January 2010 Issue

Welcome to the first issue of 2010 primeLINES and the inaugural edition of our primeLINES Clinical Opinion Poll. Each month, we will feature a clinically oriented poll for your participation. This month, we’ll begin with a simple “who are you and how are we doing” poll. The information we obtain from your responses to this and future polls will be used to further improve this publication. Thank you for your participation and your continued interest in primeLINES.

This issue is dedicated to highlights from the 51st American Society of Hematology (ASH) Annual Meeting and Exposition and 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

primeLINES CLINICAL OPINION POLL

NEWS FROM THE 51st ASH ANNUAL MEETING

Approximately 25,000 hematologists attended the ASH Annual Meeting in New Orleans from December 5-8, 2009. Many oral presentation and poster sessions took place during the conference, during which abstracts featuring the latest research in the field were chosen through blind scoring and a peer-review selection process as the most outstanding among the thousands submitted for consideration. The following key studies were presented during these sessions.

Bendamustine Challenges CHOP as First-Line Chemotherapy for Indolent Lymphoma

Abstract 405: On behalf of the Study Group Indolent Lymphomas, Germany, Mathias Rummel, MD, PhD, from Justus-Liebig University-Hospital, Gießen, Germany presented the final results of a large randomized phase III trial comparing bendamustine (Treanda^®) plus rituximab (Rituxan^®/MabThera^®) (B-R) with standard CHOP plus rituximab (CHOP-R) as first-line therapy for patients with advanced follicular, indolent, and mantle cell lymphomas. Bendamustine HCl is a bifunctional mechlorethamine derivative that has demonstrated impressive response rates in two phase II studies in patients with indolent lymphoma. The combination of B-R yielded high complete response (CR) rates and median progression-free survival (PFS) on the order of 24 months in both the first-line and recurrent settings.

This phase III trial enrolled 549 previously untreated patients with follicular, mantle cell, or other indolent lymphomas who were randomized to receive rituximab (375 mg/m² day 1) plus either bendamustine (90 mg/m² days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was PFS. Although the overall response rate (ORR) was similar in both arms (91% for B-R and 93% for CHOP-R), patients treated with B-R had a significantly higher CR rate (40% compared to 31% for CHOP-R; P = .0323). In addition, PFS, event free survival, and time to next treatment all favored bendamustine. Median PFS was 55 months for B-R versus 35 months for CHOP-R; P = .0001). Additionally, bendamustine was associated with significantly less neutropenia, thrombocytopenia, peripheral neuropathy and stomatitis compared with CHOP-R. Based on these findings, the authors concluded that B-R has the potential to become a new standard of care for first-line treatment of patients with follicular lymphoma, mantle cell lymphoma, and indolent lymphomas.

Rummel MS, et al. Blood. 2009;114: Abstract 405.

Use of Novel Agents and Maintenance Therapy Improves Outcomesfor Multiple Myeloma in Elderly Patients

Abstract 613: Antonio Palumbo, MD, from the University of Torino, Torino, Italy, presented the interim results of a large, multicenter, randomized, phase III trial evaluating the combination of lenalidomide (Revlimid^®) plus melphalan and prednisone versus melphalan/prednisone alone in elderly patients with newly diagnosed multiple myeloma (MM). This study also tested the hypothesis that the addition of lenalidomide maintenance following induction therapy would further improve clinical outcomes. A total of 459 elderly patients (≥65 years of age) with symptomatic MM were randomized to melphalan (0.18 mg/kg) and prednisone (2 mg/kg) plus either oral lenalidomide (10 mg/day) or placebo for 9 cycles. Thereafter, patients in the lenalidomide group received either lenalidomide maintenance (25 mg/day) or placebo until disease progression. At a median follow-up of 9.4 months, there was a 50% improvement in PFS among patients treated with lenalidomide (P<.001). Median PFS was 13.0 months in the melphalan/prednisone group and was not reached in the lenalidomide group. The ORR was 67% in the lenalidomide group compared to 49% in the melphalan/prednisone group. Based on these interim results, the authors concluded that the combination of lenalidomide plus melphalan/prednisone followed by maintenance lenalidomide was well tolerated and should be considered a new standard of care for elderly patients with newly diagnosed MM. This is the first study to show benefit from continuing treatment as long as the patient continues to respond and may be a first step toward revising current practice standards for MM.

