First-line Capecitabine Research Articles

Morphological response and tumor shrinkage as predictive factors in metastatic colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.

Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases. We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders." Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6months, p = 0.47; 26.6 vs. 24.6months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6months, p < 0.01; 30.7 vs. 17.8months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS. MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered.

The prognosis and risk factors for capecitabine maintenance treatment in metastatic breast cancer: a retrospective comparative cohort study.

BackgroundMaintenance treatment following efficient chemotherapy can improve the treatment outcomes of patients with metastatic breast cancer (MBC). However, there are no studies for identifying the prognostic factors for patients who could benefit from capecitabine maintenance. Therefore, this study aimed to investigate the prognosis and risk factors of capecitabine maintenance therapy and analysed the circulating tumour DNA (ctDNA) markers that may be related to the treatment response.MethodsThis study recruited 482 consecutive patients with MBC who achieved clinical benefit from capecitabine-based chemotherapy from 2011 to 2019. A total of 256 patients received subsequent capecitabine maintenance therapy. The baseline clinical factors included age at diagnosis, menopause, neoadjuvant therapy, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and subtypes, prior treatment lines, and prior capecitabine-based treatment response. Treatment outcome (progression-free survival, PFS) was assessed by imaging tools according to RSCIST 1.1 standard during the first two treatment cycles and every 3 weeks thereafter. Univariate and multivariate Cox proportional hazards models were used to analysethe association between capecitabine maintenance treatment and prognosis.ResultsThe median PFS of patients receiving capecitabine maintenance treatment was 21.7 months [95% confidence interval (CI): 15.1–36.3 months]. Capecitabine maintenance showed similar effects as endocrine maintenance or anti-HER2 therapy in hormone receptor (HR)-positive or HER2-positive patients, with adjusted HR of 1.17 (95% CI: 0.81–1.71, P=0.40). In patients with triple-negative breast cancer (TNBC), capecitabine maintenance showed a marginal benefit in PFS. Compared to late-line (≥2) capecitabine maintenance, first-line capecitabine maintenance significantly prolonged median PFS. Compared to other HR/HER2 subtypes, patients with HR-positive and HER2-positive subtypes significantly benefited from capecitabine maintenance treatment. Analysis of ctDNA revealed that among patients receiving capecitabine maintenance, TP53 aberrations were concentrated in patients with short PFS.ConclusionsCapecitabine maintenance treatment is associated with longer PFS in patients with MBC, especially those receiving first-line capecitabine-based chemotherapy and those with HR positivity/HER2 positivity. TP53 aberrations may be responsible for the poor response to capecitabine maintenance treatment.

VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer

The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.

Capecitabine, Oxaliplatin, Irinotecan, and Bevacizumab Combination Followed by Pazopanib Plus Capecitabine Maintenance for High-Grade Gastrointestinal Neuroendocrine Carcinomas

Gastrointestinal neuroendocrine carcinoma (NEC) is a lethal, uncommon, and understudied neoplasm. We present the efficacy and safety of first-line capecitabine (CP), oxaliplatin, irinotecan, and bevacizumab (CAPOXIRI-BEV) combination followed by pazopanib plus CP maintenance therapy in patients with advanced high-grade poorly differentiated gastrointestinal NEC. This was a two-stage phase II study conducted at multiple institutions. Patients were consecutively enrolled and had advanced NEC of the colon or small bowel. Patients received irinotecan 125 mg/m, oxaliplatin 80 mg/m on day 1, CP 1000 mg/m twice daily on days 1 to 14, plus bevacizumab 8 mg/kg on day 1 for six 21-day cycles. Maintenance therapy was given to those who responded (complete response/partial response) or had stable disease after 6 cycles with CAPOXIRI-BEV with pazopanib 800 mg daily plus CP 1600 mg/m daily on days 1 to 14 every 3 weeks until disease progression or unacceptable toxicity. Patients who progressed on CAPOXIRI-BEV received standard etoposide-carboplatin. The primary endpoint was overall response rate. Twenty-two patients were enrolled of whom 19 were evaluable. The median age was 60 years. The overall response rate (3 complete response/6 partial response) was 47.4% (95% confidence interval: 29.5-76.1), the overall disease control rate was 78.9% (95% confidence interval: 62.6-99.6), and, at median 30 (11 to 41 mo) months' follow-up, 5 patients (26.3%) were still alive. Median progression-free survival was 13 months, and the 1-year progression-free survival rate was 52.6%. The median overall survival was 29 months. The median overall survival of the 9 patients who responded versus those with stable disease/progressive disease was 30.5 versus 14 months, respectively. The median duration of response was 16 months. Predictable toxicity was observed. First-line CAPOXIRI-BEV followed by pazopanib plus CP maintenance therapy for advanced NEC demonstrates promising efficacy and predictable toxicity. Further investigation is warranted.

Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer

AimCapecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. MethodsDecision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. ResultsCAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. ConclusionCAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.

First-line capecitabine (X) monotherapy versus capecitabine plus oxaliplatin (XELOX) in elderly patients with advanced gastric cancer (AGC): results from the first interim analysis.

4051 Background: While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in AGC, there has been a price to pay in terms of toxicity. S...

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to fluoropyrimidine chemotherapy in patients with metastatic colorectal cancer (mCRC). We analyzed the levels of 22 miRNAs and the Dicer protein in primary tumors from patients with mCRC who were treated with first-line capecitabine monotherapy within the CAIRO trial of the Dutch Colorectal Cancer Group. Correlation between the expression status of miRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. Patients with low expression of miR-143 in their primary tumor had increased median PFS compared to those with high expression of miR-143. Furthermore, FXYD3, an ion transport regulator and a putative target of miR-143, also showed an association with PFS. These findings warrant further studies to investigate the relationship between miR-143, FXYD3 and fluoropyrimidines, and the clinical utility of miR-143 as biomarker.

Abstract P3-06-10: Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial

Abstract Background: The randomized phase III TURANDOT trial performed by the Central European Cooperative Oncology Group (CECOG) compared first-line BEV + paclitaxel (PAC) vs BEV + CAP in HER2-negative mBC in a prospective randomized trial [Lang, Lancet Oncol 2013]. In this trial, HFS was the most common adverse drug reaction in the BEV + CAP arm. In the present subanalysis, we investigated whether the occurrence of HFS constituted a predictor for improved efficacy of BEV + CAP in the study population randomized to this treatment arm. Methods: In the TURANDOT trial, patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV-PAC (BEV 10 mg/kg d1 &amp; 15 + PAC 90 mg/m2 d1, 8, &amp; 15 q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2 bid d1-14 q3w). Only patients who were randomized to the BEV-CAP arm and received at least one dose of CAP were included in the present analysis. Cox proportional hazard models with time-dependent covariate "HFS of any grade" and "HFS grade" were used to analyze the association between HFS and OS or PFS. In addition, landmark (LM) analyses were performed analyzing the impact of HFS occurrence within the first 3 treatment months on PFS and OS. Results: Baseline characteristics of patients with HFS (n=154) versus no HFS (n=123) were well balanced and showed no significant differences. Table 1 shows that with the occurrence of HFS, the hazard for progression or death was reduced by &amp;gt; 40%, while the risk reduction (RR) was &amp;gt;55% for OS. Moreover, with increasing HFS-grade an increasing RR was observed for OS. In patients with and without HFS in the first 3 months, the median PFS after the 3 months LM were 10 and 6.2 months (logrank test p=0.0026), respectively, and the corresponding OS rates at 2 years after the 3 months LM were 63% and 44% (log rank test, p=0.0842), respectively. Updated OS results will be presented at the conference. Cox Proportional Hazards Models for PFS and OS with HFS as Time-dependent CovariateUnivariateMultivariate*EndpointTime depent variableHazard ratio (95%Cl)p-valueHazard ratio (95%Cl)p-valuePFSHFS(Yes vs No)0.577(0.431,0.772)0.00020.558(0.409,0.760)0.0002HFS Grade 10.639(0.440,0.927)0.01840.536(0.350,0.821)0.0042HFS Grade 20.481(0.321,0.720)0.00040.487(0.320,0.741)0.0008HFS Grade 30.641(0.411,0.999)0.04950.740(0.466,1.178)0.2043OSHFS(Yes vs No)0.417 (0.273, 0.637)&amp;lt;.00010.436 (0.285, 0.666)0.0001HFS Grade 10.568 (0.334, 0.968)0.03750.548 (0.322, 0.934)0.0270HFS Grade 20.417 (0.227, 0.765)0.00480.448 (0.243, 0.824)0.0098HFS Grade 30.220 (0.093, 0.520)0.00060.247 (0.104, 0.586)0.0015* Significant baseline factors in multivariate models: ECOG (0 vs 1-2) in all models, ER/PR status (Any positive vs Other) in both OS models. Conclusion: HFS is a strong predictor for prolonged PFS and OS in mBC patients receiving BEV + CAP first-line treatment. Early occurrence of HFS and HFS severity might be used for treatment modifications and patient motivation. Detection of biomarkers for HFS could strengthen this approach. Citation Format: Zielinski C Christoph, Lang Istvan, Beslija Semir, Kahan Zsuzsanna, Moshe J Inbar, Stemmer M Salomon, Anghel Rodica, Vrbanec Damir, Messinger Diethelm, Brodowicz Thomas. Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-10.

