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Objective: Recent data in select pre-clinical models suggest that radiation can activate normal stroma to promote tumor metastases and aggressiveness. We hypothesized that if these were occurring clinically, there would be a lower survival after locoregional recurrence (LRR) in patients after post-mastectomy radiation therapy (PMRT) compared to mastectomy (Mx) alone. This study used two independent datasets to compare survival after LRR in women treated with versus without PMRT.Methods: Data from 229 of 1,505 patients who experienced LRR after treatment on sequential non-randomized institutional prospective trials at the MD Anderson Cancer Center (MDA) and 66 of 318 patients enrolled in the British Columbia (BC) PMRT randomized trial who experienced LRR were analyzed. All patients underwent Mx and level I/II axillary dissection. In both data sets analysis was based on treatment received. Patients from MDA received doxorubicin based chemotherapy +/- PMRT, with 45 LRR after PMRT and 184 LRR after Mx alone). Patients treated on the BC trial received CMF chemotherapy +/- PMRT, with LRR in 14/160 after PMRT versus 52/158 after Mx alone. Survival was calculated from time of LRR to death using Kaplan-Meier and log rank statistics.Results:MDA Data: Median follow up of living patients was 192 months. Analyzing data from all patients with LRR regardless of distant metastasis (DM), patients with LRR after PMRT were younger (47 vs. 51 y, p = 0.033) and had shorter time to first LRR (40mo vs. 51 mo, p = 0.018). 5-yr/10-yr OS were 31%/16% without PMRT and 20%/7% after PMRT (p = 0.008). However, PMRT-treated patients had increased risk factors for DM (advanced T and N stage) and more PMRT-treated patients developed DM prior to LRR (58% vs. 36% p = 0.009). Analyzing only patients without DM there was no difference in OS between groups (p = 0.67), and a separate analysis of all patients who developed metastatic disease (N = 385 no PMRT, 233 after PMRT) revealed no difference in 5 or 10-yr OS after DR (15%/4% without PMRT vs. 13%/6% after PMRT, p = 0.5).BC Data: Median follow up of living patients was 235 months. The distributions of age, T stage, N stage, grade, LVI, ER status, excised nodes and nodal ratio were similar between patients with LRR after Mx alone vs. Mx plus PMRT. (all p > 0.05). The mean time to first LRR was 39 mo in patients treated with Mx alone and 57 mo in patients treated with PMRT, p= 0.27). The rate of DM was similar in patients with LRR after Mx with vs without PMRT (93% vs. 96%, p=0.60). Distant relapse free survival after LRR was similar in Mx alone vs. PMRT-treated patients (log rank p=0.75). Overall survival was also similar in the two groups (5-yr/10-yr OS 21%/8% without PMRT vs. 23%/12% with PMRT, log rank p=0.93).Conclusions: Decades of randomized data have demonstrated that PMRT reduces LRR and improves overall survival. In the non-randomized dataset, removing the competing risk of DM which is higher in patients selected for PMRT by studying patients with isolated LRR, we find no difference in survival after LRR in the PMRT setting. Analysis of the randomized PMRT trial dataset confirmed the finding of similar survival among women with LRR irrespective of PMRT use. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4101.

e20674 Background: Adjuvant anastrozole (aA) is associated with arthralgias/myalgias (A/M), bone density loss, and hot flushes. Analgesics offer limited relief of musculoskeletal (MSK) symptoms and are associated with side effects of their own. The benefit of exercise on bone health, muscle strength, hot flushes, and quality of life (QOL) has been demonstrated; the objective of this trial is to determine if an exercise program improves anastrozole related A/M. Methods: This is a phase III, randomized trial of standard of care (observation) vs 48 weeks (wks) of exercise for women with BC on aA. Subjects in the control group receive literature about AIs (information on bone health, management of SEs of AIs). Subjects in the intervention group participate in a semi-supervised, individualized, and graduated 3x/wk exercise program (aerobic, resistance training, stretching) for 24 wks. From wks 25–48 independent exercise is recommended 3x/wk. The 10 endpoint is change in MSK symptoms as measured by 12 wk SF-36v2 bodily pain scores, NCI CTG toxicity, and visual analogue scale. 20 endpoints are QOL, hot flushes, bone density, and body mass. Physical activity and compliance with aA was monitored in both arms. The 1st interim analysis was planned after 10 patients were enrolled to evaluate accrual, compliance, and rate of discontinuation. Results: Accrual commenced December, 2007. Fourteen of a planned 72 patients have been enrolled (baseline data available for 13); 7 pts in the control arm (A) and 6 in the exercise arm (B). Median age was 59 (A) and 58 (B). Nine pts had baseline and 12 wk data available [5 (A), 4 (B)]. There were no withdrawals and compliance with scheduled exercise was 100%. Of the NCI CTG A/M deemed probably/definitely related to aA, there is no change in the number reported at baseline vs wk 12 in Arm A. In Arm B, 2 of 4 pts report a decrease in the number of A/M at wk 12. Mean norm-based wk 12 SF-36v2 bodily pain domain scores worsened by 4.1 in Arm A; an improvement of 1.9 in mean scores was observed in Arm B. Conclusions: Interim results show that a structured exercise program is well tolerated and compliance is high among women with aA related MSK symptoms. Early results point to a positive impact of exercise on MSK symptoms in women with early BC. Updated data will be presented. [Table: see text]

