Phosphorylated EGFR expression may predicts outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

ABSTRACT: BACKGROUND: EGFR mutation is a strong predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with EGFR wild-type are responsive to TKIs, suggesting that other determinants of outcome besides EGFR mutation might exist. We hypothesized that activation of phosphorylated EGFR could be a potential predictive biomarker to EGFR-TKIs treatment among patients in wild-type EGFR. METHOD: Total of 205 stage IIIb and IV NSCLC patients, tissue samples of whom were available for molecular analysis, were enrolled in this study. The phosphorylation of EGFR at tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were assessed by immunohistochemistry, and EGFR mutations were detected by denaturing high performance liquid chromatograph (DHPLC). RESULTS: Among 205 patients assessable for EGFR mutation and phosphorylation analysis, 92 (44.9%) were EGFR mutant and 165 patients (57.6%) had pTyr1173 expression. Superior progression-free survival (PFS) was seen after EGFR-TKIs therapy in patients with pTyr1068 expression compared to pTyr1068 negative ones (median PFS 7.0 months vs. 1.2 months, P<0.001). Inversely, patients with pTyr1173 had a shorter PFS (4.8 months VS. 7.7 months, P=0.016). In subgroup of patients with wild-type EGFR, pTyr1068 expression positive ones had a significantly prolonged PFS (4.2 months vs.1.2 months P<0.001) compared with those without pTyr1068 expression.Sixteen patients with both wild-type EGFR and pTyr1068 who responded to EGFR-TKIs had median PFS of 15.6 months (95%CI: 7.28-23.9). CONCLUSION: pTyr1068 may be a predictive biomarker for screening the population for clinical response to EGFR-TKIs treatment; especially for patients with wild-type EGFR.     

Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma

Background

Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma.

Materials and methods

Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250 mg orally once a day until tumor progression or unacceptable toxicity.

Results

Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2–18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5–30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free (p = 0.003) and overall survival (p = 0.025).

Conclusion

Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.     

化疗序贯EGFR-TKIs治疗晚期非小细胞肺癌的机制及疗效

随着肿瘤分子生物学研究的发展,表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)在晚期非小细胞肺癌治疗中占有重要地位,特别针对于EGFR突变型患者.但基于分子靶向药物并未明显改善患者的总生存时间及出现获得性耐药问题,如何将传统化疗药物与靶向药物有机结合延长晚期患者的总生存时间受到广泛关注.化疗序贯EGFR-TKIs模式被证实为其中一项颇有前景的治疗策略.本文将结合相关研究对化疗序贯EGFR-TKIs治疗晚期非小细胞肺癌(NSCLC)的机制及疗效进行综述.     

Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival

Objectives

Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation.

Materials and methods

We retrospectively analyzed NSCLC patients with 1–4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain.

Results

Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p = 0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p < 0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p = 0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p = 0.032) and initial combined modality brain therapy (HR 0.34, p = 0.046).

Conclusion

Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.     

Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery

Purpose

The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).

Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab

Background:

The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities.

Methods:

Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed.

Results:

Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (P=0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis ⩾50% (P=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab.

Conclusion:

The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity.     

First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases

This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow-up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety.     

Prognostic factors for patients with liver metastases from breast cancer

Summary Background The prognosis of patients with liver metastases from breast cancer is commonly poor. After initial diagnosis of hepatic metastases, a median survival time of 1–20 months can be expected. The definition of prognostic factors for such patients may influence therapeutic decisions. In particular, the characterization of patients who can expect long-term survival could assist in optimizing treatment. Methods We retrospectively studied n=350 patients with liver metastases from breast cancer. All patients were stratified following their survival after occurrence of liver metastases. Kaplan–Meier studies were performed, as well as univariate and multivariate analyses of several clinical, histopathological and therapeutic factors. Results Median survival time was 14 months. N=66 (18.9%) patients survived longer than 36 months after the primary diagnosis. Multivariate analysis showed prognostic relevance for the time interval between the primary diagnosis of breast cancer and the initial diagnosis of hepatic metastases (p<0.05). Furthermore, prognostic relevance was found for the pattern of metastasization (p<0.05) and for signs of hepatic dysfunction (ascites, jaundice, p<0.005). Univariate analysis showed a prognostic benefit for patients with an expression of Ki-67<20%, p53<50% and a positive hormonal receptor status. Patients who received a regional therapy survived on average longer than patients who were only treated systemically (33 versus 11 months, p<0.001). Conclusions Consideration of prognostic implications of the described parameters may help to find the most appropriate treatment for patients with liver metastases from breast cancer. The possibility of local therapeutic interventions should be considered in a defined subgroup.     

