Association of GRP78 polymorphisms with response and TTP in patients with mCRC treated with FOLFOX/BV or XELOX/BV.
Heinz‐Josef LenzW. ZhangDong‐Hoon YangAnthony B. El-KhoueiryNing YeA. PohlPierre BohanesK. D. DanenbergThomas Winder
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3590 Background: GRP78, a major endoplasmatic chaperone, is suggested to be critical for tumor angiogenesis. Recent data suggested GRP78 protein overexpression as a major player in tumor recurrence and poor survival by protecting cancer cells from apoptosis, promoting metastasis and chemoresistance to doxorubucin hydrochloride in breast tumors. We tested whether germ-line polymorphisms within the GRP78 gene were associated with clinical outcome in mCRC patients treated with FOLFOX/BV or XELOX/BV and investigated if there is a correlation with gene expression levels of VEGF and its receptors. Methods: gDNA was isolated from peripheral blood of 91 patients with mCRC and three potentially functional genotypes (rs391957, rs12009, rs17840761) within the GRP78 gene were determined using PCR-RFLP. mRNA was extracted from laser-capture-microdissected tumor tissue. Intratumoral gene expression levels of VEGF and VEGFR-1,-2 and -3 from 79 patients with mCRC were analyzed by RT-PCR. Results: In univariate analysis two GRP78 SNPs (rs391957 and rs12009) were significantly associated with TTP (Table). In multivariate analysis GRP78rs391957 remained significantly associated with TTP (adjusted p value=0.012). Moreover, two GRP78 polymorphisms (rs391957 and rs12009) were in linkage disequilibrium (D′=0.93 and r2=0.73). Patients harbouring the C-A-T haplotype were at lowest risk to develop tumor progression [HR 0.49 (CI 95 %; 0.29-0.82)] and showed the highest response rate [OR 2.56(CI 95%;1.07- 6.22)]. The three tested GRP78 polymorphisms were not associated with gene expression levels of VEGF or its receptors (p values > 0.05). Conclusions: Our data suggest that polymorphisms in GRP78 gene may be potential predictive markers to FOLFOX/BV or XELOX/BV therapy in mCRC patients. Moreover, GRP78 polymorphisms may play a major role in VEGF-independent tumor angiogenesis. Univariate analysis N Time to progression Median, months (95% CI) P* value GRP78rs391957 0.004 CC 33 7.9 (6.9, 12.4) CT 35 15.8 (10.8, 22.9) TT 5 19.9 (1.9, 38.6) GRP78rs12009 0.021 TT 31 8.1 (7.0, 11.7) TC 36 13.9 (10.8, 22.2) CC 7 19.9 (7.8, 38.6) GRP78rs17840761 0.074 AA 22 8.3 (6.9, 15.0) AG 41 12.4 (8.1, 17.0) GG 13 13.9 (12.4, 38.6) * Log-rank test. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Genentech Response GeneticsKeywords:
FOLFOX
To dissect gene expression subgroups of FOLFOX resistance colorectal cancer(CRC) and predict FOLFOX response, gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder n = 42, non-responder n = 41) are used to develop a novel iterative supervised learning method IML. IML identified two mutually exclusive subgroups of CRC patients that rely on different DNA damage repair proteins and resist FOLFOX. IML was validated in two validation sets (HR = 2.6, p Value = 0.02; HR = 2.36, p value = 0.02). A subgroup of mesenchymal subtype patients benefit from FOLFOX. Different subgroups of FOLFOX nonresponders may need to be treated differently.
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Abstract Background FOLFOX is a combination of drugs that is widely used to treat colorectal cancer. The response rate of FOLFOX in colorectal cancer(CRC) is 30-50%. We develop a method that analyzes mechanisms of FOLFOX resistance and predicts whether a patient will benefit from FOLFOX. Methods Gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder n=42, non-responder n=41) were used to develop a supervised learning method IML and analyze subgroups of FOLFOX resistance mechanism. Datasets of 32 FOLFOX treated stage IV CRC patients and 55 FOLFOX treated stage III CRC patients were used as independent validations. Results An iterative supervised learning (IML) method identified two distinct subgroups of CRC patients who resist FOLFOX. Each subgroup relies on different types of DNA damage repair proteins and they are mutually exclusive. Protein-protein networks showed the main mechanism might be the synergistic effect of resisting apoptosis and an altered cell cycle. IML method was validated in two independent validation sets, one FOLFOX treated stage IV CRC patients(HR=2.6, p-value=0.02, 3-years survival rate of the predicted responder group 61.9%, predicted nonresponder group 18.8%) and one FOLFOX treated stage III CRC patients (estimated HR=2.36, p-value=0.02). A subgroup of mesenchymal subtype patients shows the pattern as FOLFOX responders. Conclusions IML method reflects the underlying biology of FOLFOX resistance and predicts FOLFOX response.
