Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

BackgroundElevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis.Patients and MethodsWe assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4.ResultsIntratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 – 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 – 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 – 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 – 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022).ConclusionPre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.     

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

BackgroundMetastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT).ResultsEight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p = 0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p = 0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT.ConclusionThis meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.     

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial

BackgroundSurrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.Patients and methodsCox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1–4) were used to assess individual-level surrogacy of NAR for DFS.ResultsAfter a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106–7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303–2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.ConclusionOur study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.     

Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: A meta analysis

BackgroundOxaliplatin (OX), in combination with fluoropyrimidine (5-fluorouracil or Capecitabine, FU)-based regimens and radiation, has been expected to both enhance primary tumour shrinkage and reduce micrometastases at distant sites in the neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, results in terms of pathologic complete response (pCR) and toxicities were inconsistent. The aim of this meta analysis was to evaluate the short term efficacy and toxicities of adding OX to FU in CRT for LARC.MethodsWe searched PubMed, EMBASE, ISI databases, Chinese Biomedical Literature Database and the Cochrane library before December, 2011. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2011, were searched to identify relevant clinical trials. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. Summary incidence rates and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Four randomised clinical trials comparing OX/FU versus FU alone regimens in CRT for LARC met our search criteria and were assessed. A total of 3863 patients (FU, n = 1937; OX/FU, n = 1926) were included in the analysis.FindingsThe addition of OX to FU significantly improved pathologic complete response (pCR), and reduced peri-operative metastases (including intra-abdominal metastases) with an odd ratios (OR) for OX/FU compared with FU of 1.20 (95% CI, 1.01–1.42; P = 0.04) and 0.51 (95% CI, 0.34–0.77; P = 0.001), respectively. The grade 3/4 toxicity rate was significantly higher for OX/FU versus FU alone with an OR of 2.29 (95% CI, 1.31–4.00; P = 0.004). There was no difference in the rates of positive circumferential resection margin, permanent stoma, surgical complication and death within 60 d between the OX/FU and FU alone patients. The OR for the proportion of patients completing full-dose radiotherapy and completing full-dose chemotherapy were 0.32 (95% CI, 0.15–0.69; P = 0.004), and 0.71 (95% CI, 0.35–1.42; P = 0.33), respectively.InterpretationAdding weekly OX to FU in neoadjuvant CRT of LARC appeared to modestly increase the pCR rate and reduced the rate of intra-abdominal or peri-operative metastases in this meta analysis. Although OX/FU significantly increased grade 3/4 toxicity, it did not result in more surgical complications or postoperative deaths within 60 d. The concept of combination of OX and FU in the pre-operative setting for LARC still seems promising, either with a modified schedule, or as induction therapy prior to CRT or after CRT, prior to surgery.     

Clinical effectiveness of neoadjuvant chemotherapy in advanced gastric cancer: An updated meta-analysis of randomized controlled trials

Aims

To assess the efficacy and safety of neoadjuvant chemotherapy (NAC) for advanced gastric cancer (AGC).

Methods

By searching electronic databases (PubMed, Embase, Cochrane Library) and ASCO proceedings from 1990 to 2012, all randomized controlled trials (RCTs) which compared the effect of NAC-combined surgery versus surgery alone in AGC were included. All calculations and statistical tests were performed using RevMan 5.0 software.

Results

12 RCTs with a total of 1820 patients were included. All patients had locally advanced but resectable gastric cancer and received NAC. NAC can slightly improve the survival rate (OR = 1.32, 95% confidence interval (CI): 1.07–1.64, P = 0.01), with little or no significant benefits in subgroup analyses between either different population or regimens. NAC can significantly improve the 3-year progression-free survival (PFS) (OR: 1.85, 95% CI: 1.39–2.46, p < 0.0001), tumor down-staging rate (OR: 1.71, 95% CI: 1.26, 2.33, p = 0.0006) and R0 resection rate (OR: 1.38, 95% CI: 1.08–1.78, P = 0.01) of patients with AGC. There was no difference between the two arms, in terms of relapse rates (OR: 1.03, 95% CI: 0.60–1.78, p = 0.92), operative complications (OR: 1.20, 95% CI: 0.90–1.58, p = 0.21), perioperative mortality (OR: 1.14, 95% CI: 0.64–2.05, p = 0.65) and grade 3/4 adverse effects: gastrointestinal problem (OR: 0.57, 95% CI: 0.25–1.30, p = 0.18), leukopenia (OR: 0.88, 95% CI: 0.41–1.91, p = 0.75), thrombocytopenia (OR: 1.27, 95% CI: 0.27–5.93, p = 0.76).

