FROM THE LITERATURE

Is Inflammatory Breast Cancer Associated with an Increased Risk of Brain Metastases?

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer; however, recent data from large population-based epidemiology studies have shown that the incidence of IBC is increasing dramatically. At the same time, therapeutic advances have improved clinical outcomes, and 5-year survival rates have risen from <5% to 40%. As patients with metastatic IBC live longer, the incidence of brain metastases appears to be increasing. In a subset of women, progression in the brain has become the major life-limiting problem.

The authors of this retrospective study sought to better characterize the incidence of brain metastases and survival outcomes associated with brain metastases among women with IBC. The analysis was based on 203 women diagnosed with stage III/IV IBC between 2003 and 2008, which included 60 patients (29.6%) with hormone receptor-positive/HER2-negative disease, 70 (34.5%) with HER2-positive disease, and 73 (36.0%) with triple-negative breast cancer. At median follow-up of 20 months, 15.8% of patients developed brain metastases (cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively). Brain was the first site of metastasis in 5% of patients. Patients with hormone receptor–positive/HER2-negative disease had the lowest risk and those with HER2-positive disease had the highest risk of brain metastases. Median survival following a diagnosis of brain metastases was only 6 months. These data suggest that patients with newly diagnosed stage III/IV IBC are at high risk of developing brain metastases early in the course of their disease, and brain metastases are associated with short survival. The authors concluded that this may be an ideal cohort to target for site-specific screening.

Brain metastases of breast cancer represent unmet need for better multimodality treatment, a fact that was highlighted at the well-attended educational session at the 2010 CTCR-AACR San Antonio Breast Cancer Symposium.

Ann Oncol. 2010;21(12):2348-2355.

Exploring the Link Between Diabetes and Breast Cancer

An editorial by DeCensi and Gennari in the January 1 issue of the Journal of Clinical Oncology highlighted the emerging data presented in four separate papers in the same issue on the influence of type 2 diabetes and insulin resistance on the risk of breast cancer recurrence and breast cancer–specific mortality. In recent years, extensive research has attempted to evaluate and clarify the possible links between type 2 diabetes and breast cancer. In particular, the role of insulin in breast cancer etiology and prognosis has received considerable attention. A growing body of evidence suggests that diabetes and hyperinsulinemia may contribute to an increased risk of developing breast cancer and an increased risk of breast cancer recurrence among women with early-stage breast cancer. This is consistent with the strong anabolic effect of insulin, which can activate members of the insulin-like growth factor (IGF) receptor family leading to downstream activation of the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/AKT pathways.

The article by Peairs et al presents the results of a systematic review and meta-analysis designed to examine the effect of pre-existing diabetes on breast cancer–related outcomes. This analysis showed that breast cancer patients with pre-existing diabetes had a 49% increase risk of all-cause mortality compared to breast cancer patients without diabetes. Diabetes was also associated with more advanced-stage breast cancer at diagnosis. The report by Erickson et al was based on a retrospective analysis of data from the WHEL (Women’s Healthy Eating and Living) study. An analysis of 3003 women with early breast cancer showed that baseline hemoglobin A1c levels (a marker of chronic hyperglycemia) correlated with a significantly increased risk of all-cause mortality, and women with a hemoglobin A1c level >7% had a nonsignificant 26% increased risk of breast cancer recurrence. The studies by Irwin et al and Duggan et al analyzed data from the HEAL (Health, Eating, Activity, and Lifestyle) study and showed that biochemical markers of obesity and hyperinsulinemia such as high fasting C-peptide and low levels of adiponectin are associated with an increased risk of all-cause and breast cancer–specific mortality.

These data have important clinical implications. Most importantly, they suggest that insulin-lowering drugs, such as metformin, may improve prognosis in breast cancer patients with diabetes. Indeed, recent evidence suggests that metformin has antiproliferative effects on tumor cells in vitro and may decrease the risk of breast cancer among patients with diabetes. A large adjuvant trial is currently ongoing to determine if the addition of metformin to standard adjuvant therapy will reduced the risk of recurrence. DeCensi and Gennari also suggest that physicians need to be more vigilant with regard to identifying visceral obesity in their patients with breast cancer and could use the HOMA (Homeostatic Model Assessment) index, which measures the association between adiponectin, insulin, and glucose levels, to detect insulin resistance.