Association between ABCB1 G2677T/A polymorphisms and chemosensitivity of paclitaxel in advanced gastric cancer

To investigate the association between ABCB1 polymorphisms and chemosensitivity of paclitaxel in Chinese advanced gastric cancer(AGC) patients. Clinical data and peripheral blood prior to chemotherapy of 412 AGC patients treated with first-line capecitabine plus paclitaxel(pactitaxel group, n=268) or cisplatin(cisplatin group, n=268) in Peking University Cancer Hospital from December 2008 to April 2013 were retrospectively collected. ABCB1 G2677T/A polymorphisms were determined using PCR amplification and Sanger Sequencing. Clinical response evaluation and survival analysis were performed using RECIST1.1 criteria and Kaplan-Meier curve, respectively. The associations of ABCB1 G2677T/A polymorphisms with clinical response and survival were analyzed statistically. The genotypes of ABCB1 were detected in all the patients and the frequency of wild type(G2677G), single allele variants(G2677T+G2677A), and two allele variants (T2677T+T2677A+A2677A) was 22.8%(94/412), 49.8%(205/412), and 27.4%(113/412), respectively. In paclitaxel group, the disease control rate(DCR)[89.9%(116/129)] and median progression-free survival(PFS)(190 days) of patients with single allele variants of G2677T/A were significantly higher than those of wild type patients[76.1%(51/67) and 110 days, all P<0.05], and did not differ statistically from those with two allele variants. In cisplatin group, no significant differences were observed among patients with different genotypes of ABCB1 in terms of the DCR or PFS(all P>0.05). ABCB1 G2677T/A polymorphisms are associated with chemosensitivity of paclitaxel in gastric cancer.

