Quality of life and pain in patients with metastatic bone disease from solid tumors treated with bone-targeted agents- a real-world cross-sectional study from Switzerland (SAKK 95/16).

BACKGROUND: Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors. Knowledge of the impact of their routine care use on patient-reported pain and bone pain-related quality of life (QoL) is limited. METHODS: This real world, cross-sectional study enrolled patients over a 3-month period through oncologists across Switzerland. Patients were ≥ 18 years, had solid tumors and at least one bone metastasis, and received routine care for bone metastases. Physicians provided data on BTA-related practices, risk of bone complications and BTA regimen. Patients completed questionnaires about pain (BPI-SF), general and bone pain-related QoL (FACT-G, FACT-BP) and treatment satisfaction (FACIT-TS-G). RESULTS: Eighteen sites recruited 417 patients. Based on the FACT-BP, 42% of the patients indicated not having bone pain. According to the BPI-SF, 28% reported no, 43% mild, 14% moderate, and 15% severe pain, respectively. Patients not treated with a BTA had better overall QoL (FACT-G: p = 0.031) and bone pain-related QoL (FACT-BP, p = 0.007) than those treated with a BTA. All pain and other QoL scales did not differ between groups. Patients perceived at 'low risk of bone complications' by their physician not receiving a BTA reported less pain and better QoL than those considered at 'low risk' but receiving BTA treatment or those considered at 'high risk' regardless of BTA treatment. Overall satisfaction with the treatment was good; almost 50% of patients reporting that they were completely satisfied. CONCLUSIONS: Overall, pain and QoL did not differ according to BTA treatment or physicians' risk perception. Patient with low risks not receiving BTA treatment reported least pain and highest QoL scores. These results may suggest that treating physicians assess bone complication risk appropriately and treat patients accordingly, but they need to be confirmed by objective determination of longitudinal skeletal complication risk.

Quality of life, effectiveness, and safety of aflibercept plus FOLFIRI in older patients with metastatic colorectal cancer: An analysis of the prospective QoLiTrap study.

INTRODUCTION: Colorectal cancer (CRC) mainly affects older patients. The pivotal VELOUR phase III trial of aflibercept plus FOLFIRI in metastatic CRC (mCRC) included only 5.9% of patients aged ≥75 years. Herein, we report a preplanned analysis from QoLiTrap, a large prospective observational study evaluating the impact of age on quality of life (QoL), effectiveness, and safety of aflibercept plus FOLFIRI in daily clinical practice in Europe. MATERIALS AND METHODS: Enrolled patients had progressive mCRC, had failed a prior oxaliplatin-based regimen, and had received aflibercept (4 mg/kg) plus FOLFIRI every two weeks until disease progression, death, unacceptable toxicity, or physician/patient decision. Analyses were performed by age classes (<60, 60-64, 65-69, 70-74, and ≥ 75 years). The primary endpoint was the percentage of patients whose global health status (GHS) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was maintained (i.e., no worsening from baseline by at least 5% over a 12-week treatment). Secondary endpoints included tumor objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 1277 patients (<60 years, n = 327; 60-64 years, n = 231; 65-69 years, n = 227; 70-74 years, n = 259; and ≥ 75 years, n = 233) were treated, of whom 872 were evaluable for QoL. GHS was maintained in 36.5%, 41.6%, 38.9%, 41.8%, and 44.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. Age did not influence PFS (median 7.8 months), OS (median 14.4 months), or ORR (20.8%). Number of cycles, dose delays for any cause, and dose reductions for adverse events (AEs) were comparable between age classes. Grade ≥ 3 AEs occurred in 47.7%, 51.9%, 51.5%, 55.2%, and 55.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. The main grade ≥ 3 AEs were hypertension (11.2%) and diarrhea (9%) in patients aged ≥75 years. DISCUSSION: The results suggest that aflibercept plus FOLFIRI maintains QoL and retains its activity, including a high objective tumor response, regardless of age and treatment line. In fit older patients, the safety profile seems manageable, with no new safety signals.

Real-World Evaluation of Quality of Life, Effectiveness, and Safety of Aflibercept Plus FOLFIRI in Patients with Metastatic Colorectal Cancer: The Prospective QoLiTrap Study.

