A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma

Iseas, Soledad; Golubicki, Mariano; Robbio, Juan; Ruiz, Gonzalo; Guerra, Florencia; Mariani, Javier; Salanova, Rubén; Cabanne, Ana; Eleta, Martín; González, Joaquín V.; Basiletti, Jorge; Picconi, Marı́a Alejandra; Masciangioli, Guillermo; Carballido, Marcela; Roca, Enrique; Méndez, Guillermo; Coraglio, Mariana; Abba, Martı́n C.

doi:10.1016/j.tranon.2021.101084

Cited by 19 publications

(22 citation statements)

References 35 publications

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“…Tumor infiltrating lymphocytes may be of superior prognostic value for anal cancer (30) and will be prospectively evaluated in the PLATO study (ISRCTN88455282). Additional biomarkers under investigation include circulating tumor HPV DNA (31,32) and PD-L1 (33). Only a minority of patients in this study were treated with MMC, potentially limiting the generalizability of our results.…”

Section: Parametersmentioning

confidence: 96%

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma

De¹,

Ludmir²,

Messick³

et al. 2021

J Gastrointest Oncol

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Background: Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints. Methods: We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards.Results: Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasisfree survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively.Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophillymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively. Conclusions: Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophillymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.

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Section: Parametersmentioning

confidence: 96%

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma

De¹,

Ludmir²,

Messick³

et al. 2021

J Gastrointest Oncol

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“…Racial disparity in stage distribution and survival is multifactorial and is reported to be due to socioeconomic factors, insurance status, comorbidities, and tumor characteristics. 31 Studies by Iseas et al, 19 Wessely et al, 22 Balermpas et al, 32 and Chamseddin et al 33 showed better survival rates from ASCC in PD-L1 þ patients. Mitra et al 24 did not find PD-L1 to be prognostic but found a different biomarker, indoleamine 2,3 dioxygenase 1 (IDO1), to be associated with poor outcome.…”

Section: Pd-l1 Expression and Outcomesmentioning

confidence: 97%

“…of viable tumor cells] 3 100) of 1% or higher was defined as PD-L1 positive (PD-L1 þ ) in the Keynote-028 clinical trial 16 and has also been used in a few other studies. 16,[18][19][20] Because other studies evaluating PD-L1 in anal cancer have used TPS, we also evaluated TPS. [21][22][23][24][25] Tumor proportion score is the percentage of viable tumor cells showing partial or complete membrane staining and of any intensity…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The other studies that showed improved survival in PD-L1 þ ASCC also examined a distinctly different patient population with a predominance of female, Caucasian, and nonimmunocompromised patients. 19,22,32,33 The PD-L1 positivity rate in several studies was wide, ranging from 22% to 82.5%, with Koncar et al 23 reporting 22% PD-L1 positivity using TPS and Steiniche et al 20 reporting 82.5% PD-L1 positivity using CPS. Our PD-L1 positivity is within this range.…”

Section: Pd-l1 Expression and Outcomesmentioning

confidence: 99%

“…Although differences in patient population could be a potential explanation for variation in PD-L1 positivity, the method used for establishing PD-L1 positivity is also different in different studies. Some studies used CPS 18,19 ; some used TPS 21,22,25 ; some used greater than or equal to 1%, 19,20,22 greater than 1%, 24,33 or greater than 5% as a cutoff value 18 ; and others used ''any positivity'' as evidence of PD-L1 expression. 21 In our study the criterion of an overall average TPS of greater than or equal to 1% of tumor cells with partial or complete membrane staining as PD-L1 þ resulted in lower PD-L1 positivity than using CPS of greater than or equal to 1%.…”

Section: Pd-l1 Expression and Outcomesmentioning

confidence: 99%

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Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

Monsrud

Avadhani

Mošunjac

et al. 2021

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Upregulation of programmed death ligand-1 (PD-L1), an immunoregulatory protein, is associated with an adverse outcome in several malignancies. Very few studies have evaluated PD-L1 expression in invasive anal squamous cell carcinoma (ASCC). Objective.— To assess PD-L1 expression in patients with ASCC and correlate it with clinicopathologic factors and clinical outcomes. Design.— Fifty-one cases of ASCC were immunostained for PD-L1. PD-L1 expression by combined positive score and tumor proportion score was correlated with age, gender, HIV status, HIV viral load, CD4 count, stage, and outcomes. Kaplan-Meier curves for overall survival were plotted and compared using the log-rank test. Cox regression analysis was performed to identify significant prognostic factors (2-tailed P < .05 was considered statistically significant). Results.— PD-L1 was positive in 24 of 51 cases (47%) by combined positive score and in 18 of 51 (35%) by tumor proportion score. The median cancer-specific survival and 5-year overall survival were significantly lower in PD-L1+ patients. Age, gender, HIV status, HIV viral load, stage, and cancer progression were not significantly different between the two groups. CD4 count of more than 200/μL was significantly higher in PD-L1+ patients. PD-L1+ status remained statistically significant for worse overall survival on multivariate analysis. Conclusions.— PD-L1+ status is an independent adverse prognostic factor for overall survival in ASCC. This study highlights the potential of PD-L1 targeted therapy in better management of ASCC.

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Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection

Hamza,

Masliah‐Planchon,

Neuzillet

et al. 2023

Intl Journal of Cancer

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The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer‐related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV‐positive tumors, while HPV‐negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV‐positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV‐positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.

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A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma

Cited by 19 publications

References 35 publications

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma

Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection

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