Hepatic resection prolongs overall survival in the selected patients with nasopharyngeal carcinoma liver metastases

BackgroundThe role of surgery in nasopharyngeal carcinoma liver metastases (NCLM) remains elusive, and the current application is limited. We aim to investigate whether hepatic resection (HR) of NCLM improves survival compared with non-hepatic resection (NHR) treatment.MethodsOne hundred and thirty-three patients with NCLM from 2007 to 2017 were divided into two groups. Propensity score matching (PSM) analysis was used to compare the clinical outcomes.ResultsAfter PSM the median overall survival (OS) and the 1, 3 and 5-year OS rates in HR group were 32.60 months, 86.2%, 37.3% and 37.3%, respectively; while for NHR group these values were 19.57 months, 61.5%, 12.9% and 2.9%, respectively (P = 0.008). Multivariate analysis indicated hepatitis B virus infection (P = 0.029) and hepatic resection (P = 0.018) were independent prognostic factors.ConclusionOur study revealed that hepatectomy yields a survival benefit safely compared with systemic treatments, especially for patients with the size of largest metastasis < 5 cm, unilobar distribution of liver tumor and received unanatomical hepatectomy.     

Reaction of plasma hepatocyte growth factor levels in non-small cell lung cancer patients treated with EGFR-TKIs

Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non-small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post-treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty-one patients were enrolled. Plasma hepatocyte growth factor levels on post-treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post-treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut-off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.     

HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer

Objective

In this study, we evaluate the frequency of HER-2 and HER-3 expression in liver metastases from patients with colorectal cancer (CRLM). We analyzed the potential of HER-2 and HER-3 as therapeutic targets and evaluated their prognostic value.

Patients and Methods

Overall 208 patients with CRLM were enrolled. HER-2 and HER-3 expression were determined in metastatic tissue of diagnostic punch biopsies (n = 29) or resection specimens (n = 179). The results of immunohistochemistry (IHC) scoring and In-situ-hybridization (ISH)-amplification were correlated with clinical parameters and for the 179 resected patients with cancer-specific (CSS) and overall survival (OS). The mean follow-up time was 56.7 months.

Results

Positivity of HER-2 status (IHC score 2+/ISH+ and IHC 3+) was found in 8.2% of CRLM. High expression of HER-3 (IHC score 2+ and IHC 3+) was detected in 75.0% of liver metastases. CSS after liver surgery was determined and was independent from the HER-2 status (p = 0.963); however HER-3 was prognostic with a favorable course for patients showing an overexpression of HER-3 (p = 0.037).

Conclusions

HER-2 overexpression occurs in only 8% of patients with CRLM but with 75% of cases HER-3 is frequently overexpressed in CRLM. Therefore, HER-2 and particularly HER-3 could serve as novel targets to be addressed within multimodal treatment approaches.     

Chemotherapy plus percutaneous radiofrequency ablation in patients with inoperable colorectal liver metastases

AIM:To access the efficacy of chemotherapy plus radiofrequency ablation(RFA)as one line of treatment in inoperable colorectal liver metastases.METHODS:Eligible patients were included in three PhaseⅡstudies.In the first study percutaneous RFA was used first followed by 6 cycles of 5-fluorouracil,leucovorin and irinotecan combination(FOLFIRI)(adjunctive chemotherapy trial).In the other two,chemotherapy(FOLFIRI or 5-fluorouracil,leucovorin and oxaliplatin combination)up to 12 cycles was used first with percutaneous RFA offered to responding patients (primary chemotherapy trials).RESULTS:Thirteen patients were included in the adjunctive chemotherapy trial and 17 in the other two.At inclusion they had 1-4 liver metastases(up to 6.5 cm in size).Two patients died during chemotherapy.All patients in the adjunctive chemotherapy trial and 44%in the primary chemotherapy studies had their metastases ablated.Median PFS and overall survival in the adjunctive study were 13 and 24 mo respectively while in the primary chemotherapy studies they were 10 and 21 mo respectively.Eighty one percent of the patients had tumour relapse in at least one previously ablated lesion.CONCLUSION:Chemotherapy plus RFA in patients with low volume inoperable colorectal liver metastases seems safe and relatively effective.The high local recurrence rate is of concern.     