Aflibercept plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer after the failure of oxaliplatin-containing therapy. QoLiTrap prospectively evaluated the quality of life (QoL) and effectiveness of this regimen in daily clinical practice, according to RAS status, sex, and prior targeted therapy, especially epidermal growth factor receptor inhibitors (EGFR-I). The primary endpoint was the percentage of patients whose EORTC QLQ-C30 global health status (GHS) improved or reduced by <5% from baseline during the first 12 weeks of therapy. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. One thousand two hundred and seventy-seven patients were treated with aflibercept plus FOLFIRI and 872 were evaluable for QoL. GHS improved or decreased by <5% in 40.3% of cases. The ORR was 20.8%, the median PFS was 7.8 months (95% confidence interval (CI), 7.3−8.3), and the median OS was 14.4 months (95% CI, 13.1−18.1). After prior EGFR-I, the ORR was 23.7%, median PFS was 9.4 months (95% CI, 6.5−12.9), and median OS was 17.4 months (95% CI, 10.5−33.7). The safety profile was consistent with previously reported data. Aflibercept plus FOLFIRI given in daily practice maintained QoL in mCRC patients, was associated with a high objective tumor response, and retained its activity regardless of sex, RAS status, and prior EGFR-I therapy.

Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma.

The cluster of differentiation 44 (CD44) signaling pathway is crucial in cancer-cell growth, invasion, proliferation and metastasis. CD44 is a transmembrane receptor for hyaluronan and osteopontin, and has recently attracted attention as a gastric cancer stem cell marker. Previous studies showed that polymorphisms in the CD44 gene can influence both human cancer survival and determine cellular response to cytotoxic chemotherapeutics. In addition, CD44 protein overexpression has been associated with poor prognosis in gastric adenocarcinoma (GA). We tested the hypothesis whether polymorphisms involved in the CD44 pathway will predict clinical outcome in patients with localized GA. Either blood or formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 137 patients with localized GA at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was isolated and polymorphisms within the CD44 pathway were determined by PCR-RFLP technique. In univariate analysis CD44 rs187116 and CD44 rs7116432 were significantly associated with time to tumor recurrence (TTR) and overall survival (OS). After adjusting for covariates, patients harboring at least one G allele of CD44 rs187116 remained significantly associated with TTR (adjusted p=0.009) and OS (adjusted p=0.045). Further, patients harboring CD44 T-A haplotype were at the lowest risk of developing tumor recurrence (HR: 0.255; 95% CI: 0.11-0.591; adjusted p=0.001) and death (HR 0.198; 95% CI: 0.07-0.563; adjusted p=0.002). These results provide the first evidence that CD44 polymorphisms predict clinical outcome in patients with localized GA. This may help to identify localized GA patients at high risk for tumor recurrence.

SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial.

PURPOSE: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab. METHODS: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. RESULTS: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related. CONCLUSION: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.

Patterns of care for patients with metastatic bone disease in solid tumors: A cross-sectional study from Switzerland (SAKK 95/16).

BACKGROUND: Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors, but knowledge of their routine care use and the therapeutic implications remains limited. This non-interventional study aimed to characterize real-world BTA patterns of care in Switzerland. MATERIALS AND METHODS: Non-interventional, cross-sectional study involving oncologists from across Switzerland who completed a Treating Physician questionnaire, providing data on their clinical setting and BTA-related practices, and a Patient Characteristics and Treatment questionnaire, providing data on their patients' disease status, risk of bone complications, BTA regimen and related outcomes. Eligible patients were aged ≥ 18 years, with solid tumors and at least one bone metastasis and were receiving routine management at the participating physician's center over the 3-month study period. RESULTS: A total of 86 oncologists recruited 417 patients from across 18 centers in Switzerland (80% public hospitals; 20% private clinics). The majority of physicians (70.9%) reported prescribing BTAs in line with international guidelines; denosumab was the treatment of choice in 78.5% of patients. BTAs were widely administered (94.2%) according to a 3-4-weekly dosing regimen; 33.7% of physicians reported extending intervals to 12 weeks after an initial 2 years of treatment. Physicians appeared to use clinical judgement, as well as formal risk assessment, to guide treatment for symptomatic skeletal events. No association was seen between either BTA use, or risk of complications, and incidence of skeletal complications. Only 4.3% of patients were reported to be experiencing severe bone pain at the time of the study. CONCLUSIONS: This cross-sectional, non-interventional study found high implementation of guideline-recommended BTA prescribing, good pain control and low incidence of skeletal-related events. Long-term BTA randomized controlled trials have the potential to further optimize routine care outcomes for patients.

Impact of sex, age, and ethnicity/race on the survival of patients with rectal cancer in the United States from 1988 to 2012.

