Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection

Abstract

IMPORTANCE High-risk human papillomavirus (HPV) has been associated with Barrett dysplasia and esophageal adenocarcinoma. Nevertheless, the prognostic significance of esophageal tumor HPV status is unknown.

 

This case-control study compares disease-free and overall survival among patients with Barrett high-grade dysplasia or esophageal adenocarcinoma with vs without underlying human papillomavirus (HPV) infection demonstrated on biopsy.

OBJECTIVE

To determine the association between HPV infection and related biomarkers in highgrade dysplasia or esophageal adenocarcinoma and survival.

DESIGN, SETTING, AND PARTICIPANTS

Retrospective case-control study. The hypothesiswas that HPV-associated esophageal tumors would show a favorable prognosis (as in viral-positive head and neck cancers). Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction, in situ hybridization for E6 and E7 messenger RNA (mRNA), and immunohistochemistry for the proteins p16INK4A and p53. Sequencing of TP53 was also undertaken. The study took place at secondary and tertiary referral centers, with 151 patients assessed for eligibility and 9 excluded. The study period was from December 1, 2002, to November 28, 2017.

MAIN OUTCOMES AND MEASURES

Disease-free survival (DFS) and overall survival (OS).
RESULTS Among 142 patients with high-grade dysplasia or esophageal adenocarcinoma (126 [88.7%] male; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, and wild-type TP53. There were more Tis, T1, and T2 tumors in HPV-positive patients compared with HPV-negative patients (75.7%vs 54.3%; difference, 21.4%; 95%CI, 4.6%-38.2%;
P = .02). Mean DFS was superior in the HPV-positive group (40.3 vs 24.1 months; difference, 16.2 months; 95%CI, 5.7-26.8; P = .003) as was OS (43.7 vs 29.8 months; difference, 13.9 months; 95% CI, 3.6-24.3; P = .009). Recurrence or progression was reduced in the HPV-positive cohort (24.3%vs 58.1%; difference, −33.8%; 95%CI, −50.5%to −17.0%; P < .001) as was distant metastasis (8.1%vs 27.6%; difference, −19.5%; 95%CI, −31.8%to −7.2%; P = .02) and death from esophageal adenocarcinoma (13.5%vs 36.2%; difference, −22.7%; 95%CI, −37.0% to −8.3%; P = .01). Positive results for HPV and transcriptionally active virus were both associated with a superior DFS (hazard ratio [HR], 0.33; 95%CI, 0.16-0.67; P = .002 and HR, 0.44; 95%CI, 0.22-0.88; P = .02, respectively [log-rank test]). Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS. On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95%CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95%CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95%CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95%CI, 0.27-0.89; P = .02).

 

CONCLUSIONS AND RELEVANCE

Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are positive for HPV are distinct biological entities with a favorable prognosis compared with viral-negative esophageal tumors. Confirmation of these findings in larger cohorts with more advanced disease could present an opportunity for treatment deescalation in the hope of reducing toxic effects without deleteriously affecting survival.


Key Points

Question

What is the prognostic significance of esophageal tumor humanpapillomavirus (HPV) status?

Findings

In this case-control study involving 142 patients with Barrett highgrade dysplasia and esophageal adenocarcinoma, HPV positivity was associated with a significantly improved disease-free survival compared with viral negativity. Recurrence and progression were reduced in the HPV-positive cohort as were distant metastasis and death from esophageal adenocarcinoma.

Meaning

Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are HPV positive have a favorable prognosis compared with viral-negative esophageal tumors and may benefit from treatment de-escalation.


Authors

Shanmugarajah Rajendra, MSc,MD, FRACP;Wei Xuan, PhD; Neil Merrett, FRACS; Preeti Sharma, BSc; Prateek Sharma, MD; Darren Pavey, FRACP; Tao Yang, PhD, FRCPA;Leonardo D. Santos, FRCPA; Omar Sharaiha, FRACP; Girish Pande, PhD, FRACS; Peter Cosman, PhD, FRACS; XiaojuanWu, MBBS, MSc; BinWang, MBBS, MMed, PhD

Published

Full article details can be found here:  JAMA Network Open. 2018;1(4):e181054. doi:10.1001/jamanetworkopen.2018.1054

Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis.

Abstract

Published February 2007

BACKGROUND:

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a minimally invasive alternative technique for mediastinal staging of non-small cell lung cancer. A metaanalysis was performed to estimate the diagnostic accuracy of EUS-FNA for staging mediastinal lymph nodes (N2/N3 disease) in patients with lung cancer.

METHODS:

Relevant studies were identified using Medline (1966 to November 2005), CINAHL, and citation indexing. Included studies used histology or adequate clinical follow-up (> 6 months) as the “gold standard,” and provided sufficient data for calculating sensitivity and specificity. Summary receiver operating characteristic curves metaanalysis was performed to estimate the pooled sensitivity and specificity.

RESULTS:

In 18 eligible studies, EUS-FNA identified 83% of patients (95% confidence interval [CI], 78 to 87%) with positive mediastinal lymph nodes (pooled sensitivity) and 97% of patients (95% CI, 96 to 98%) with negative mediastinal lymph nodes (pooled specificity). In eight studies that were limited to patients who had abnormal mediastinal lymph nodes seen on CT scans, the sensitivity was 90% (95% CI, 84 to 94%) and the specificity was 97% (95% CI, 95 to 98%). In patients without abnormal mediastinal lymph nodes seen on CT scans (four studies), the pooled sensitivity was 58% (95% CI, 39 to 75%). Minor complications were reported in 10 cases (0.8%). There were no major complications.