Palumbo A, et al. Blood. 2009;114: Abstract 613.

Abstract 3: Though the VISTA trial previously demonstrated that the combination of bortezomib (Velcade^®) plus melphalan/prednisone (VMP) is superior to melphalan/prednisone (MP) alone in patients with MM, this regimen was associated with a high incidence of peripheral neuropathy. The Spanish Myeloma Group directly compared a less intense VMP regimen with a novel regimen combining bortezomib with thalidomide and prednisone (VTP) to determine the optimal combination for elderly patients. Maria-Victoria Mateos, MD, PhD, from University Hospital in Salamanca, Spain, presented the results of this randomized, double-blind, phase III trial. Patients were randomized to induction therapy with VMP or VTP for 6 cycles followed by either VP or VT maintenance therapy. Of 260 elderly patients with MM randomized, 253 were evaluated for response to induction therapy. Both induction regimens demonstrated similar efficacy with respect to ORR, CR rate, time to progression (TTP), and overall survival (OS), and outcomes were also good in the high-risk subgroup. After induction therapy, the ORR was ~80% with a CR rate of ~25% in both arms, 2-year TTP was 75% for VMP and 70% for VTP, and 2-year OS was 81% and 84% respectively. Subsequently, 178 patients were randomized to maintenance therapy, and 143 were evaluable for efficacy. Maintenance therapy with either VT or VP markedly improved the quality of responses, increasing the CR rate from ~25% to 42% in both arms. However, there was a trend toward better 1-year TTP in the VT group (84% versus 71%; P = .05). With regard to safety, during induction therapy the VMP regimen was associated with more neutropenia, thrombocytopenia, and infections, but less cardiac toxicity compared with VTP. During maintenance therapy, more ≥grade 3 cardiac and gastrointestinal toxicities were observed in patients receiving VT compared to VP. The authors concluded that both VMP and VTP induction regimens are highly effective with similar ORR and CR rates, but with clearly different toxicity profiles. Maintenance therapy with either VT or VP markedly improved the quality of responses with a good safety profile; however, it appears that the combination of VMP followed by VT is significantly superior to VTP/VP. Finally, data from this trial suggest that the combination of VMP/VTP induction and VP/VT maintenance schedules can overcome the poor prognosis of high-risk cytogenetic abnormalities in elderly patients with MM.

Mateos M-V, et al. Blood. 2009;114: Abstract 3.

Taken together, these two studies demonstrate that the use of lenalidomide, bortezomib, and thalidomide can lead to significant improvements in treatment outcomes of elderly patients with MM. Physicians should choose the best treatment strategy for each patient based on data from randomized studies, as well as individualization of therapy based on the patient’s biologic age, comorbidities, and the expected toxicity profile of different regimens

Nilotinib Trumps Imatinib for Newly Diagnosed CML: Is It Time for a New Standard?

Imatinib is the current standard of care in patients with newly diagnosed chronic myelogenous leukemia (CML) intolerance or development of resistance are limiting factors. Nilotinib (Tasigna^®), a highly potent and selective inhibitor of BCR-ABL, is currently indicated for adults with Philadelphia chromosome–positive (Ph+) CML in chronic phase (CP) or accelerated phase (AP) who are resistant or intolerant to imatinib. Two studies presented at the ASH Annual Meeting suggest that nilotinib is superior to the current standard of care, imatinib, for the treatment of newly diagnosed, Ph+ CP-CML. These studies raise the question of whether second-generation BCR-ABL tyrosine kinase inhibitors (TKIs) should replace imatinib as the preferred first-line therapy for CP-CML.