Abstract #4134 Background Medial (inner quadrants) tumor location has been shown to adversely influence survival in breast cancer. We investigated whether tumor location should alter the choice of local-regional treatments (surgery, with or without radiation therapy - RT), in women with node-negative breast cancer. Materials and methods Data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) 2006's database for 58,709 women aged 25-95 years, diagnosed between 1988-1997 with non-metastatic T1-2 node-negative breast cancer, who underwent breast conserving surgery (BCS) and axillary dissection. We used Cox proportional hazards to examine the effect of tumor location (medial versus other) on overall mortality after accounting for other prognostic factors (covariates listed in footnote table 1) and interactions identified by the Akaike Information Criteria. Results There were no notable differences in patients' characteristics according to tumor location. Among them, 25,232 had BCS, 33,477 had mastectomy. However the distribution according to the use of adjuvant RT showed marked heterogeneity. RT was used in 88% of BCS and in 3% of mastectomy patients. In the multivariate analysis that adjusted against the imbalances, medial location was associated with an increased mortality, hazard ratio (HR) 1.08 (95% confidence interval 1.04-1.13). Mastectomy had no significant impact on survival, HR=0.99 (0.92-1.07). RT was associated with a significant mortality reduction, HR=0.81 (0.75-0.88). There was no interaction between tumor location and surgery, or between tumor location and RT, while the interaction between surgery and RT was significant, HR=1.31 (1.14-1.51). The corresponding factorial summary showed no subgroup effect of tumor location: RT after BCS was associated with the same mortality reduction of 19% regardless of tumor location, and RT after mastectomy was associated with the same relative increase of 7% regardless of tumor location (Table 1). Conclusion We confirm the poorer prognosis associated with tumor medial location. However there was no subgroup effect. The survival outcomes of local-regional treatments were not affected by tumor location, arguing that tumor location is not a sufficient indication to modify local-regional treatments in node-negative patients. Local-regional treatment should be based on tumor characteristics and not tumor location. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4134.

Background: This analysis evaluates the prognostic significance of primary tumor location and examines the question of whether the effect of adjuvant radiation therapy (RT) on survival varies according to tumor location in women with node-positive breast cancer. Methods: Data were abstracted from the Surveillance, Epidemiology, and End Results database for 24,410 women aged 25- 95 years, diagnosed between 1988–1997 with nonmetastatic T1-T2 axillary node-positive primary breast carcinoma. Subgroup analyses were performed using interactions within proportional hazards models in which the event was defined as death from any cause. Prognostic variables were selected using the Akaike Information Criteria. The joint significances of subgroups were evaluated with the Wald test. Results: The median follow-up time was 10 years. In joint models, statistically significant interactions were found between tumor location, nodal involvement, type of surgery, and RT use. A factorial presentation of these interactions showed a consistent 13% proportional reduction of mortality in all subgroups (Table). The sole exception was in women with medial tumors with ≥4 positive nodes treated with mastectomy. In this subgroup, the use of RT was associated with a 16% proportional increase in mortality. Conclusions: Medial tumor location is a significant adverse prognostic factor that should be considered in treatment decision making for women with node-positive breast cancer. Improved survival was observed with RT use in all subgroups, except in women with medial tumors and ≥4 positive nodes treated with postmastectomy RT. These findings generate the hypothesis that the favorable effect of RT may have been offset by excess toxicities in the latter subgroup with the use of large fields to encompass the internal mammary nodes.

In patients with hematologic malignancies, chemotherapy has the potential to further suppress bone marrow production. While measures to correct anemia including transfusion and growth factor support can improve patients’ function and quality of life, the intervention threshold and the methods of correcting anemia among clinicians managing patients with malignant lymphoma are not clear. The present study evaluates the frequency, severity and corrective interventions for anemia used before and during the delivery of the four most common chemotherapeutic regimens used at the BC Cancer Agency to treat patients with Hodgkin’s and Non-Hodgkin’s Lymphoma. A retrospective, electronic chart review was conducted of 316 patients who received cytotoxic chemotherapy for lymphoma at four BC Cancer Agency centers from June 1, 2004 to December 31, 2005. Initial hemoglobin (Hgb) and dates of first Hgb in the ranges, 110–119g/L, 100–109g/L, 90–99g/L and Anemia-related symptoms and interventions during chemotherapy for patients with malignant lymphoma Hgb Range (g/L) Number of cases Symptoms Present Interventions Discussed but Not Given Transfusion Only EPO only Both Transfusion and EPO 110–119 137 21 0 0 0 0 100–109 96 31 1 0 0 0 90–99 59 27 7 4 0 0

PURPOSE: To evaluate the prognostic significance of primary tumor location and to examine whether the effect of adjuvant radiotherapy on survival varies according to tumor location in women with axillary node-positive (ALN+) breast cancer (BC). PATIENTS AND METHODS: Data were abstracted from the SEER database for 24,410 women aged 25-95 years, diagnosed between 1988-1997 with nonmetastatic T1-T2, ALN+ BC. Subgroup analyses were performed using interactions within proportional hazards models. Event was defined as death from any cause. Prognostic variables were selected using Akaike Information Criteria. Joint significances of subgroups were evaluated with Wald test. RESULTS: Median follow-up was 10 years. In joint models, statistically significant interactions were found between tumor location, nodal involvement, type of surgery, and radiotherapy. Factorial presentation of interactions showed consistent 13% proportional reduction of mortality in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with mastectomy. In this subgroup, use of radiotherapy was associated with a 16% proportional increase in mortality. CONCLUSION: Medial tumor location is a significant adverse prognostic factor that should be considered in treatment decision- making for women with ALN+ BC. Improved survival was observed with radiotherapy use in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with postmastectomy radiotherapy. These findings raise concern that the favorable effect of radiotherapy may be offset by excess toxicities in the latter subgroup.

Introduction Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. Methods The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. Results In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes. Conclusions ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.