Hillman, DW

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.

5069 Background: Inhibition of androgen receptor (AR)-signaling results in increases in double-strand DNA breaks and genomic instability. PARP inhibitors (PARPi) are a standard treatment option for patients (pts) with homologous recombination repair mutations (HRRm). Combinations of PARPi and AR pathway inhibitors (ARPI) are associated with synthetic lethality in multiple pre-clinical studies. Clinical trials have suggested potential benefits with co-targeting PARPi and ARPI in pts with and without HRRm. Methods: Alliance A031902 compared radiographic progression-free survival (rPFS) and overall survival (OS) as co-primary endpoints with enzalutamide and rucaparib (Enz/Ruca) versus enzalutamide plus placebo (Enz/Plac) for pts with metastatic castration resistant prostate cancer (mCRPC) regardless of BRCA/HRRm status. This trial was conducted by the Alliance for Clinical Trials in Oncology in 36 centers in the US. Target sample size was 1,002 patients. Eligibility required mCRPC with or without measurable metastatic disease and was agnostic regarding HRRm status. The trial was discontinued in 10/2023 due to changes in the treatment landscape for this pt population. Results: Between 10/21 and 4/23, 61 pts were randomized to Enz/Ruca (n=30) or Enz/Plac (n=31). Known BRCA1/2 or PALB2 mutations were present in 1 pt (3.3%) in the Enz/Ruca arm and 1 pt (3.2%) in the Enz/Plac arm; wildtype in 14 (46.7%) vs 15 (48.4%), and unknown in 15 (50%) vs 15 (48.4%), respectively. Three patients (11.5%) in the Enz/Ruca arm discontinued due to an adverse event (AE) vs 0 in the Enz/Plac arm. Among response-evaluable pts, 7/26 (27%) in the Enz/Ruca arm discontinued due to disease progression vs 10/31 (33%) in the Enz/Plac arm. Most common grade 3+ AEs were anemia (33% vs 3%) and hypertension (17% vs 10%) in the Enz/Ruca arm and Enz/Plac arm, respectively. All 61 pts were evaluable for response assessment. PSA declines ≥50% and ≥90% were observed in 79% vs 45% and 60% vs 43% of pts receiving Enz/Ruca versus Enz/Plac, respectively. Median PFS in the Enz/Ruca vs Enz/Plac arms was 17.1 vs 14.2 mos, respectively (HR 1.13 [95% CI: 0.42-3.01], p=0.81), median rPFS (inclusive of unequivocal clinical progression) was 17.1 vs 11.7 mos ( HR 0.72; 95% CI: 0.31-1.67, p = 0.44), and median OS was not reached vs 27.0 mos (HR 0.65; 95% CI: 0.29-1.45, p=0.29). Conclusions: In this prematurely terminated phase III study, Enz/Ruca was generally well tolerated, with the safety profile consistent with prior PARPi/ARPI combinations. Efficacy outcomes for rPFS and OS are inconclusive due to limited sample size. Definitive conclusions regarding the clinical benefit of this combination cannot be determined from this study. Clinical trial information: NCT04455750 .