Abstract LBA1: Giuseppe Saglio, MD, from the University of Torino, Torino, Italy, presented the results of the ENESTnd trial, an international, randomized, phase III study involving 846 patients who were randomized to either nilotinib (300 mg or 400 mg bid) or standard imatinib therapy (400 mg/day). Patients treated with nilotinib had significantly higher rates of major molecular response (MMR) at 12 months and significantly higher rates of complete cytogenetic response (CCyR) at 12 months compared with the imatinib group. Patients treated with nilotinib were also significantly less likely to have progressed at 12 months. Both doses of nilotinib were superior to imatinib, and treatment with nilotinib resulted in higher MMR rates in the subset of patients with a high Sokal score. Participating investigators suggest that, based on results from this trial, nilotinib may replace imatinib as the standard of care in patients with newly diagnosed CML.

Abstract 341: The second presentation, by Jorge Cortes, MD, from the University of Texas M. D. Anderson Cancer Center, Houston, Texas, detailed the results of the single-arm phase II study of nilotinib (400 mg bid) in 67 patients with newly diagnosed, Ph+ CP-CML, and the results were compared with historical control cohorts treated with imatinib (either 400 mg/day or 800 mg/day). After 3 months of therapy with nilotinib, 81% of patients had a CCyR, and this improved to 95% at 12 months. This compares very favorably to imatinib, which produces a CCyR in 40% to 60% of patients at 3 months and 60% to 90% at 12 months depending on the dose. Moreover, 91% of patients in the nilotinib group maintained a CCyR at 30 months, which was better than either imatinib control group. The majority of patients (71%) treated with nilotinib also achieved a MMR at 12 months. These data demonstrate that nilotinib is highly active in patients with newly diagnosed Ph+ CP-CML and induces rapid responses with a favorable tolerability profile. Additional data evaluating nilotinib as front-line treatment for patients with CML in early chronic phase were recently published in the Journal of Clinical Oncology (Cortes J, et al. J Clin Oncol. 2010;28(3):392-397.).

Saglio G, et al. Blood. 2009;114: Abstract LBA1

Cortes J, et al. Blood. 2009;114: Abstract 341.

Dasatinib Also Effective for Newly Diagnosed, Chronic Phase CML

Abstract 338: Jorge Cortes also presented the results of a phase II study investigating the efficacy and safety of dasatinib in patients with newly diagnosed, Ph+ CP-CML. Dasatinib (Sprycel^®), another second-generation BCR-ABL inhibitor, is indicated for the treatment of adults with all phases of CML who exhibit resistance or intolerance to prior therapy, including imatinib. Patients in this trial (N = 71) were treated with dasatinib (100 mg/day) and the results were compared with historical control cohorts treated with imatinib (400 or 800 mg/day). After 3 months of therapy with dasatinib, 80% of patients had a CCyR, and this improved to 94% at 12 months. The rate of MMR achieved with dasatinib was 74% at 12 months and 89% at 24 months, which compares favorably with imatinib. Data from this study demonstrated the safety and efficacy of dasatinib as front-line therapy in patients with previously untreated CP-CML. The dasatinib 100 mg qd arm continues to accrue patients due to improved response and favorable adverse event profile. Additional data regarding the use of dasatinib in patients with early chronic-phase CML were recently published in the Journal of Clinical Oncology (Cortes J, et al. J Clin Oncol. 2010;28(3):398-404.).

Cortes J, et al. Blood. 2009;114: Abstract 338.

Together, these three studies demonstrate that nearly all patients with newly diagnosed Ph+ CP-CML who are treated with a second-generation TKI will achieve a rapid CCyR and the majority will achieve a MMR. Several phase III trials are currently underway to further define the optimal use of second-generation TKIs in Ph+ CML.

