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512 Background: Adjuvant radiotherapy (RT) is currently the standard of care for women with early-stage invasive breast cancer (BC) treated with breast conserving surgery (BCS). However, some women may have very low risk of recurrence and could safely be spared RT. This study aimed to identify these women using a molecularly-based approach. Methods: We performed an analysis of the SweBCG91-RT cohort, a trial randomizing women with node-negative stage I-II invasive BC +/- RT following breast conserving surgery, with sparse use of adjuvant systemic therapy. Only patients with ER+, HER2- tumors, and not treated with adjuvant systemic therapy, were included in this analysis. Transcriptome-wide profiling of tumors was performed using the Affymetrix Human Exon 1.0 ST microarray. The SweBCG91-RT cohort was divided into a training cohort of 243 patients and a validation cohort of 354 patients. Biological gene sets and individual genes related to locoregional recurrence in patients not receiving RT of the training set were identified, and a 16-gene signature was trained using elastic net regression. The signature, named Profile for the Omission of Local Adjuvant Radiation (POLAR), was locked prior to validation. Results: In the validation cohort, POLAR was prognostic for locoregional recurrence (LRR) in patients not treated with RT (multivariable Cox model adjusting for age, grade, tumor size, and luminal A vs luminal B: HR = 1.7 [1.2,2.3], p < 0.001). Patients categorized as POLAR low-risk had a 10-year locoregional recurrence rate of 7% in the absence of RT. Notably, there was no significant benefit from RT for these POLAR low-risk patients (HR = 1.1 [0.38,3.3], p = 0.83), whereas patients categorized as POLAR high-risk had a significant decreased risk of locoregional recurrence when treated with RT (recurrence rate without RT at 10-years 19%, HR = 0.43 [0.24,0.78], p = 0.0053). Conclusions: These data suggest that the novel POLAR genomic signature based on LRR biology can not only identify patients who have a low risk of LRR without adjuvant RT after BCS but who also would not benefit from RT, thus being prime candidates for RT omission.

Purpose Predicting the pattern of recurrence can aid in the development of targeted surveillance and treatment strategies. We identified patient populations that remain at risk for an event at a median follow-up of 24 years from the diagnosis of operable breast cancer. Patients and Methods International Breast Cancer Study Group clinical trials I to V randomly assigned 4,105 patients between 1978 and 1985. Annualized hazards were estimated for breast cancer–free interval (primary end point), disease-free survival, and overall survival. Results For the entire group, the annualized hazard of recurrence was highest during the first 5 years (10.4%), with a peak between years 1 and 2 (15.2%). During the first 5 years, patients with estrogen receptor (ER) – positive disease had a lower annualized hazard compared with those with ER-negative disease (9.9% v 11.5%; P = .01). However, beyond 5 years, patients with ER-positive disease had higher hazards (5 to 10 years: 5.4% v 3.3%; 10 to 15 years: 2.9% v 1.3%; 15 to 20 years: 2.8% v 1.2%; and 20 to 25 years: 1.3% v 1.4%; P < .001). Among patients with ER-positive disease, annualized hazards of recurrence remained elevated and fairly stable beyond 10 years, even for those with no axillary involvement (2.0%, 2.1%, and 1.1% for years 10 to 15, 15 to 20, and 20 to 25, respectively) and for those with one to three positive nodes (3.0%, 3.5%, and 1.5%, respectively). Conclusion Patients with ER-positive breast cancer maintain a significant recurrence rate during extended follow up. Strategies for follow up and treatments to prevent recurrences may be most efficiently applied and studied in patients with ER-positive disease followed for a long period of time.

546 Background: The antitumoral immune response is dynamic and changes with tumor progression. Previous studies show that immunohistochemical (IHC) assessment of TILs in local recurrences can predict prognosis. It is not clear how adjuvant radiotherapy (RT) can alter the local immune response or if gene expression analyses of TILs in recurrences can provide prognostic information. Methods: Matched biopsies from primary tumors and ipsilateral breast tumor recurrences (IBTRs) from the randomized SweBCG91RT trial were assessed for TILs. Analyses were performed using gene expression (86 matched pairs) and IHC assessment (126 matched pairs). Results: The median time to IBTR was 8.0 years among irradiated patients and 3.6 years among unirradiated patients. In the gene expression analyses, higher absolute values of CD8+ T cells, CD4+ effector memory and CD8+ effector memory T cells in the recurrence could significantly predict a decreased risk of subsequent distant metastasis. In addition, a net increase of these cells in the IBTR compared to the primary tumor was associated with a significantly lower risk of metastasis. TILs did not change significantly between the matched tumors for the whole group or among irradiated patients versus unirradiated patients in the gene expression or IHC analyses. Surprisingly, the group with unchanged TILs levels as measured by IHC had the lowest risk of metastasis while an increase or a decrease in TILs was significantly associated with an increased risk. Conclusions: Cytotoxic and memory T cells in the recurrence protect against subsequent distant metastasis although IHC measurement of TILs could not confirm these results. No significant differences in TILs infiltration between irradiated versus unirradiated patients could be determined in the recurrences. Further analyses including changes of subtypes between the primary tumor and the recurrence will be presented.

Purpose Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. Patients and Methods Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. Results There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, −3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer–specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. Conclusion Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated.