5004 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated continuously with testosterone suppression (TS) plus an androgen receptor pathway inhibitor (ARPI) can experience cumulative toxicity. We conducted this single-arm phase 2 trial (NCT05241860) to test the hypothesis that pts who achieve favorable response to TS + ARPI can have prolonged treatment-free interval with testosterone recovery after treatment interruption (TI). Here we report on the primary endpoint. Methods: Eligible pts had mHSPC by conventional imaging with prostate-specific antigen (PSA) ≥ 5 ng/ml and testosterone ≥ 150 ng/dl prior to starting TS+ARPI, with PSA < 0.2 ng/ml and testosterone < 50 ng/dl at the time of enrollment after having received TS for 540-750 days and ARPI for ≥ 360 days. Prior local therapy, radiation to metastases and docetaxel were permitted. After enrollment, pts discontinued TS and ARPI and were followed with PSA and testosterone levels every 3 months (mo), CT/MRI and bone scan at least every 6 mo, and FACT-P questionnaire for patient-reported outcomes (PROs) every 6 mo. Treatment was resumed for PSA ≥ 5 ng/ml, radiographic change (progressive disease [PD] per RECIST 1.1 on CT/MRI or unconfirmed PD per PCWG3 on bone scan), or prostate cancer-related symptoms. The primary endpoint was proportion of men remaining treatment-free 18 mo after TI with eugonadal testosterone ( > 150 ng/dl). Target enrollment was 75 pts to differentiate 18-mo treatment-free rates of 0.30 (H 0 ) and 0.45 (H a ). Results: Of 79 pts enrolled between 07/2022 and 03/2024, 78 were eligible and underwent TI. Among these 78, median PSA prior to starting TS+ARPI was 19 (range 5-6759), 27 (35%) had high volume disease, 31 (40%) never received local therapy, and 55 (71%) did not receive radiation to metastases. By 18 mo after TI, 67% (52/78) recovered testosterone and 58% (45/78) remained treatment-free; 41% (32/78) remained treatment-free with testosterone recovery (80% CI 33.5-48.9%, one-sided p 0.0249). At median follow-up of 21.2 mo, 35% (27/78) resumed initial TS+ARPI after meeting re-initiation criteria (of whom 1 required treatment switch for PD 9 mo later); 5% (4/78) resumed prior to meeting criteria; 9% (7/78) pursued alternative therapy instead of resuming TS+ARPI per protocol; 5% (4/78) withdrew; 1 died of myocardial infarction prior to resuming treatment. 4 pts died, 1 of prostate cancer. Conclusions: The primary objective was achieved with 41% of favorable responders to TS+ARPI remaining treatment-free with testosterone recovery at 18 mo after TI. Analyses of biomarkers and PROs are in progress, and pts will be followed for long-term outcomes. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org, Veracyte Inc. Clinical trial information: NCT05241860 .

1071 Background: N0234 is a phase II trial of gemcitabine at 1000 mg/m2 days 1 and 8 of a 21 day cycle and erlotinib at 150 mg daily in patients with previous therapy with either an anthracycline or a taxane for MBC. A partial response (PR) rate of 17% has been reported (ASCO 2005). Recent information suggests that over-expression of the EGFR pathway is frequent in patients with TNeg MBC. Methods: Tissue and serum were obtained for translational studies of ER, PR, HER2, and proteins related to EGFR pathway on tissue using immunohistochemistry; CK19, mammoglobin, and TTK on circulating tumor cells (CTCs). Markers were evaluated centrally, blinded to patient outcome. Complete data were available in 57 of 59 eligible patients; 20/57 patients (pts) were TNeg. Results: A PR rate of 25% and clinical benefit rate (PR + stable disease > 6 months)of 25% was observed in TNeg pts as compared to a PR rate of 14% (p = 0.30) and clinical benefit rate 22% (p= 0.75) for non-TNeg pts. Median progression free survival 72 days vs 98 days (p=0.13) and overall survival 227 days vs 738 days (p<0.001) were shorter for TNeg pts. Translational results for the EGFR pathway proteins and CTC analysis is forthcoming. Conclusions: The combination of gemcitabine and erlotinib appears to be as active in the non-TNeg and TNeg subset of patients on this trial. TNeg patients had an inferior clinical result, confirming the poor outcome seen in these patients. Data for the remaining biomarkers potentially predictive of activity will be presented. Supported by CA-25224, CA-37404. [Table: see text]

Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with substantial risks of disease recurrence. While cytotoxic chemotherapy is commonly administered and reduces recurrence, disease outcomes vary considerably and few prognostic tools are available for risk stratification for TNBC patients. We constructed and validated clinical calculators for invasive-disease free survival (IDFS) and overall survival (OS) for TNBC and compared their performance against AJCC-based models which include only tumor size and nodal status. Methods: From a surgical cohort of 9,982 patients who underwent breast cancer surgery at Mayo Clinic between January 1985 and December 2012, 605 centrally reviewed TNBC patients were identified and used to construct Cox models for IDFS and OS. Patients treated with neoadjuvant chemotherapy were excluded. Variables considered included age, menopausal status, tumor size, nodal status, Nottingham grade, type of breast surgery (mastectomy vs. lumpectomy), adjuvant radiation therapy, adjuvant chemotherapy, Ki67, stromal tumor infiltrating lymphocytes (sTILs), and neutrophil-to-lymphocyte ratio (NLR). Missing values were imputed using single imputation with all variables (including outcomes) included in the imputation model. Backward step-down procedure was used for model selections. The final models were internally validated for calibration and discrimination using bootstrapping methods and compared with AJCC-based models. Results: For both IDFS and OS, higher sTIL's, less extensive nodal involvement, use of adjuvant chemotherapy, and lower NLR were significant predictors of improved clinical outcomes. Premenopausal status and younger age were additionally predictive of improved IDFS and OS, respectively. Models for IDFS and OS have good calibration and are associated with bias-corrected C-indices of 0.68 and 0.71, respectively, as compared with C-indices of 0.59 and 0.62 for AJCC-based models. Conclusions: Our data indicate that a clinical calculator that includes sTIL's, NLR, menopausal status, age, nodal involvement as well as chemotherapy use can provide significantly greater prediction of clinical risk than tumor size and nodal status alone. These tools may be used to identify TNBC patients at elevated risk of disease relapse and to aid physician's communication with patients regarding their long-term disease outlook and planning treatment strategies. External validation is required to further evaluate broader applicability of this tool, which was developed utilizing a single-institutional experience. Citation Format: Polley M-YC, Leon-Ferre RA, Liu H, Gilbert J, Cafourek V, Hillman DW, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch F, Visscher DW, Goetz MP. Mayo clinic TNBC outcome calculator: A clinical calculator to predict disease relapse and survival in women with triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-07.

Abstract Purpose Dual HER2 targeting increases pathologic complete response (pCR) rate to neoadjuvant therapy and improves outcomes in both early and metastatic HER2-positive disease. CALGB 40601 is a randomized phase III trial examining the impact of dual HER2 blockade consisting of trastuzumab (H) and lapatinib (L) added to paclitaxel (T) on pCR, considering tumor and microenvironment molecular features. We previously found that pCR was numerically but not significantly increased with dual therapy, and that tumor molecular subtype and evidence of immune activation significantly and independently affected pCR (Carey et al, JCO 2016). In this secondary analysis, we sought to evaluate the effects of treatment arm and gene expression-defined subgroups on invasive disease free survival (IDFS). Patients and Methods Patients (Pts) with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment with equal probabilityto paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. A paclitaxel plus lapatinib (TL) arm was closed early based on reports of futility from other trials. A secondary endpoint was IDFS, defined as the time from surgery until local or distant recurrence, new primary, or death from any cause, whichever was first. Gene expression signatures were identified by RNA sequencing. Results Between 12/2008 and 2/2012, 305 pts were enrolled. 