CONFERENCE NEWS

Highlights from 15th Congress of European Hematology Association

More than 8000 hematologists gathered in Barcelona, Spain, June 10-13, for the 15^th Congress of the European Hematology Association (EHA). The 2010 program included sessions on clinical, laboratory, and oncologic hematology, as well as hemostasis and transfusion medicine. Among the many important developments reported in oncologic hematology were those of improved patient’s outcomes—with maintenance rituximab in first-line therapy for follicular lymphoma, with second generation tyrosine kinase inhibitors (TKIs; nilotinib, dasatinib) in newly diagnosed chronic-phase CML, and with zoledronic acid in multiple myeloma. In addition to recently presented data of improved remission duration with maintenance lenalidomide therapy after ASCT in younger myeloma patients, the studies of interest presented at the EHA Congress were those evaluating the benefits of maintenance therapy in elderly patients with multiple myeloma.

Myeloma in the Elderly: Maintenance Is Effective

Antonio Palumbo, MD (University of Torino, Italy), presented results from 2 randomized, phase III studies evaluating whether continuous maintenance therapy (either lenalidomide or thalidomide and bortezomib) improves clinical outcomes in elderly (aged ≥65 years) patients with newly diagnosed multiple myeloma. Both of these large studies showed that addition of maintenance therapy to standard induction regimens improved clinical outcomes in this patient population but resulted in more toxicity. The first study showed that induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R) reduced the risk of disease progression by 58% (P<.001) and improved median progression-free survival (PFS; not reached vs 13 months) compared with melphalan/prednisone (MP) alone. However, grade 3/4 mainly hematologic toxicity was substantially increased in patients receiving MPR-R. The second study with longer follow up showed that bortezomib, melphalan, prednisone, and thalidomide followed by continuous bortezomib and thalidomide (VMPT-VT) significantly improved the 3-year PFS rate (56% vs 41%; P = .008) and complete response rate (38% vs 24%, P<.001) but did not improve OS. Moreover, in this study the VMPT-VT regimen significantly increased the occurrence of not only hematologic toxicity (neutropenia), but also cardiac toxicity, which was not observed in the study with lenalidomide. These regimens appear promising in term of efficacy, but the added toxicity may limit the potential benefits in those over 75 years and/or frail patients.

Haematologica. 2010;95(suppl 2): Abstract 0566.

Haematologica. 2010;95(suppl 2): Abstract 0568.

FROM THE LITERATURE

BRCAness Profile in Epithelial Ovarian Cancer Predictive for Response to Platinum and PARP inhibitors

BRCA1/2 germline mutations in epithelial ovarian cancer (EOC) render tumor cells deficient in the homologous recombination (HR) DNA-repair pathway and make them more sensitive to platinum compounds and PARP inhibitors, a new targeted therapy that has shown impressive results in patients with BRCA-positive advanced EOC.

Although only about 10% to 15% of women with EOC carry these germ-line mutations, it appears that up to one-third of all sporadic EOC may be deficient in HR as a result of both genetic and epigenetic mechanisms, and this is referred to as the “BRCAness” phenotype. These tumors may behave similarly to tumors with BRCA mutations.

Konstantinopoulos and colleagues attempted to identify a gene expression profile of "BRCAness" that correlates with responsiveness to platinum and PARP inhibitors. For development of the gene expression profile they used a publicly available microarray data set that included tumor expression data from 61 patients with pathologically confirmed EOC, including 34 with BRCA1/2 germline mutations and 27 without mutations (ie, sporadic cancers). They used genome-wide hierarchical clustering to define BRCA-like (BL) and non–BRCA-like (NBL) tumors. Based on these results they developed a 60-gene signature for BRCAness in familial and sporadic EOC. The authors tested the validity of this gene-expression profile by several methods and showed that the BRCAness profile accurately predicted platinum sensitivity and BRCA mutation status and was able to track development of platinum resistance. In addition, the BRCAness profile in vitro could distinguish between PARP-inhibitor–sensitive and PARP-inhibitor–resistant BRCA2 mutated pancreatic cancer cell line (Capan-1) clones.

Finally, the investigators tested tumor samples from 70 patients with sporadic EOC to evaluate whether the BRCAness profile correlated with clinical outcome. They found that the BRCAness profile was associated with predominantly high-grade serous tumors and with significantly improved disease-free survival (DFS; 34 months vs 15 months; P = .013) and OS (72 months vs 41 months; P = .006) compared to patients with a non-BRCAness profile. BRCAness profile remained an independent predictor of DFS and OS in multivariate analysis. Although these preliminary tests suggest that this gene signature could be a useful biomarker of BRCAness, prospective validation in patients treated with PARP inhibitors will be the true test of whether the BRCAness signature can predict responsiveness of PARP inhibitors and usher in a new era of molecularly targeted therapy for EOC.

