Prognostic value of blood-based protein biomarkers in non-small cell lung cancer: A critical review and 2008-2022 update.

BACKGROUND: Therapeutic possibilities for non-small cell lung cancer (NSCLC) have considerably increased during recent decades. OBJECTIVE: To summarize the prognostic relevance of serum tumor markers (STM) for early and late-stage NSCLC patients treated with classical chemotherapies, novel targeted and immune therapies. METHODS: A PubMed database search was conducted for prognostic studies on carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase, squamous-cell carcinoma antigen, progastrin-releasing-peptide, CA125, CA 19-9 and CA 15-3 STMs in NSCLC patients published from 2008 until June 2022. RESULTS: Out of 1069 studies, 141 were identified as meeting the inclusion criteria. A considerable heterogeneity regarding design, patient number, analytical and statistical methods was observed. High pretherapeutic CYFRA 21-1 levels and insufficient decreases indicated unfavorable prognosis in many studies on NSCLC patients treated with chemo-, targeted and immunotherapies or their combinations in early and advanced stages. Similar results were seen for CEA in chemotherapy, however, high pretherapeutic levels were sometimes favorable in targeted therapies. CA125 is a promising prognostic marker in patients treated with immunotherapies. Combinations of STMs further increased the prognostic value over single markers. CONCLUSION: Protein STMs, especially CYFRA 21-1, have prognostic potential in early and advanced stage NSCLC. For future STM investigations, better adherence to comparable study designs, analytical methods, outcome measures and statistical evaluation standards is recommended.

Correlation of serum level of squamous cell carcinoma antigen with severity of cutaneous psoriasis, assessed using the simplified psoriasis index.

BACKGROUND: Squamous cell carcinoma antigen (SCCA) is a biomarker of disease progression in squamous cell carcinoma but also contributes to the pathogenesis of psoriasis. Eight previous studies have shown a correlation between psoriasis severity, assessed using the Psoriasis Assessment Severity Index or body surface area, and serum level of SCCA, mainly SCCA2, assessed by means of non-commercial tests. We examined the correlation between serum SCCA level, measured with a commercial kit, and psoriasis severity assessed using the Simplified Psoriasis Index (SPI). METHODS: We conducted a prospective, non-interventional, single-centre study at the University Hospital of Tours over 18 months. The primary endpoint was same-day measurement of serum SCCA level and the psoriasis severity score on the professional version of the SPI (proSPI-s) at both baseline and follow-up. Secondary endpoints were same-day measurement of serum SCCA level and the proSPI psychosocial score (proSPI-p), proSPI treatment score, Dermatology Life Quality Index (DLQI), and inflammation parameters (C-reactive protein level, neutrophil-to-lymphocyte ratio). RESULTS: We included 50 psoriasis patients. Serum SCCA level was correlated with the proSPI-s at baseline and follow-up (Spearman r = 0.686 and r = 0.674, p < 0.0001) for both. It was correlated with the proSPI-p and DLQI. Serum SCCA level was not correlated with either neutrophil-to-lymphocyte ratio (r = 0.083) or C-reactive protein level (r = 0.192). CONCLUSION: This study is the first to correlate serum SCCA level with proSPI-s. Moreover, SCCA was measured using a widely available kit. SCCA may be used to assess the severity of psoriasis.

The Role of Immunotherapy in the Treatment of Anal Cancer and Future Strategies.

OPINION STATEMENT: Despite being markedly sensitive to chemoradiotherapy, patients with locally advanced (T3-4 and/or node-positive) squamous cell carcinoma of the anal canal (SCCA) still present high rates of disease recurrence, which is characterized by meaningful morbidity and mortality. Abdominoperineal resection as salvage surgery may be considered for patients with local recurrence, but with an important negative impact in the quality of life. Systemic therapy of advanced SCCA is an unmet clinical need. Palliative chemotherapy for the management of unresectable or metastatic disease yields approximately 60% of objective response rate; however, it still portends a grim prognosis. Based on the recently published InterAACT trial, carboplatin plus paclitaxel has become the standard of care of advanced disease; modified DCF (docetaxel, cisplatin, and 5-fluorouracil) may also be considered for fit patients amenable to intensive therapy. There are no FDA-approved therapies for the treatment of chemorefractory patients. Nevertheless, both nivolumab and pembrolizumab may be considered for these patients with promising results, regardless of PD-L1 expression or other predictive biomarkers. It is estimated that approximately 1 out of 5 patients with SCCA will derive large benefit from PD-1 inhibitors, which may produce considerable durations of response. Ongoing clinical trials exploring the combination of chemotherapy plus immune checkpoint inhibitors in the first-line therapy, combination of anti-PD-1/PD-L1 plus anti-CTLA-4, and emerging immunotherapeutic approaches, such as adoptive T cell therapies, are eagerly awaited and may bring practice-changing results in the next few years for the treatment of this challenging disease.

