Resolution of some of these issues was attempted by analyzing the pathologic features of 573 examples of DCIS obtained from a larger cohort of 790 women with DCIS enrolled in Protocol B-17 of the National Surgical Adjuvant Breast Project. This prospective randomized clinical trial was performed to assess the efficacy of local breast irradiation to reduce the incidence of second ipsilateral breast tumors (IBT) after lumpectomy., Results: Tumor and patient characteristics, including significantly less IBT for those treated by lumpectomy and irradiation than lumpectomy alone, were almost identical for the subset comprising this analysis and the total B-17 cohort reported previously. The presence of moderate/marked comedo necrosis, which was evaluated as an independent parameter rather than as a specific histologic type of DCIS and uncertain/involved lumpectomy margins were the only statistically significant independent predictors of IBT for patients treated by lumpectomy as well as irradiation. The latter markedly reduced the annual hazard rates for the IBT associated with these indicators., Conclusions: Although not an endpoint of this study, the authors' findings suggest that the beneficial effect of irradiation in reducing IBT after lumpectomy for DCIS occurs with small (< 1.0 cm.) and larger lesions. Moderate/marked comedo necrosis and uncertain/involved lumpectomy margins represent independent predictors of IBT.

Background: The relationships among the involvement of tumor at the final margins of resection, the presence of an extensive intraductal component (EIC), and the risk of local recurrence are important considerations in patients treated with conservative surgery and radiation therapy for early stage breast cancer but have not been defined adequately., Methods: Between 1982 and 1985, 885 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 181 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A positive margin was defined as tumor present at the inked margin of resection, a close margin as tumor within 1 mm of the inked margin, and a negative margin as no tumor within 1 mm of the inked margin. A focally positive margin was defined as tumor at the margin in three or fewer low-power fields. In 157 patients (87%), the tumor was evaluable for the presence or absence of an EIC. The median follow-up was 86 months., Results: In 12 of 181 patients (7%), a recurrence developed at or near the primary site (true recurrence/marginal miss [TR/MM]) within 5 years. The 5-year rate of TR/MM (with 95% confidence intervals) among patients with negative, close, focally positive, and more than focally positive margins was 0% (0-4%), 4% (0-20%), 6% (1-17%) and 21% (10-37%), respectively. Patients with positive margins also were more likely to have a distant failure within 5 years (14%, 8%, 25%, and 32% in the four groups, respectively). However, patients with positive margins more often had positive axillary lymph nodes than patients with negative or close margins (59% vs. 38%, P < 0.02). The 5-year rate of TR/MM was 20% for patients with an EIC-positive tumor and 7% for patients with an EIC-negative tumor. However, among the 127 patients with an EIC-negative tumor, the 5-year rate of TR/MM was less than 10% in all margin groups. Among the 30 patients with an EIC-positive tumor, the 5-year rate of TR/MM was 0% when margins were negative or close but 50% when margins were more than focally positive., Conclusions: These results provide support for the use of breast-conserving surgery and breast irradiation in all patients with uninvolved margins, whether the tumor is EIC-positive or EIC-negative. This study suggests that breast-conserving therapy (including a radiation boost to the primary site) also may be a reasonable option for some patients with an EIC-negative tumor and margin involvement.

Background: The traditional surgical treatment for operable breast carcinoma larger than 3 cm is mastectomy. To avoid mutilating surgery, the authors administered primary chemotherapy to 158 patients with operable nonmetastatic large breast carcinoma with a TNM classification of T2 greater than 3 cm and T3 with a lymph node status of N0-N1. Conservative treatment was proposed for patients responding to the chemotherapy and whose tumor was reduced to 3 cm or less. The purpose of the study was to evaluate the feasibility and treatment results of this strategy., Methods: The mean patient age was 50.4 years. Eighty-two patients had T2 carcinomas greater than 3 cm, and 76 had T3 carcinoma. Fifty-four tumors were classified as lymph node status N0, and 104 as N1. Mean tumor size was 5.6 cm. Patients were treated with three courses of the NVCF regimen (mitoxantrone, vindesin, cyclophosphamide, and 5-fluorouracil) or the EVCF regimen, in which mitoxantrone was replaced by epirubicin every 4 weeks, and then administered with a radiosurgical combination., Results: The overall response rate to induction chemotherapy was 60.8% with 20.2% complete tumor regression. Twenty-one percent of the patients experienced grade 3 or 4 chemotherapy toxic effects, which were all acceptable and reversible. Breast-conserving treatment was feasible in 48.7% of patients (77 of 158). Forty-five patients (28.5%) were treated with a radiosurgical combination (tumorectomy plus radiation therapy), whereas 32 (20.2%) were treated with radiotherapy alone (external irradiation and brachytherapy). Other patients were treated with mastectomy. Age, tumor stage, histology, hormonal status, and hormonal receptor rate had no influence on the frequency of the observed regressions. Isolated recurrences occurred in 11 patients, 6 who were treated conservatively and 5 who were treated with mastectomy. Metastatic relapses were observed in 38 patients (14.6% in the chemotherapy responders and 38.7% in the nonresponders) (P < 0.02). Five-year actuarial survival was 73.2% and was significantly higher for responders to the induction treatment., Conclusion: These preliminary results suggest that primary chemotherapy and radiosurgical breast-conserving treatment is feasible and is an alternative to mastectomy for patients with large operable breast carcinoma who are responders to the induction treatment. The long term benefit of this strategy must be evaluated in well designed controlled trials.

Background: Needle-guided breast biopsy has become a regularly recommended procedure to excise nonpalpable, questionable breast lesions detected by mammography. Whether cancers detected in this manner have a more favorable outcome than those detected by clinical examination is not clearly documented., Methods: To address questions about the biology of mammographically detected cancer and likelihood of axillary node metastasis, as well as the accuracy of screening mammography, data from 3752 needle-guided breast biopsies and 1175 nonpalpable breast cancers were reviewed., Results: Between 1974 and 1992, 3752 needle-guided biopsies were performed in 3441 women for nonpalpable breast lesions. Benign disease was disclosed in 2575 (68.7%) biopsies and malignancy in 1175 (31.3%). Of 1130 malignancies, 61.8% were invasive carcinomas; 4.8% were microinvasive ductal carcinomas; 28.5% were ductal carcinomas in situ; and 4.8% were lobular carcinomas in situ. Axillary dissection in 558 patients with invasive carcinoma revealed that 27.1% had at least one positive axillary node. Of patients with invasive cancers presenting as nonpalpable calcifications alone, 27.5% had at least one positive axillary node., Conclusions: More than one fourth of patients with nonpalpable, invasive cancer in this series had axillary node metastasis. Therefore, axillary dissection is an important treatment consideration for all patients with invasive carcinoma, despite technique of detection. Ductal carcinomas in situ detected as limited calcifications do not require axillary dissection. In this study, 31% of biopsies proved the presence of malignancy, an acceptable and appropriate benign-to-malignant ratio.