CONCLUSIONS:

EUS-FNA is a safe modality for the invasive staging of lung cancer that is highly sensitive when used to confirm metastasis to mediastinal lymph nodes seen on CT scans. In addition, among lung cancer patients with normal mediastinal adenopathy seen on CT scans, despite lower sensitivity, it has the potential to prevent unnecessary surgery in a large proportion of cases missed by CT scanning.

Authors:

Micames CG, McCrory DC, Pavey DA, Jowell PS, Gress FG.

PMID: 17296659 [PubMed – indexed for MEDLINE]

 

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.

Abstract

Published November 2017

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/29132146

Active human papillomavirus involvement in Barrett’s dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.

Abstract

Published November 2017

We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett’s dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett’s metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA /RNA (n = 94) and HPV DNA+ /RNA cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/28722212

Circumferential ablation of Barrett’s esophagus that contains high-grade dysplasia: a U.S. Multicenter Registry.

Abstract

Published July 2008

BACKGROUND:

The management strategies for Barrett’s esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy.

OBJECTIVE:

To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD.

DESIGN:

Multicenter U.S. registry.

SETTING:

Sixteen academic and community centers; treatment period from September 2004 to March 2007.

PATIENTS:

Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation.

INTERVENTION:

Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment.

OUTCOMES:

Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM).

RESULTS:

A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%.

LIMITATIONS:

A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up.

CONCLUSIONS:

Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

Focal or diffuse “fullness” of the pancreas on CT. Usually benign, but EUS plus/minus FNA is warranted to identify malignancy.

Abstract

Published January 2009

CONTEXT:

The role of EUS to evaluate subtle radiographic abnormalities of the pancreas is not well defined.

OBJECTIVE:

To assess the yield of EUS+/-FNA for focal or diffuse pancreatic enlargement/fullness seen on abdominal CT scan in the absence of discrete mass lesions.

DESIGN:

Retrospective database review.

SETTING:

Tertiary referral center.

PATIENTS AND INTERVENTIONS:

Six hundred and 91 pancreatic EUS exams were reviewed. Sixty-nine met inclusion criteria of having been performed for focal enlargement or fullness of the pancreas. Known chronic pancreatitis, pancreatic calcifications, acute pancreatitis, discrete mass on imaging, pancreatic duct dilation (greater than 4 mm) and obstructive jaundice were excluded.

MAIN OUTCOME MEASUREMENT:

Rate of malignancy found by EUS+/-FNA.

RESULTS:

FNA was performed in 19/69 (27.5%) with 4 new diagnoses of pancreatic adenocarcinoma, one metastatic renal cell carcinoma, one metastatic colon cancer, one chronic pancreatitis and 12 benign results. Eight patients had discrete mass lesions on EUS; two were cystic. All malignant diagnoses had a discrete solid mass on EUS.

CONCLUSIONS:

Pancreatic enlargement/fullness is often a benign finding related to anatomic variation, but was related to malignancy in 8.7% of our patients (6/69). EUS should be strongly considered as the next step in the evaluation of patients with focal enlargement of the pancreas when clinical suspicion of malignancy exists.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/19129613

The prognostic and predictive value of serum CA19.9 in pancreatic cancer.

Abstract

Published July 2012

BACKGROUND:

Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.

METHODS:

We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.

RESULTS:

By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.

CONCLUSIONS:

Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.

Collaborators:

Biankin A, Merrett N, Cosman P, Das A, Pavey D, Asghari R, Ismail K, Samra J, Gill A, Pavlakis N, Toon C, Guminski A, Lam V, McLeod D,Pleass H, James V, Sandroussi C, Crawford M, Joseph D, Kench J, Cooper C.

PMID: 22241899 [PubMed – indexed for MEDLINE] PMCID: PMC3387824

RON is not a prognostic marker for resectable pancreatic cancer.

Abstract

Published September 2012

BACKGROUND:

The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown.

METHODS:

RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed.

RESULTS:

RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study.

CONCLUSIONS:

Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/22958871

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Abstract

Published October 2012

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/23103869

Transcriptionally active human papillomavirus is strongly associated with Barrett’s dysplasia and esophageal adenocarcinoma.

Abstract

Published April 2013

OBJECTIVES:

The role of human papillomavirus (HPV) in Barrett’s esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence.

METHODS:

HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6/7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barrett’s dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ).

RESULTS:

Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0%), HPV positivity was significantly more common in BD (68.6%, incidence rate ratio (IRR) 2.94, 95% confidence interval (CI) 1.78-4.85, P<0.001) and EAC (66.7%, IRR 2.87, 95% CI 1.69-4.86, P<0.001), but not in BE (22.1%, IRR 1.06, 95% CI 0.60-1.85, P=0.85). Of the patients, 92.6% were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1%, IRR 17.0 (95% CI 4.86-59.6, P<0.001), 44.4%, 17.0 (95% CI 4.87-59.4, P<0.001), and 10.6%, 3.93 (95% CI 1.01-15.3, P=0.048) respectively). In 66 HPV DNA-positive patients tested for E6/E7 mRNA, none of the control (n=16) or BE (n=13) individuals were positive, whereas 9/22 BD and 9/15 EAC patients demonstrated oncogene expression (P<0.001). When HPV DNA, p16INK4A, and E6/E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95% CI 20.3-529, P<0.001; lesion: OR 62.2, 95% CI 12.4-311, P<0.001) than when all were negative.

CONCLUSIONS:

Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

Authors:

Rajendra S, Wang B, Snow ET, Sharma P, Pavey D, Merrett N, Ball MJ, Brain T, Fernando R, Robertson IK.

 

PMID: 23588239 [PubMed – indexed for MEDLINE]