The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients

There are many active drugs to treat metastatic renal cell carcinoma (mRCC) patients who progress through their first-line vascular endothelial growth factor (VEGF) inhibitor. Many clinicians choose a second-line VEGF inhibitor based on the type of response to first-line VEGF inhibitor, without data supporting this practice. This study was conducted to determine the association of response to second-line VEGF inhibitor with response to first-line VEGF inhibitor. All mRCC patients in participating centers of the International mRCC Database Consortium who were treated from January 2004 through June 2011 with a second-line VEGF inhibitor after failure of a different first-line VEGF inhibitor were retrospectively identified. The primary outcome is objective response rate (ORR) and the secondary outcome is progression-free survival (PFS) in each line of therapy. Of 1,602 total database patients, 464 patients received a first- and second-line VEGF inhibitor. The ORR to first-line therapy was 22 %, and the ORR to second-line therapy was 11 %. The ORR to second-line therapy was not different among patients achieving partial response versus stable disease versus progressive disease to first-line therapy (14 % vs. 10 % vs. 11 %, respectively; chi-squared trend test p?=?0.17). The median PFS on first-line VEGF-targeted therapy was 7.5 months (95 % CI, 6.6–8.1), and the median PFS on second-line VEGF inhibitor was 3.9 months (95 % CI, 3.6–4.5). There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p?=?0.59). The clinical response to a second-line VEGF inhibitor is not dependent on response to the first-line VEGF-inhibitor. Further studies are needed to define clinical parameters that predict response to second-line therapy to optimize the sequence of VEGF-targeted therapy in metastatic RCC patients.     

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.     

Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma

In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI.BackgroundAlthough sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).Patients and methodsRetrospective multicenter study (2004–2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). End points: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).ResultsSequence effect in the overall cohort was in favor of the TKI–TKI sequence over the TKI–mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI–TKI superiority was attributed in large part to the 11–22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9–12.2) versus 3.9 (3.0–5.5), P = 0.003; TTF(months): 8.0 (5.5–11.0) versus 3.6 (3.0–4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.Conclusionsm-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.     

Assessment of the associations between three VEGF polymorphisms and risk of prostate cancer

Vascular endothelial growth factor (VEGF) plays a crucial role in the regulation of angiogenesis and is involved in the development and metastasis of common cancers. There were several case–controls studies published to assess the associations of VEGF polymorphisms with risk of prostate cancer, but the findings were inconsistent. We performed a meta-analysis to provide a comprehensive assessment of the associations of three VEGF polymorphisms with risk of prostate cancer. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to assess the associations. Eleven individual case–control studies with a total of 5,209 cases of prostate cancer and 5,233 controls were finally included into our meta-analysis. Overall, VEGF rs833061 polymorphism was not associated with risk of prostate cancer (T versus C, OR?=?1.14, 95 % CI 0.91–1.44, P?=?0.26; TT versus CC, OR?=?1.09, 95 % CI 0.67–1.76, P?=?0.74; TT versus CC/CT: OR?=?1.46, 95 % CI 0.67–3.18, P?=?0.34; TT/CT versus CC, OR?=?1.08, 95 % CI 0.82–1.43, P?=?0.59). VEGF rs3025039 polymorphism was also not associated with risk of prostate cancer (T versus C, OR?=?1.03, 95 % CI 0.91–1.16, P?=?0.66; TT versus CC, OR?=?1.82 95 % CI 0.16–20.53, P?=?0.63; TT versus CC/CT, OR?=?2.00, 95 % CI 0.18–22.41, P?=?0.57; TT/CT versus CC, OR?=?0.72, 95 % CI 0.38–1.36, P?=?0.31). VEGF rs2010963 polymorphism was not associated with risk of prostate cancer under three models (C versus G, OR?=?1.17, 95 % CI 0.92–1.48, P?=?0.20; CC versus GG, OR?=?2.28, 95 % CI 0.90–5.75, P?=?0.08; CC versus GG/GC, OR?=?1.57, 95 % CI 0.67–3.68, P?=?0.30). In conclusison, current data suggest that those three VEGF polymorphisms are not obviously associated with risk of prostate cancer.     

