ADVANCED BREAST CANCER FIRST CONSENUS CONFERENCE

Advanced Breast Cancer in the Spotlight

A forum exclusively focused on metastatic breast cancer, the Advanced Breast Cancer First Consensus Conference (ABC1), was held in Lisbon, Portugal on 3-5 November 2011. Organized by the European School of Oncology (ESO), this conference was chaired by Fatima Cardoso, MD (Lisbon), Larry Norton, MD (New York), Eric Winer, MD (Boston), and Alberto Costa, MD (Bellinzona, Switzerland and Milan, Italy). More than 800 international delegates participated in the conference, which featured two days of multidisciplinary sessions focusing on many aspects of diagnosis and management of advanced breast cancer. On the final day of the conference, 40 invited panelists convened to attempt to develop consensus guidelines for the management of advanced breast cancer. These guidelines will be published in The Breast, and hopefully will fill a void not previously systematically addressed for patients with metastatic breast cancer. Below please find a link to a press release provided by ESO, summarizing the goals and objectives of ABC1.

http://www.abc-lisbon.org/pagine-interne/downloads.html

FROM THE LITERATURE

Long-Awaited BCIRG 006 Trial Results Fail to Deliver a Definitive Answer on Use of Nonathracycline Regimen in HER2-Positive Breast Cancer

Based on the final results of the Breast Cancer International Research Group (BCIRG) 006 trial reported by Slamon and colleagues, the nonanthracycline regimen of docetaxel and carboplatin (every 3 weeks for 6 cycles) concurrently with trastuzumab (TCH) is not superior to standard anthracycline-based AC-TH as adjuvant therapy for HER2-positive early breast cancer. Although TCH was associated with significantly less cardiac toxicity and secondary leukemia, as expected, doxorubicin and cyclophosphamide for 4 cycles followed by docetaxel for 4cycles plus trastuzumab for 52 weeks (AC-TH) was numerically, but not significantly, better at reducing the risk of breast cancer recurrence or death. The 5-year disease-free survival rates were 84% among patients receiving AC-TH compared to 81% among those receiving TCH, and there was no difference in overall survival (OS; 92% vs 91%). However, the incidence of congestive heart failure and cardiac dysfunction was significantly higher in the AC-TH group (P<.001), and there were 7 cases of acute leukemia compared to only 1 case in the TCH group. The bottom line, according to Daniel Hayes, MD (University of Michigan Comprehensive Cancer Center, Michigan, United States), is that the absolute number of women who had a life- threatening adverse event (either toxicity or cancer recurrence) was almost identical in both groups. The reduced risk of cardiac dysfunction and secondary leukemia associated with TCH is counterbalanced by a slight increased risk of breast cancer recurrence. Thus, despite the authors’ assertion that the risk/benefit ratio favored the TCH regimen, Dr Hayes argues that the data do not clearly favor one regimen over the other and that the findings of the study establish TCH as another (but not "the") standard of care.

N Engl J Med. 2011;365(14):1273-1283
N Engl J Med. 2011;365(14):1336-1338 (editorial).

Outpatient Management of Low-Risk Patients With Febrile Neutropenia Is Safe and Effective