Abstract CT322: Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC)

Abstract BACKGROUND: Analysis of data from 2203 patients (pts) with HER2-negative LR/mBC treated in the single-arm ATHENA study suggested that overall survival (OS) expectancy of a well-defined subset of pts with hormone receptor-positive LR/mBC was similar to that of pts with triple-negative breast cancer (TNBC). We used prognostic factors from ATHENA to analyze efficacy in the CAP cohort of the RIBBON-1 trial. PATIENTS AND METHODS: In the CAP cohort of RIBBON-1, pts with LR/mBC were randomized 2:1 to receive CAP with either BEV 15 mg/kg q3w (N=409) or placebo (PLA; N=206). The primary endpoint was investigator-assessed progression-free survival (PFS). Objective response rate (ORR) and 1-year OS rate were secondary endpoints. Exploratory efficacy analyses were done in three subgroups: TNBC; high-risk hormone receptor positive (&amp;gt;2 risk factors); and low-risk hormone receptor positive (≤2 risk factors) using the remaining risk factors identified in ATHENA (liver metastases/≥3 involved organs; disease-free interval [DFI] ≤24 months; prior anthracycline/taxane). The data cut-off was July 31, 2008. RESULTS: In all three subgroups, PFS and ORR numerically favored BEV-CAP, consistent with the significant PFS and ORR benefit in the intent-to-treat population. Median PFS, median OS, and 1-year OS rate with PLA-CAP suggested a similarly poor prognosis in pts with TNBC and pts with high-risk hormone receptor-positive LR/mBC. CONCLUSIONS: In these exploratory analyses, median OS in pts with high-risk hormone receptor-positive LR/mBC was short and similar to that in pts with TNBC, as seen in the ATHENA exploratory analysis. OutcomePLA-CAPBEV-CAPTNBCN=50N=87PFS events, n (%)42 (84)74 (85)PFS unstratified HR (95% CI)0.72 (0.49-1.06)Median PFS, months (95% CI)4.2 (3.5-5.9)6.1 (4.3-8.2)ORR, % (95% CI)10.6 (3.5-23.1)30.3 (20.2-41.9)1-year OS rate, % (95% CI)71 (55-81)70 (59-79)Deaths, n (%)26 (52)47 (54)Median OS, months (95% CI)20.5 (15.8-NR)19.7 (14.6-23.2)Hormone receptor-positive disease with additional risk factors*N=56N=92PFS events, n (%)42 (75)72 (78)PFS unstratified HR (95% CI)0.80 (0.54-1.17)Median PFS, months (95% CI)4.4 (3.1-6.2)7.1 (4.3-8.6)ORR, % (95% CI)22.4 (11.8-36.6)27.7 (18.4-38.6)1-year OS rate, % (95% CI)66 (52-77)80 (70-87)Deaths, n (%)32 (57)52 (57)Median OS, months (95% CI)19.6 (12.9-23.4)20.8 (17.5-25.7)Hormone receptor-positive disease with limited additional risk factors**N=90N=220PFS events, n (%)68 (76)139 (63)PFS unstratified HR (95% CI)0.67 (0.50-0.89)Median PFS, months (95% CI)7.7 (6.0-8.4)10.6 (9.1-12.0)ORR, % (95% CI)36.8 (24.4-50.7)41.5 (33.8-49.6)1-year OS rate, %86 (77-92)85 (80-89)Deaths, n (%)34 (38)83 (38)Median OS, months (95% CI)28.4 (23.4-NR)29.0 (25.8-NR)*ER and/or PgR positive with &amp;gt;2 risk factors (liver metastases/≥3 involved organs; DFI ≤24 months; prior anthracycline/taxane); **ER and/or PgR positive with ≤2 risk factors. Citation Format: Nicholas J. Robert, Veronique Dieras, Christian Jackisch, Stefanie Srock, Ulrich Freudensprung, Leonardo Faoro, Joyce O’Shaughnessy. Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2014-CT322

