Citations

55 Background: The aim of this retrospective study was to examine the overall survival (OS) of metastatic breast cancer patients over a decade and assess for any differences with respect to age, tumor characteristics, and ECOG status. Methods: Data on metastatic breast cancer cases from 1999-2010 were retrieved from the institutional cancer registry and linked to electronic medical records. Through chart review of 240 metastatic breast cancer cases, we determined hormone receptor (HR), HER2/neu (HER2), ECOG, age at diagnosis of metastatic cancer and mortality data. Kaplan-Meier survival curves for OS were used and compared between HR status, HER2 status, ECOG, and age at diagnosis using log-rank regression and Cox Regression analysis was performed to control for these variables. A 95% confidence interval (CI) was used. Results: The median OS of the sampled cases was 2.2 years (CI: 1.8-2.5 years). Analysis for overall survival by pre-determined age groups demonstrated no significant difference between the age groups (p value 0.46), but did yield a statistical difference based on ECOG status (p value 0.0001). Cox regression analysis showed consistent findings where survival was significantly affected by HR, HER2 status and ECOG but not age (HR: p value <0.0001; HER2: p value 0.0132; ECOG: p value <0.0001; age at diagnosis: p value 0.8462). Analysis for OS based on HR yielded a median survival of 1.4 years (CI: 0.9-1.6 years) for HR negative and 2.5 years (CI: 2.2-3.0 years) for HR positive (p value 0.0018). HER2 yielded a median survival of 1.8 years (CI: 1.4-2.3 years) for no amplification and 3.0 years (CI: 2.5 - 3.4 years) for amplification (p-value 0.0043). HR negative, HER2 non-amplified tumors had the poorest median OS at 0.7 years (CI: 0.5 - 1.1 years) whereas those tumors with HR positive, HER2 amplified had the best median OS at 3.0 years (CI: 2.5 - 4.7 years) with a p value < 0.0001. Conclusions: In this retrospective analysis, there was no significant survival difference with respect to age. Age continued to have no significant effect on survival when adjusting for ECOG, hormone status, and HER2/neu status. Those factors that did act as determinants of survival were ECOG status, hormone status and HER2/neu status of the tumor.

5 Background: The 11/2009 USPSTF breast cancer screening update recommended against routine screening mammography for women age 40-49, created confusion and prompted organizations to release opposing statements. We aimed to determine if the USPSTF update for breast cancer screening impacted screening mammography utilization in women age 40-49. Methods: We conducted a time-series analysis utilizing administrative claims data from over 100 health plans. Women ages 40-64 with at least one month of enrollment from 01/2006-12/2010 were included. Medicare claims are not included and thus women ≥65 were excluded. The start date of 01/2006 was chosen to account for possible effects of the recent recession. We developed claims-based algorithms to identify the number of monthly screening mammograms. Time series models were fit using SAS PROC AUTOREG; strong seasonal fluctuations were adjusted by including an autoregressive error of order 12. Results: Over 7.9 million women were included. Prior to the intervention, the baseline monthly mammography rate was 40.9/1,000 women for the 40-49 group and 47.4/1,000 women for the 50-64 group. Based on projections from pre-intervention trends, the update was associated with a 5.72% (1.27,10.18) and 4.97% (1.11,8.84) decrease in mammography rate at 3 and 10 months post-intervention, respectively in the 40-49 group. The intervention had no effect on mammography rates in the 50-64 group. This translates to 53,969 fewer mammograms performed in the year following the update for women ages 40-49 in this dataset. Conclusions: We present the first estimates of the impact of the USPSTF breast cancer screening update using a large nationally representative database. The update was associated with a small but significant decrease in mammography rates for women ages 40-49, while no change was seen for women ages 50-64, which is consistent with the context of the guideline change. A modest effect is also in line with public backlash and the release of numerous conflicting guidelines. These findings underscore the need for further research on benefits and risks of screening mammography as it is difficult to act on numerous sources of contradictory information.