三维适形放疗结合TACE在结直肠癌患者根治术后肝转移的临床应用

目的：探讨对于不宜或不能手术治疗的结直肠癌肝转移灶行TACE后根治性三维适形放射治疗的可行性,不良反应及疗效。方法：对20例结直肠癌根治术后出现肝转移灶的病人,行TACE（ADM＋碘油）后3周内,针对其肝转移灶行三维适形放疗,常规分割2Gy,总剂量60—66Gy。结果：4例（20％）患者出现Ⅲ度恶心呕吐,3例（15％）出现Ⅲ度中性粒细胞减少,1例（5％）出现Ⅲ度血小板减少,4例（20％）出现Ⅲ度肝功能异常。治疗结束后,4例（20％）CR,11例（55％）PR,5例（25％）SD,无1例进展,有效率为75％。结论：对于结直肠癌根治术后出现不宜或不能手术的肝转移癌,应用三维适形放疗结合TACE的治疗模式,是可行的,无严重不良反应,近期疗效显著。     

非小细胞肺癌脑转移厄洛替尼和吉非替尼治疗临床比较

目的比较和评价厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效。方法回顾性分析2009-01-01-2012-11-25广州医科大学附属第一医院81例晚期NSCLC初诊有脑转移患者和111例晚期NSCLC初诊无脑转移患者,192例患者均为肺腺癌合并EGFR基因突变,分为吉非替尼和厄洛替尼治疗组,生存分析采用Kaplan-Meier法统计,组间生存率比较采用Log-rank检验。结果初诊有脑转移患者颅内病灶,客观有效率为45.68%(37/81),疾病控制率为90.12%(73/81)。吉非替尼、厄洛替尼治疗的无进展生存期(progression-free survival,PFS)分别为9.5和9.0个月,P=0.344;不同EGFR突变类型(19外显子序列缺失突变、21外显子突变)PFS比较分别为10.4和8.6个月,P=0.408。初诊无脑转移患者PFS分别为14.0和15.0个月,P=0.369;不同EGFR突变类型的PFS分别为14.0和15.0个月,P=0.408。结论厄洛替尼和吉非替尼一线治疗肺癌EGFR突变脑转移效果无显著性差异。     

血脂与结直肠癌肝转移关系的临床研究

目的:检测结直肠癌患者的血脂水平,包括总胆固醇(TC)和甘油三酯(TG),探讨血脂异常与结直肠癌肝转移的关系.方法:收集本院282例结直肠癌患者的临床病理资料并检测空腹血脂水平.测定患者血清白蛋白和计算体重指数(BMI)评估患者的营养状态,对血脂等临床病理因素与结直肠癌肝转移的关系进行统计学分析.结果:结直肠癌肝转移患者的高胆固醇血症及高甘油三酯血症比率高于无肝转移者,差异有统计学意义(P＜0.05).多元Logistic回归分析显示,高胆固醇血症是结直肠癌发生肝转移的独立危险因素之一,而与高甘油三酯血症无关.结论:高胆固醇血症与结直肠癌肝转移相关,血脂水平的增高可能促进结直肠癌肝转移.     

大肠癌伴肝转移患者的预后因素

目的探讨影响大肠癌伴肝转移患者预后的因素.方法1995年5月-1999年12月间本院外科手术治疗的64例大肠癌伴肝转移患者,部分患者全身化疗或肝动脉插管化疗,并对其临床资料进行统计分析.结果本组大肠癌肝转移患者占大肠癌患者10.2%.肝转移灶大小、术前CEA水平、原发灶切除、辅助治疗方式为影响生存的独立的预后因素.年龄、性别、肿瘤部位、分化程度、肝转移灶数目与预后无关.肝转移灶＞5cm、术前CEA＞100μg/ml、原发灶未切除的患者的生存时间(3.52月)显著低于其他患者(21.60月).结论治疗方式对肠癌肝转移患者预后影响显著,应积极切除原发灶、治疗转移灶.肝动脉插管化疗优于全身化疗.肝转移灶大小、术前CEA水平是重要的预后指标.     

三维立体定向适形放射治疗在治疗肝脏转移性肿瘤中的应用

目的探讨三维立体定向适形放射治疗在肝脏转移性肿瘤中的应用价值。方法用三维立体定向适形放射技术治疗转移性肝瘤，优化指标：每次剂量2—3Gy时，90％的等剂量面包绕PTV；每次剂量8Gy时，70％～80％等剂量面包绕PTV平均肝脏剂量小于30Gy。给量2Gy／次，1次／日，5天／周。照射次数25～30次，总剂量为50Gy～60Gy。或者8Gy／次，3次／周，共3次。结果在放疗结束后2个月用腹部CT进行评价，有效率(CR PR)50％。3年局部无进展生存率75％。放疗中后无严重并发症发生。结论三维立体定向适形放射治疗在不增加治疗并发症基础上，能明显提高肝转移性癌的局部控制率。我们认为晚期病人出现肝转移时，在其它部位病灶尚稳定的情况下可选择三维立体定向适形放射治疗。     

Local therapy and survival in breast cancer with distant metastases

This review article presents an evaluation of the effects of local therapy on survival of breast cancer patients with distant metastases along with a discussion of their relevance. Primary and recurrent breast cancers with distant metastases are systemic diseases with poor prognosis. However, several retrospective studies have demonstrated that surgical removal of the primary breast tumor has a favorable impact on the prognosis of stage IV breast cancer patients. Similarly, it has been reported that surgical resection of metastatic lesions in the lung as well as the liver yields unexpectedly promising results. The interaction of local treatment and systemic therapy may be important, because surgery and radiotherapy are only local treatments. However, it remains uncertain whether these encouraging findings are due to the surgical procedure itself or preoperative patient selection. Only a randomized prospective study can definitively show whether local treatment can prevent death from stage IV disease or recurrent breast cancer with distant metastases. Until data from prospective studies are available, clinicians must weigh retrospective experiences and clinical judgment in deciding whether to offer surgery or radiotherapy to these patients.     

Progress of transformational therapy in colorectal liver metastases

Colorectal cancer liver metastases(CLM) treatment is very important given the high incidence of colorectal cancer with liver metastases, which are primarily treated by surgical resection. Transformational therapy such as systemic chemotherapy, hepatic arterial infusion(HAI), portal vein embolization(PVE), ablation therapy, and targeted therapy, should be applied to CLM patients who are unable to undergo immediate surgery to improve patients’ survival and quality of life.     

一代EGFR-TKI联合同步放疗治疗EGFR-TKI耐药晚期肺腺癌患者的有效性和安全性

目的:探索第一代EGFR酪氨酸激酶抑制剂（EGFR-TKI）耐药后继续口服EGFR-TKI并联合局部放疗治疗晚期肺腺癌的有效性和安全性。方法:回顾性纳入2014年1月至2017年7月期间本中心符合纳入标准的、接受第一代EGFR-TKI联合局部放疗治疗的晚期肺腺癌患者,分析其疗效及不良事件发生情况。结果:研究纳入了64例符合纳入标准及排除标准的患者,继续口服原EGFR-TKIs并联合局部放疗的平均PFS为（5.48±3.85）个月。PFS与患者进展病灶不同数量相关,出现1、2、3个病灶进展患者的无进展生存期分别为6.60个月、5.17个月和 2.82个月,组间比较有显著统计学差异（P=0.006）。继续口服原EGFR-TKIs并联合局部放疗总体3-4级不良事件发生率为10.9%。结论:第一代EGFR-TKI联合局部放疗是EGFR-TKI治疗晚期肺腺癌后局部进展的有效治疗方式之一。