Abstract P4-12-08: Final efficacy results from a single-arm multicenter phase II study evaluating first-line trastuzumab, bevacizumab, and capecitabine (HAX) therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: After median follow-up of 8.8 months, the primary efficacy results from the HAX study [Martín et al., Oncologist 2012] demonstrated a 73% overall response rate (ORR) according to RECIST (primary endpoint), median progression-free survival (PFS) of 14.4 months and a safety profile typical of the component agents; overall survival (OS) data were immature at that time. We present final efficacy results. Methods: Patients with measurable HER2-positive LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 15 mg/kg day 1, trastuzumab 6 mg/kg day 1 (8 mg/kg loading dose in cycle 1), and capecitabine 1000 mg/m2 bid days 1–14, repeated every 3 weeks until progression, unacceptable toxicity, or withdrawal of consent. Results: At the time of data cut-off, median follow-up was 31.8 months (range 1.2–44.5 months). Median duration of study therapy was 9.0, 9.4, and 10.3 months for bevacizumab, capecitabine, and trastuzumab, respectively. More than 8 cycles were administered in 67%, 65%, and 70%, respectively. Efficacy results in the intent-to-treat population (n = 88) and clinically important subgroups are shown below. Patient subgroupBest ORR,% (95% CI)PFS events, n (%)Median PFS, months (95% CI)Deaths, n (%)Median OS, months (95% CI)1-year OS rate,% (95% CI)All patients (n = 88)75 (65-84)70 (80)14.2 (10.5-14.9)40 (45)31.8 (26.3-38.2)94 (86-98)ER and/or PgR positive (n = 37)73 (56-86)32 (86)14.1 (8.5-17.0)19 (51)31.8 (24.4-42.6)100 (*-*)ER and PgR negative (n = 51)77 (63-87)38 (75)14.5 (10.5-18.9)21 (41)33.1 (23.6-44.5)90 (77-96)No prior chemotherapy (n = 37)81 (65-92)27 (73)14.9 (10.5-24.8)14 (38)31.8 (26.3-44.4)94 (80-99)Prior chemotherapy (n = 51)71 (56-83)43 (84)13.6 (8.5-14.8)26 (51)30.9 (24.3-42.1)94 (82-98)Taxane pretreated (n = 28)57 (37-76)26 (93)9.5 (5.2-14.0)17 (61)27.4 (21.4-33.2)93 (74-98)Prior anti-HER2 therapy (n = 22)73 (50-89)18 (82)12.1 (5.2-17.0)11 (50)30.9 (24.3-*)95 (72-99)Age &amp;gt;60 years (n = 25)72 (51-88)16 (64)14.2 (10.5-21.7)11 (44)33.2 (22.0-*)100 (*-*)*Not reached The most common grade ≥3 adverse events were hand-foot syndrome (26% of patients), diarrhea (11%), and hypertension (11%). The majority of deaths (38/40) were from progressive/underlying disease. The cause of the two remaining deaths was described as unknown; one was reported at the primary analysis and the other occurred 19 months after last study drug administration, following progression. Detailed long-term safety results will be presented. Conclusion: Long-term follow-up results from the HAX study show that this is an active and tolerable first-line triplet therapy for HER2-positive mBC, demonstrating median OS of 31.8 months. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-08.

Association of DNA promoter hypermethylation of decoy receptor 1 (DCR1) with poor response to irinotecan in metastatic colorectal cancer.

3552 Background: Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Methods: The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase 3 CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88). Results: Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)). Conclusions: CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy.

Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study.