Conclusion

NAC is effective and safe. However, further prospective multi-national and multi-center RCTs are still needed in order to investigate the long-term oncological and functional outcomes to define the clinical benefits of NAC and the most effective strategies for AGC.     

EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC

BackgroundThe phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC.MethodsFISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712.ResultsOf 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen.ConclusionsIn NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.     

Risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 or BRCA2 mutation carriers: A systematic review and meta-analysis

AimBRCA mutation carriers have a high lifetime risk of developing breast cancer (BC) and ovarian cancer (OC). Risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce OC risk. This meta-analysis was aim to analyze the effect of RRSO on the BC risk among BRCA1/2 mutation carriers.MethodsEmbase, PubMed, Web of Science, and Cochrane databases were searched for all studies investigating the effect of RRSO on BC risk. The pooled results were used to evaluate the association between RRSO and BC risk.ResultsThis meta-analysis included 13,965 BRCA1 and 7,057 BRCA2 mutation carriers from 14 observational studies. The pooled results showed that RRSO lowered BC risk among BRCA1 mutation carriers [hazard ratio (HR) = 0.63, 95% confidence interval (CI): 0.49–0.81, P < 0.01] and BRCA2 mutation carriers (HR = 0.51, 95% CI: 0.34–0.75, P < 0.01). RRSO reduced BC risk in younger women with BRCA1 mutation (HR = 0.48, 95% CI: 0.30–0.77, P < 0.01) and BRCA2 mutation (HR = 0.22, 95% CI: 0.08–0.65, P < 0.01). Analysis of the efficacy of RRSO at different time intervals after surgery showed a reduction of BC risk at <5 years after surgery in BRCA1 mutation carriers (HR = 0.60, 95% CI: 0.40–0.89, P = 0.01) and BRCA2 mutation carriers (HR = 0.42, 95% CI: 0.20–0.86, P = 0.02).ConclusionsRRSO is an effective way to reduce BC risk among women with BRCA1/2 mutation, especially in younger women. BRCA1/2 mutation carriers could benefit from RRSO in the immediate 5 years after surgery.     

Is postoperative adjuvant chemoradiotherapy efficacious and safe for gastric cancer patients with D2 lymphadenectomy? A meta-analysis of the literature

BackgroudAdjuvant chemoradiotherapy (CRT) for patients with gastric cancer after D2 lymphadenectomy remains controversial. The objective of the present meta-analysis was to analyze efficacy and safety of postoperative CRT and establish a consensus on whether it is suitable for the patients.MethodsWe searched PubMed, Ovid, Cochrane, and Web of Science. Statistical analysis was carried out by STATA version 12.0 software. The quality of evidence was assessed by Jadad and the Newcastle–Ottawa quality assessment scale.ResultsSix studies involving 2135 patients were included for the meta-analysis. The results showed that, compared with non-CRT, postoperative adjuvant CRT was associated with a significant improvement in 5-year overall survival (OS) (HR = 0.79, 95% CI 0.68–0.92, P = 0.002) and 5-year relapse-free survival (RFS) (HR = 0.81, 95% CI 0.70–0.93, P = 0.004). However, there were no differences in distant metastasis (RR = 0.93, 95% CI 0.82–1.06, P = 0.304) and treatment-related toxicity between the two groups.ConclusionsFrom the results of our study, postoperative adjuvant CRT may be associated with longer 5-year OS and 5-year RFS in patients with D2 lymphadenectomy, but might not improve 5-year disease-free survival compared to non-CRT. Methodologically high-quality comparative studies are needed for further evaluation.     

Comparative Effectiveness of Total Neoadjuvant Therapy Versus Standard Adjuvant Chemotherapy for Locally Advanced Rectal Cancer

IntroductionThe use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown.MethodsWe performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the 2 arms.ResultsOf the 4300 patients in our cohort, 3502 (81%) received adjuvant therapy and 798 (19%) received TNT. At baseline, patients who received TNT were more likely to have higher clinical T and N stages (P< .001). The 5-year OS was 77% for both TNT and adjuvant therapy patients (hazard ratio [HR] 1.06, 95% confidence interval [CI], 0.88-1.28, P = .57). After propensity score matching and adjusting for potential confounders, there were no significant differences in OS (HR_adj 1.00, 95% CI, 0.71-1.40, P = .99). After propensity score matching, there were higher pCR rates among TNT patients (16.1%) compared to adjuvant therapy patients (12.0%) (P = .037).ConclusionIn this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings.     