Thrombopoietin Receptor Agonists: Promising Long-Term Treatment for Chronic ITP

Chronic immune (idiopathic) thrombocytopenic purpura (ITP) is characterized by increased platelet destruction and suboptimal platelet production. Currently available immunosuppressive therapies, such as corticosteroids, immunoglobulin, or rituximab, produce only short-term improvements in platelet counts and may have issues with toxicity. Consequently, there is a significant unmet need for safe and effective long-term maintenance therapy for ITP. Data presented suggest that thrombopoietin receptor agonists may address that need.

Abstract 681: James Bussel, MD, from New York Presbyterian Hospital, New York, New Yorkpresented the results of a 5-year, open-label, extension study of subcutaneous romiplostim (Nplate™) in 291 adult patients with chronic ITP who had completed a previous study. Romiplostim was administered once weekly with dose adjustments to maintain platelet counts in the target range (50 to 200 x 10⁹/L). Patients maintaining a stable dose for 3 consecutive weeks could self-administer romiplostim at home. Overall, 75% of patients were eligible for self-injection at home, and 94% maintained a platelet count ≥50 x 10⁹/L throughout the study. Many patients were also able to decrease their use of concomitant medications. Importantly, the incidence of adverse events and bleeding events remained stable or decreased over time, and the incidence of thromboembolic events was low (~2%) throughout the study. Therefore, romiplostim appears to be well tolerated with long-term use and effectively maintains platelet counts within the target range with minimal dose adjustments.

Abstract 682: The second presentation, by Mansoor Saleh, MD, from Georgia Cancer Specialists, Atlanta, Georgia described the results of the EXTEND study investigating the long-term efficacy and safety of eltrombopag (Promacta^®) for chronic ITP. Eltrombopag is the first oral, small molecule, thrombopoietin receptor agonist approved in the United States for the treatment of chronic ITP. In this study, 299 patients were treated for up to 2 years (only 18 patients have completed 2 years of therapy), and median platelet counts were maintained above 50 x 10⁹/L throughout the study with a concomitant decrease in bleeding events. Overall, 86% of patients maintained a platelet count ≥50 x 10⁹/L. Moreover, 43% of patients receiving concomitant medications for ITP (mainly corticosteroids) were able to reduce or permanently discontinue those medications. Additionally, eltrombopag was well tolerated with thromboembolic events occurring in only 4% of patients.

Bussel JB, et al. Blood. 2009;114: Abstract 681.

Saleh MN, et al. Blood. 2009;114: Abstract 682.

Oral Thrombin Inhibitor, Dabigatran Etexilate: An Effective Alternative to Warfarin

Abstract 1: For decades, warfarin (Coumadin^®) has been the standard for managing venous thromboembolism (VTE), but is plagued by the need for constant monitoring of the international normalized ratio (INR), and frequent dose adjustments. Recently, the direct thrombin inhibitors have begun to challenge warfarin use in various clinical situations. Although this class suffered a significant setback because of safety issues (mainly liver toxicity) associated with ximelagatran (Exanta™), the data presented at the ASH Annual Meeting regarding the efficacy and safety of dabigatran (Prodaxa^®) are encouraging. In the plenary presentation, Sam Schulman, MD, from McMaster University, Hamilton, Canada, presented the results of the randomized, placebo-controlled RE-COVER trial comparing dabigatran etexilate with standard warfarin therapy. Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor with a half life of 12-17 hours and predictable, consistent anticoagulant effects. This trial enrolled 2539 patients with acute symptomatic unilateral or bilateral VTE of the leg and/or pulmonary embolism who were treated with low molecular weight or unfractionated heparin for 5 to 11 days. Patients were then randomized to warfarin (INR 2.0-3.0) or dabigatran (150 mg bid) for 6 months. Based on the rate of recurrent VTE or related death and all secondary efficacy endpoints, dabigatran was as effective as warfarin, and it significantly reduced the risk of clinically relevant bleeding events compared to treatment with warfarin (hazard ratio = 0.63; P = .002). Importantly, deaths, acute coronary syndromes, and liver function abnormalities were infrequent and similar in the 2 treatment groups. Based on these results, the authors concluded that dabigatran offers a safe and effective alternative to warfarin for the treatment of acute VTE. Moreover, dabigatran does not require monitoring and may simplify therapy. Therefore, it is a step in the right direction in the search for an optimal anticoagulant.