Evaluation of 2 Commercially Systems for Detection of Serum Squamous Cell Carcinoma Antigen in Pan Squamous Cell Carcinoma.

BACKGROUND: This study compared the analytical performance of the Elecsys 602 (Roche Diagnostics) system with the I2000 (Abbott laboratories) system for the quantitative measurement of squamous cell carcinoma antigen (SCCA) to assess its role as an indicator in pan squamous cell carcinoma. METHODS: 435 serum samples included pan squamous cell cancer group (n = 318) and healthy subjects (n = 52) and non-squamous cell group (n = 41) and benign diseases group (n = 24) were measured by 2 systems and compared. RESULTS: The within-run precision coefficient of variation (CV) for Abbott and Roche systems were 3.34-4.88% and 0.95 -1.96%, and the total precision CV were 2.89-9.48% and 3.97-5.38%, respectively. Good correlation was showed in Abbott and Roche systems (slopes = 0.749, r = 0.9658). Serum SCCA in the groups of nasopharyngeal carcinomas, lung squamous cell carcinoma, esophageal squamous cell carcinoma, bladder cancer and cervical squamous cell carcinoma under the curve area (AUC) was more than 0.5, while the AUC in the non- nasopharyngeal carcinomas head and neck squamous cell carcinoma was less than 0.5. The AUC of 2 systems was statistically different in lung squamous cell carcinoma and nasopharyngeal carcinomas (P < 0.05). The levels of SCCA of 2 systems were similarities in esophageal squamous cell carcinoma(stage IV vs. stage 0a-II)and bladder cancer(stage I vs. stage Oa)and cervical squamous cell carcinoma(stage IIB-III vs. stage I-IIA), which advanced stage had higher level of SCCA than early stage. But the SCCA levels of 2 systems were inconsistent in bladder cancer (stage II-IV vs. stage Oa in Abbott), head and neck squamous cell carcinoma (stage IV vs. stage Oa-I in the Roche) and lung squamous cell carcinoma (stage III vs. stage I-II in the Roche). (P < 0.05). CONCLUSIONS: 2 systems correlated well in SCCA detection of squamous cell carcinoma, but there were individual differences. Serum SCCA may also contribute to the diagnosis of bladder cancer.

SERPINB3 and B4: From biochemistry to biology.

Human SERPINB3 and SERPINB4 are evolutionary duplicated serine/cysteine protease inhibitors. Genomic analysis indicates that these paralogous genes were encoded from independent loci arising from tandem gene duplication. Although the two molecules share 92% identity of their amino acid sequences, they are distinct in the Reactive Center Loop (RCL) including a hinge region and catalytic sequences which accounts for altered substrate specificity. Elevated expression of the two molecules has been reported to contribute to numerous pathological conditions such as inflammatory diseases and cancer. In this review, we focus on summarizing the biochemical features of SERPINB3/B4 and discussing the mechanistic basis for their biological functions and implications in human diseases.

Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity.

Squamous cell carcinoma antigen-1 (SCCA1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma (EAC). In our series of patients with EAC, free SCCA1 serum levels were associated with significantly worse overall survival, and SCCA1-IgM serum levels showed a trend to a worse overall survival. Serum SCCA1 and intratumoral SCCA1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA1 induced the expression of the immune checkpoint molecule programmed death ligand-1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA1 presence, as cells overexpressing SCCA1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.

Behavior of the extremophile green alga Coccomyxa melkonianii SCCA 048 in terms of lipids production and morphology at different pH values.

