LRIG1 and the liar paradox in prostate cancer: a study of the expression and clinical significance of LRIG1 in prostate cancer.

The course of prostate cancer varies greatly, and additional prognostic markers are needed. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is an endogenous inhibitor of growth factor signaling and a proposed tumor suppressor. Publicly available gene expression datasets indicate that LRIG1 may be overexpressed in prostate cancer. In our study, the expression of LRIG1 protein in prostate cancer was evaluated for the first time. Immunohistochemistry was performed on tissue microarrays from two different patient series: 355 Swedish patients diagnosed by transurethral resection and 293 American patients who underwent radical prostatectomy. In the Swedish series, high expression of LRIG1 correlated with Gleason score, T-stage, tumor cell proliferation, vascular density and epidermal growth factor receptor (EGFR) phosphorylation. Among the 256 Swedish patients, followed by watchful waiting, high LRIG1 expression was significantly associated with short overall and prostate cancer-specific survival. In contrast, in the US series, high LRIG1 expression was significantly associated with long overall survival. In vitro cell experiments showed that LRIG1 was induced by androgen stimulation, and its expression inhibited prostate cancer cell proliferation. Thus, LRIG1 expression was an independent marker for poor survival in the untreated patient series, perhaps as a secondary marker of androgen receptor and/or EGFR activation. On the contrary, LRIG1 was a marker for good prognosis after prostatectomy, which might be due to its growth inhibiting properties. We propose that LRIG1 is an important determinant of prostate cancer growth, and the implications of its expression on patient outcome depend on the clinical and biological circumstances.

ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer.

PURPOSE: We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition). MATERIALS AND METHODS: Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects. RESULTS: Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray's test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control. CONCLUSION: Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.

Survival advantage of upfront cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma compared with systemic and palliative treatments in a real-world setting.

BACKGROUND: Recently, the CARMENA and SURTIME studies, suggested that upfront cytoreductive nephrectomy (CN) should be abandoned for patients with intermediate and high-risk metastatic renal cell carcinoma (mRCC). However, CN remains an indication in low-risk and when immediate systemic treatment is not required. The aim was to evaluate the long-term overall survival (OS) in patients with primary mRCC, based on the first line treatment. METHODS: There were 1483 patients with primary mRCC in the National Kidney Cancer Registry from 2005 to 2013. Data on primary treatment, TNM stage, RCC type, tumor size, patient age and sex were extracted. Survival time was calculated from time of diagnosis to time of death or until July 2019. Mann-Whitney U and Chi-square tests, the Kaplan-Meyer method and Cox regression analyses were used. RESULTS: Patients primary treated with CN had a significantly longer OS (p < .001) than patients primary treated with systemic therapy or palliation. In a Cox regression multivariate analysis, the hazard ratio for CN compared with no CN was 1.600, 95%Ci (1.492 - 1.691), p < .001. Also occurrence of lymph node metastases, T-stage, patients age and year of diagnosis, remained as independent predictors of OS. CONCLUSION: Patients primary treated with CN survived significantly longer than patients primary treated with systemic therapy or palliation, in all age groups. CN was an important first-line treatment option in mRCC patients.

Increased copy number at 3p14 in breast cancer.

INTRODUCTION: The present study was conducted to investigate if chromosome band 3p14 is of any pathogenic significance in the malignant process of breast cancer. Genetic studies have implicated a tumour suppressor gene on chromosome arm 3p and we have proposed LRIG1 at 3p14 as a candidate tumour suppressor. The LRIG1 gene encodes an integral membrane protein that counteracts signalling by receptor tyrosine kinases belonging to the ERBB family. LRIG1 mRNA and protein are expressed in many tissues, including breast tissue. METHODS: In the present report we analysed the LRIG1 gene by fluorescence in situ hybridisation (FISH), LRIG1 mRNA by quantitative RT-PCR, and LRIG1 protein by western blot analysis. Two tumour series were analysed; one series consisted of 19 tumour samples collected between 1987 and 1995 and the other series consisted of 9 tumour samples with corresponding non-neoplastic breast tissues collected consecutively. RESULTS: The LRIG1 gene showed increased copy number in 11 out of 28 tumours (39%) and only one tumour showed a deletion at this locus. Increased LRIG1 copy number was associated with increased levels of LRIG1 mRNA (two of three tumours) and protein (four of four tumours) in the tumours compared to matched non-neoplastic breast tissue, as assessed by RT-PCR and western blot analysis. CONCLUSION: The molecular function of LRIG1 as a negative regulator of ERBB receptors questions the biological significance of increased LRIG1 copy number in breast cancer. We propose that a common, but hitherto unrecognised, breast cancer linked gene is located within an amplicon containing the LRIG1 locus at 3p14.3.

Gene expression pattern of the epidermal growth factor receptor family and LRIG1 in renal cell carcinoma.

BACKGROUND: Previous studies have revealed altered expression of epidermal growth factor receptor (EGFR)-family members and their endogenous inhibitor leucine-rich and immunoglobulin-like domains 1 (LRIG1) in renal cell carcinoma (RCC). In this study, we analyzed the gene expression levels of EGFR-family members and LRIG1, and their possible associations with clinical parameters in various types of RCC. METHODS: Gene expression levels of EGFR-family members and LRIG1 were analyzed in 104 RCC samples, including 81 clear cell RCC (ccRCC), 15 papillary RCC (pRCC), and 7 chromophobe RCC (chRCC) by quantitative real-time RT-PCR. Associations between gene expression levels and clinical data, including tumor grade, stage, and patient survival were statistically assessed. RESULTS: Compared to kidney cortex, EGFR was up-regulated in ccRCC and pRCC, LRIG1 and ERBB2 were down-regulated in ccRCC, and ERBB4 was strongly down-regulated in all RCC types. ERBB3 expression did not differ between RCC types or between RCC and the kidney cortex. The expression of the analyzed genes did not correlate with patient outcome. CONCLUSIONS: This study revealed that the previously described up-regulation of EGFR and down-regulation of ERBB4 occurred in all analyzed RCC types, whereas down-regulation of ERBB2 and LRIG1 was only present in ccRCC. These observations illustrate the need to evaluate the different RCC types individually when analyzing molecules of interest and potential biological markers.

ErbB4 is downregulated in renal cell carcinoma--a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family.

In the present study the authors evaluated the expression of the EGFR family members ErbB2-4 in renal cell carcinoma (RCC). Thirty-one RCCs were examined for gene expression of ErbB2-4 mRNA by quantitative real-time RT-PCR. For eight of the patients samples of nonneoplastic kidney cortex were also evaluated. Expression of ErbB4 mRNA was analysed in the eight matched tumour and kidney cortex samples by isoform-specific real-time RT-PCR analysis. ErbB4 protein expression was analysed by immunohistochemistry. In summary the results showed that ErbB2 mRNA was downregulated in conventional (clear cell) RCC; ErbB3 mRNA levels were low and heterogeneous in both tumours and kidney cortex; ErbB4 mRNA and protein were strongly downregulated in conventional and papillary RCC. Thus, ErbB2 and ErbB4 are not likely to be oncogenes in the majority of RCCs; instead, the observed downregulations suggest that these receptors might function as tumour suppressors in RCC.