J Clin Oncol. 2010 June 14. [Epub ahead of print]. 10.1200/JCO.2009.27.5719 (article)

J Clin Oncol. 2010 June 14. [Epub ahead of print]. 10.1200/JCO.2010.28.5791 (editorial)

G-CSF Support and Risk of AML/MDS

Growth factor support with granulocyte colony-stimulating factors (G-CSF) is commonly used in patients receiving myelosuppressive chemotherapy to reduce the risk of neutropenic complications and the necessity for dose reductions and delays. Administration of G-CSF is also used to enable the safe delivery of dose-intense chemotherapy regimens. However, concerns have been raised that use of G-CSF may increase the risk of developing acute myelogenous leukemia (AML) and/or myelodysplastic syndromes (MDS). This debate prompted Lyman and colleagues to conduct a metaanalysis of 25 randomized, controlled trials in which 12,804 patients were randomly assigned to initial G-CSF support or not. The outcomes of this analysis showed that use of G-CSF in patients receiving chemotherapy increased both chemotherapy dose intensity and the risk of developing AML/MDS (relative risk = 1.92; P = .007 and absolute risk = 0.41%; P = .009) but decreased all-cause mortality (relative risk = 0.897; P<.001). These results suggest that increasing chemotherapy dose intensity may increase its leukemogenic potential, but the authors point out that the analysis cannot rule out the possibility that G-CSF itself may contribute to the increased risk of secondary malignancies. However, use of G-CSF appears to improve OS as a result of either improved disease control or by preventing early deaths due to hematologic toxicity.

J Clin Oncol. 2010;28(17):2914-2924.

Can Biomarkers Predict DCIS Behavior?

Although ductal carcinoma in situ (DCIS) is a relatively common diagnosis, there are currently no validated methods to predict the risk of subsequent invasive cancer for women diagnosed with DCIS. It is estimated that 5% to 10% of women with DCIS treated with lumpectomy alone develop a subsequent invasive breast cancer within 5 years, and another 5% to 10% develop a subsequent DCIS.

To identify clinical, histopathologic, and molecular characteristics of initial DCIS lesions that might distinguish patients with a low risk versus a high risk of developing subsequent invasive breast cancer, Kerlikowske and colleagues conducted a case-controlled, retrospective study in a cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. Pathology review of initial paraffin-embedded DCIS tissue and immunohistochemistry to determine biomarkers (ER, PR, HER2, Ki67, p53, p16, and cyclooxygenase-2 [COX2]) in a subset of the reviewed cases was performed. Of the 1162 women, 324 women developed a subsequent breast tumor in the ipsilateral breast (170 invasive cancer and 154 DCIS) during median follow-up of 8.2 years. Interestingly, factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Multivariable analyses competing factors with univariate statistical significance confirmed that DCIS lesions that were p16⁺COX-2⁺Ki67⁺ or detected by palpation were associated with a significantly higher risk of subsequent invasive breast cancer; whereas classic histopathologic features, such as nuclear grade, were not able to distinguish high-risk disease. In contrast, factors that were independently associated with subsequent DCIS included positive or uncertain margins, DCIS lesions that were p16⁺COX-2-Ki67⁺, and those that were ER-HER2⁺Ki67⁺. The authors concluded that biomarkers, not histopathology, hold the key to identifying which tumors are associated with a high risk of progressing to invasive breast cancer and in need of immediate treatment.

In an accompanying editorial, Craig Allred noted that this is a thought-provoking study that addresses an important issue, but these data are not practice changing and require independent validation. He highlighted that, currently, DCIS is rarely treated with lumpectomy alone, as in this study, and it will be critical to determine whether the results of this study would have been influenced by adjuvant radiation and hormonal therapy.

J Natl Cancer Inst. 2010;102(9):627-637.

J Natl Cancer Inst. 2010;102(9):585-597.

Targeted Intraoperative Radiotherapy: A New Standard of Care?

The randomized phase III TARGIT-A (TARGeted Intraoperative RadioTherapy-A) trial reported by Vaidya et al showed that a single dose of targeted intraoperative radiotherapy was noninferior to standard whole-breast external-beam radiotherapy in women older than 45 years with invasive ductal breast carcinoma undergoing breast-conserving surgery. The primary outcome was local recurrence in the conserved breast. Among 2021 women, there were only 6 local recurrences in the intraoperative radiotherapy group and 5 in the external beam radiotherapy group (1.20% versus 0.95%, respectively; P = .41) at 4 years. In addition, targeted intraoperative radiotherapy was associated with significantly less Radiation Therapy Oncology Group (RTOG) grade 3 toxicity (0.5% vs 2.1%; P = .002).

