Citations

Abstract Background: Tumor-infiltrating lymphocytes (TILs) at diagnosis are reported to be prognostic in triple-negative breast cancer (BC). Analysis of a small subset of 209 HER2+ patients (pts) with 49 events concluded that higher levels of S-TILs are associated with increased trastuzumab benefit (Loi, 2014). Here we report the largest study to date evaluating S-TILs and their prognostic and predictive association with clinical outcome in N9831 pts treated with either chemotherapy or chemotherapy plus trastuzumab. Methods: Samples assessed were from primary tumors of pts on N9831 arm A (standard AC→T chemotherapy) and arm C (concurrent chemotherapy with trastuzumab) (Perez, 2011). S-TILs were evaluated on H&E whole tumor slides by a single pathologist with ∼10% of cases read by two pathologists in tandem. The percent of stromal lymphocytic infiltrates (S-TILs) was quantitated in deciles; ≥60% S-TILs was used for the categorical cutoff (Denkert, 2010). The association between S-TILs, treatment (tx) and recurrence-free survival (RFS) was studied and the interaction between S-TILs, trastuzumab benefit and RFS was calculated. Results: 489 pts from arm A (chemo) and 456 pts from arm C (chemo with trastuzumab) were assessed and were similar to pts in the overall trial; all had RFS information and a median follow-up of 4.4yr. Tumors from 54% of pts in arms A and C were HR+; 14% were node-negative. Tumors with high S-TILs were more likely to be hormone receptor-negative (p< 0.0001). In multivariable analyses including nodal status, hormone receptor status, tx arm, tumor size, tumor grade, and age, ≥60% S-TILs was significantly associated with RFS (HR 0.20; 95%CI 0.064–0.65, p=0.007) in arm A but not in arm C (HR 1.1; 95%CI 0.42–2.8, p=0.87); the interaction term of arm and ≥60% S-TILs was significant (p=0.042). Semi-continuous deciles were associated with RFS in arm A (p<0.0002) but not in C (p=0.37). Hormone receptor status was an independent prognostic factor in arm A (HR 0.61; 95%CI 0.41-0.93, p=0.02) but not in C (HR 0.79; 95%CI 0.44-1.41, p=0.42). In arm A the 10yr Kaplan-Meier estimates for RFS were 90.9% and 64.5% for high S-TILs and low S-TILs pts, respectively (HR 0.23; 95%CI 0.073–0.73, p=0.013). In arm C the 10yr Kaplan-Meier estimates for RFS were 80.0% and 80.1% for high S-TILs and low S-TILs pts, respectively (HR 1.26; 95%CI 0.5–3.2, p=0.63). Arm A (N=489)Arm C (N=456)VariableHR (95% CI)p-valueHR (95% CI)p-valueNodal statusLymph node(-)1.00 (ref)<0.00011.00 (ref)0.0131-3+0.58 (0.25, 1.35) 2.99 (0.40, 22.70) 4-91.46 (0.64, 3.35) 3.29 (0.42, 25.80) 10+2.42 (1.04, 5.64) 8.22 (1.06, 63.60) HR statusnegative1.00 (ref)0.01981.00 (ref)0.42positive0.61 (0.41, 0.93) 0.79 (0.44, 1.41) S-TILs status<60%1.00 (ref)0.0071.00 (ref)0.87≥60%0.2 (0.06, 0.65) 1.08 (0.42, 2.79) Tumor gradeGrade 1 or 21.00 (ref)0.501.00 (ref)0.51Grade 31.18 (0.73, 1.91) 1.24 (0.65, 2.39) Tumor size1.08 (0.98, 1.19)0.121.00 (0.93, 1.07)0.92Age0.99 (0.97, 1.00)0.131 (0.98, 1.03)0.87 Conclusions: In exploratory analyses from this subset HER2+ population from N9831, S-TILs were associated with RFS in patients treated with chemotherapy alone, and were not shown to be associated with RFS in patients treated with chemotherapy plus trastuzumab. Citation Format: Edith A Perez, Karla V Ballman, S Keith Anderson, E Aubrey Thompson, Sunil S Badve, Helen Bailey, Frederick L Baehner. Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-06.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Purpose Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS. Patients and Methods In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs. Results In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab. Conclusion The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.

Amyloidosis is caused by deposition in tissues of abnormal protein in a characteristic fibrillar form. There are many types of amyloidosis, classified according to the soluble protein precursor from which the amyloid fibrils are derived. Accurate identification of amyloid type is critical in every case since therapy for systemic amyloidosis is type specific. In ∼20–25% cases, however, immunohistochemistry (IHC) fails to prove the amyloid type and further tests are required. Laser microdissection and mass spectrometry (LDMS) is a powerful tool for identifying proteins from formalin-fixed paraffin-embedded tissues. We undertook a blinded comparison of IHC, performed at the UK National Amyloidosis Centre, and LDMS, performed at the Mayo Clinic, in 142 consecutive biopsy specimens from 38 different tissue types. There was 100% concordance between positive IHC and LDMS, and the latter increased diagnostic accuracy from 76% to 94%. LDMS in expert hands is a valuable tool for amyloid diagnosis.

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Abstract Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. Results: Thirty-nine patients, median age 11.8 years (range, 1–21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2,946 ng • h/mL (range, 937–5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245–3,675). Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Clin Cancer Res; 21(7); 1558–65. ©2014 AACR.