126 Background: Inflammatory breast cancer (IBC) is an aggressive breast cancer variant, with 5-yr overall survival (OS) typically reported at 40-45%. We recently presented our results with once-daily radiotherapy (RT) as a component of trimodality therapy, with 5-yr OS of 64%. Herein we report patient and treatment factors associated with locoregional control (LRC). Methods: With permission of the IRB, review of medical records at the Mayo Clinic in Rochester, MN was performed to identify patients treated with RT for IBC from 2000-2010. Patients with non-metastatic, clinically diagnosed IBC were included. OS, LRC and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. First recurrence in the chest wall or regional lymph nodes was defined as a locoregional recurrence (LRR). Results: 52 women were included in the analysis. Median age at diagnosis was 54 years (range 23-83). Median follow-up for the population was 3.6 years (range 0.7 – 11.9). All patients were treated with adjuvant RT to the chest wall and draining nodal basins in once-daily fractions of 1.8-2.25 Gy (median 2 Gy), to a median of 50 Gy (range 46-60 Gy). Actuarial 5-yr LRC was 85%. LRR was associated with poorer DMFS and OS (p < 0.01). Factors significantly associated with improved LRC included lack of extracapsular extension (ECE) and use of adjuvant chemotherapy (p < 0.05). Factors associated with a trend towards LRC included use of bolus, absence of boost, node negativity at time of surgery and pathologic complete response (pCR). Daily bolus was employed in 90% of patients and was most commonly (68%) 1 cm in thickness. There was a trend towards improved 5-yr LRC when bolus ≥ 1 cm was employed daily (93% v. 67%, p = 0.06). Patients who received a boost to the mastectomy scar (62% of the population, median of 10 Gy, range 10-16 Gy) had poorer LRC (78% v. 100%, p = 0.08), but superior 5-yr DMFS (78% v. 34%, p = 0.035) and OS (77% v. 34%, p = 0.04). Conclusions: LRC is associated with improved OS in IBC. Lack of ECE and use of adjuvant chemotherapy are associated with improved LRC in women with IBC. Node negativity, pCR and use of daily bolus ≥1 cm in thickness are associated with a trend towards improved LRC. The impact of boost requires further analysis.

111 Background: Limited data exist on patient (pt) experience and work productivity (WP) in MBC. VIRGO is a prospective OCS following >1,200 pts with locally advanced or MBC receiving 1st-line hormonal therapy (HT) or chemotherapy (CT) in a real-world setting. We report baseline characteristics of 277 pts from the VIRGO PRO substudy and correlations between health-related quality of life (HRQoL), symptoms, activities of daily living, and WP. Methods: Symptom severity and interference (M.D. Anderson Symptom Inventory [MDASI]), functional status (Activity Level Scale [ALS] from the Rotterdam Symptom Checklist) and WP (Work Productivity and Activity Impairment Questionnaire) were assessed. Pts rated their HRQoL during the past week on a scale of 0–10. Results: See table. The five most severe symptoms at baseline were fatigue, decreased sexual interest, disturbed sleep, drowsiness, and emotional distress; these were reported with less severity in the HT cohort (24%-37% vs 42%-59%). Overall MDASI severity and interference correlated with WP measures in the CT (R=0.46 to 0.78) and HT cohorts (0.36 to 0.94). Mean of the 5 most severe symptoms also significantly correlated with WP indices (R=0.47 to 0.66). HRQoL correlated (p<0.05) with all WP measures (R=-0.46 to -0.56) in the CT cohort and with % impairment while working (R=-0.65) and % overall work impairment (R=-0.71) in the HT cohort. In univariate regression analysis, MDASI symptom interference score was the best predictor of reduced WP (R2=0.52 while working; R2=0.48 for non-work activities). Conclusions: MBC pts receiving CT and HT report significant work impairment. Results indicate moderate correlations between WP indices, HRQoL and symptom burden. [Table: see text]