In the accompanying editorial, Azria and Bourgier commented that this technique is appropriate in selected patients, and they support the recommendations of the American Society for Therapeutic Radiology and Oncology task force proposing that intraoperative accelerated partial-breast irradiation is appropriate for women age ≥60 years with estrogen receptor–positive, T1N0, invasive ductal carcinoma and tumor size ≤1 cm. Indeed, these selection criteria are consistent with the population of patients enrolled in the TARGIT-A trial. One of the great advantages of this approach is that treatment is completed for the majority of patients at the time of surgery. Unless there is an indication for additional radiotherapy based on pathology (eg, lobular carcinoma) or other reasons, patients do not need to return to the clinic for up to 5 weeks of daily fractionated radiotherapy. This could greatly cut cost and improve convenience.

Lancet. 2010;376(9735):91-102.

BRIEF REPORTS

Gefitinib Superior to Standard Chemotherapy in Selected Patients with NSCLC

Maemondo et al reported the results of a randomized phase III trial of gefitinib (250 mg/day) versus standard carboplatin/paclitaxel chemotherapy in newly diagnosed patients with metastatic non-small cell lung cancer (NSCLC) who were selected based on the presence of epidermal growth factor receptor (EGFR) mutations. A planned interim analysis of the first 200 patients demonstrated that gefitinib significantly improved PFS (10.8 months vs 5.4 months; HR = 0.30; P<.001) and objective response rate (74% vs 31%, P<.001), with acceptable toxicity, compared with chemotherapy; therefore, the trial was halted. Median OS was 30.5 months for patients treated with gefitinib and 23.6 months in the chemotherapy group (P = .31). This is a practice-changing study, and the authors strongly recommend testing for EGFR mutations in all patients with newly diagnosed NSCLC.

N Engl J Med. 2010;362(25):2380-2388.

Better Outcome in HPV-Positive Oropharyngeal Cancer

Human papillomavirus (HPV) is a growing cause of oropharyngeal squamous-cell carcinoma (SCC) in the industrialized world, and it appears to define a molecularly distinct subtype of oropharyngeal SCC. Ang et al performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal SCC who were enrolled in a RTOG 0129 randomized trial comparing treatment with accelerated-fractionation or standard-fractionation radiotherapy plus cisplatin. After a median follow-up of 4.8 years, there was no significant difference in the 3-year rate of OS between the accelerated-fractionation and the standard-fractionation treatment groups. Interestingly, patients with HPV-positive tumors (64% of total study population) had a significantly better 3-year survival rate compared to patients with HPV-negative tumors (82% versus 57%; P<.001). This suggests that HPV-positive disease is a distinct entity, and that these patients could benefit from a tailored treatment approach.

N Engl J Med. 2010;363(1):24-35.

ADDITIONAL PUBLICATIONS WORTH READING

• Benefit of Bone-Targeted Radioisotope Therapy in Prostate Cancer. This review article discusses the role of bone-targeted radioisotopes as part of multimodality treatment of advanced prostate cancer. The authors examine the antitumor mechanism of action, dosing strategies, the activity of new-generation radiopharmaceuticals, and the benefit of combining radioisotopes with hormonal therapy, chemotherapy, or targeted therapy. Clin Adv Hematol Oncol. 2010;8(5):341-351.
• The Future of Stem Cell Transplantation for Multiple Myeloma. In this review article, the authors describe the current state of the art in autologous and allogeneic stem cell transplantation for multiple myeloma and discuss the prospects for improvement in patient outcomes with incorporation of the new agents in transplantation programs. Blood. 2010;115(18):3655-3663.
• Role of Trastuzumab in Gastric Cancer. This review article describes the use of trastuzumab in patients with HER2-positive advanced gastric and esophagogastric junction adenocarcinoma and highlights the practice-changing results of the ToGA study, which demonstrated that addition of trastuzumab to cisplatin/fluoropyrimidine chemotherapy significantly improved PFS and OS. Eur J Cancer. 2010;46(10):1949-1959.
• American Society of Clinical Oncology Guidelines: Serum Tumor Markers in Men with Germ Cell Tumors. This article summarizes the American Society of Clinical Oncology practice guidelines for the use of serum tumor markers for screening, tumor staging, treatment selection, and monitoring relapse in men with germ cell tumors. J Clin Oncol. 2010;28(20):3388-3404.
• Managing Blood Pressure in Patients Receiving VEGF Inhibitors. This article summarizes the recommendations of an expert panel, convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee, for the management of blood pressure during treatment with vascular endothelial growth factor (VEGF) signaling pathway inhibitors. The panel made recommendations for risk identification, active monitoring, and treatment goals. J Natl Cancer Inst. 2010;102(9):596-604.

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