4021 Background: In the EXPAND study adding cetuximab to first-line capecitabine and cisplatin chemotherapy (CT) failed to improve clinical outcome in patients (pts) with advanced gastric or gastroesophageal junction cancer. This analysis assessed treatment outcome according to tumor HER2 status (a pre-defined subgroup) and EGFR expression in EXPAND study pts. Methods: Tumor HER2 status was determined primarily by immunohistochemistry (IHC), HER2 +ve tumors were IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH) +ve. EGFR expression was assessed by IHC. A continuous scoring system (scale of 0–300) was used to determine the level of EGFR expression. Biomarker status was correlated with clinical outcome. Results: In both treatment arms, pts with HER2 +ve tumors (n=144) vs HER2 -ve tumors (n=535) had a longer median overall survival (OS): 13.3 (95% CI 10.9–15.5) vs 9.2 (95% CI 8.1–10.5) months in the CT + cetuximab arm and 14.0 (95% CI 11.3–17.1) vs 9.7 (95% CI 8.6–11.0) months in the CT arm, and a better overall response rate, 51.4 (95% CI 39.3–63.3) vs 27.0 (95% CI 21.9–32.6) % and 37.5 (95% CI 26.4–49.7) vs 26.4 (95% CI 21.1–32.3) % respectively. In stepwise multivariable models, pts with HER2 -ve vs HER2 +ve tumors showed an increased risk of death (adjusted hazards ratio 1.552, 95% CI 1.244–1.936) and reduced odds of response (adjusted odds ratio 0.477, 95% CI 0.316–0.720). EGFR tumor expression was evaluable in 774 pts from the intent to treat population (n=904). The EGFR IHC score was low (median 0, range 0–300). No discriminating threshold for the IHC score was identified. However in pt subgroups defined by a series of cut-off points from an IHC score of 10 upwards (rising incrementally by 10), there was a tendency for improved OS, progression-free survival, and tumor response when adding cetuximab to CT in pts with high tumor EGFR IHC scores. Conclusions: In this analysis of EXPAND study pts, those with HER2 +ve tumors were associated with better outcome irrespective of the treatment arm compared with pts with HER2 -ve tumors. Tumor EGFR expression was generally low. Adding cetuximab to CT failed to improve outcome overall, but may benefit a small proportion of pts with high EGFR tumor expression. Clinical trial information: 2007-004219-75.

Abstract 1155: Promoter CpG island hypermethylation of Decoy Receptor 1 (DCR1) is associated with poor response to irinotecan in colorectal cancer.

Abstract Background Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Material and Methods The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase III CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88). Results Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)). Conclusion CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy. Citation Format: Linda JW Bosch, Geert Trooskens, Petur Snaebjornsson, Josien C. Haan, Lorraine Pelosof, Miriam Koopman, Jolien Tol, Joost Louwagie, Luc Dehaspe, Bauke Ylstra, Henk Verheul, Manon van Engeland, Iris D. Nagtegaal, James G. Herman, Cornelis JA Punt, Wim van Criekinge, Beatriz Carvalho, Gerrit A. Meijer. Promoter CpG island hypermethylation of Decoy Receptor 1 (DCR1) is associated with poor response to irinotecan in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1155. doi:10.1158/1538-7445.AM2013-1155

MTHFR polymorphisms and capecitabine-induced toxicity in patients with metastatic colorectal cancer

The availability of current chemotherapeutic options for metastatic colorectal cancer (mCRC) has increased survival, but it is also accompanied by considerable morbidity. Fluoropyrimidines are the mainstay of systemic therapy. Germline pharmacogenetic markers involved in 5-fluorouracil pharmacodynamics could provide individualized pretreatment tools for predicting toxicity. Research on methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and fluoropyrimidine treatment outcome has focused on intravenous 5-fluorouracil and has yielded inconclusive results. The literature on pharmacogenetics in capecitabine-based chemotherapy is scarce. Therefore, we analysed the association of MTHFR gene polymorphisms and the occurrence of serious toxicity of first-line capecitabine monotherapy and combination therapy. One hundred and twenty-seven patients treated with first-line monotherapy capecitabine and 141 patients on capecitabine-irinotecan combination therapy were recruited from the CAIRO trial, an open-label phase III randomized trial, comparing sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in mCRC. All patients were genotyped for MTHFR 1298A>C and 677C>T polymorphisms and analysed in both cohorts separately for the association between the MTHFR genotype and incidence of grade 3-4 overall toxicity and specific adverse events, as well as efficacy parameters. MTHFR 1298A>C and 677C>T genotypes were not associated with grade 3-4 overall toxicity, febrile neutropenia or hand-foot syndrome. MTHFR 1298CC homozygotes showed a borderline significantly higher incidence of grade 3-4 diarrhoea compared with MTHFR 1298AC or AA individuals (25 vs. 5%, P=0.041) in the monotherapy cohort. No significant association was found between the MTHFR genotypes and efficacy parameters in either treatment cohort. MTHFR polymorphisms are not associated with toxicity or efficacy in mCRC patients treated with capecitabine-based chemotherapy.

