Setting Of Refractory Disease Research Articles

Targeting HER2 in breast cancer: beyond trastuzumab

Trastuzumab has altered the natural history of HER2+ breast cancer. In the metastatic setting, it has improved progression-free and overall survival. In patients with operable breast cancer, adjuvant trastuzumab, when added to chemotherapy, has improved disease-free and overall survival. Unfortunately, virtually all patients with metastatic breast cancer develop disease that is at least partially resistant to trastuzumab. In these patients, there is still value in continuing trastuzumab in combination with other treatments, but trastuzumab alone is unable to fully suppress tumor growth. Multiple mechanisms of resistance to trastuzumab have been suggested including activation of other growth factor receptors, preferential finding of HER2 to HER3, loss of the extracellular domain of HER2, and activation of the PI3 kinase pathway as a result of PTEN loss or a PIK3CA mutation. It is unknown to what extent these mechanisms are relevant in individual patients, but it is probable that many different mechanisms of resistance are clinically important. Over the past decade, a number of treatments have been developed for patients with trastuzumab-resistant disease. At present, only lapatinib, a small-molecule inhibitor of HER1 and HER2, is commercially available. It is active when administered with either chemotherapy or trastuzumab. A variety of other therapies are under investigation in phase III clinical trials. Pertuzumab, a monoclonal antibody that inhibits HER2-HER3 heterodimers, appears to be effective when combined with trastuzumab ± chemotherapy. T-DM1, an antibody-drug conjugate, has also displayed remarkable activity in the setting of refractory disease and has limited toxicity. It is presently under investigation in multiple randomized trials. Neratinib is an oral irreversible tyrosine kinase inhibitor that targets HER1, HER2, and HER4. As a single agent, it appears to be more active than lapatinib, but is associated with more significant toxicity. It, too, is under evaluation in phase III trials in the adjuvant and metastatic settings. A variety of other agents are under active study including the mTOR inhibitors, the PI3kinase inhibitors, angiogenesis inhibitors, and IGFR antagonists. It is likely that a number of new agents will be available for the treatment of HER2+ breast cancer in the next several years, and outcomes for this group of patients will continue to improve.

Influence of NPM1 and FLT3-ITD Status On Outcome in Relapsed/Refractory AML Patients with Normal Karyotype and Receiving Salvage Therapy Including Gemtuzumab Ozogamicin (GO).

Abstract 3110Poster Board III-47The aim of this study was to investigate the influence of the NPM1/FLT3-ITD status on outcome in relapsed/refractory AML patients with normal karyotype who received a salvage regimen using GO as monotherapy or in combination with other agents.For this purpose, we analyzed the outcome of 57 AML patients with normal karyotype treated between 2001 and 2009. Patients received GO as monotherapy or in combination with other chemotherapeutic agents at time of relapse (n=36) or in the setting of refractory disease (n=21). There were 26 males and 31 females with a median age of 52 (range, 20-70) years at time of leukemia diagnosis. The FAB distribution included 2, 13, 15, 11, 12 and 1 AML cases from the M0, M1, M2, M4, M5 and M6 subgroups, respectively. Three cases were considered as unclassified. In addition, 5 patients had secondary AML. All patients were CD33 positive with a median CD33 expression level of 98%. As salvage treatment, 46 patients received the MIDAM regimen (GO: 9 mg/m2 at day 4 + Cytarabine 1g/m2/12 hours day 1-5 + Mitoxantrone 12 mg/m2/day day 1-3).3 In 2 patients receiving the MIDAM regimen, Mitoxantrone was omitted to avoid cardiac toxicity. Four patients received GO as monotherapy at 9 mg/m2 (n=3) or at 6 mg/m2 (n=1). The 5 remaining patients received GO 3 to 9 mg/m2 combined with other chemotherapeutic agents (Cytarabine + VP16 + GO, n=2; Cytarabine + Idarubicine + GO, n=2; Cytarabine + Amsacrine + GO, n=1). After salvage therapy, 25 patients could proceed and receive consolidation with an allogeneic stem cell transplant.In this series, all patients could be screened in the blood or bone marrow for mutations in the NPM1 and in the FLT3 gene (ITD mutations) at diagnosis. Numbers of patients according to NPM1/FLT3-ITD status were as follow: (+/−): n=14, (+/+): n=9, (−/−): n=19, (−/+): n=15. The same proportion of refractory patients was observed in the favourable NPM1+/FLT3-ITD- sub-group as compared to the other sub-groups (36%, n=5/14 vs 37%, n=16/43).With a median follow-up of 23.3 (range, 2.3-94.5) months for surviving patients, OS was 46.5% (95%CI, 33.6-59.9%) at 2 years. CR, relapse and death rates according to NPM1/FLT3-ITD status were as follow: CR: (+/−): 85%, (+/+): 66%, (−/−): 47%, (−/+): 73%, P=NS; Relapses: (+/−): 33%, (+/+): 33%, (−/−): 33%, (−/+): 54%, P=NS; Deaths: (+/−): 28%, (+/+): 78%, (−/−): 58%, (−/+): 66%, P=0.02 Also, the death rate was significantly lower in FLT3-ITD- patients as compared to FLT3-ITD+ cases (45% vs. 71%, P=0.05). OS was significantly higher in the NPM1+/FLT3-ITD- sub-group as compared to other patients (78% vs. 36% at 2 years, P=0.026).In conclusion, and although this needs to be confirmed in a prospective setting, refractory/relapsed AML patients combining a normal karyotype and a NPM1+/FLT3-ITD- molecular status are likely to remain in a “favorable prognosis” category when receiving salvage therapy. Such information is of major interest for patients counselling and for the design of salvage therapy approaches. DisclosuresNo relevant conflicts of interest to declare.

First-Line Use of Anti–Epidermal Growth Factor Receptor Monoclonal Antibodies in Metastatic Colorectal Cancer

Several molecular pathways have been shown to play key roles in the development and progression of colorectal cancer (CRC). This enhanced understanding of tumor biology has provided the rationale for the design and development of novel agents that are directed against important targets, including growth factors, receptors, and tumor-specific/tumor-selective antigens. The epidermal growth factor receptor (EGFR) signaling pathway has received much attention over the past 5-10 years because it is overexpressed in more than 85% of tumors from patients with metastatic CRC. Cetuximab and panitumumab are monoclonal antibodies presently approved for use by the FDA in the refractory disease setting, and they have provided significant advances in the treatment of advanced CRC. However, much focus has shifted toward using these biologic therapies in combination with cytotoxic chemotherapy in up-front settings, such as first-line therapy and in the neoadjuvant therapy of liver-limited disease. The clinical studies conducted to date suggest that cetuximab can be safely and effectively combined with oxaliplatin- and irinotecan-based chemotherapy in the first-line treatment of metastatic CRC. Moreover, the results of the CRYSTAL phase III study provide support for the use of the combination of FOLFIRI (5-fluorouracil/leucovorin/irinotecan) and cetuximab in the neoadjuvant setting and allow for R0 surgical resection with curative intent. Much work continues to investigate the critical molecular biomarkers that can be used to predict clinical response to chemotherapy and/or targeted therapies as well as to identify which patients might be at increased risk for developing drug-specific side effects.