Is Elective Inguinal or External Iliac Irradiation During Neoadjuvant (Chemo)radiotherapy Necessary for Locally Advanced Lower Rectal Cancer With Anal Sphincter Invasion?

PurposeTo investigate the impact of excluding irradiation of inguinal lymph nodes (ILNs) and external iliac lymph nodes (ELNs) during neoadjuvant (chemo)radiotherapy in a locally advanced lower rectal cancer (LALRC) with anal sphincter invasion.Methods and MaterialsA total of 214 LALRC patients with anal sphincter invasion according to pre-treatment magnetic resonance imaging who underwent neoadjuvant (chemo)radiotherapy followed by surgery between September 2010 and May 2019 were enrolled. ILNs and ELNs were clinically negative pre-treatment and were excluded from irradiation. Failure rates and patterns of ILNs and ELNs and survival were analyzed. Nomograms for predicting ILN and ELN failure risk were also constructed.ResultsThe median follow-up was 53.3 months. The 3-year failure rates were 3.7% for ILNs and 3.3% for ELNs. Only 1 patient developed isolated ILN failure, and no patient experienced isolated ELN failure. Multivariate analyses demonstrated that lower edge of tumors invaded or located below the dentate line (odds ratio [OR], 7.513; P = .013), high histological grade (OR, 6.892; P = .017), and perineural invasion (OR, 7.111; P = .023) were significantly related to ILN failure. Both perineural invasion (OR, 8.923; P = .011) and high histological grade (OR, 8.129; P = .011) showed a strong correlation with ELN failure. The concordance index of nomograms for predicting ILN and ELN failure risk were 0.842 and 0.880, respectively. The 3-year local recurrence free survival, disease-free survival, and overall survival were 94.6% (95% confidence interval [CI], 91.3%-97.9%), 77.7% (95% CI, 71.8%-83.6%), and 91.9% (95% CI, 87.8%-96.0%), respectively, for the whole cohort.ConclusionsExcluding ILNs and ELNs from irradiation was associated with an acceptably low failure risk for LALRC invading the anal sphincter. These findings help to refine existing guidelines for clinical target volume delineation of ILNs and ELNs during neoadjuvant (chemo)radiotherapy in rectal cancer.     

Impact of neoadjuvant therapy on postoperative complications in non-small-cell lung cancer patients subjected to anatomic lung resection

ObjectiveTo study the impact of neoadjuvant therapies on postoperative complications and mortality among non-small-cell lung cancer (NSCLC) patients subjected to anatomic lung resection and included in the Spanish cohort of the video-assisted thoracic surgery (GE-VATS) multicenter database.MethodsThe study included a total of 3085 patients from 33 centers between December 2016 and March 2018. We performed a comparative analysis of the complications and mortality in patients who received neoadjuvant therapies (n = 263) versus those who did not (n = 2822). A propensity score-matched analysis was used to adjust for potential confounders. Association between exposure in two groups and outcomes were estimated by logistic regression weighted by inverse of probability of receiving the treatment that actually received.ResultsIn the unadjusted analysis, the chemotherapy (CT) and chemoradiotherapy (CRT) group presented a higher frequency of ICU readmissions, reinterventions, empyema, cardiovascular complications, a greater frequency of atrial fibrillation, and an increased need for blood product transfusions. In the adjusted group, CT and CRT patients had a higher rate of cardiovascular complications (CT p = 0.002; OR 2.29; 95% CI 1.34–3.94 and CRT p = 0.001; OR 2.90; 95% CI 1.52-5-52), arrhythmias (CT p = 0.013; OR 2.23; 95% CI 1.18–4.20 and CRT p = 0.046; OR 2.22; 95% CI 1.01–4.90) and transfussions (CT p = 0.042; OR 2.95; 95% CI 1.04–8.35 and CRT p < 0.001; OR 7.74; 95% CI 3.01-19-92).ConclusionsBased on our series, neoadjuvant CT and CRT were associated with a higher rate of cardiovascular complications, arrhythmias and transfussions in patients with NSCLC subjected to anatomic lung resection.     