J Clin Oncol. 2010;29(1):7-10.

J Clin Oncol. 2010;29(1):40-46.

J Clin Oncol. 2010;29(1):54-60.

J Clin Oncol. 2010;29(1):47-53.

J Clin Oncol. 2010;29(1):32-39.

Can Trabectedin Reverse Partial Platinum Resistance in Relapsed Ovarian Cancer?

The effectiveness of platinum retreatment in relapsed ovarian cancer is highly correlated with the platinum-free interval (PFI). A PFI >6 months predicts platinum sensitivity, and retreatment with a platinum-based regimen is recommended. However, a PFI of 6-12 months is considered an indication of only partial platinum sensitivity, and there is little consensus regarding the best second-line chemotherapy regimen for these patients.

The phase III OVA-301 study enrolled 672 patients who had relapsed after first-line platinum-based chemotherapy, and patients were randomized to trabectedin (T) plus PLD or PLD alone. In comparison to PLD, the combination of T/PLD significantly prolonged progression-free survival (PFS) with a median of 7.3 months versus 5.8 months and a hazard ratio (HR) of 0.79; better efficacy was seen in patients with PFI > 6 months (median PFS 9.2 months vs 7.5 months, HR = 0.73), which led to the approval of this combination in Europe for relapsed platinum-sensitive ovarian cancer. However, most intriguing was the recently observed survival benefit of T/PLD in an exploratory analysis in the subset of 214 patients with a PFI of 6-12 months (ie, partial platinum sensitivity) reported by Poveda et al. In this analysis, a median PFS of 7.4 months versus 5.5 months (HR = 0.65; P = .0152) and median OS of 23 months versus 17 months (HR = 0.59; P = .0015) was demonstrated for T/PLD compared to PLD alone. Moreover, the analysis showed that patients treated with T/PLD had significantly prolonged survival after subsequent platinum-based therapy with a median of 13.3 versus 9.8 months from initiation of subsequent platinum-based therapy (HR = 0.63; P = .0357). Based on these results, the authors suggested that the extension of the PFI achieved with T/PLD may account for the observed improvement in survival perhaps by allowing greater recovery from toxicity. Another exploratory analysis of subsequent therapies and survival benefit reported by Kaye et al reached the same conclusion.

Although it is tempting to speculate that the extension of the PFI achieved with T/PLD may reverse partial resistance to platinum in this subset of patients, Sessa and D’Incalci commented in their editorial that “the retrospective nature of this exploratory analysis and the lack of information on response to subsequent treatments and duration do not allow us to draw conclusions on a possible beneficial effect of trabectedin on a longer PFI and survival.” Hopefully, a planned prospective, international, randomized, phase III INOVATYON trial, conducted by the MaNGO (Mario Negri Gynecologic Oncology Group) in patients with relapsed ovarian cancer and a PFI of 6-12 months, will clarify a role of trabectedin and nonplatinum-containing combinations for this patient population and the effect of longer PFI on response to subsequent platinum therapy and OS.

Ann Oncol. 2011;22(1):7-8.

Ann Oncol. 2011;22(1):39-48.

Ann Oncol. 2011;22(1):49-58.

Long-Term Survival Benefit of TPF Regimen in Head and Neck Cancer

The final results of TAX324, with a median follow-up of 6 years, confirmed that induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) significantly improved both PFS and OS compared with cisplatin plus fluorouracil (PF) in locally advanced head and neck cancer. Both regimens were followed by chemoradiotherapy for 7 weeks with concomitant weekly carboplatin. Median OS was 71 months in the TPF group versus 35 months in the PF group (P = .014), and the estimated 5-year survival rate was 52% versus 42%. Progression-free survival was also significantly better in patients treated with TPF (median, 38 months versus 13 months). The TPF regimen not only decreased distant metastases, but also improved locoregional control. Toxic effects measured by rate of dependence on gastric feeding tubes and numbers of patients needing tracheostomies did not differ between treatment groups.

Therefore, patients who are candidates for induction chemotherapy should be treated with TPF, and the authors suggest that sequential therapy with TPF followed by chemoradiotherapy may be a good therapeutic strategy in patients at high risk for distant failure. However, whether this treatment approach is superior to standard concomitant chemoradiotherapy regimens is not known and has not been tested. In an accompanying editorial, Corry and Rischin also raise the question whether the TPF induction regimen is equally effective in both human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancer. This is an important issue for the design of clinical trials in patients with head and neck cancer. Corry and Rischin voice concern that the inclusion of both HPV-positive and HPV-negative head and neck cancer in TAX324 and other similar trials, without stratification by HPV status, might confound interpretation of the results.