Schulman S, et al. Blood. 2009;114: Abstract 1.

A detailed analysis of the RE-COVER trial, providing more information regarding patient characteristics, efficacy, and safety, was recently published in the New England Journal of Medicine.

Schulman S, et al. N Engl J Med. 2009;361(24):2342-2352.

NEWS FROM THE 32nd ANNUAL SABCS

More than 9000 breast cancer clinicians, researchers, and other healthcare professionals attended the 32nd Annual SABCS held from December 9-13, 2009, in San Antonio. This meeting was conducted in collaboration with the University of Texas Health Sciences Center, the American Association for Cancer Research, and Baylor College of Medicine. During the symposium a comprehensive review of current breast cancer management and clinical research today was presented via oral presentations, symposia, and posters. The highlights of some major findings are presented below.

TEAM Trial: Exemestane Effective Upfront or in Sequence

Abstract 11: The long awaited 5-year results of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study were presented by Dan Rea, MD, from University of Birmingham, Birmingham, United Kingdom, on behalf of the TEAM investigators. This study enrolled nearly 10,000 postmenopausal women with estrogen receptor–positive (ER+) and/or progesterone receptor–positive (PgR+) early breast cancer and compared exemestane (Aromasin^®) as initial adjuvant therapy with sequential therapy (tamoxifen followed by exemestane). This open-label study was initiated in 2001, and the original objective was to compare disease-free survival (DFS) for patients treated with exemestane (25 mg/day) versus tamoxifen (20 mg/day). However, in 2004, the study design was modified based on new data from the IES study showing that sequential therapy was superior to tamoxifen alone. As a result, all patients initially receiving tamoxifen were switched to exemestane after 2.5 to 3 years, an additional 2500 patients were randomized, and the statistical plan was modified to include two coprimary endpoints: (1) DFS of tamoxifen versus exemestane that was previously reported at 2.75 years median follow-up (Jones S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 15.); and (2) DFS after 5 years of exemestane versus sequential therapy with tamoxifen followed by exemestane.

Results of the first coprimary endpoint after 2.75 years of follow-up, using a censored analysis to account for early crossover, suggested a significant DFS advantage of exemestane versus tamoxifen. However, after 5.1 years of follow-up, the intent-to-treat analysis of the second coprimary endpoint showed no DFS difference between the treatment arms with a hazard ratio of 0.97 (P = .604), and a censored analysis to account for early crossover did not alter the conclusion. Similar outcomes were observed for time to recurrence and OS. Moreover, there was no significant DFS benefit for exemestane in the subset analysis based on nodal status. As expected, upfront exemestane was associated with an increased incidence of osteoporosis, fractures, arthralgia, nerve compression, vaginal dryness, hypertension, and hyperlipidemia; tamoxifen followed by exemestane was associated with an increased incidence of hot flushes, vaginal bleeding, vaginal discharge, endometrial abnormalities, endometrial cancer, and venous thrombosis. The question that now must be answered is whether there are subsets of patients based on clinical characteristics or biomarkers who may benefit from either sequential tamoxifen followed by exemestane or upfront exemestane for 5 years.

Rea D, et al. Cancer Res. 2009;69(24 Suppl): Abstract 11.

RIBBON-2 Extends the Benefit of Bevacizumab in Metastatic Breast Cancer

Previous studies (E2100, AVADO, and RIBBON-1) have demonstrated that the addition of bevacizumab (Avastin^®) to standard first-line chemotherapy improves response rates and PFS in patients with metastatic breast cancer. However, bevacizumab’s role as an adjunct to chemotherapy in the second-line setting is not well defined. A previous phase III study that combined bevacizumab with capecitabine (Xeloda^®) in heavily pretreated patients showed an improvement in response rate but not in PFS. Therefore, RIBBON-2 was designed to investigate the clinical benefit of adding bevacizumab to a variety of chemotherapy agents (at the discretion of the investigator) as second-line treatment for HER2-negative metastatic breast cancer.

