Bryan P. Schneider

Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100

PURPOSE No biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. PATIENTS AND METHODS DNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. RESULTS The VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio = 0.58; 95% CI, 0.36 to 0.93; P = .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio = 0.62; 95% CI, 0.46 to 0.83; P = .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P = .005 and P = .022, respectively). CONCLUSION Our data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors. METHODS A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life. RESULTS A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. RECOMMENDATIONS On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.

Triple-Negative Breast Cancer: Risk Factors to Potential Targets

Triple-negative breast cancer has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, a molecularly distinct subtype of breast cancer, the basal-like subtype. We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms. Moreover, the established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Finally, because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay. Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets. This CCR focus article will review the current state of the art on triple-negative breast cancer.

Angiogenesis of Breast Cancer

Angiogenesis, the process of new blood vessel formation, plays a central role in both local tumor growth and distant metastasis in breast cancer. Extensive laboratory data suggest that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis. Hyperplastic murine breast papillomas and histologically normal lobules adjacent to cancerous breast tissue support angiogenesis in preclinical models, suggesting that angiogenesis precedes transformation of mammary hyperplasia to malignancy. Transfection of tumor cells with angiogenic stimulatory peptides has been shown to increase tumor growth, invasiveness, and metastasis. Conversely, transfection of tumor cells with inhibitors of angiogenesis decreases growth and metastasis. The matrix metalloproteinase (MMP) family of enzymes degrades the basement membrane and extracellular matrix and is associated with a family of endogenous inhibitors, tissue inhibitors ofmetalloproteinases (TIMPs). Under normal physiologic conditions, the MMPs and TIMPs exist in anexquisitebalance.Thisbalance isdisrupted during active angiogenesis. Expression of MMPs increases with the progression from benign to preinvasive, invasive, and metastatic breast cancer and is associated with increasing histologic tumor grade. Microscopic metastases are growth restricted and remain dormant until they undergo an angiogenic switch, presumably a result of further mutation. This angiogenic switch often results in increased expression of MMPs. Hypoxia is a key signal for the induction of angiogenesis. Hypoxia-inducible factors (HIF-1 and HIF-2) are heterodimeric transcription factors consisting of and subunits. The subunit is constitutively expressed while the subunit is protected from degradation only under hypoxic condition. HIF-1 expression progressively increases from normal breast tissue to usual ductal hyperplasia to ductal carcinoma-insitu to invasive ductal carcinoma. HIF-1 expression is higher in poorly differentiated than in well-differentiated lesions and is associated with increased proliferation and expression of the estrogen receptor and vascular endothelial growth factor (VEGF). Similarly, expression of carbonic anhydrase IX, an HIF-1 -dependant enzyme important in pH regulation, is associated with worse relapse-free and overall survival in patients with invasive breast cancer.

Drug Insight: VEGF as a therapeutic target for breast cancer

Angiogenesis is implicated in the pathogenesis of malignancy and metastasis. Inhibition of angiogenesis has demonstrated clinically significant improvements in outcomes in a variety of malignancies, including breast cancer. The humanized monoclonal antibody against VEGF, bevacizumab, is the clinically most mature of the antiangiogenic agents and has recently been shown to improve outcome when combined with chemotherapy in the first-line metastatic setting of breast cancer. A variety of other antiangiogenic agents are currently under investigation, including drugs that inhibit the VEGF receptor 2, the cognate receptor for VEGF found on endothelial cells. The combination of antiangiogenic drugs with one another and with other biologic agents is also being explored in an attempt to improve efficacy and to overcome the drug resistance seen with the initial studies of antiangiogenic agents. This Review will focus on the current state of therapeutics designed to inhibit this angiogenic process in breast cancer.

The Role of Vascular Endothelial Growth Factor Genetic Variability in Cancer

Angiogenesis is a hallmark of tumor pathogenesis. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and its inhibition has become a successful approach to antitumor therapy across tumor types. The VEGF gene is highly polymorphic with multiple common single nucleotide polymorphisms (SNPs) in the promoter, 5′ untranslated region and 3′ untranslated region. There is evidence that these SNPs in the regulatory regions can affect VEGF expression. In vitro and in vivo data show that genetic variability affects the activity and expression of VEGF. Case-control and cohort studies suggest that genetic variability may affect risk and outcome of a variety of disease states that are tightly regulated by angiogenesis. Recently, genetic variability in VEGF has been studied as a potential predictive biomarker for bevacizumab. The VEGF-1154 AA and -2578 AA genotypes predicted an improved median overall survival, whereas the VEGF-634 CC and -1498 TT genotypes predicted protection from grade 3-4 hypertension in the pivotal trial, E2100. If validated, these finding could help direct which subgroup of patients should receive bevacizumab. (Clin Cancer Res 2009;15(17):5297–302)

Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants

Most premenopausal women diagnosed with primary breast cancer receive adjuvant chemotherapy, and many experience chemotherapy-induced ovarian failure (CIOF). CIOF is associated with menopausal symptoms, fertility concerns and long-term implications including bone loss. Ironically, CIOF might confer a disease-specific benefit to women whose breast cancers express hormone receptors. Risk factors of CIOF include the womans age at the time of therapy, and the type, dose and schedule of chemotherapy. Because inherited genetic factors have an important role in determining who will experience CIOF, genetic testing has the potential to provide optimal counselling about risks and possible interventions.

Neuropathy Is Not Associated With Clinical Outcomes in Patients Receiving Adjuvant Taxane-Containing Therapy for Operable Breast Cancer

PURPOSE Neuropathy is a common and potentially disabling complication of adjuvant taxane therapy. Recent studies have identified candidate single nucleotide polymorphisms associated with taxane-induced neuropathy. Therefore, we sought to determine whether neuropathy was associated with breast cancer recurrence in a clinical trial population who received adjuvant taxane therapy. PATIENTS AND METHODS Trial E1199 included 4,554 eligible women with operable breast cancer who received up to four cycles of doxorubicin and cyclophosphamide every 3 weeks followed by paclitaxel 175 mg/m(2) every 3 weeks for four cycles (P3), paclitaxel 80 mg/m(2) weekly for 12 cycles (P1), docetaxel 100 mg/m(2) every 3 weeks for four cycles (D3), or docetaxel 35 mg/m(2) weekly for 12 cycles (D1). A Cox proportional hazards model was used to determine the relationship between neuropathy and disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS) by treating neuropathy status as a time dependent covariate and using a landmark analysis. RESULTS Of 4,554 patients who received at least one taxane dose, grade 2 to 4 neuropathy developed in 18%, 22%, 15%, and 13% of patients in the P3, P1, D3, and D1 arms, respectively. In a model that included age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, neuropathy, and hyperglycemia, no significant relationship was found between neuropathy and DFS, OS, or RFS. CONCLUSION There was no association between taxane-induced neuropathy and outcome.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: Little evidence of improvement over the past 30 years

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability.

Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP–PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP–PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.