261 pts had IDFS and gene expression information available (THL, n = 103; TH, n =101; TL, n = 57); there were no significant differences in clinical characteristics between this subset and the entire population. The median IDFS follow-up was 4.6 years with 40 IDFS events having occurred (THL, n=7; TH, n=19; TL, n=14). IDFS was significantly longer in the THL arm compared to standard TH (HR=0.34; 95% CI: 0.14-0.82; p=0.02). IDFS was also significantly longer among pCR than non-pCR pts (HR=0.40; 95% CI: 0.19-0.81; p=0.01), and did not differ by hormone receptor (HR) status, clinical stage, tumor size, race, menopausal status or age. Among gene expression signatures, only immune activation measured by an IgG signature was associated with longer IDFS (HR=0.71; 95% CI: 0.51-0.98; p=0.04); this signature was previously also associated with pCR. Multivariate analysis showed dual therapy (HR=0.35; p=0.02), pCR (HR=0.36; p=0.01), IgG (HR=0.69; p=0.05), and molecular subtype (LumA vs HER2E, HR=0.24, p=0.005) were associated with longer IDFS. A subgroup analysis by hormone receptor status revealed that among pts with HR+ disease, pts with luminal A experienced longer IDFS (HR=0.23; p=0.02) compared to those with luminal B or HER2-enriched molecular subtypes. Conclusion Dual HER2-targeting with lapatinib added to 16 weeks of TH produced significantly longer IDFS than TH alone, despite modest effects on pCR. Similar to pts with HER2-negative disease, pts with luminal A had better IDFS than those with other molecular subtypes. Immune activation as measured by RNA-based signature independently predicted both pCR and IDFS. Support: U10CA180882, U10CA180821, U24CA196171, P50-CA58823, Susan G Komen, BCRF Citation Format: Krop IE, Hillman D, Polley M-Y, Tanioka M, Parker J, Huebner L, Henry NL, Tolaney SM, Dang C, Harris L, Berry DA, Perou CM, Partridge A, Winer EP, Carey LA. Invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-02.

Abstract Background Tumors that are negative for estrogen and progesterone receptors and do not over express HER2 are referred as “triple negative” breast cancer (TNBC). These tumors are characterized by unique molecular profiles on gene expression arrays, aggressive behavior with a high recurrence rate, an increased risk of visceral metastases, poor prognosis and lack of targeted therapies. Brostallicin is a novel synthetic compound from the class of DNA minor groove binding (MGB) anti-cancer agents. It retains activity in cancer cells resistant to alkylating agents, topoisomerase I inhibitors and is fully active against DNA-mismatch repair deficient tumor cells. Cells expressing relatively high glutathione/glutathione S-transferase (GSH/GST) levels are more susceptible to brostallicin antitumor efficacy. Cisplatin administration increases expression of GST in tumor cells leading to an increased anti-tumor efficacy of brostallicin. Trial design: Single-stage phase II study — based on the effects of cisplatin on GSH/GST levels in preclinical models, the most reasonable sequence to explore was cisplatin on Day 1 followed by brostallicin on Day 2 repeated every 21 days. Eligibility criteria: Women or men ≥18 years of age with confirmed adenocarcinoma of the breast with clinical evidence of measurable metastatic disease and triple negative subtype according to current ASCO CAP guidelines [ER/PR ≤1%; HER2 negative), who received 0–4 prior chemotherapy regimens in the metastatic setting; with adequate hematologic, renal and hepatic functions; and no active CNS metastases. Aims: To study the efficacy of the novel drug, brostallicin, as well as to serve as proof of concept of its mechanism of action in TNBC. The primary endpoint is to evaluate clinical efficacy of the combination of brostallicin and cisplatin in the treatment of patients with metastatic TNBC, as measured by progression-free survival (PFS) at 3 months with 89% power (0.10 significance level) to detect an absolute difference of 20%. Secondary endpoints include ORR by RECIST, duration of response, 6-month PFS, overall survival (OS) and adverse event profile. Tertiary endpoints include assessment of 1) GSH levels prior to the administration of cisplatin and of brostallicin; and 2) the prevalence of BCRA-1 mutation by IHC in the primary or metastatic tumor. Statistical methods: The largest 3-month PFS proportion where the proposed treatment regimen would be considered ineffective in this population was estimated at 35% based on the median PFS of 60 days in patients with metastatic TNBC enrolled in the N0234 trial (erlotinib and gemcitabine as 1st/2nd line), and the smallest 3-month PFS success proportion that may warrant subsequent studies with the proposed regimen in this patient population was estimated at 55%. The interim analysis will be reported when the 20th eligible patient has been followed for 3 months. Present accrual and target accrual: 21 patients have been accrued at the time of abstract submission (June 2011). Target accrual is 42 evaluable patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-14.