Factors Associated With Acute Toxicity in Pediatric Patients Treated With Proton Radiation Therapy: A Report From the Pediatric Proton Consortium Registry

PurposeLimited prospective information regarding acute toxicity in pediatric patients receiving proton therapy (PT) exists. In this study, Pediatric Proton Consortium Registry (PPCR) data was analyzed for factors associated with development of acute toxicity in children receiving passively scattered or pencil beam scanning PT.Methods and MaterialsPediatric patients treated with PT and enrolled on the PPCR from 2016 to 2017 at 7 institutions were included. Data were entered on presence versus absence of acute general, cardiac, endocrine, eye, gastrointestinal, genitourinary, hematologic, mouth, musculoskeletal, neurologic, psychological, respiratory, and skin toxicities before (baseline) and at the end of PT (acute). Associations between patient and treatment variables with development of acute toxicity were assessed with multivariable modeling.ResultsOf 422 patients included, PT technique was passively scattered in 241 (57%), pencil beam scanning in 180 (43%), and missing in 1 (<1%) patient. Median age was 9.9 years. Daily anesthesia for treatment was used in 169 (40%). Treatments were categorized as craniospinal irradiation (CSI; n = 100, 24%), focal central nervous system PT (n = 157, 38%), or body PT (n = 158, 38%). Passively scattered PT was associated with increased risk of hematologic toxicity compared with pencil beam scanning PT (odds ratio [OR]: 3.03; 95% confidence interval [CI], 1.38-6.70; P = .006). There were no other differences toxicities between PT techniques. Uninsured patients had increased risk of GI (OR: 2.71; 95% CI, 1.12-6.58; P = .027) and hematologic toxicity (OR: 10.67; 95% CI, 2.68-42.46; P <.001). Patients receiving concurrent chemotherapy were more likely to experience skin (OR: 2.45; 95% CI, 1.23-4.88; P = .011), hematologic (OR: 2.87; 95% CI, 1.31-6.25; P = .008), GI (OR: 2.37; 95% CI, 1.33-4.21; P = .003), and mouth toxicities (OR: 2.03; 95% CI, 1.10-3.73; P = .024). Patients receiving 49 to 55 Gy were more likely to experience skin (OR: 2.18; 95% CI, 1.06-4.44; P = .033) toxicity than those receiving <49 Gy.ConclusionsThe PPCR registry highlights broad differences in acute toxicity rates in children receiving PT, and identifies opportunities for improvements in prevention, monitoring, and treatment of toxicities.     

Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers

BackgroundWhether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery.AimThis multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population.MethodsEligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia.ResultsOf 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80–5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59–8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24–7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I–II disease. No serous uterine cancers were reported.ConclusionsOur findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.     

BMPR1B Polymorphisms (rs1434536 and rs1970801) are Associated With Breast Cancer Susceptibility in Northwest Chinese Han Females: A Case-Control Study

BackgroundBone morphogenetic proteins receptor type 1B (BMPR1B) was a multifunctional signaling molecule and its abnormal expression associated with poorer prognosis. We aimed to explore the relationship between BMPR1B polymorphisms and breast cancer susceptibility among northwest population.MethodsA total of 450 healthy controls and 434 patients with breast cancers were recruited in this study. Two candidate polymorphisms, rs1434536 and rs1970801 were genotyping using Sequenom MassArray technique. Expression quantitative trait loci analysis in the GTEx portal was adopted to determine the correlation between the rs1434536 and rs1970801 polymorphism and level of BMPR1B expression.ResultsWe found that the T allele of rs1434536 was associated with an increased susceptibility of breast cancer [CT+TT vs. CC: adjusted OR (95% CI) = 1.35(1.02-1.78), P_adjusted = 0.034; CT vs. CC adjusted OR (95% CI) = 1.39(1.03-1.87), P_adjusted = 0.029]. For rs1970801, carrying minor allele T was significantly associated with an increased risk of breast cancer [GT+TT vs. GG: adjusted OR (95% CI) = 1.52(1.14-2.01), P_adjusted = 0.004; GT vs. GG adjusted OR (95% CI) = 1.56(1.15-2.09), P_adjusted = 0.004]. Stratified analyses found statistical significance existing in women under 49 years of age, BMI less than 24 kg/m², and premenopausal women for both rs1434536 and rs1970801. Expression quantitative trait loci analysis in the GTEx portal proved that the minor alleles of rs1434536 T and rs1970801 T was significantly associated with higher expression level of BMPR1B.ConclusionBMPR1B polymorphisms (rs1434536 and rs1970801) may increase susceptibility to breast cancer in Chinese Han women.     