The extremophile green alga Coccomyxa melkonianii SCCA 048 was investigated to evaluate its ability to grow in culture media with different pH. Specifically, Coccomyxa melkonianii was sampled in the Rio Irvi river (Sardinia, Italy) which is severely polluted by heavy metals as a result of abandoned mining activities. In this study, the strain was cultivated in growth media where the pH was kept fixed at the values of 4.0, 6.8 and 8.0, respectively. During the investigation, a significant phenotypic plasticity of this strain was observed. The strain grew well in the pH range 4.0-8.0, while the optimal value for its growth was 6.8. Furthermore, maximum lipid contents of about 24 and 22 %wt were achieved at the end of cultivation when using pH 4.0 and 8.0, respectively. Finally, the analysis of fatty acid methyl esters (FAMEs) highlights the presence of suitable amounts of compounds which can be profitably exploited in the food, nutraceutical, and cosmetic industry. This aspect, coupled with the possibility of cultivating Coccomyxa melkonianii under extreme pH conditions in economic open ponds, makes this strain an interesting candidate for several biotechnological applications.

Characterization of SCCA-IgM as a biomarker of liver disease in an Asian cohort of patients.

Viral hepatitis infection is a major global issue and a leading cause of liver disease and associated deaths. Over time, patients infected with hepatitis B (HBV) or C virus (HCV) develop cirrhosis and, eventually, hepatocellular carcinoma (HCC). For this reason, they need to be constantly monitored. Current Asian guidelines recommend the determination of serum alpha-fetoprotein (AFP) together with liver ultrasounds every six months to detect HCC nodules. However, both methods have several limitations, and other biomarkers have been studied for monitoring cirrhosis, including SCCA-IgM, an immune-complex formed by Squamous Cell Carcinoma Antigen and IgM. To date, SCCA-IgM has been validated as a novel biomarker for liver diseases only in European populations. The aim of our study was to analyze SCCA-IgM as a biomarker to monitor cirrhosis evolution in an Asian cohort of patients and to compare its performance to that of AFP. We analyzed the concentration of AFP and SCCA-IgM in serum samples obtained from a group of Asian adult patients with cirrhosis or HCC and a control group of patients admitted for gastrointestinal disorders. In untreated patients and similarly to AFP, SCCA-IgM levels were significantly higher in patients with cirrhosis compared to those with HCC. In addition, SCCA-IgM, but not AFP serological levels, were significantly lower in HCC patients who were treated with surgical resection compared to those who received a different therapy.

Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases.

Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.

Prognostic importance of lymph node-to-primary tumor standardized uptake value ratio in invasive squamous cell carcinoma of uterine cervix.

PURPOSE: Using integrated PET/CT, we evaluated the prognostic value of [18F]FDG uptake ratio between pelvic lymph node (LN) and primary tumor in invasive squamous cell carcinoma (SCCA) of the uterine cervix. METHODS: We retrospectively reviewed patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB to IIA cervical SCCA who underwent preoperative [18F]FDG PET/CT scans. PET/CT parameters such as maximum standardized uptake value (SUV) of the primary cervical cancer (SUVcervix) and LN (SUVLN), and the LN-to-cervical cancer SUV ratio (SUVLN/SUVcervix) were assessed. Prognostic values of PET/CT-derived metabolic and volumetric variables and clinicopathology parameters were analyzed to predict progression-free survival (PFS) in regression analyses. RESULTS: Clinical data, treatment modalities, and results were reviewed for 103 eligible patients. Median post-surgical follow-up was 29 months (range, 6-89), and 19 (18.5%) patients experienced recurrence. Multivariate logistic regression analysis showed that SUVLN / SUVcervix > 0.1747(P = 0.048) was the independent risk factor of recurrence. Patient group categorized by SUVLN/SUVcervix showed significant difference in PFS (log-rank test, P < 0.001). CONCLUSIONS: Preoperative SUVLN/SUVcervix measured by [18F]FDG PET/CT was significantly associated with recurrence, and has an incremental prognostic value for PFS in patients with cervical SCCA.

Elective neck management for squamous cell carcinoma metastatic to the parotid area lymph nodes.