100 Background: Combining BEV with CT significantly improved progression-free survival (primary endpoint) in the E2100, AVADO, and RIBBON-1 trials in the 1st-line setting and the RIBBON-2 trial in the 2nd-line setting. Primary efficacy and safety results from RIBBON-2 have been published; here we present final OS results. Methods: Eligible patients (pts) had MBC that had progressed on 1st-line CT without BEV. 2nd-line CT (taxane, gemcitabine, capecitabine, or vinorelbine) was chosen before 2:1 randomization to CT with either BEV (10 mg/kg q2w or 15 mg/kg q3w) or PL continued until progression. Stratification factors were 2nd-line CT, hormone receptor status, and time from MBC diagnosis to 1st progression. All pts could receive BEV at progression. The primary endpoint was PFS. Final analysis of OS, a secondary endpoint, in the intent-to-treat population was planned after 557 events and provided 80% power to detect a hazard ratio (HR) of 0.77 (median OS increased from 14.0 to 18.2 months) at α=0.04. Results: At the time of data cutoff (Oct. 31, 2011), 184 (82%) of 225 pts in the CT/PL arm and 376 (82%) of 459 pts in the CT/BEV arm had died. BEV was administered in subsequent treatment lines in 12% vs 6% of pts, respectively. There was no difference in OS between treatment arms: HR 1.013 (95% CI 0.845–1.215), log-rank p=0.8843. Median OS was 17.8 months with CT/PL vs 18.6 months with CT/BEV. The 1-year OS rates were 69% vs 71%, respectively. Subgroup analyses by CT cohort showed HRs ranging from 0.86 (95% CI 0.58–1.29) in the capecitabine cohort (n=144) to 1.44 (95% CI 0.82–2.53) in the vinorelbine cohort (n=76). HRs were close to 1 for the two largest CT cohorts (taxane and gemcitabine). Exploratory analysis in the subgroup of patients with triple-negative MBC showed a HR of 0.85 (95% CI 0.58–1.26). Updated safety results were similar to those previously reported from the primary analysis. There were fewer fatal adverse events in the CT/BEV arm (1.5%) than in the CT/PL arm (3.2%). Conclusions: Final OS results from RIBBON-2 reveal no difference between treatment arms. No new safety signals were observed.

LBA1000 Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR=1.1; p=0.27) and 80.1 % (HR=0.97; p=0.71) in TAC group. 5-year OS was 90.8% in DD AC→PG group as compared with 89.1% (HR=.89; p=0.25) in DD AC→P group and 89.6 % (HR=0.90; p=0.32) in TAC group. HR for DFS and OS of DD AC→P vs. TAC were 0.89 (p=0.14) and 1.01 (p=0.92) respectively. Toxicities for TAC, DD AC→P, DD AC→PG, respectively: febrile neutropenia (Gr 3/4: 9%, 4%, 4% [p<0.001]), sensory neuropathy (Gr 3/4: <1%, 7%, 6% [p<0.001]), diarrhea (Gr 3/4: 8 %, 2%, 2% [p<0.001]). Hgb was <10 in 12%, 26%, 33% with ESA use in 35.2%, 47%, 51.6% and transfusions in 3.7%, 6.3%, 9.4%. Deaths on treatment: N=13, 5, 7 (p=0.2). AML/MDS: N=5, 8, 11. All cycles completed in 91% for TAC and 88% for DD regimens. Conclusions: Addition of G to DD AC→P did not improve outcomes. No significant differences in efficacy endpoints were identified between DD AC→P and TAC, though toxicity profiles differed. Funding: NCI PHS U10-CA-37377, -69974, -12027, -69651 and NCCTG U10-CA25224, with additional funding from Eli Lilly & Company, and Amgen, Inc.

CRA1002 Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) naïve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P. Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease. Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P. Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.

90 Background: Biochemical recurrence (BCR) may be an indicator of metastatic prostate cancer; however, it isn't specific enough to differentiate patients who will experience rapid onset of metastases from those who do not. Such lack of specificity leads to overtreatment of men who will likely never experience metastatic disease in their lifetime. We hypothesize that genomic biomarkers, detectable in primary tumor tissue, may better identify rapidly progressing metastatic prostate cancer. Methods: FFPE prostatectomy specimens (n = 309) from the Mayo Clinic tumor registry were profiled using a high-density expression array. Patients were retrospectively classified into three outcome groups: NED (no evidence of disease recurrence); BCR-only (patients that experienced BCR but no metastatic progression); and MET (metastatic disease confirmed by positive CT or bone scans) and were matched on several criteria for analysis . Uni- and multi-variable analyses between outcome groups were used to analyze clinical and genomic variables (adjusting for adjuvant hormone therapy as a confounding factor). Results: Median follow-up was 16.8 years and MET patients were diagnosed a mean of 3.1 years following BCR. Univariable and multivariable analysis of clinical variables failed to show statistically significant differences between NED and BCR-only outcome groups. Differential expression analysis between NED and BCR-only groups showed no significant differences after false discovery correction. Conversely, 6,277 and 52,020 biomarkers were differentially expressed between MET and the BCR-only and NED groups, respectively. Conclusions: Considering the clinical and genomic results together, patients who experienced rapid metastatic disease were significantly different from both the NED and BCR-only groups. However, no significant differences were identified between the BCR-only and NED outcome groups. These results imply that BCR is not a good surrogate for men who are likely to experience rapid onset of metastatic disease and lethal prostate cancer.