Abstract 42: Sara Hurvitz, MD, from University of California, Los Angeles, California, presented the results of RIBBON-2 trial on behalf of Adam Brufsky, MD. The pooled analysis of all chemotherapy cohorts showed that bevacizumab significantly improved PFS compared with placebo (median, 7.2 months versus 5.1 months; P = .007) and the ORR was also improved (39.5% versus 29.6%; P = .019). Across all chemotherapy cohorts, the safety profile of bevacizumab was consistent with the literature; hypertension was the only bevacizumab-related adverse event that was consistently increased. Analysis of individual chemotherapy agents did not show any clear benefit of one over another. This is the first positive phase III study of bevacizumab in the second-line treatment of metastatic breast cancer, and it provides compelling data that bevacizumab is beneficial, thereby confirming what many oncologists have seen in clinical practice.

Brufsky A, et al. Cancer Res. 2009;69(24 Suppl): Abstract 42.

The AVADO Trial: Why No Overall Survival Benefit?

Abstract 41: The mature OS data from the AVADO trial, presented by David Miles, MD, from Mt Vernon Cancer Center, London, United Kingdom, are sure to fuel the ongoing controversy regarding PFS as a regulatory endpoint. Bevacizumab was approved in the United States and Europe in combination with taxanes for first-line treatment of metastatic breast cancer based on data from the E2100 and AVADO trials. The recently reported RIBBON-1 trial also confirms that the addition of bevacizumab to chemotherapy significantly improves PFS and ORR compared with chemotherapy alone. The AVADO trial compared docetaxel plus placebo with docetaxel plus bevacizumab (7.5 mg/kg or 15 mg/kg) every 3 weeks, and the outcomes were clearly better with the higher dose of bevacizumab. The AVADO trial showed a highly significant 2-month improvement in median PFS (10 months with 15 mg/kg bevacizumab versus 8 months for placebo; HR = 0.67; P = .0002), but this did not translate into an OS benefit (median, 30.2 months with 15 mg/kg bevacizumab versus 31.9 months for placebo). However, this is not unexpected because of the cross-over design and subsequent treatment with bevacizumab in the second-line setting. This led the investigators to conduct an exploratory analysis of outcomes based on subsequent treatment with bevacizumab, and the data suggested that this could explain the lack of an OS benefit.

Miles D, et al. Cancer Res. 2009;69(24 Suppl): Abstract 41.

Combination of Lapatinib and Trastuzumab Improves Overall Survival in HER2-Positive Metastatic Breast Cancer

Abstract 61: Kim Blackwell, MD, from Duke University Medical Center, Durham, North Carolina, presented the mature survival analysis of a randomized study comparing lapatinib (Tykerb^®) alone with lapatinib plus trastuzumab in heavily pretreated patients with HER2-positive metastatic breast cancer who had received a median of 3 prior trastuzumab-containing regimens for metastatic disease. This study had a planned crossover if patients progressed within 4 weeks on lapatinib alone. Despite the fact that 52% of patients randomized to lapatinib crossed over to the combination arm, the study demonstrated a statistically significant OS benefit in favor of the combination (median, 61 weeks compared with 41 weeks for lapatinib alone; HR = 0.74; P = .026). The authors concluded that the actual survival benefit associated with combination therapy may even be underestimated due to the high frequency of crossover. This impressive result provides clinical validation of preclinical models showing that lapatinib and trastuzumab act synergistically to inhibit growth of HER2-positive breast cancer. These findings suggest that lapatinib may augment the activity of trastuzumab by enhancing blockade of HER2 signaling and/or by providing additional blockade of signaling via ErbB1 (epidermal growth factor receptor), which could be a mechanism of resistance to anti-HER2 therapy. The results of this study are likely to change clinical practice.