Abstract Abstract #6149 Background: Internal Review Boards and Data and Safety Monitoring Boards often require protocol-specified adverse event (AE) stopping rules for safety monitoring. However, availability of safety data for investigational agent(s) may be limited at the time of protocol development in the phase II setting. This meta-analysis was undertaken to quantify the variability of AE rates in North Central Cancer Treatment Group (NCCTG) phase II metastatic breast cancer (MBC) clinical trials and to investigate whether study factors are associated with AE rates for the development of AE stopping rules in future phase II clinical trials.&#x2028; Methods: All closed NCCTG phase II MBC clinical trials using CTC v2.0 or CTCAE v3.0 for AE monitoring were selected. Rates of G3/4 AEs (overall, hematologic [H], and non-hematologic [NH]) and of study discontinuation [SD] due to AEs were calculated for each trial. Associations between study factors [number of agents (single vs combination); line of therapy (first-line only vs other); and type of therapy (chemotherapy vs other)] and AE rates were assessed via Wilcoxon rank sum tests.&#x2028; Results: 15 trials met inclusion criteria. 7 used CTCAE v3.0; 6 investigated single agents; 5 investigated first-line therapy; and 11 investigated chemotherapy regimens. 694 pts were evaluable for AE analysis. The G3/4 AE rate across trials was 68% (16-98%) overall, 45% (0-96%) H, and 51% (16-78%) NH. The overall rate of SD due to AEs was 13% (0-40%). The overall rate of G3/4 AEs was significantly lower in single agents vs combination regimens (30% vs 86%, p=0.004). This association held for H (2% vs 66%, p&lt;0.0001) and NH (27% vs 57%, p=0.03) Aes. The rate of SD due to AEs was also significantly lower in single agents vs combination regimens (0.5% vs 15%, p=0.04). The rate of G3/4 AEs was significantly higher in first-line only trials vs other trials (overall: 90% vs 47%, p=0.04; H: 73% vs 5%, p=0.02; NH: 66% vs 41%, p=0.08). The rate of SD due to AEs was also significantly higher in first-line only trials (18% vs 4%, p=0.008). The only significant association with chemotherapy vs other therapy was G3/4 H AE rates (51% vs 2%, p=0.02).&#x2028; Discussion: High variability in G3/4 AE rates overall and in H and NH AEs was noted in these 15 trials. There is also high variability in the rates of SD due to AEs. The data suggest that clinical trials with single agent regimens have lower AE rates than combination regimens and, surprisingly, trials of first-line therapy only have higher AE rates than other trials. This may be due to more aggressive therapy being tested in the first-line setting. Although data from previous trials with the investigational agent(s) should be used for developing AE stopping rules when available, this study suggests that study factors such as number of agents and line of therapy can be useful when previous data are limited. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6149.