Lancet Oncol. 2011;12(2):153-159.

Lancet Oncol. 2011;12(2):113-114.

BRIEF REPORTS

Should FOLFIRINOX Be the New Standard for Advanced Pancreatic Cancer?

At the American Society of Clinical Oncology meeting in 2010, Conroy et al reported the results of the PRODIGE 4/ACCORD 11 trial, a randomized phase III trial comparing FOLFIRINOX (5FU/leucovorin, irinotecan, and oxaliplatin) with gemcitabine as first-line therapy for metastatic pancreatic cancer. This study demonstrated a highly significant and impressive improvement in OS in the FOLFIRINOX group (median, 11 months versus 7 months; P<.0001), and nearly half of the patients in the FOLFIRINOX group were alive after 1 year. Moreover, the observed 32% objective response rate in the FOLFIRINOX group is the highest response rate seen in a phase III trial in metastatic pancreatic cancer. Although these results are groundbreaking, Richard Kim put these data into perspective in a recent commentary in Lancet Oncology. He pointed out that the FOLFIRINOX regimen was quite toxic. Importantly, 46% of patients developed grade 3 or 4 neutropenia and 5% had grade 3 and 4 febrile neutropenia, which is particularly concerning in this patient population because of the risk of developing cholangitis. In addition, the patient population was highly selected. Only 39% of patients had a primary tumor in the head of the pancreas, whereas in clinical practice, about two-thirds of patients will present with a primary tumor in the pancreatic head, often with biliary obstruction that requires a biliary stent. Therefore, he concluded that for patients with good performance status, normal bilirubin, and a good supportive care system, FOLFIRINOX could be a viable option, and this regimen should be further studied in neoadjuvant and adjuvant settings. However, due to the high toxicity, it is unlikely FOLFIRINOX will become the new standard of care for all patients.

Lancet Oncol. 2011;12(1):8-9.

J Clin Oncol. 2010;28(15s): Abstract 4010.

ADDITIONAL PUBLICATIONS WORTH READING

• Understanding Radiation Recall. This review describes the current state of knowledge regarding radiation recall, an acute inflammatory reaction confined to previously irradiated areas that can be triggered when patients receive subsequent chemotherapy. This poorly understood phenomenon occurs most frequently in patients treated with doxorubicin, taxanes, and pyrimidine analogues. Oncologist. 2010;15(11):1227-1237.
• 2010 Update of EORTC Guidelines for the Use of G-CSF. These guidelines update the 2006 evidence-based recommendations of the EORTC European Guidelines Working Party for the use of G-CSF in adult patients with cancer at risk of chemotherapy-induced febrile neutropenia (FN). The evidence supporting the use of prophylactic filgrastim (including approved biosimilars), lenograstim, or pegfilgrastim to reduce the risk of chemotherapy-induced neutropenia is reviewed, and an updated list of chemotherapy agents associated with FN is provided. For a prIME Oncology Virtual Journal Club regarding the 2010 EORTC guidelines, go to http://primeoncology.org/fn2010. Eur J Cancer. 2011;47(1):8-32.
• Novel Targeted Strategies for the Treatment of Lymphoma. This review summarizes the current status of novel targeted agents in development for the treatment of lymphoma and discusses future strategies on this field. The article focuses on monoclonal antibodies that target cell surface receptors and small-molecule inhibitors of oncogenic pathways and highlights importance of biomarker driven clinical trials to optimize personalized treatment strategies. Nat Rev Clin Oncol. 2011;8(2):85-96.
• BRAF Testing in the Management of Papillary Thyroid Cancer. This review summarizes the current literature regarding the role of BRAF in the pathogenesis of papillary thyroid cancer and the clinical implications of BRAF mutational analysis in the management of thyroid nodules and papillary thyroid cancer. In particular, the BRAF V600E mutation is associated with constitutive activation of the MAP kinase pathway and more aggressive tumors and should alert clinicians to consider adjuvant therapy and more frequent surveillance. Potential BRAF targeted therapy is addressed. Oncologist. 2010;15(12):1285-1293.

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