Blackwell KL, et al. Cancer Res. 2009;69(24 Suppl): Abstract 61.

Adjuvant Non-Anthracycline Trastuzumab-Containing Regimens: Is the Data Definitive?

Several large adjuvant trials have demonstrated the DFS benefit of adding trastuzumab to standard adjuvant chemotherapy in patients with HER2-positive early breast cancer. However, this benefit must be weighed against the potential for cardiac toxicity, particularly when trastuzumab is combined with anthracyclines. The BCIRG 006 trial randomized patients with HER2-positive (FISH+) breast cancer (axillary node–positive or high-risk node-negative) to standard doxorubicin plus cyclophosphamide (AC) followed by either docetaxel alone (AC-T) or docetaxel plus trastuzumab for 1 year (AC-TH). A third arm tested a non-anthracycline-containing regimen consisting of docetaxel plus carboplatin (6 cycles) plus trastuzumab for 1 year (TCH). An important question addressed by this trial was whether TCH would be associated with less cardiac toxicity. A total of 3222 patients were randomized (1072 to AC-T, 1076 to AC-TH, and 1074 to TCH).

Abstract 62: Dennis Slamon, MD, PhD, from University of California, Los Angeles, California, presented results of the third protocol-specified analysis conducted after 656 DFS events and discussed the DFS and OS benefits of trastuzumab in the context of the risk of cardiac toxicity. The 5-year analysis of DFS confirmed the statistically significant benefit of both AC-TH and TCH compared with the control arm (AC-T) with hazard ratios of 0.64 and 0.75, respectively. The 5-year DFS rates were 84% for AC-TH, 81% for TCH, and 75% for AC-T. Both experimental arms also demonstrated a significant OS benefit. The 5-year OS rates were 92% for AC-TH (HR = 0.63) and 91% for TCH (HR = 0.77) compared with 87% in the AC-T arm. Importantly, there was no significant difference between AC-TH and TCH in the overall analysis or the subset analysis by nodal status. In particular, the highest-risk cohort of patients with ≥4 positive nodes benefitted equally from the two trastuzumab-containing regimens. In terms of safety, however, TCH was associated with a better overall safety profile compared to AC-TH, and a 5-fold lower incidence of grade 3/4 congestive heart failure, which occurred in 21 patients treated with AC-TH compared with only 4 patients in the TCH arm. There were also 7 acute leukemias in the AC-TH arm. Therefore, the authors concluded that both trastuzumab-containing regimens are equally effective (although AC-TH had a slight numerical DFS advantage), but that TCH has a better long-term safety profile. This study has important implications with respect to the choice of adjuvant chemotherapy for patients with HER2-positive early breast cancer.

Slamon D, et al. Cancer Res. 2009;69(24 Suppl): Abstract 62.

Concurrent Trastuzumab Is Better Than Sequential: 5-Year Follow-Up of the NCCTG N9831 Trial

Abstract 80: There is no question whether the addition of trastuzumab to anthracycline-based chemotherapy improves DFS in patients with HER2-positive early breast cancer, but the NCCTG N9831 trial is the only study to ask whether it is better to combine trastuzumab concurrently with paclitaxel chemotherapy or to add it sequentially after completing chemotherapy. The results of this trial, first reported in 2005, demonstrated that concurrent addition of trastuzumab to standard chemotherapy (AC-T+H→H) significantly reduced the risk of recurrence by 52% compared with AC-T alone. Sequential therapy with trastuzumab also improved DFS by 30% compared with chemotherapy alone (5-year DFS improved from 72% with AC-T to 80% with AC-T→H). Early indications suggested that concurrent therapy slightly increased the risk of cardiac toxicity compared with sequential therapy. Edith Perez, MD, from Mayo Clinic, Jacksonville, Florida, reported the first planned interim analysis of the trastuzumab arms at a median follow-up of 5.3 years with 312 DFS events. After adjusting for tumor size, number of positive nodes, and ER status, the 5-year DFS rate was increased from 80% with AC-T→H to 84% with AC-T+H→H (HR = 0.75). Therefore, based on this 25% reduction in the risk of recurrence and a positive risk/benefit ratio, the authors recommended that trastuzumab be used concurrently with taxanes as the current standard of care.