The multicenter, randomized study reported by Talcott and colleagues showed that low- risk, medically stable cancer patients with febrile neutropenia (FN) can be treated effectively with antibiotics at home without increased risk of adverse medical consequences. For decades, cancer patients with chemotherapy-related FN have typically been admitted to the hospital and managed with broad-spectrum intravenous (IV) antibiotic therapy and close surveillance until their fevers resolved. However, validated decision tools have been developed to identify patients with FN at low risk for significant medical complications, thereby justifying less intensive surveillance and early discharge from the hospital. These tools have allowed effective management of FN in the outpatient setting with either IV and/or oral antibiotic regimens. Patients considered at low risk are generally those who have not received intensive myelosuppressive regimens, have well- controlled tumors, are outpatients when they develop fever and neutropenia, and have no significant medical comorbidities. In their editorial remarks, Alison Freifeld, MD (University of Nebraska Medical Center, Nebraska, United States), and Kent Sepkowitz, MD (Memorial Sloan-Kettering Cancer Center, New York, United States), applaud the study reported by Talcott et al, saying that it lends support to the cumulative evidence that outpatient treatment of selected low-risk patients with FN is as safe and effective as management in the hospital setting. Although the study was underpowered due to early closure, the conclusions are supported by a recent meta- analysis of 10 clinical trials involving more than 1100 patients that found no significant differences in mortality or treatment response between inpatient and outpatient management of FN. With regard to the best decision tool for identifying low-risk patients, they recommend the scoring system developed by the Multinational Association for Supportive Care in Cancer (MASCC). The MASCC system is based on numerically weighted good risk factors, and a cumulative score ≥21 points is strongly associated with an uneventful clinical course and low rates of bacteremia or medical complications.

J Clin Oncol. 2011;29(30):3977-3983.
J Clin Oncol. 2011;29(30):3952-3954. (editorial)

Gemcitabine Plus nab-Paclitaxel Show Synergy in Pancreatic Cancer

In a phase I/II study, the combination of gemcitabine and nab-paclitaxel yielded a response rate of 48% with a median OS of 12.2 months among patients treated at the maximum tolerated dose (MTD). Standard first-line treatment with gemcitabine for metastatic pancreatic adenocarcinoma typically yields a response rate <10% and median OS of only 6-8 months. In this study, 67 patients with previously untreated advanced pancreatic cancer received 100 mg/m², 125 mg/m², or 150 mg/m² nab-paclitaxel and gemcitabine 1000 mg/m² on days 1, 8, and 15, every 28 days. The MTD was 1000 mg/m² of gemcitabine plus 125 mg/m² nab-paclitaxel once a week for 3 weeks, every 28 days. Further dose escalation was limited by myelosuppression and sepsis. Decreases in CA19- 9 levels were correlated with increased response rate, progression-free survival (PFS), and OS. Interestingly, only SPARC in the stroma, but not in the tumor, was correlated with improved survival. The authors also reported the results of a mouse xenograft study showing that the intratumoral concentration of gemcitabine was increased 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine compared with mice receiving gemcitabine alone. nab-Paclitaxel depleted the peritumoral desmoplastic stroma. Therefore, the investigators speculated that reducing the dense tumor stroma, a hallmark of pancreatic adenocarcinoma, may allow chemotherapy to penetrate the tumor more effectively. Based on these exciting results, suggesting substantial synergy between these agents, a randomized phase III trial has been initiated. J Clin Oncol

J Clin Oncol. 2011 October 3. [Epub ahead of print].

Docetaxel Plus Aflibercept Demonstrates Promising Activity in Recurrent Ovarian Cancer

The combination of docetaxel plus intravenous aflibercept, a novel fusion protein that binds both vascular endothelial growth factor (VEGF) and placental growth factor with high affinity, is active in patients with platinum-sensitive as well as platinum-resistant or platinum-refractory disease. In the phase II portion of this study, 25 of 46 evaluable patients (54%) had an objective response, including 11 complete responses (CRs) and 14 partial responses (PRs). More impressively, responses (3CRs and 12 PRs) were confirmed in 15 of 33 patients (45%) who were resistant or refractory to previous platinum and taxane therapy, and at least 1 patient who was previously treated with bevacizumab. Aflibercept was well tolerated at the recommended phase II dose of 6 mg/kg in combination with docetaxel (75 mg/m2) every 21 days. Adverse events specifically attributed to aflibercept were grade 1-2 hypertension in 11% of patients and grade 2 proteinuria in 1 patient. The authors concluded that the substantial antitumor activity of this combination warrants further study.

Lancet Oncol. 2011;12(12):1109-1117.

Can Immunotherapy Boost the Efficacy of Standard Chemotherapy for Lung Cancer?