Purpose To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2–positive advanced breast cancer. Patients and Methods Patients naive to chemotherapy for advanced disease were randomly assigned to docetaxel 100 mg/m2 day 1 or vinorelbine 30 to 35 mg/m2 on days 1 and 8, both combined with trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance dose) on day 1 every 3 weeks. The primary end point was time to progression (TTP). Results A total of 143 patients were randomly allocated to docetaxel, and 141 patients were assigned to vinorelbine. The median TTP for docetaxel and vinorelbine respectively was 12.4 months versus 15.3 months (hazard ratio [HR] = 0.94; 95% CI, 0.71 to 1.25; P = .67), median overall survival was 35.7 months versus 38.8 months (HR = 1.01; 95% CI, 0.71 to 1.42; P = .98), and the 1-year survival rate was 88% in both arms. Median time to treatment failure for study chemotherapy was 5.6 months versus 7.7 months (HR = 0.50; 95% CI, 0.38 to 0.64; P < .0001). The investigator-assessed overall response rate among 241 patients with measurable disease were 59.3% in both arms. More patients in the docetaxel arm discontinued therapy due to toxicity (P < .001). Significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% v 10.1%), leucopenia (40.3% v 21.0%), infection 25.1% v 13.0%), fever (4.3% v 0%), neuropathy (30.9% v 3.6%), nail changes (7.9% v 0.7%), and edema (6.5% v 0%) were reported with docetaxel. Conclusion The study failed to demonstrate superiority of any drug in terms of efficacy, but the vinorelbine combination had significantly fewer adverse effects and should be considered as an alternative first-line option.

535Background: Some women with early stage breast cancer (BC) may not require additional systemic therapy after breast-conserving surgery (BCS). While this subgroup of ultra low-risk women has been difficult to identify with conventional clinical metrics, transcriptomic profiling may offer improved risk stratification. Previously described genomic signatures perform well on the group level, but reports indicate that there may be substantial disagreement between signatures for an individual patient. Methods: We analyzed tumors from 765 patients in the SweBCG91-RT trial, which randomized node-negative BC patients to +/- radiation following BCS, with minimal use of adjuvant systemic treatment (9%). Median follow-up was 18.6 years for breast cancer-specific survival (BCSS). The original study demonstrated a benefit from radiation on locoregional events, but not BCSS. Tumors were profiled with the Affymetrix Human Exon 1.0 ST microarray and 14 genomic signatures from literature (including Mammaprint-like, Onco...

Purpose To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT). Patients and Methods Prognostic factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT. Results No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001). Conclusion Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.

503 Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. Sensitization to reintroduction of estrogen withdrawal by letrozole was hypothesized to improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomly assigned to an additional 5 yrs continuous letrozole (2.5 mg daily; n = 2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n = 2443). The primary endpoint was DFS (randomization until invasive local, regional, distant recurrence or contralateral BC; 2nd malignancy; death). Final analysis was at 665 DFS events, after 2 interim analyses. SOLE required 4800 pts for 80% power to detect a 20% DFS hazard reduction with 2-sided α = 0.05 using a stratified log rank test. Analysis is by intention-to-treat. Results: At 60 mos median follow-up, 5 yr DFS from randomization was 85.8% vs 87.5% for patients assigned intermittent vs continuous letrozole (HR = 1.08; 95% CI 0.93-1.26; P = 0.31). Similar outcome was observed for breast cancer-free interval (HR = 0.98; 95% CI 0.81-1.19), distant recurrence-free interval (HR = 0.88; 95% CI 0.71-1.09), and overall survival (HR = 0.85; 95% CI 0.68-1.07). AEs of grade > 3 were reported for 43.5% vs 41.6% of pts assigned intermittent vs continuous letrozole. Overall 24% pts discontinued letrozole early in both groups. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. The similar observed outcomes and incidence of AEs provides clinically relevant information on the intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks. Clinical trial information: NCT00553410.

e12036 Background: Although adjuvant polychemotherapy (ACT) improves outcomes for early breast cancer (BC), the significant interpatient variability in pharmacokinetics result in differences in efficacy and both short and long term toxicities. Dose tailored ACT has been shown to improve outcomes, while tailored and dose dense therapy improved 5-year event free survival in the phase 3 PANTHER trial. Methods: The SBG 2004-1 trial was a randomized feasibility/phase II study which assessed dose tailored epirubicin and cyclophosphamide (EC) followed by docetaxel (T), compared to the same fixed dose schedule and to the TAC regimen (table 1). Women aged 18-65 years old, ECOG PS 0-1 with at least one positive lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the administered treatment. The secondary endpoint of the study was to evaluate the dose-intensity of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term safety results of the trial have been previously published. Here, we report safety and efficacy data after 10 years follow-up. Results: A total of 124 patients were included and >95% of patients without relapse were followed for 10 years.Five secondary malignancies but no myelodysplastic syndrome / acute myeloid leukemias were reported. Long term disease-free and overall survival results will be presented at the meeting. Conclusions: Long term safety results from this study in combination with efficacy results from the PANTHER trial imply the feasibility of a tailor-based approach for ACT in early BC. [Table: see text]

699 Background: At present, there are no predictive markers for different types/scheduling of cytotoxic agents. We have recently shown 5 putative biomarkers dicriminating patients with ER and PgR p...