Most studies report on colon and rectal cancers collectively, even though biologic and prognostic differences exist between these disease entities. Here, we investigated the effects of sex, age, and ethnicity/race on rectal cancer (RC) mortality by stage focusing on differences before and after 2004.Using the SEER database, we identified 105,511 patients diagnosed with RC from 1988-2012. Main outcomes were disease-specific survival (DSS) and overall survival (OS).In patients with stage I-III RC, women achieved a longer DSS (HR 0.87, P < 0.001) than men, independent of age, from 1988-2012. In stage IV disease, the sex disparity favoring women was limited to the age 18-44 yr cohort (DSS HR 0.79, P < 0.001). The sex difference in DSS (Pinteraction = 0.009) was significantly reduced from 2004 to 2012 across all ages. Hispanics and Native Americans with locoregional RC had inferior DSS relative to Whites from 1988-2003, but these differences were not evident from 2004-2012 (Pinteraction = 0.001). Additionally, Asians with stage I-III RC had superior DSS from 2004 on compared to Whites. Mortality in African American patients improved modestly overall and remained significantly higher than other ethnicities/races across all stages.Sex disparities have narrowed in patients with metastatic RC, but persist in patients with stage I-III disease. These differences are most evident among young patients (18-44 years), where sex disparities have even widened in stage I-III disease. While outcomes have improved for Asians, Hispanics, and Native Americans with stage I-III rectal cancer, black-white disparities remain in all disease stages.

Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.

PURPOSE: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. EXPERIMENTAL DESIGN: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). CONCLUSION: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.

Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab.

PURPOSE: The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included. EXPERIMENTAL DESIGN: To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and ß = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. RESULTS: Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05-1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95-1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082-1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14). CONCLUSION: This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.

Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States.

Lemur tyrosine kinase-3 (LMTK3) was recently identified as an estrogen receptor (ER)-α modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer. Because different predominant ER distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was carried out to clarify the prognostic role of these polymorphisms in gastric cancer. One-hundred and sixty-nine Japanese and 137 U.S. patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival [HR, 4.37; 95% confidence interval (CI), 2.08-9.18; P < 0.0001] and overall survival (OS; HR, 3.69; 95% CI, 1.65-8.24; P = 0.0014) in the Japanese males and time to recurrence (HR, 7.29; 95% CI, 1.07-49.80; P = 0.043) in the U.S. females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR, 3.04; 95% CI, 1.08-8.56; P = 0.035) and the U.S. males (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patients with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer.

Cancer dormancy: a model of early dissemination and late cancer recurrence.

Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period of time. Dormant tumor cells can be present as one of the earliest stages in tumor development, as well as a stage in micrometastases, and/or minimal residual disease left after an apparently successful treatment of the primary tumor. The general mechanisms that regulate the transition of disseminated tumor cells that have lain dormant into a proliferative state remain largely unknown. However, regulation of the growth from dormant tumor cells may be explained in part through the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system. An understanding of the regulatory machinery of these processes is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cells. This review focuses on the different signaling models responsible for early cancer dissemination and tumor recurrence that are involved in dormancy pathways.

Influence of sex on the survival of patients with esophageal cancer.

PURPOSE: The prognostic value of sex for esophageal cancer survival is currently unclear, and growing data suggest that hormonal influences may account for incidence disparities between men and women. Therefore, moving from the hypothesis that hormones could affect the prognosis of patients with esophageal cancer, we investigated the primary hypothesis that sex is associated with survival and the secondary hypotheses that the relationship between sex and survival depends, at least in part, on age, histology, and race/ethnicity. PATIENTS AND METHODS: By using the SEER databases from 1973 to 2007, we identified 13,603 patients (34%) with metastatic esophageal cancer (MEC) and 26,848 patients (66%) with locoregional esophageal cancer (LEC). Cox proportional hazards model for competing risks were used for analyses. RESULTS: In the multivariate analysis, women had longer esophageal cancer-specific survival (ECSS) than men in both MEC (hazard ratio [HR], 0.949; 95% CI, 0.905 to 0.995; P = .029) and LEC (HR, 0.920; 95% CI, 0.886 to 0.955; P < .001) cohorts. When age and histology were accounted for, there was no difference for ECSS between men and women with adenocarcinoma. In contrast, women younger than age 55 years (HR, 0.896; 95% CI, 0.792 to 1.014; P = .081) and those age 55 years or older (HR, 0.905; 95% CI, 0.862 to 0.950; P < .001) with squamous cell LEC had longer ECSS than men. In the squamous cell MEC cohort, only women younger than age 55 years had longer ECSS (HR, 0.823; 95% CI, 0.708 to 0.957; P = .011) than men. CONCLUSION: Sex is an independent prognostic factor for patients with LEC or MEC. As secondary hypotheses, in comparison with men, women age 55 years or older with squamous cell LEC and women younger than age 55 years with squamous cell MEC have a significantly better outcome. These last two findings need further validation.