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目的：FOLFOX 是第三期大腸直腸癌術後標準輔助性化學治療。但是許多病人無法完成完整療程。本研究欲探討完成完整FOLFOX 療程的比率及其無法完成的原因。方法：由台北榮總大腸直腸外科資料庫收集2009 年一月至2015 年十二月第三期大腸直腸癌術後接受FOLFOX 治療之病人之基本資料、接受Oxaliplatin 之劑量及無法完成之原因做分析。結果：研究期間內內共866 個第三期大腸直腸癌病人接受手術。其中110 人沒有接受後續輔助性化學藥物治療，199 人接受其他療法，5 人於其他他醫院治療。最後收集572人分析。290 人 (50.6%) 完成完整療程，其Oxaliplatin 累計計劑量之中位數為984 mg/m^2(644~1210 mg/m^2)。無法完成完整療程的病人中，78 人 (27.7%) 是因為主治醫師預防性停藥，72 人 (25.5%) 因週邊神經病變，30 人 (10.6%) 因疾病進展更換療法，18 人 (6.4%)因對Oxaliplatin 過敏，19 人 (6.7%) 因為白血球過低過肝腎功能惡化，17 人 (6.0%) 因嚴重噁心嘔吐，12 人 (4.3%) 因為整體身體狀況變差，36 人 (12.8%) 自行要求停藥。因週邊神經病變而中斷治療的患者，其Oxaliplatin 的累積劑量中位數為746 mg/m^2，而因對Oxaliplatin 過敏中斷治療的患者，其累積劑量中位數為680.4 mg/m^2。結論：半數病人能完成完整療程，週邊神經病變及及醫師預防性停藥是無法完成完整療程之主因。研發預防或減緩週邊神經經病變副作用之化學治療方法應能增加完整療程達成率。
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Colon cancer is a leading global cancer-related cause of morbidity and mortality. The oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) regimen is a standard chemotherapeutic approach used to treat colon cancer. However, chemoresistant tumor cells typically lead to the emergence of recurrent FOLFOX-resistant tumors after initial treatment. As such, it is vital that novel approaches to identifying and eliminating such chemoresistant tumors be developed in an effort to improve patient chemotherapy outcomes.In total, 100 samples of serum were obtained between April 2014 and April 2019 from patients who had been pathologically diagnosed with colon cancer from the Xiamen Haicang Hospital, and after these patients received FOLFOX chemotherapy treatment, serum samples were collected again. The expression of has_circ_0055625 in these serum samples was assessed via qPCR. Additionally, 5-FU IC50 values were detected via CCK-8 assay.We found has_circ_0055625 to be significantly upregulated in colon cancer patient serum. After FOLFOX treatment, chemotherapy-resistance was associated with the upregulation of has_circ_0055625.In summary, these data may provide a foundation for future studies of chemotherapeutic resistance in patients undergoing FOLFOX treatment, potentially guiding treatment adjustment strategies. However, further work will be necessary to expand upon these findings.
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Abstract FOLFOX (5‐fluorouracil, leucovorin and oxaliplatin) is one of the main chemotherapy regimens for colorectal cancer (CRC), but only half of CRC patients respond to this regimen. Using gene expression profiles of 96 metastatic CRC patients treated with FOLFOX, we first selected gene pairs whose within‐sample relative expression orderings (REO) were significantly associated with the response to FOLFOX using the exact binomial test. Then, from these gene pairs, we applied an optimization procedure to obtain a subset that achieved the largest F ‐score in predicting pathological response of CRC to FOLFOX. The REO‐based qualitative transcriptional signature, consisting of five gene pairs, was developed in the training dataset consisting of 96 samples with an F ‐score of 0.90. In an independent test dataset consisting of 25 samples with the response information, an F ‐score of 0.82 was obtained. In three other independent survival datasets, the predicted responders showed significantly better progression‐free survival than the predicted non‐responders. In addition, the signature showed a better predictive performance than two published FOLFOX signatures across different datasets and is more suitable for CRC patients treated with FOLFOX than 5‐fluorouracil‐based signatures. In conclusion, the REO‐based qualitative transcriptional signature can accurately identify metastatic CRC patients who may benefit from the FOLFOX regimen.