Meta-analysis on prognostic value of KRAS mutation in resected mass-forming cholangiocarcinoma

BackgroundDespite survival improvements for other cancers, the prognosis of resected mass-forming cholangiocellular carcinoma (MFCCC) remains dismal. As a possible background of that, biologic factors could play some role. KRAS mutation has been investigated in the present systematic review and meta-analysis.MethodsMEDLINE, Embase and Cochrane Library databases were searched for studies reporting overall survival (OS) following liver resection for MFCCC with known KRAS status. Secondary outcomes included completeness of resection (R1 vs R0), pathological lymph node (LN) rate, tumor burden (multiple vs single), perineural invasion (PI) rate.ResultsEight studies comprising 604 patients resected for MFCCC were eligible for analysis. Of these, 23% of patients were mKRAS. The mKRAS MFCCC showed lower 1-year OS [odd ratio (OR) 3.45, 95% confidence interval (CIs) 1.85–6.42; p < 0.001], 3-years OS (OR 4.82, 95% CI 2.63–8.84; p < 0.001), and 5-years OS (OR 10.60, 95% CI 3.12–36.03; p < 0.001) compared to wtKRAS. Pooled-R1 resection rate was 18% for mKRAS and 23% for those with wtKRAS (OR 1.71, 95%CIs 0.70–4.19; p = 0.239). The pooled-pathological LNs rate was 23% in mKRAS vs 17% (OR 2.36, 95%CIs 0.75–7.48; p = 0.144). The pooled-multifocality rate was 55% in mKRAS vs 19% (OR 5.38, 95%CIs 1.76–16.48; p = 0.003), while the pooled-PI was 77% vs 31% (OR 6.59, 95%CIs 2.13–20.37; p = 0.001).ConclusionThe KRAS mutation is relatively frequent in MFCCC. The mKRAS is strongly associated with a shortened survival and higher tumoral aggressiveness. Testing for KRAS mutations could be a valuable adjunct in opening a scenario to new treatments and improving prognosis of patients with MFCCC.     

Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis

BackgroundResponse to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis.MethodsA systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval.ResultsNine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7–2.72, p = 0.35).ConclusionThis meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.     

Comparative Oncologic Outcomes of Upper Third Rectal Cancers: A Meta-analysis

IntroductionPreoperative radiation combined with mesorectal excision has reduced local recurrence rates in rectal cancer. The role for neoadjuvant therapy in upper third rectal cancer remains unclear. The current study aimed to use meta-analytical techniques to compare outcomes of upper third rectal tumors relative to those of the middle and lower rectum.Materials and MethodsMeta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases were searched for studies comparing outcomes between patients with upper third and more distal rectal cancer undergoing primary resection. Patients receiving neoadjuvant treatment were excluded. Results were reported as odds ratios (ORs) with 95% confidence intervals (95% CIs).ResultsA total of 174 citations were reviewed; 5 studies comprising 3381 patients were included in the analysis. There was no difference in the rate of T3/4 tumors (OR, 1.303; 95% CI, 0.920-1.847; P = .137), lymph node positivity (OR, 1.004; 95% CI, 0.865-1.165; P = .961), and circumferential resection margin positivity (OR, 0.898; 95% CI, 0.556-1.450; P = .660) between upper third and more distal rectal cancers. However local recurrence (OR, 0.495; 95% CI, 0.302-0.811; P = .005) and distant recurrence (OR, 0.613; 95% CI, 0.511-0.734; P < .001) were reduced in patients with upper third rectal cancer.ConclusionsThese data suggest that upper third rectal cancer has reduced local and distant recurrence rates despite similarity in disease stage and margin positivity. Further studies examining effects of neoadjuvant radiation in rectal cancer should consider upper rectal tumors as a distinct entity to middle and lower rectal tumors.     

Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings

BackgroundML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Patients and methodsEvaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.ResultsOf 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49–0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56–0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53–0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71–1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).ConclusionsBevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.     

Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer

Background and purposeMicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).Material and methodsWe measured serum miR-155, miR-221 and miR-21, before and during week 1–2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression.ResultsWe found that patients with stage IIIB–IV disease, higher mean esophagus dose or esophageal V₅₀ had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1–2 of CRT were also risk factors for severe RIET (miR-155: OR = 1.53, 95% CI: 1.04–2.25, P = 0.03; miR-221: OR = 2.07, 95% CI: 1.17–3.64, P = 0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR = 1.18, 95% CI: 1.02–1.37, P = 0.026). However, pretreatment miRNAs was not predictive of severe RIET.ConclusionsHigh serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.