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study

Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67?±?12.7 years, women: 69 %, non smokers: 68 %, PS 0–1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p?=?0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p?=?0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p?=?0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p?=?0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, 相似文献   

Activity of Single-Agent Bevacizumab in Patients With Metastatic Renal Cell Carcinoma Previously Treated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

PurposeThe activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population.MethodsWe conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed.ResultsTwenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%).ConclusionsSingle-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted.     

A Population-Based Overview of Sequences of Targeted Therapy in Metastatic Renal Cell Carcinoma

BackgroundSeveral TTs are available to treat mRCC; however, the optimal sequence of therapy remains unknown.Patients and MethodsConsecutive population-based samples of patients with mRCC treated with TT were collected from 12 cancer centers via the International Metastatic Renal Cell Carcinoma Database Consortium. Patient characteristics, first-line and second-line progression-free survival rates and overall survival data were collected based on sequencing of TT. Multivariable analysis was performed when there were significant differences on univariable analysis.ResultsA total of 2106 patients were included with a median follow-up of 36 months; 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics were well matched among different sequences apart from more patients with non–clear-cell histology in the vascular endothelial growth factor (VEGF) to mammalian target of rapamycin (mTOR) group compared with the VEGF to VEGF group sequence. When adjusting for the Heng risk criteria and non–clear-cell histology, the hazard ratio for death for the VEGF to mTOR group versus the VEGF to VEGF group was 0.833 (95% confidence interval [CI], 0.669-1.037; P = .1016). More specifically, the adjusted hazard ratio for death for the sunitinib to everolimus versus sunitinib to temsirolimus sequences was 0.774 (95% CI, 0.52-1.153; P = .2086).ConclusionIn this large multicenter analysis evaluating different sequences of TT in mRCC, no substantial effect on outcome based on sequence of TT was identified.     

Clinical Outcomes in Patients With Metastatic Papillary Renal-Cell Carcinoma: A Multi-Institutional Study in Japan

Background

Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC.

Comparison of overall survival between the early use and delayed use of Trastuzumab therapy groups: a retrospective analysis of 128 patients with HER-2-positive advanced breast cancer

Trastuzumab has been the standard treatment in first-line treatment of HER-2-positive advanced breast cancer (H2ABC). This study explored whether the delayed and repeated use of trastuzumab could influence overall survival (OS). A total of 128 patients with H2ABC who had received at least one line of trastuzumab-based regimens were included. The primary endpoint was OS defined as from the date of first diagnosis of H2ABC to death. The median OS of initiating trastuzumab in first-line group (n?=?56), in the second-line group (n?=?32), and the third- or more-line group (n?=?40) was 40.6?m, 39.5?m, and 38?m, respectively (P?=?0.867). For patients who had received over one line of trastuzumab (n?=?46), the median OS was 44?m, and for those receiving only one line (n?=?67), it was 27.6?m (P?=?0.059). The delayed use of trastuzumab has no negative effect on the OS of patients with H2ABC. There is a trend of improved OS over the repeated use of trastuzumab.     

C-KIT mutations were closely associated with the response to Imatinib in Chinese advanced gastrointestinal stromal tumor patients

To investigate the correlation between C-KIT/PDGFR?? mutations and Imatinib response or survival in Chinese advanced gastrointestinal stromal tumor (GIST) patients. Clinical data and paraffin-embedded tumor specimens were collected from 158 advanced GIST patients receiving first-line Imatinib. Mutation analyses of C-KIT gene (Exons 9, 11, 13, and 17) and PDGFR?? gene (exons 12 and 18) were performed by PCR amplification and Sanger sequencing. A total of 135 patients harboring C-KIT mutations (exon 11 mutation: 108; exon 9 mutation: 23; exon 13 mutation: 2; exon 17 mutation: 2) and one patients carrying PDGFR?? mutation (exon 18) were found in this study. Twenty-two patients (13.9?%) with neither C-KIT nor PDGFR?? mutations were named as wild type. The response rate (64.7 vs. 36.4?%, P?=?0.000) and median progression-free survival (28 vs. 8?months, P?=?0.000) of mutant patients (n?=?136) were significantly higher than those of wild-type patients (n?=?22). Moreover, the response rate and median progression-free survival in patients with exon 11 mutations (n?=?108), exon 9 mutations (n?=?23), and wild-type patients (n?=?22) were 68.5, 47.8, and 36.4?% (P?=?0.001), and 31?months, 13?months, and 8?months (P?=?0.000), respectively. No significant differences of response rate or median progression-free survival were seen in patients with exon 11 deletion mutations, point mutations, and mixed-type mutations. C-KIT mutations were closely associated with Imatinib response and progression-free survival of Chinese advanced GIST patients. Other predictive markers for Imatinib would be further investigated.     

Pre-treatment hormonal receptor status and Ki67 index predict pathologic complete response to neoadjuvant trastuzumab/taxanes but not disease-free survival in HER2-positive breast cancer patients

Trastuzumab-containing neoadjuvant chemotherapy achieves a pathologic complete response (pCR) rate of about 40?% in HER2-positive breast cancers, and pCR predicts better survival. A cohort of 102 consecutive Chinese HER2-positive stage II/III patients with neoadjuvant trastuzumab/taxanes were retrospectively analyzed, to evaluate the role of hormonal receptor (HR) status and Ki67 index, along with other parameters, in pCR and survival prediction. pCR rate of the cohort was 44.1?% (45/102). Fifty-three patients were HR-positive and 49 were HR-negative. Median Ki67 index was 40?%, and 49 patients had a high Ki67 index (>40?%) whereas 53 had a low Ki67 index (??40?%). HR status and Ki67 index were confirmed as the only two parameters associated with pCR in multivariate analysis (hazard ratio?=?2.952; 95?% CI, 1.227?C7.105; P?=?0.016 for HR status and hazard ratio?=?2.583, 95?% CI 1.107?C6.026, P?=?0.028 for Ki67 index). Patients with coexisting HR-negative and high Ki67 index had higher pCR rate (69.2?%), compared to those with either HR-negative alone or high Ki67 alone (hazard ratio?=?3.038; 95?% CI, 1.102?C8.372; P?=?0.029), and to those with coexisting HR-positive and low Ki67 index as well (hazard ratio?=?7.071; 95?% CI, 2.150?C23.253; P?=?0.001). In a median follow-up duration of 25.9?months, 11 disease-free survival events (DFS) were recorded. pCR predicted better DFS (log rank P?=?0.018) and was the only significant factor in Cox regression analysis (hazard ratio?=?0.184; 95?% CI, 0.038?C0.893; P?=?0.036). Our study indicates that HR status and Ki67 index are predictors for pCR but not for DFS in HER2-positive patients with neoadjuvant trastuzumab/taxanes, which deserves further investigations.     

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study

IntroductionContinuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non–small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients’ disease gradually progressed after first-line EGFR-TKI treatment.Patients and MethodsPatients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients’ progression-free survival (PFS) and overall survival times.ResultsNinety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038).ConclusionFor patients with advanced non–small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.     

Prognostic factors and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer treated with immune checkpoint blockage

Our aim was to describe the incidence and characteristics of immune-related adverse events (irAEs) in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and to evaluate their impact on outcome. All cases of NSCLC patients treated with ICIs in the second-line setting between December 2015 and May 2018 were evaluated. Seventy patients were included. Mean age was 65.9?years, and the majority of male (n?=?53, 75.7%), with PS of 0-1 (n?=?62, 88.6%) treated with nivolumab (n?=?51; 72.9%). Thirty-one patients (44.3%) experienced an AE, 5 (7.1%) were grades 3–4. Median OS in patients with AE was 30.1?months (95% CI, 16.7–43.5) compared with 5.1?months (95% CI, 1.2–9.0) in cases without AE (log-rank test: p?=?0.010). The adjusted HR for OS was 0.46 (95% CI, 0.25–0.86) for the irAE occurrence and 3.60 (95% CI, 1.56–8.32) for PS 2-3 group. The development of irAEs was associated with improved patient outcome.     

A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy

BackgroundThis retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy.Patients and methodsWe evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy.ResultsMedian progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7–5.4], hemoglobin (Hb) level: ≥10 g/dl (HR 2.2, 95% CI 2.1–2.4) and time-to-progression (TTP) under first-line therapy: ≥5 months (HR 0.5, 95% CI 0.3–0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001).ConclusionsWith inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.     

Impact of vascular endothelial growth factor expression on overall survival in patients with osteosarcoma: a meta-analysis

Osteosarcoma is the most common primary malignant bone tumor of childhood. Vascular endothelial growth factor (VEGF) expression has been implicated in tumor development and progression of osteosarcoma, but previous studies investigating the impact of VEGF expression on overall survival in patients with osteosarcoma report conflicting findings. A meta-analysis of published studies was performed. The pooled hazard ratio (HR) with its 95 % confidence interval (95 % CI) was used to assess the impact of VEGF expression on overall survival in patients with osteosarcoma. Nine studies with a total of 432 osteosarcoma patients were included into this meta-analysis. There was no between-study heterogeneity among those nine studies (I ²?=?0.0 %). Overall, high VEGF expression was obviously associated with poorer overall survival (HR?=?1.68, 95 % CI 1.33–2.12, P?<?0.001). Sensitivity analysis performed by excluding single study in turns showed the pooled estimate was stable. Egger’s test also did not suggest evidence for publication bias (P?=?0.216). Therefore, this meta-analysis suggests that VEGF expression has an important impact on overall survival in patients with osteosarcoma and high VEGF expression is associated with poorer overall survival.     

Prognostic Impact of the Components of Progressive Disease on Survival After First-Line Tyrosine Kinase Inhibitor Therapy for Metastatic Renal Cell Carcinoma

Background

According to the Response Evaluation Criteria in Solid Tumors (RECIST) classification, progressive disease (PD) is defined as target lesion growth (TLG), unequivocal non-target lesion growth (NTLG), or new lesion appearance (NLA). The prognostic impact of the components of PD in tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC) remains unknown.

Objective

We retrospectively evaluated the prognostic impact of these PD components on survival in patients with mRCC after first-line TKI therapy.

Patients and Methods

Patients were divided into three groups (TLG, NTLG, and NLA) based on the components of PD. Progression-free survival (PFS) and overall survival (OS) after first-line TKI therapy were compared between groups using the Kaplan-Meier method and log-rank test. The predictive impact of the PD components was evaluated using multivariate analyses.

Results

Among the 116 patients included, 80 (69.0%) had TLG, 18 (15.5%) NTLG, and 69 (58.6%) NLA. The mean PFS and OS were shorter for patients with TLG than those without TLG (PFS, 7.1 vs. 11.6 months, p?=?0.0071; OS, 18.2 vs. 25.5 months, p?=?0.0091). TLG was an independent predictor of PFS (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.02–2.51; p?=?0.0395) and OS (HR, 1.67; 95% CI, 1.02–2.83; p?=?0.040). NTLG and NLA were not associated with survival.

Conclusions

In this retrospective single-center study, patients with TLG had poor survival after first-line TKI therapy for mRCC. Thus, individual components of PD influence patient prognosis.

     

Vascular endothelial growth factor +936C/T polymorphism and breast cancer risk: a meta-analysis of 13 case–control studies

The association between vascular endothelial growth factor (VEGF) +936C/T polymorphism and breast cancer risk has been widely reported, but results were inconsistent. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. Eligible articles were identified through search of databases including PubMed, Embase, and Chinese Biomedical Literature Database (CBM). The association between the VEGF +936C/T polymorphism and breast cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). Finally, a total of 13 studies with 6,879 cases and 7,219 controls were included in our meta-analysis. Overall, a significant association was found between VEGF +936C/T polymorphisms and the risk of breast cancer in overall populations under five models (T vs. C: OR?=?0.83, 95 % CI?=?0.73–0.94, P?=?0.002; TT vs. CC: OR?=?0.74, 95 % CI?=?0.61–0.91, P?=?0.004, Fig. 1a; TC vs. CC: OR?=?0.83, 95 % CI?=?0.71–0.96, P?=?0.014; TT vs. CC/CT: OR?=?0.77, 95 % CI?=?0.62–0.94, P?=?0.010; TT/TC vs. CC: OR?=?0.82, 95 % CI?=?0.72–0.95, P?=?0.006). In the subgroup analysis by ethnicity, there were also significant associations found between VEGF +936C/T polymorphism and breast cancer risk in Asians and Caucasians. In conclusion, the results of our meta-analysis suggest that the VEGF +936C/T polymorphism is significantly associated with breast cancer development and the VEGF 936T allele carriers may be associated with decreased breast cancer risk.     

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program

BackgroundEGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.Patients and methodsOf 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.ResultsEGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41–0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61–0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02–2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49–0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96–2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53–0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.ConclusionEGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.     

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?C1.0) 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.     

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

BackgroundA subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria.MethodsData from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers.ResultsOne thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors.ConclusionsPrimary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.