The combination of at least one functional technique with free-to-total PSA ratio is more accurate than combining only imaging variables in cancer detection. The use of more than two imaging variables does not increase the detection rate. Functional MRI has the potential to help avoid a large number of negative biopsies.
Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.
Objective: To assess the thymidylate synthase protein (TS) in tumor cells of resected gastric cancer patients treated with adjuvant tegafur (TG), we reviewed the outcome of 94 randomized patients treated either with adjuvant TG plus mitomycin C (MMC) or MMC alone. Methods: TS was determined in 76 out of 94 patients, previously randomized to receive adjuvant TG, 500 mg/m2/day p.o. for 6 months plus four courses of MMC, 10– 20 mg/m2 i.v. every 6 weeks or MMC alone. An immunohistochemical assessment with the monoclonal antibody TS-106 was performed. Results: Low TS was observed in 38 patients (20 treated with TG-MMC and 18 with MMC) and high TS in the other 38 patients (21 treated with TG-MMC and 17 with MMC). After 10 years’ median follow-up time, 61% of adjuvant TG-MMC patients and 43% of MMC patients were alive and disease-free. Disease-free survival and overall survival were significantly better for patients treated with TG-MMC compared to MMC adjuvant (p = 0.0277 and p = 0.05), and low-TS compared to high-TS patients (p = 0.0184 and p = 0.0198). In 38 low-TS patients we observed an 83% chance to be disease-free in TG-MMC-treated patients and 55% in MMC-treated patients (p = 0.04). Conclusions: A low TS level determines a subset of patients that may benefit from adjuvant oral TG when added to MMC showing a 5-year cure rate of more than 80%.
Introduction
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and DM1 (a microtubule inhibitor). T-DM1 prolonged PFS and OS compared with standard therapy in a phase 3 study in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane and was well tolerated (Verma, NEJM 2012). When combined with docetaxel (D) or pertuzumab (P), T-DM1 antitumor activity was enhanced in preclinical models of HER2-positive breast cancer (Lewis-Phillips, AACR 2008; Fields, AACR 2010). The feasibility of combining T-DM1 with D±P in patients with HER2-positive MBC and early-stage breast cancer (EBC) was demonstrated in phase 1b of study BP22572, in which the maximum tolerated doses (MTDs) were defined (Martin, SABCS 2012). Here we report on patients with EBC who were treated at the MTDs in phases 1b and 2a of the study.
Methods
BP22572 is a phase 1b/2a open-label, multicenter study evaluating neoadjuvant T-DM1 with D±P in patients with centrally confirmed HER2-positive EBC (clinical stage IIa–IIIc) who have not received prior anticancer therapy. Patients with EBC were treated for up to 6 cycles at the doses specified in the Table.
Results
Recruitment into the neoadjuvant cohorts was completed in November 2012; the data cutoff date for analyses presented here was May 2, 2013. A total of 70 patients were treated with the combinations (median age, 51.5 years [range, 34–76]). Grade 3/4 adverse events (AEs) were reported for 51 (72.9%) patients; those occurring in >1 patient are shown in the Table. One patient in the T-DM1 + D 100 mg/m2 cohort experienced grade 5 pneumonitis shortly after an episode of neutropenic fever. As of the data cutoff date, all patients had received neoadjuvant treatment, but not all had undergone surgery. Pathologic complete response (pCR; ypT0/is ypN0, absence of invasive disease or in situ disease only in the breast and negative axillary nodes) was achieved in 40 of 70 treated patients (preliminary pCR rate, 57.1%).
Grade 3/4 AEs occurring in >1 patientAE, n (%)All patients (N = 70)T-DM1 3.6 mg/kg + D 75 mg/m2 q3w (n = 15)T-DM1 3.6 mg/kg + D 100 mg/m2 q3w (with G-CSF) (n = 22)T-DM1 3.6 mg/kg + D 60 mg/m2 + P 840 mg LD, then 420 mg q3w (n = 11)T-DM1 3.6 mg/kg + D 75 mg/m2 + P 840 mg LD, then 420 mg q3w (with G-CSF) (n = 22)Neutropenia21 (30)7 (47)2 (9)7 (64)5 (23)Thrombocytopenia14 (20)2 (13)6 (27)—6 (27)ALT increased11 (16)3 (20)3 (14)3 (27)2 (9)Asthenia6 (9)2 (13)2 (9)1 (9)1 (5)AST increased5 (7)2 (13)1 (5)—2 (9)Lymphopenia3 (4)—2 (9)—1 (5)Mucosal inflammation3 (4)—2 (9)—1 (5)Anemia2 (3)—1 (5)—1 (5)Febrile neutropenia2 (3)—1 (5)—1 (5)Leukopenia2 (3)1 (7)—1 (9)—Diarrhea2 (3)——1 (9)1 (5)
Conclusions
Grade 3/4 AE profiles were consistent with the known safety profiles of the 3 agents in patients with MBC. There was 1 grade 5 event (pneumonitis) in the T-DM1 + D 100 mg/m2 cohort. Preliminary pCR data are encouraging. Final safety and efficacy data from all patients in phase 2a of the study will be available for the presentation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-07.
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