The objective of this study is to determine if radiotherapy (RT) alone to the cervical lymphatics is a suitable alternative to elective neck dissection (END) in patients who undergo parotidectomy and postoperative RT for squamous cell carcinoma metastatic to the parotid area lymph nodes (PALN). We retrospectively reviewed the medical records of 107 patients consecutively treated from November 1969 to March 2012 for cutaneous squamous cell carcinoma metastatic to the PALN with a clinically node-negative neck. Primary therapy consisted of parotidectomy in all cases. We compared regional (cervical) control in two subgroups: 42 patients treated with END and RT and 65 patients treated with elective neck irradiation (ENI) alone. The median time of follow-up was 5.5 years (range 0.3-30 years) for all patients and 11 years for living patients (range 1.8-26 years). There was 1 neck recurrence in each subgroup: END and RT, 1/42 (2 %); and ENI alone, 1/65 (1.5 %). No patient experienced a complication related to neck RT. ENI to a dose of approximately 50-60 Gy is a suitable alternative to END and postoperative RT in patients with squamous cell carcinoma metastatic to the PALN.

Psoriasis pathogenesis - Pso p27 is generated from SCCA1 with chymase.

Psoriasis is a chronic inflammatory skin disease with unknown aetiology. Infiltration of inflammatory cells as the initial event in the development of new psoriatic plaques together with the defined inflamed areas of such lesions argues for an immunological disease with a local production of a causal antigen. The auto-antigen Pso p27 is a protein expressed in the skin lesions. We recently demonstrated that Pso p27 is homologous to the core amino acid sequences of squamous cell carcinoma antigens 1 and 2 (SCCA1/2) and it is apparently generated from SCCA molecules by digestion with highly specific endoproteases. In this communication we demonstrate the generation of Pso p27 from SCCA1 with extracts from psoriatic scale and even more remarkably, the generation of Pso p27 from SCCA1 in the presence of mast cell associated chymase. These findings open up for new therapeutic strategies in psoriasis and probably also in other autoimmune diseases as Pso p27 epitopes have been detected in diseased tissues from patients with various chronic inflammatory diseases.

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.

[Preparation of recombinant serpins B3 and B4 and investigation of their specific interactions with antibodies using hydrogel-based microarrays].

The objective of this work was to obtain preparations of recombinant squamous-cell carcinoma antigens (serpins B3 and B4) and to investigate their interactions with different monoclonal antibodies using hydrogel-based microarrays (biochips). Two genetic constructs encoding full-length serpin B3 and serpin B4 molecules were created to produce recombinant SPB3 and SPB4 proteins carrying a N-terminal His6-tag. Monoclonal antibodies against serpin B3 (H3, C5, H5, H81, and G9) were also obtained. An experimental gel-based biological microchip was designed to contain gel elements that carry immobilized antibodies against SPB3, immobilized commercial monoclonal SCC107 and SCC140 antibodies against squamous-cell carcinoma antigen (SCCA), and gel elements with immobilized SPB3 or SPB4. Judging by the specificity of recombinant SPB3 and SPB4, which bind to monoclonal antibodies against SCCA and, according to the manufacturer's data, can recognize conformational epitopes of both SPB3 and SPB4, it was concluded that the obtained recombinant serpins had the correct tertiary structure. A biochip-based direct immunoassay showed that SPB4 could bind effectively only to SCC107 and SCC140 antibodies, while SPB3 interacted specifically not only with these antibodies, but also with H3 and C5 monoclonal antibodies. Using biochip-based sandwich immunoassay, a pair of monoclonal antibodies SCC107/C5 that interacted specifically with serpin B3 but did not interact with serpin B4 was identified. Thus, it has been demonstrated that serpin B3 can be selectively determined in the presence of highly homologous serpin B4 using a biochip-based assay.

Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC).

BACKGROUND AND AIM: The serpin squamous cell carcinoma antigen complexed with IgM (SCCA-IgM) has been reported as a promising serological marker for hepatocellular carcinoma (HCC). We aimed to further evaluate SCCA-IgM diagnostic accuracy and to determine its prognostic role. METHODS: SCCA-IgM levels were determined in 327 sera obtained from 81 HCC patients, 206 cirrhotics and 40 healthy blood donors (controls). Sensitivity, specificity, correlation with clinical and tumor parameters and with survival were evaluated. RESULTS: HCC patients had SCCA-IgM levels significantly higher than controls and cirrhotics (P < 0.0001). Sensitivity, specificity, positive and negative predictive values for HCC were 89%, 50%, 41% and 92%, respectively. In comparison, sensitivity and specificity for alphafetoprotein were 48% and 85%. SCCA-IgM levels were not significantly correlated with clinical or biological variables. With a cut-off of 130 AU/mL (receiver operating characteristic curves), SCCA-IgM proved efficient in the prediction of prognosis, identifying the patients with long overall survival (efficiency validated in the homogenous subgroup of patients with intermediate-stage HCC undergoing transarterial chemoembolization) and predicting progression-free survival. A Cox multivariate analysis confirmed SCCA-IgM predictive value, identifying tumor size and SCCA-IgM levels as independent predictors of survival. A reduction in SCCA-IgM levels correlated with response to treatment. CONCLUSIONS: SCCA-IgM is a sensitive marker of HCC in patients with cirrhosis even though lacking in specificity. The determination of the levels of the marker in HCC patients is highly efficient in predicting the patients' prognosis, identifying those with long overall and progression-free survival and the responders and should be introduced in the clinical practice.