Abstract Abstract #6147 Background: Phase II metastatic breast cancer (MBC) clinical trials evaluating efficacy of cancer treatments are often designed using a binary primary endpoint (i.e., each evaluable patient [pt] is classified as a “success” or “failure”). In the era of novel agents in cancer research, endpoints such as 6-month progression-free survival [PFS6] for measuring efficacy of cytostatic agents are more commonly being used. This meta-analysis was undertaken to compare two binary classifications of PFS6 and to compare these binary endpoints with other efficacy endpoints in the phase II setting.&#x2028; Material and Methods: All closed North Central Cancer Treatment Group (NCCTG) phase II MBC clinical trials using Response Evaluation Criteria in Solid Tumors (RECIST) with at least 1 year of follow-up since last pt accrued were selected. All eligible pts initiating treatment were included. Two binary classifications of PFS6 were computed for each trial. Success for PFS6-1 is defined as on study treatment 6 months from registration without documentation of disease progression. Success for PFS6-2 does not require a pt to be on study treatment at 6 months. Also computed for each trial are Kaplan-Meier (KM) estimates of PFS6 (PFS6-KM) and 1-year overall survival (OS1-KM). Trial-level endpoints were summarized using descriptive statistics and compared using weighted (by trial sample sizes) Pearson correlations. Lastly, the concordance rate of PFS6-1 and PFS6-2 status with OS status at 1 year at the pt level was computed across all pts (pts censored for OS prior to one year were excluded [n=10]).&#x2028; Results: 11 trials met inclusion criteria. All trials required measurable disease and had a single arm. 485 evaluable pts were accrued (median 48 pts per trial [range 19-77]). Median PFS6-1 was 27% (range 10-44%) and median PFS6-2 was 34% (range 10-73%). The median trial-level difference between PFS6-1 and PFS6-2 was 5% (range 0-43%). The correlation between PFS6-1 and PFS6-2 was 0.81 (p&lt;0.01). Among the endpoints, PFS6-2 and PFS6-KM had the highest correlation (&gt;0.99, p&lt;0.01) due to only 2 pts being censored for PFS prior to 6 months. Among the PFS endpoints, OS1-KM was most highly correlated with PFS6-1 (0.79, p&lt;0.01) with the correlations with PFS6-2 and PFS6-KM not being statistically different from zero (both 0.59 with p&gt;0.05). However, overall patient-level concordance between PFS6 status and OS status at 1 year was higher using PFS6-2 (68%) than PFS6-1 (59%).&#x2028; Discussion: Differences were observed between the two binary classifications of PFS6. PFS6 with (as compared to without) the requirement that a pt be on study treatment at 6 months appears to have higher correlation with OS at 1 year at the trial level but lower concordance with OS status at 1 year at the pt level. Selection of the historical control should take into consideration the definition of PFS6 being used. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6147.

Abstract Abstract #6074 Objective: To analyze blood-serum biomarkers (HER2, EGFR, uPA, and TIMP-1) for prediction of response to treatment in conjunction with Study 96-32-55, a multicenter phase II trial assessing the efficacy and tolerability of two irinotecan schedules in anthracycline- or taxane-refractory MBC patients.&#x2028; Methods: MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest or 240 mg/m2 every 3 weeks. During this study the serum samples from each patient were collected at a possibility of three time points; prior to treatment, at the first occurrence of response, and at completion of or withdrawal from treatment. Response prediction was analyzed using predetermined elevated/non-elevated serum biomarker cutoffs. Percentage changes from baseline to first response and disease progression were analyzed.&#x2028; Results: In the weekly arm, the objective response (CR+PR) rate was 23% (95% CI, 13% to 37%), and in the every-3-weeks arm, the objective response rate was 14% (95% CI, 6% to 26%). Serum biomarker levels were determined for HER2, EGFR, uPA, and TIMP-1 prior to treatment for 91 patients. Of these 91 patients, 17 had serum measurements at first response, and 38 had serum measurements at their completion of study due to disease progression. Only 7 patients had serum-levels collected at all three event-points. The baseline levels of sHER2, EGFR, uPA, and TIMP-1 were not different among responders and non-responders (Fisher's Exact p=0.41, 0.26, 0.68, 0.75). sHER2 level increased by 20.6% from baseline to disease progression (p=0.01). TIMP-1 level was 15.2% lower than baseline at first response (p=0.03), 16.5% higher than baseline at disease progression (p=0.01), and for 7 patients with all three event-point measures, TIMP-1 was 21.8% lower than baseline at first response and was 22.3% higher than baseline at disease progression (p=0.02, 0.04).&#x2028; Conclusions: In this study, serum levels of HER2, EGFR, uPA, and TIMP-1 do not appear to be predictive of response. However, interpretation of the data is compromised due to limited availability of serum at all 3 points. Serum HER2 appears higher at disease progression than at baseline. Serum TIMP-1 appears to decrease from baseline to first response, and then appears to increase at disease progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6074.