Polymorphism of TS 3′-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel

Capecitabine-containing chemotherapy was widely used in clinic medication. We investigated the association of the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD) polymorphisms with the clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. Blood samples were collected prior to treatment from 125 patients with advanced gastric cancer and the TS (two or three repeats of a 28bp sequence in 5'-untranslated region and 6bp insertion or deletion in 3'-untranslated region), MTHFR (C677T) and DPD (IVS14+1G>A) polymorphisms were determined using PCR amplification and Sanger sequencing. The median age of 125 patients was 58years (range, 23-76) with female 42 and male 83, and the response rate, median progression-free survival and overall survival (OS) were 43.2%, 5.2 and 11.0months. The median OS in patients with TS ins6/ins6 genotype (6.8months) was significantly shorter than those in patients with ins6/del6 (11.0months, P=0.016) and del6/del6 (11.5months, P=0.039) genotypes. Cox multivariate analysis also showed that TS ins6/ins6 genotype was the independent poor OS predictor (P=0.001, HR=3.182). No significant associations were found between the polymorphisms of TS 5'-UTR/MTHFR and clinical outcome, and no IVS14+1G>A polymorphism of DPD was found in this study. We first reported that TS 3'-UTR ins6/ins6 genotype could predict the poor survival of advanced gastric cancer patients treated with capecitabine plus paclitaxel, which would be further verified in a large multicenter study.

Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0 %, respectively, odds ratio 0.70; 95 % CI: 0.5-1.0) and significantly shorter progression-free survival (PFS: median 112.0 days [3.7 months] vs. 150.0 days [4.9 months]; p < 0.0001) and overall survival (OS: median 396.0 days [13.0 months] vs. 666.0 days [21.9 months]; p < 0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p = 0.0036), PFS (p < 0.0001) and OS (p < 0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63 % of patients. Overall, 7 % of patients discontinued and two patients (<1 %) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p < 0.0001 PFS/OS) or diarrhea (p = 0.004 OS; p = 0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.

Outcome of first line systemic treatment in elderly compared to younger patients with metastatic colorectal cancer: A retrospective analysis of the CAIRO and CAIRO2 studies of the Dutch Colorectal Cancer Group (DCCG)

Background. Metastatic colorectal cancer (CRC) is predominantly a disease of the elderly, therefore the current standards should be evaluated in this population. Material and methods. We evaluated in different age groups the outcome in terms of median overall and progression-free survival, response rate, disease control rate, relative dose intensity (RDI), tolerability, and global quality of life (QoL) of first-line capecitabine monotherapy (CAP) versus capecitabine + irinotecan (CAPIRI) and capecitabine + oxaliplatin + bevacizumab (CAPOX + BEV) in the CAIRO and CAIRO2 study, respectively. Patients were categorized into three age groups: age > 75, 70–75 and < 70 years. Results. Clinical outcomes were not significantly different among age groups, with the exception of a higher response rate from CAP treatment in the elderly. Elderly patients treated with CAPOX + BEV showed a trend towards a worse median overall survival compared to younger patients. Only treatment with CAP resulted in a higher incidence of grade 3–4 toxicity and a lower RDI in elderly versus younger patients. Treatment with CAP and CAPOX + BEV in elderly patients was significantly more often discontinued due to toxicity instead of progression to disease compared to younger patients. The increase in global QoL was comparable for the three age groups for each treatment regimen. Conclusion. We did not observe significant differences in survival outcomes between elderly and younger metastatic CRC patients with three different first-line systemic treatment regimens. Our data suggest that initial dose reduction of CAP monotherapy may be indicated in elderly patients.