82 Background: Metastatic malignant melanoma is a nearly uniformly fatal disease. Systemic therapy has notable but limited success. Novel therapeutic strategies are urgently needed. To that end, we’ve pursued combinatorial therapeutics using conventional chemotherapy added to an inhibitor of angiogenesis (bevacizumab) with some evidence of clinical benefit. Preliminary analysis of one of our trials suggested a previously unrecognized immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma, and this may have a potential impact on clinical outcome. Herein we evaluate the immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma. Methods: We measured levels of peripheral blood mononuclear cell phenotypes in addition to 42 cytokines, chemokines and growth factors in plasma of 55 patients who received albumin-bound paclitaxel and carboplatin (AC) and of 73 patients who received AC with bevacizumab (ACB) on clinical trials N057e and N0775 respectively. The relative percent change in PBMC cell counts and cytokine levels were determined from baseline at their restaging evaluation after two cycles of therapy. The Mann Whitney U test was used to compare responses between the groups. Results: There was a significant increase in CD197+type 1 macrophages in the group that received ACB (35.3%, -11.8-142.7%) compared to AC (-11.6%, -45.9-38.3%; p=0.004). There was a significant decrease in IL-6 in the group that received ACB (-42.4%, -87.7-0.0%) compared to AC (28.4%, -37.4-480%; p=0.0018). Conclusions: The addition of bevacizumab to chemotherapy for the treatment of metastatic melanoma modulates cellular immunity and a pro-inflammatory cytokine. Patients who received bevacizumab had a significant increase in CD197+ type 1 macrophages and a significant decrease in IL-6. Clinical significance of these findings is the subject of ongoing work.

40 Background: Gleason score (GS) is the most widely used grading system of cell differentiation in prostate cancer and one of the best pathological predictors of disease progression. Patients with high GS (> 7) are the most likely to experience metastasis, whereas patients with low GS (< 7) are expected to have favorable long-term outcomes. In addition to the subjective nature of GS assessment, patients with GS 7 represent a heterogeneous group in terms of patient outcomes. In this study a biomarker signature is developed and validated which could improve the prediction of high risk disease among GS 7 radical prostatectomy (RP) patients. Methods: Patient specimens from the Mayo Clinic RP Registry (n = 764) were used for feature selection and training of a 392-feature K-nearest neighbor (KNN, k = 11) classifier. These 392 genomic features were identified by assessing differential expression between patients with GS < 7 and those with GS > 7, using a Bonferroni adjusted T-Test with a p-value threshold of 0.05. The classifier was subsequently validated in two independent patient cohorts (Memorial Sloan Kettering [MSKCC] and German Cancer Research Center [DKFZ]) and compared to a state of the art biomarker signature (Penney et al. 2011). Results: In the MSKCC dataset (GSE21034) our model segregated GS < 7 from GS > 7 patients (n = 56) with an area under the receiver operating characteristic curve (AUC) of 0.97, comparable to the AUC of 0.94 obtained by Penney et al. in their independent validation set (n = 45). Strong performance was observed by our model when discriminating between primary Gleason grade (pGG) 3 and pGG 4 & 5 patients in the MSKCC (n = 130) and DKFZ prostate cancer (GSE29079, n = 47) datasets, achieving AUCs of 0.75 and 0.87, respectively. In the challenging GS 7 subset, our model segregated GS 3 + 4 and 4 + 3 patients in the DKFZ dataset (n = 64) with an AUC of 0.81 outperforming the Penney et al. signature (AUC = 0.60). Conclusions: A biomarker signature was developed which discriminates between low and high GS patients, outperforming a previously reported signature. Further validation of this biomarker signature in additional post RP patients, as well as, pretreatment biopsy specimens is warranted.