Analysis of influencing factors of serum SCCA elevation in 309 CAP patients with normal CEA,NSE and CYFRA21-1.

Introduction: Squamous cell carcinoma antigen (SCCA) is one of the auxiliary diagnostic indicators of lung squamous cell carcinoma, and an increase in serum SCCA can predict the occurrence of lung squamous cell carcinoma. However, whether SCCA is also elevated in pneumonia patients without malignancy is still not clear. Therefore, we studied influencing factors of elevated serum SCCA in patients with community-acquired pneumonia. Methods: We retrospectively enrolled 309 patients who were admitted to the Respiratory department with normal serum Carcinoembryonic antigen (CEA), Neuron specific enolase (NSE), and Cytokeratin 19 fragment (CYFRA21-1) level and were diagnosed with community-acquired pneumonia (CAP). The patients' serum SCCA level, body temperature, age, sex, white blood cell (WBC) count, hypersensitive C-reactive protein (Hs-CRP) level, and serum amyloid A (SAA) were recorded. Logistic regression models were used to analyze the risk factors of SCCA elevation. The dose-response relationship between temperature and risk of SCCA increase was analyzed using Restricted cubic splines (RCS). Results: Of the 309 patients, 143(46.3%) showed elevated SCCA levels. The logistic regression analysis revealed a significant influence of age and body temperature on elevated SCCA (P<0.05) levels. For every one-year increase in age, the probability of elevated SCCA decreased by 3% [OR=0.97,95%CI:0.95,0.99].For every 1°C increase in body temperature, the risk of elevated SCCA increased by 2.75 times [OR=3.75,95%CI:2.55,5.49].The patients were sorted into quartiles based on body temperature. Compared with patients in the Q1 of body temperature group, patients in the Q3 group were at 7.92 times higher risk [OR=7.92, 95%CI:3.27,19.16].and the risk of elevated SCCA was increased by 22.85 times in the Q4 group [OR=23.85,95%CI:8.38,67.89] after adjusting for age, gender, Hs-CRP, SAA, and WBC. RCS analysis showed there was a linear relationship between temperature index and risk of elevated SCCA. Conclusion: In summary, for CAP patients with normal CEA,NSE and CYFRA21-1 level, age and body temperature are influencing factors of SCCA elevation. Higher body temperature has a strong association with the occurrence of SCCA elevation.

Metastasis of cervical cancer indicated by elevation of serum CA125 produced by mediastinal lymph nodes: a case report.

BACKGROUND: In patient assessment for recurrence of neoplasia, a biomarker that shows an elevated serum value before the first treatment is a candidate for follow-up examination. The biomarker squamous cell carcinoma antigen is usually utilized for follow-up of squamous cell cancer of the cervix. CASE PRESENTATION: We herein report a 30-year-old Japanese woman of postoperative metastasis of cervical squamous cell cancer to the mediastinal and supraclavicular lymph nodes as indicated by an elevated serum cancer antigen 125 concentration and not by the squamous cell carcinoma antigen value. After chemoradiotherapy and chemotherapy, the serum cancer antigen 125 concentration decreased to a normal value. Squamous cell carcinoma antigen was found to be distributed in both the squamous cell cancer tissue of the cervix and the supraclavicular lymph node metastatic tissue. By contrast, cancer antigen 125 was distributed in the supraclavicular lymph node metastatic tissue but not in the original squamous cell cancer tissue of the cervix. CONCLUSION: In this case, metastasis of cervical cancer to the mediastinal and supraclavicular lymph nodes was shown by the biomarker cancer antigen 125, which was not present in the original neoplasia.

Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer.

Background: Cervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients. Objective: We investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A). Methods: This single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes. Results: Among the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed. Conclusion: HPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.