Evaluations of biomarkers associated with sensitivity to 5-fluorouracil and taxanes for recurrent/advanced breast cancer patients treated with capecitabine-based first-line chemotherapy

The aim of the present study was to investigate the gene expression of biomarkers associated with the sensitivity to fluoropyrimidine and taxanes in recurrent/advanced breast cancer patients treated with first-line capecitabine chemotherapy. We evaluated the clinicopathological/prognostic significance of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), class III β-tubulin (βIII-tubulin), and stathmin-1 or oncoprotein-18 (STMN1). Formalin-fixed, paraffin-embedded tumor specimens from 42 patients were used for analysis of TS, DPD, TP, βIII-tubulin, and STMN1 expression with a real-time reverse transcription-PCR technique. Patients were classified into the high-expression and low-expression groups according to the median value of the expression level of each biomarker. There was a significantly longer time to progression (TTP) in the high-TP group (P=0.018). The multivariate analysis revealed that the TP expression (hazard ratio for the low-TP group vs. the high-TP group, 2.873; 95% confidence interval, 1.143-7.223; P=0.025) is independent of prognostic factors for TTP. In the subgroup of patients treated with capecitabine plus taxanes as first-line chemotherapy, TTP was significantly longer in the low-βIII-tubulin group (P=0.047). The gene expression of TS, DPD, and STMN1 failed to have any significant impact on the outcome. These results provide further evidence that the TP expression may be a prognostic factor in breast cancer patients treated with capecitabine-based first-line chemotherapy, and βIII-tubulin can be used to predict the outcome of capecitabine in combination with taxanes as first-line chemotherapy. Therefore, these potential biomarkers should be further evaluated.

Simultaneous peripheral facial palsies (SPFP) and bilateral foot drops after initiation of eribulin in a patient with triple-negative breast cancer.

e11085 Background: Simultaneous peripheral facial palsy (SPFP) is extremely rare. Unlike Bell’s palsy it is seldom idiopathic. We describe a case of acute SPFP and bilateral foot drops attributed to the novel chemotherapeutic agent, eribulin mesylate (EM), a synthetic microtubule inhibitor. Methods: Utilizing the medical record as well as physical evaluation and assessment, we diagnosed SPFP and bilateral foot drops temporally related to administration of EM for metastatic triple negative (ER neg/PR neg/HER2 neg) breast cancer. Results: A 71-year-old woman initially diagnosed with Stage I, T1N0M0, ER neg/PR neg/HER2 neg invasive ductal carcinoma of the left breast treated with adjuvant radiotherapy recurred 3 years later with liver metastases. Salvage treatment included first-line capecitabine for 6 months followed by paclitaxel for 13 months with residual grade 1 peripheral neuropathy. Fourteen days following last paclitaxel dosing, EM was started. Within 3 weeks of initiation of therapy, the patient presented with bilateral SPFP, as well as bilateral complete foot drops. She was unable to speak or take liquid or solid oral intake and unable to bear weight. Extensive work-up including initial CT of the brain, followed by MRI and LP revealed no metastatic or infectious (i.e. – Lyme disease, ACE, TSH, ANA, SPEP) etiology. After discontinuation of EM, physical and speech therapy were instituted including in-patient rehab. After follow-up of 16 weeks, she has partial resolution of the facial palsy and improved ambulation with bilateral foot braces and walking cane. Conclusions: Unlike unilateral Bell’s palsy, the differential diagnosis for SPFP includes many conditions that can potentially turn fatal within a short period of time if they are not diagnosed and treated promptly. To the best of our knowledge, CIN presenting with SPFP or foot drop due to EM has not been reported. We highlight the need to screen patients for pre-existing neuropathy and continued close monitoring for development of neuropathy to avoid potentially dose-limiting disabilities before initiating eribulin.