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A 73-year-old man had undergone right hemicolectomy for advanced colon cancer in May 2006, and he concurrently had multiple liver metastases. After the operation, the patient was given chemotherapy with FOLFIRI. A partial response was achieved for twelve months, and then the liver tumors enlarged. Second-line chemotherapy with FOLFOX was delivered. After several months the liver tumors further enlarged and a new pulmonary lesion appeared with an increased serum CEA level. Therefore, chemotherapy with S-1 (120 mg/day) was started, with 2 weeks' administration followed by a one-week drug-free period. Several months later, the liver tumors and tumor makers decreased. S-1 is expected to be an effective agent for the treatment of advanced colon cancer with liver metastases after FOLFIRI and FOLFOX.
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Objective To investigate the effects of preoperative FolFox neoadjuvant chemotherapy on the expression of Smad4 in colorectal carcinoma.Methods Fifteen cases of advanced colorectal carcinoma were treated by preoperative FolFox neoadjuvant chemotherapy(the FolFox neoadjuvant chemotherapy group),18 cases by 5-FU chemotherapy(the 5-FU chemotherapy group) and 21 cases by operation(the control group).The expression of Smad4 was detected by immunohistochemical SP method.Results Among the three groups,the expression level of Smad4 gradually increased(P 0.05).The positive expressions of Smad4 in the three groups were 19.0 %(4/21) in the control group,61.1%(11/18) in the 5-FU chemotherapy group and 93.3%(14/15) in the FolFox neoadjuvant chemotherapy group respectively.The difference was significant(P 0.05).Conclusion Preoperative FolFox neoadjuvant chemotherapy could induce high level of Smad4 expression,which could be an effective chemotherapy.
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The decision for adjuvant therapy of colon cancer by both physicians and patients requires many factors, including knowledge of the risk for recurrence (prognosis), the likelihood of significant clinical benefit (prediction), toxicity of treatment, comorbidities, and the patient's understanding and acceptance of both the relative and absolute benefit of therapy. To predict the risk of recurrence, clinicopathologic features have typically been used such as the number of positive and negative nodes, T stage, tumor differentiation, obstruction and lymphovascular invasion. More recent quantitative prognostic markers include microsatellite instability, with MSI-H conferring better prognosis. In addition, in combination with MSI, gene expression profiles have been developed which may be especially helpful in stage II disease, and in some low risk stage III patients to decide on whether they should receive combination chemotherapy, capecitabine or no adjuvant treatment. The standard treatment for most stage III patients is a combination of oxaliplatin with infusional and bolus 5-FU (FOLFOX) or with an oral agent such as capecitabine (XELOX), with equivalent results. Although irinotecan is active in advanced colorectal cancer, two trials of this drug with 5-FU failed to show improvement over the fluoropyrimidines alone. The antiangiogenic agent bevacizumab also failed to improve treatment compared to FOLFOX alone, as did the EGFR agent, cetuximab. Studies are currently underway to compare the standard 6 months of FOLFOX with 3 months of therapy, to reduce the risk of neurotoxocity associate with oxaliplatin, while maintaining treatment efficacy.
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9530 Background: Although 12 cycles of Adj FOLFOX are recommended for stage III and high risk stage II colon cancer, toxicity may preclude completion of treatment. We used the NCCN Colorectal Cancer Outcomes Database to identify how frequently Adj FOLFOX is discontinued prematurely for toxicity in a non-clinical trial population. Methods: Newly diagnosed stage II-III colon cancer pts treated with Adj FOLFOX at 7 NCI-designated comprehensive cancer centers between 9/05–12/07 were identified. We assessed completion of the prescribed adjuvant chemotherapy (AC) course, including Adj FOLFOX and 5FU-based adjuvant treatment alone subsequent to discontinuation of oxaliplatin (oxal). Dose limiting toxicity (DLT) of Adj FOLFOX was defined as premature discontinuation of Adj FOLFOX due to toxicity. We evaluated potential predictors of Adj FOLFOX DLT, including older age and history of diabetes in a multivariable logistic model controlling for stage and center. We measured the duration of Adj FOLFOX use in weeks, from first to last dose. Results: 293 pts began Adj FOLFOX. Pts who experienced DLT (40%) had a shorter duration of Adj FOLFOX and were less likely to complete AC, even after oxal was discontinued. The only significant predictor of experiencing a DLT was a history of diabetes. Conclusions: Our analysis of patients treated outside of a clinical trial demonstrated a notably high rate of discontinuation of Adj FOLFOX due to DLT, particularly in pts with diabetes. The results underscore the need for systematic assessment of toxicity especially among diabetics. [Table: see text] [Table: see text]
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