This phase IIb study suggests that addition of the TG4010 vaccine to cisplatin plus gemcitabine may improve PFS compared with chemotherapy alone in patients with stage IIIb (wet) or stage IV non-small cell lung cancer (NSCLC). The TG4010 vaccine contains a recombinant modified vaccinia virus strain that codes for the MUC1 tumor-associated antigen and interleukin-2. In order for a patient to be eligible for this study, the patient’s tumor had to express the MUC1 antigen by immunohistochemistry. In total, 148 patients were randomized to receive TG4010 (10⁸ plaque forming units) plus cisplatin (75 mg/m² on day 1) and gemcitabine (1250 mg/m² on days 1 and 8) every 3 weeks for up to 6 cycles, or the same chemotherapy regimen without the vaccine. The 6-month PFS rate was 43.2% (exceeding the target of 40%) in the TG4010 plus chemotherapy arm versus 35.1% with chemotherapy alone, and the vaccine was well tolerated. Response rate was also higher in the combination group, and objective response was associated with longer survival in this group. Additionally, a retrospective analysis of lymphocyte immunophenotypes identified pretreatment percentage of CD16+CD56+CD69+ lymphocytes as a potential biomarker predictive of the efficacy and safety of TG4010. Based on the results of this study, the authors concluded that TG4010 may enhance the effect of chemotherapy in advanced NSCLC, and a confirmatory Phase IIb/III trial has been initiated.

Lancet Oncol. 2011;12(12):1125-1133.

ADDITIONAL PUBLICATIONS WORTH READING

• Integrating Novel Therapies Into The Treatment of Sarcoma. The authors of this supplement review the clinicopathologic features of sarcoma, including the new therapeutic targets, and discuss the role of current chemotherapy options based on histologic subtype, as well as novel chemotherapeutic agents, and their adverse events. They address emerging data on the efficacy and safety of promising targeted agents that may lead to improved individualization of therapy for patients with sarcoma.
  Semin Oncol. 2011;38(Suppl 3):S1-S2.
  Semin Oncol. 2011;38(Suppl 3):S3-S18.
  Semin Oncol. 2011;38(Suppl 38):S19-S29.
  Semin Oncol. 2011;38(Suppl 3):S30-S42.
  
  To view a discussion between Richard Riedel, MD, and David D’Adamo, MD, PhD, regarding this entire supplement to Seminars in Oncology, please visit the prIME Oncology Virtual Journal Club in Sarcoma at http://primeoncology.org/virtualjournalclub_Sarcoma.

• Will Whole Cancer Genome Sequencing by Next-Generation Methods Revolutionize Cancer Treatment? This review summarizes advances in next- generation sequencing (NGS) techniques and the potential clinical implications for oncology practice. The authors suggest that NGS holds a number of potential advantages over traditional sequencing methods, including the ability to fully sequence large numbers of genes (hundreds to thousands) in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and base substitutions in all known cancer-related genes. However, the authors acknowledge the need to better understand tumor biology before this information can be translated into treatment decisions.
  Am J Clin Pathol. 2011;136(4):527-539.

• Updated ASCO Guidelines for Use of Antiemetics in Oncology. Based on a systematic review of literature published since 2006, the American Society of Clinical Oncology (ASCO) panel updated recommendations for prevention of chemotherapy-induced nausea and vomiting (CINV) and/or radiation-induced NV. An important change in the updated guidelines is reclassification of the anthracycline/cyclophosphamide regimen as highly emetogenic, and the recommendation that patients receiving this or another highly emetic regimen should receive a 5-HT3 receptor antagonist, dexamethasone, and a neurokinin-1 receptor antagonist as an optimal treatment for CINV prevention. For patients receiving moderate emetic chemotherapy, the panel recommends palonosetron as the preferred 5 HT3 antagonist (in combination with corticosteroid).
  J Clin Oncol. 2011;29(31):4189-4198.

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