Perez E, et al. Cancer Res. 2009;69(24 Suppl): Abstract 80.

PARP Inhibitor Improves Survival in Triple-Negative Breast Cancer

Abstract 3122: For years, an effective therapy has been sought for patients with triple-negative (ER-negative, PgR-negative, and HER2-negative) breast cancer (TNBC), a clinically aggressive subtype associated with a poor prognosis, but the lack of a therapeutic target has been a major impediment. However, TNBC shares molecular and pathologic features with BRCA1-related breast cancers, suggesting that inhibition of poly (ADP-ribose) polymerase (PARP), a critical enzyme for DNA excision repair, is a rational therapeutic strategy. Joyce O’Shaughnessy, MD, from US Oncology at the Baylor-Sammons Cancer Center, Dallas, Texas, presented a poster with updated results of a randomized phase II study in which 120 patients with metastatic TNBC were randomized to gemcitabine (1000 mg/m²) plus carboplatin (AUC2) with or without the addition of BSI-201 (5.6 mg/kg), a novel PARP inhibitor. In preclinical studies, BSI-201 has been shown to enhance chemotherapy-induced DNA damage. The results of this study showed that BSI-201 significantly improved objective response rate, PFS, and most importantly OS. Updated results presented at SABCS showed a median OS of 12 months in the BSI-201 arm versus 8 months with gemcitabine/carboplatin alone (HR = 0.5; P = .005). The investigators also showed that TNBC is associated with increased expression of PARP1 compared to expression in normal breast tissue, thus confirming earlier observations that provided the rationale for use of PARP inhibitors. BSI-201 was well tolerated with minimal added toxicity. These exciting results suggest that PARP inhibition may be a major advance in the treatment of TNBC. Currently, a randomized phase III trial of the same design (NCT00938652) is ongoing to confirm these encouraging results.

O’Shaughnessy J, et al. Cancer Res. 2009;69(24 Suppl): Abstract 3122.

A Novel Breast Cancer Biomarker: Real or Imaginary?

Abstract 32: At present, mammography is the gold standard for early detection of breast cancer but is not without its limitations and fair share of controversy. Development of a clinically validated biomarker for the early detection of breast cancer would be a major advance, but this has been an elusive goal. Therefore, the report by Helen Heneghan, MD, from the National University of Ireland, Galway, Ireland, was viewed with both excitement and some skepticism. This group of researchers reported the characterization of several novel microRNAs that appear to have all the characteristics of an ideal breast cancer–specific biomarker. Circulating microRNAs have great potential as biomarkers because they are inherently stable and easy to detect by PCR. Two markers in particular, miR-195 and let-7a, appeared to be significantly elevated in the circulation of 148 women with breast cancer compared with 24 age-matched controls, and they correlated with disease stage and tumor burden. Most intriguing was the observation that circulating levels of let-7a were highest in carcinoma in situ and decreased as tumor stage increased. Both markers also decreased after tumor resection. These findings suggest that these novel biomarkers could potentially be useful as a noninvasive blood test for early diagnosis of breast cancer with approximately 75% accuracy. Although these biomarkers appear very promising, further testing will determine if their potential is real or imaginary.

Heneghan HM, et al. Cancer Res. 2009;69(24 Suppl): Abstract 32.

An overview of the current knowledge regarding microRNAs in solid tumors and hematologic malignancies was recently published in the Journal of Clinical Oncology.  This editorial broadly discusses the involvement of microRNAs in cancer pathogenesis, as well as the potential role(s) of microRNAs in cancer diagnosis and treatment.

Iorio M, et al. J Clin Oncol. 2009;27(34):5848-5456.

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