The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models.

Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-κB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis, and angiogenesis that was superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.

A review of excision repair cross-complementation group 1 in colorectal cancer.

Oxaliplatin-based chemotherapy is the standard of care in patients with high-risk stage II and stage III colorectal cancer as well as in patients with advanced disease. Unfortunately, a large proportion of patients offered oxaliplatin fail to benefit from it. In the era of personalized treatment, there are strong efforts to identify biomarkers that will predict efficacy to oxaliplatin-based treatments. Excision repair cross-complementation group 1 (ERCC1) is a key element in the nucleotide excision repair (NER) pathway, which is responsible for repairing DNA adducts induced by platinum compounds. ERCC1 has recently been shown to be closely associated with outcome in patients with non-small-cell lung cancer (NSCLC): both high ERCC1 protein and gene expression are associated with resistance to cisplatin-based chemotherapy and better outcome without treatment. Therefore, ERCC1 has the potential to be used as a strong candidate biomarker, both predictive and prognostic, for colorectal cancer. This review will focus on the preclinical and clinical evidences supporting ERCC1 as a major molecule in oxaliplatin resistance. In addition, the important technologies used to assess ERCC1 gene and protein expression will be highlighted.

Predictive molecular classifiers in colorectal cancer.

The introduction of predictive molecular markers has radically enhanced the identification of which patients may benefit from a given treatment. Despite recent controversies, KRAS mutation is currently the most recognized molecular predictive marker in colorectal cancer (CRC), predicting efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibodies. However, other relevant markers have been reported and claimed to identify patients that will benefit from anti-EGFR therapies. This group of markers includes BRAF mutations, PI3KCA mutations, and loss of PTEN expression. Similarly, molecular markers for cytotoxic agents' efficacy also may predict outcome in patients with CRC. This review aims to summarize the most important predictive molecular classifiers in patients with CRC and further discuss any inconsistent or conflicting findings for these molecular classifiers.

Survival predictors for second-line chemotherapy in Caucasian patients with metastatic gastric cancer.

PRINCIPLES: There are very limited data suggesting a benefit for second-line chemotherapy in advanced gastric cancer. Therefore, the number of patients who receive further treatment after failure of first-line chemotherapy varies considerably, ranging from 14% to 75%. In the absence of a demonstrated survival benefit of second-line chemotherapy, appropriate selection of patients based on survival predictors is essential. However, no clinico-pathologic parameters are currently widely adopted in clinical practice. We looked exclusively at Caucasian patients with metastatic gastric cancer treated with second-line chemotherapy to see if we could establish prognostic factors for survival. METHODS: This study retrospectively evaluated 43 Caucasian patients with metastatic gastric cancer treated with second-line chemotherapy at the Geneva University Hospital. Prognostic values of clinico-pathologic parameters were analysed by Cox regression for overall survival (OS). RESULTS: Univariate analysis found three variables to be associated with survival: progression-free survival (PFS) at first-line chemotherapy of more than 26 weeks (hazard ratio (HR) = 0.33, confidence interval (CI) 95% 0.16-0.65, p = 0.002), previous curative surgery (HR = 0.51, CI 95% 0.27-0.96, p = 0.04) and carcinoma embryonic antigen (CEA) >6.5 µg/l (HR = 1.97, CI 95% 1.06-3.65, p = 0.03). CONCLUSIONS: In line with published data, sensitivity to previous chemotherapy identifies Caucasian patients who will survive the longest following second-line chemotherapy. A low tumour burden and previous curative gastrectomy also seem to have a positive prognostic value.

S0356: a phase II clinical and prospective molecular trial with oxaliplatin, fluorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma.

PURPOSE: Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. PATIENTS AND METHODS: Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. RESULTS: Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. CONCLUSION: Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

Common cancer stem cell gene variants predict colon cancer recurrence.

PURPOSE: Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. EXPERIMENTAL DESIGN: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing. RESULTS: The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001). CONCLUSION: This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients.