Bevacizumab plus chemotherapy for patients with advanced pulmonary adenocarcinoma harboring <Emphasis Type="Italic">EGFR</Emphasis> mutations

Purpose

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and bevacizumab plus chemotherapy were effective for EGFR-mutant patients. However, the appropriated treatment orders remained controvertible. We investigated the efficacy of treatment orders between bevacizumab plus chemotherapy and EGFR-TKIs for EGFR-mutant patients with advanced pulmonary adenocarcinoma.

Patients and methods

This study involved 40 EGFR-mutant patients with advanced pulmonary adenocarcinoma who were treated with bevacizumab plus carboplatin and paclitaxel (Bev + CP) and EGFR-TKIs in different treatment orders or gemcitabine plus cisplatin (GP) in first-line setting. Seventeen patients were treated with Bev + CP and 10 cases with GP in first-line treatment. Thirteen patients received EGFR-TKIs after first-line Bev + CP regimen, while 13 patients were treated with first-line EGFR-TKIs. Progression-free survival (PFS), the response rate (ORR) and overall survival (OS) were evaluated.

Results

Median PFS of Bev + CP treatment was significantly longer in first-line than non-first-line settings (11.7 vs. 5.6 months, P = 0.003). Median OS was 37.8 months for EGFR-mutant patients with first-line Bev + CP followed by second-line EGFR-TKIs and 31.0 months for those with first-line EGFR-TKIs and non-first-line Bev + CP, respectively (P = 0.509). Median PFS was 11.7 (95% CI 10.6–12.8) months for Bev + CP group and 4.7 (95% CI 4.4–5.0) months for GP group with the hazard ratio of 0.17 (P = 0.001). ORR was 70.6 and 50.0% in the two groups, respectively (P = 0.415). However, there was no significant difference in median OS (33.7 vs 27.8 months, P = 0.293).

Conclusions

First-line Bev + CP followed by EGFR-TKIs might possibly provide favorable prognosis for EGFR-mutant patients. Bev + CP regimen significantly prolonged PFS in first-line than non-first-line settings. These findings warrant further investigations.

     

Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials

Background

The strategy of dual inhibiting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has been extensively investigated in advanced non-small-cell lung cancer (NSCLC), but the benefit-to-risk ratio of dual-targeted regimen versus EGFR-tyrosine kinase inhibitors (TKIs) alone is still unclear. We thus perform this meta-analysis to assess the efficacy and safety of this regimen versus EGFR-TKIs alone in those patients.

Methods

Databases from PubMed, Web of Science and the Cochrane Library up to March 31, 2015 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in advanced NSCLC. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3 or 4 adverse events. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies.

Results

A total of 1918 patients with advanced NSCLC from 4 RCTs were identified for the analysis. The pooled results demonstrated that dual inhibiting EGFR and VEGF pathways significantly improved the PFS (HR 0.71, 95 % CI 0.58–0.86, p < 0.001) and ORR (OR 1.54, 95 % CI 1.14–2.08, p = 0.005) in unselected NSCLC when compared to EGFR-TKIs alone, but it did not translate into OS benefit (HR 0.94, 95 % CI 0.84–1.05, p = 0.24). No evidence of publication bias was observed.

Conclusions

Our study suggests that dual inhibition of EGFR and VEGF pathways significantly improves PFS and ORR, but it does not translate into survival benefit in unselected NSCLC patients. Prospective clinical trials investigating the role of this regimen in EGFR mutation-positive NSCLC are still warranted.

     

Effects of trastuzumab on locoregional recurrence in human epidermal growth factor receptor 2-overexpressing breast cancer patients treated with chemotherapy and radiotherapy

Purpose

In the present study, the ability of adjuvant trastuzumab to reduce locoregional recurrence in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer receiving adjuvant chemotherapy and radiotherapy (RT) was investigated.

Materials and methods

We retrospectively included 520 patients with HER2-overexpressing breast cancer who received surgery followed by adjuvant RT and cytotoxic chemotherapy from 2003 to 2011. Adjuvant trastuzumab was administered to 286 patients. Propensity score matching was conducted to compare trastuzumab-treated and non-treated cohorts.

Results

Median follow-up duration was 7.1 years (range 1.1–14.1 years). Propensity score matching yielded 171 matched pairs of patients with no significantly different clinical factors. An improved 7-year locoregional control (LRC) rate was observed in the trastuzumab-treated cohort compared with the non-treated cohort (95.6% vs. 89.9%, p?=?0.014). Based on multivariate analysis, hormone receptor negativity (hazard ratio [HR]?=?5.348, p?=?0.007), positive lymph node ratio?>?0.25 (HR?=?2.549, p?=?0.040), and lack of adjuvant trastuzumab (HR?=?3.401, p?=?0.017) were identified as significant risk factors for poor LRC. Adjuvant trastuzumab significantly reduced the locoregional recurrence rate in patients with one or two risk factors (7-year LRC?=?95.0% vs. 84.2%, p?=?0.007); however, the benefit of adjuvant trastuzumab was non-significant in patients with no risk factors (7-year LRC?=?95.8% vs. 97.9%, p?=?0.75).

Conclusions

Adjuvant trastuzumab improved LRC in patients with HER2-overexpressing breast cancer receiving adjuvant RT and cytotoxic chemotherapy, especially in hormone receptor-negative, HER2-enriched subtype, and high positive lymph node ratio breast cancer.

     

What Is the Best Systemic Therapy for Left-sided <Emphasis Type="Italic">RAS</Emphasis> Wild-type Metastatic Colorectal Cancer?

Purpose of Review

There is a significant difference in embryological origin, gene expression, gene mutation profile, and microbiome between the right-sided and left-sided colon. It has been shown that the sidedness of primary colorectal cancer is a significant prognostic factor and predictive to the clinical benefit of anti-epidermal growth factor receptor (EGFR) antibody-containing chemotherapy in patients with metastatic CRC. Herein, current clinical recommendations for the treatment of patients with left-sided RAS wild-type mCRC are reviewed.

Recent Findings

Retrospective analyses of prior randomized trials (CRYSTAL, PRIME, FIRE-3, CALGB 80405, and PEAK trials) showed that primary tumor sidedness is predictive to anti-EGFR antibody therapy in the first-line treatment of patients with RAS wild-type mCRC, and patients with left-sided RAS wild-type mCRC had a significantly better survival benefit with anti-EGFR antibody plus chemotherapy when compared with anti-VEGF treatment plus chemotherapy.

Summary

The primary tumor sidedness is a significant prognostic factor and predictive to anti-EGFR antibody-containing chemotherapy in patients with metastatic CRC. Based on the currently available data, chemotherapy plus anti-EGFR antibody is recommended for the first-line treatment of patients with left-sided RAS wild-type mCRC. Chemotherapy plus bevacizumab or anti-EGFR antibody is recommended for the second-line therapy of RAS wild-type mCRC regardless of sidedness. However, these recommendations are based on the limited data from the retrospective analyses of prior trials, warranting further prospective randomized trials.

     

Inflammatory Indexes as Prognostic and Predictive Factors in Ovarian Cancer Treated with Chemotherapy Alone or Together with Bevacizumab. A Multicenter,Retrospective Analysis by the MITO Group (MITO 24)

Background

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking.

Objective

The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab.

Patients and Methods

Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms.

Results

In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p?<?0.0001). In multivariate analyses, the NLR was significantly associated with OS (p?=?0.016), and the PLR was significantly associated with PFS (p?=?0.024). Inflammatory indexes were significantly correlated with patient prognosis in the chemotherapy-alone group (p?<?0.0001). Patients in the chemotherapy with bevacizumab group with a high NLR had a higher PFS and OS (p?=?0.026 and p?=?0.029, respectively) than those in the chemotherapy-alone group. Conversely, PFS and OS were significantly poorer in patients with a high SII (p?=?0.024 and p?=?0.017, respectively).

Conclusion

Our results suggest that bevacizumab improves clinical outcome in patients with a high NLR but may be detrimental in those with a high SII.

     

New pre-treatment eosinophil-related ratios as prognostic biomarkers for survival outcomes in endometrial cancer

Background

Systemic inflammation has long been related with adverse survival outcomes in cancer patients, and its biomarkers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), are recognized as poor prognostic indicators. However, the role of eosinophils in this field has been largely overlooked. Here, we describe two new pre-treatment biomarkers, expressed as Eosinophil-to-Lymphocytes Ratio (ELR) and Eosinophil*Neutrophil-to-Lymphocytes ratio (ENLR), and we analyse their impact on prognosis of endometrial cancer (EC) patients.

Methods

A total of 163 consecutive patients diagnosed with EC and treated with postoperative radiotherapy +/? chemotherapy in our institution from January 2011 to December 2015 were evaluated. The cohort was divided in two groups applying the cut-off value of 0.1 and 0.5 according to ROC curve for pre-treatment ELR and ENLR, respectively. After patients’ stratification according to the ESMO-ESGO-ESTRO modified risk assessment, subgroup analyses were conducted.

Results

Higher values of ELR and ENLR were associated with worse OS (p?=?0.004 and p?=?0.010, respectively). On univariate analysis, the factors associated with shorter OS were ELR?≥?0.1 (HR?=?2.9, p?=?0.017), ENLR ≥ 0.5 (HR?=?3.0, p?=?0.015), advanced FIGO stage (HR?=?3.4, p?=?0.007), endometrioid histology (HR?=?0.26, p?=?0.003) and ESMO-ESGO-ESTRO high-risk (HR?=?10.2, p?=?0.023). On multivariate Cox regression, higher ELR and ENLR were independently associated with a worse outcome adjusted for the standardly applied prognostic factors.

Conclusions

Increased values of ELR and ENLR portend worse OS in EC, especially in patients classified by the ESMO-ESGO-ESTRO guidelines as a high-risk group. To our best knowledge, this is the first report describing eosinophils-related ratios as prognostic biomarkers in malignant tumours.

     

Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial

Background

C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib.

Methods

Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437.

Results

Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p?=?0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p?=?0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p?=?0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p?=?0.021) and OS (HR 0.31; p?=?0.006) in all and EGFR mutated patients.

Conclusions

A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.

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The effect of dose escalation for large squamous cell carcinomas of the anal canal

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (>?5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors?>?5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p?=?0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR?=?0.998, CI 0.805–1.239, p?=?0.9887). On multivariate analysis, high-dose RT (HR?=?0.948, CI 0.757–1.187, p?=?0.6420) was not associated with improved OS but older age (HR?=?1.535, CI 1.233–1.911, p?=?0.0001), male sex (HR?=?1.695, CI 1.382–2.080, p?<?0.0001), comorbidities (HR?=?1.389, CI 1.097–1.759, p?=?0.0064), and long RT (HR?=?1.299, CI 1.047–1.611, p?=?0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers?>?5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

     

Associations between physical activity and comorbidities in Korean cancer survivors

Purpose

To examine the associations between physical activity, metabolic risk factors, and comorbidities in Korean cancer survivors.

Methods

We used multiple cross-sectional data sets from the 2007–2013 Korean National Health and Nutrition Examination Surveys (KNHANES) that included 1225 cancer survivors. Physical activity and comorbidities were self-reported. Metabolic risk factors were measured via blood analyses and included fasting glucose, insulin, total cholesterol, triglycerides, and blood pressure.

Results

The sample was 38.4% male with a mean age of 59.9?±?12.4 years. The most common cancers were stomach (22.5%), cervical (14.6%), breast (14.4%), and colorectal (11.8%). Cancer survivors meeting aerobic physical activity guidelines, compared to those completely inactive, had significantly lower fasting glucose (p?=?.001), HbA1c (p?=?.006), and systolic blood pressure (p?=?.001), and significantly lower risks of hypertension (odds ratio [OR]?=?0.55, 95% confidential interval [CI]?=?0.32 to 0.93), diabetes (OR?=?0.64, 95% CI?=?0.43 to 0.95), and arthritis (OR?=?0.64, 95% CI?=?0.41 to 0.99). Moreover, cancer survivors meeting strength exercise guidelines, compared to those not meeting guidelines, had significantly lower levels of fasting glucose (p?=?.001), HbA1c (p?<?.001), and total cholesterol (p?=?.031), and significantly lower risks of arthritis (OR?=?0.42, 95% CI?=?0.25 to 0.85) and back pain (OR?=?0.50, 95% CI?=?0.30 to 0.83).

Conclusion

Aerobic physical activity and strength exercise were significantly associated with lower risks of metabolic disturbances and comorbidities in Korean cancer survivors.

Implications for Cancer Survivors

Cancer survivors should engage in at least 150 min/week of aerobic exercise and at least 2 days/week of strength exercise to lower their risk of metabolic disturbances and comorbidities.

     

The effect of post-progression survival on overall survival among patients with sensitive relapse of small cell lung cancer

Recent studies have suggested that, among patients with advanced lung cancer, subsequent treatment after failure of first-line or second-line chemotherapy has a greater effect on overall survival (OS) than tumor shrinkage or progression-free survival (PFS). However, no studies have examined this issue among patients with sensitive relapse of small cell lung cancer (SCLC). We retrospectively evaluate 77 patients with sensitive relapse of SCLC who received second-line chemotherapy after first-line platinum doublet chemotherapy between January 1999 and November 2013. The analyses included patient characteristics, treatment parameters, tumor shrinkage, PFS, post-progression survival (PPS), and OS. Spearman rank correlation analysis and linear regression analysis revealed that PPS was strongly correlated with OS (r?=?0.91, p?<?0.01, R²?=?0.96), PFS was moderately correlated with OS (r?=?0.58, p?<?0.01, R²?=?0.28), and tumor shrinkage was weakly correlated with OS (r?=?0.34, p?<?0.01, R²?=?0.12). A multivariate Cox proportional hazards model with a stepwise regression procedure revealed that PPS was significantly associated with age at the start of second-line chemotherapy, best response to second-line and third-line chemotherapy, and the number of regimens after progression beyond second-line chemotherapy (p?<?0.05). These findings suggest that PPS has a stronger effect than PFS on OS among patients with sensitive relapse of SCLC. Thus, response to second-line chemotherapy and subsequent treatment for disease progression after second-line chemotherapy may be important factors that influence OS.     

Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)

Background

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.

Patients and Methods

We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman’s rank correlation coefficient.

Results

In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p?=?0.0003; 42.8 vs. 9.0 months, HR 0.40, p?=?0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r _s?=?0.314, p?=?0.027) as well as post-progression survival (PPS) (r _s?=?0.366, p?=?0.017). Interestingly, DpR was moderately associated with OS and PPS (r _s?=?0.587, r _s?=?0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities.

Conclusions

Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

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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.

     

Assessing the relationship between fear of cancer recurrence and health care utilization in early-stage breast cancer survivors

Purpose

The purpose of this study was to determine whether fear of cancer recurrence (FCR) is associated with greater health care utilization (HCU) in early-stage breast cancer survivors.

Methods

Three hundred early-stage breast cancer survivors diagnosed within the past 7 years reported on FCR as well as calls and visits to oncology providers and primary care providers during the preceding 3 months. Participants also reported on use of mental health services and psychotropic medications since diagnosis. Structural equation modeling was used to create a latent FCR factor and evaluate this factor as a predictor of various HCU outcomes controlling for age at diagnosis, years since diagnosis, generalized anxiety, objective risk of recurrence, and number of comorbidities.

Results

FCR predicted more visits to both oncology providers (RR?=?1.53, p?=?.002) and primary care providers (RR?=?1.31, p?=?.013), as well as more phone calls to oncology providers (RR?=?2.08, p?=?.007). FCR was not a significant predictor of phone calls to primary care providers (RR?=?1.39, p?=?.054), utilization of mental health treatment (OR?=?1.27, p?=?.362), or use of psychotropic medications (OR?=?1.37, p?=?.178).

Conclusions

FCR was associated with increases in some types of HCU, which may reflect excessive medical reassurance-seeking and lead to unnecessary medical costs.

Implications for Cancer Survivors

FCR is a serious concern that warrants greater attention to reduce distress-related health care utilization. Utilization of mental health services to address FCR may represent higher-value health care.

     

Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Background

The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

Methods

The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy.

Results

Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p?<?0.001) and extracapsular spread (p?=?0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p?=?0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p?=?0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p?=?0.048), lymphovascular invasion (p?=?0.041), extracapsular spread (p?=?0.015), and esophageal invasion (p?=?0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p?=?0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p?=?0.005) remained significant factors associated with 5-year DSS.

Conclusion

Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

     

miRNA-197 and miRNA-184 are associated with brain metastasis in <Emphasis Type="Italic">EGFR-</Emphasis>mutant lung cancers

Introduction

The prognostic value of EGFR mutation in lung cancer patients with brain metastases is uncertain and therapeutic efficacy with EGFR TKI is limited. Looking for biomarkers closely related with early tumor changes and brain metastases in non-small cell lung cancer is warranted. MicroRNAs (miRNAs) are frequently deregulated in lung cancer. The objective of this study was to investigate whether some miRNAs are related with brain metastasis risk in EGFR-mutant non-small cell lung cancer patients.

Materials and methods

miRNA quantification was retrospectively performed in formalin-fixed, extracranial paraffin-embedded adenocarcinoma tumor tissue available from 17 human samples of advanced non-small cell lung cancer patients. Samples were classified as brain metastasis group (5 EGFR-mutant patients with initial BM, EGFRm-BM+; and 6 EGFR wild-type patients with initial BM) and the control group (6 EGFR-mutant NSCLC patients without BM). The RNA obtained was preamplified and retro-transcribed, and the miRNA was quantified with the TaqMan OpenArray Human MiRNA Panel in the QuantStudio? 12 K Flex Real-Time PCR system.

Results

miRNA-197 and miRNA-184 showed a significant higher expression in EGFRm-BM+ group than in the control group (p = 0.017 and p = 0.01, for miRNA-197 and miRNA-184, respectively), with a trend toward overexpression in BM group compared with the control group (p = 0.08 and p = 0.065, for miRNA-197 and miRNA-184, respectively), without differences in expression in BM group according to EGFR mutational status (EGFR wild type vs. EGFR-mutant: p = 0.175 and p = 0.117, for miRNA-197, miRNA-184 respectively).

Conclusions

miRNA-197 and miRNA-184 are overexpressed in EGFR-mutant patients with BM and they might be a new biomarker for stratifying the risk of BM in this subpopulation.

     

Malignant and borderline phyllodes tumors of the breast: a multicenter study of 362 patients (KROG 16-08)

Purpose

To identify risk factors for local recurrence (LR) and investigate roles of adjuvant local therapy for malignant and borderline phyllodes tumors of the breast.

Methods

From 1981 to 2014, 362 patients with malignant (n?=?235) and borderline (n?=?127) phyllodes tumors were treated by breast-conserving surgery (BCS) or total mastectomy (TM) at 10 centers. Thirty-one patients received adjuvant radiation therapy (RT), and those who received adjuvant chemotherapy were excluded from the study.

Results

Median follow-up was 5 years. LR developed in 60 (16.6%) patients. Regional recurrence occurred in 2 (0.6%) patients and distant metastasis (DM) developed in 19 (5.2%) patients. Patients receiving BCS (p?=?0.025) and those not undergoing adjuvant RT (p?=?0.041) showed higher LR rates. For malignant subtypes, local control (LC) rates at 5 years for BCS alone, BCS with adjuvant RT, TM alone, and TM with adjuvant RT were 80.7, 93.3, 92.4, and 100%, respectively (p?=?0.033). Multivariate analyses revealed BCS alone, tumor?size ≥?5 cm, and positive margins as independent risk factors for LR. Margin-positive BCS alone showed poorest LC regardless of tumor size (62.5%, p?=?0.007). For margin-negative BCS alone, 5-year LC rates for tumors?≥?5 cm versus those?<?5 cm were 71.8% versus 89.5% (p?=?0.012). For borderline subtypes, only positive margins (p?=?0.044) independently increased the risk of LR. DM developed exclusively in malignant subtypes and a prior LR event increased the risk of DM by sixfold (HR 6.2, 95% CI 1.6–16.1, p?=?0.001).

Conclusions

Malignant and borderline phyllodes tumors with positive margins after surgery have high LR rates. After treatment by margin-negative BCS alone, patients with large malignant phyllodes tumors?≥?5 cm also have heightened risk of LR. Thus, such patients should be considered for additional local therapy.

     

Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy

Purpose

Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer.

Patients and methods

This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis.

Results

The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08–1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥?1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p?=?0.038) and in patients with one to three lymph node metastases (HR 1.32, p?=?0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p?=?0.085 and HR 1.53, p?=?0.067). No significant interaction was observed between the treatment arm and dNLR.

Conclusion

Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer.

Trial registration

EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7–11, 2016, Copenhagen, Denmark (oral presentation).

     

Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers

Purpose

Microsatellite instability in colorectal cancer (CRC) and its long-term outcomes remains poorly studied in Asians. We investigate the prognostic significance of microsatellite instability in an Asian population and assess its clinical impact in patients who undergo adjuvant chemotherapy.

Methods

Six hundred fifty-four consecutive CRC patients who underwent surgical resection between January 2010 and December 2012 were recruited. Survival was estimated using the Kaplan-Meier approach. Univariate Cox proportional hazard models were used to estimate the hazard ratios for variables associated with survival. A subgroup analyses was performed for stage III patients who underwent chemotherapy to evaluate the prognostic significance of microsatellite instability in this group.

Results

Five hundred ninety-one (90.4%) patients were microsatellite stable (MSS) while 63 (9.6%) were microsatellite instable (MSI). Three years recurrence-free survival (RFS) and disease-specific survival (DSS) were 83.7 versus 73.7% (p = 0.295) and 87.1 versus 91.2% (p = 0.307) in MSS and MSI tumors, respectively. Among stage III patients who received adjuvant therapy, MSI status was found to be an adverse prognostic factor for RFS (HR 2.74 (95% CI 1.43–5.26), p = 0.002). This remained significant on multivariate analysis (HR 2.38 (95% CI 1.15–4.93), p = 0.018). Adjuvant chemotherapy was associated with survival benefit for patients with MSS tumors (HR 0.35, 95% CI 0.17–0.69, p = 0.002) but not MSI tumors (HR 0.67, 95% CI 0.08–8.15, p = 0.750).

Conclusions

MSI status is not a prognostic indicator in the general CRC population but appears to be an adverse prognostic indicator for RFS in stage III CRC patients who received adjuvant chemotherapy.

     

Dietary patterns and prostate cancer risk in Japanese: the Japan Public Health Center-based Prospective Study (JPHC Study)

Purpose

The development of prostate cancer may be impacted by environmental factors, including diet. The aim of this study was to evaluate the association between dietary patterns and risk of prostate cancer in a large prospective cohort study among Japanese men.

Methods

A total of 43,469 men who participated in the Japan Public Health Center-based Prospective Study were followed from 1995 to 1998 to the end of 2012, during which 1,156 cases of prostate cancer were newly identified. Dietary intake was assessed using a validated food frequency questionnaire in the 5-year follow-up survey.

Results

Three major dietary patterns were derived using exploratory factors analysis: prudent, westernized, and traditional dietary patterns. The westernized dietary pattern was associated with a higher risk of total prostate cancer (HR: 1.22; 95% CI 1.00–1.49; p trend?=?0.021), localized cancer (HR: 1.24; 95% CI 0.97–1.57; p trend?=?0.045), and advanced cancer (HR: 1.23; 95% CI 0.82–1.84; p trend?=?0.233). The prudent dietary pattern was associated with a lower risk of total and localized prostate cancer, with respective multivariable HRs for the highest and lowest quintiles of 0.71 (95% CI 0.50–1.02; p trend?=?0.037) and 0.63 (95% CI 0.38–1.03; p trend?=?0.048) among subjects detected by subjective symptoms. No association was found between the traditional dietary pattern and prostate cancer risk among our subjects.

Conclusion

Our results suggest that a western-style diet may lead to a higher risk of prostate cancer in the total population, whereas the prudent diet contributes to a lower risk among subjects detected by subjective symptoms.