Could molecular profiling be helpful in daily practice in the treatment of anal carcinoma?

Anal carcinoma (AC) is an uncommon malignancy; however, the incidence has been rising in the past years. Squamous cell carcinoma is the most frequent histological type, related most of the time to Human Papillomavirus (HPV) infection. Therapeutical options are limited with poor survival. The development of Next Generation Sequencing (NGS) molecular profiling has provided a better tumor characterization and understanding, offering a window of opportunity for patients (pts). Lately, circulating tumor DNA (ctDNA) sequencing has emerged as a novel and less invasive approach for molecular diagnosis, disease monitoring and treatment possibilities.

We reviewed retrospectively the results of liquid biopsies obtained at progression or at initial diagnosis. We compared the results with archival tissue profiling for available patients. Genomic analysis was done using Foundation One liquid and tissue CDx panel. Data on demographics, tumor type, HPV status, clinical outcomes and molecular alterations (MA) have been collected.

A total of 38 pts with AC were included in the analysis; the majority (n=31; 82%) with metastatic disease and squamous histology (n=34, 89%). The main characteristics were as follows: 50% (n=19) were female, 50% (n=19) males, median age of 62 years (IQR; 58-69); 21(55%) pts had HPV tissue-positive tumor (p16+); only 3 (8%) pts were HIV positive.Liquid biopsy was performed in 33(87%) pts but results were available for 32 pts (97%) due to one failed sample. Lymph nodes (n=27; 71%) and liver (n=15, 40%) were the most common metastatic sites. The majority received systemic chemotherapy (all were progressive) (n=19, 58%) with median number of previous lines of 1 (range: 0-7). The circulating tumor fraction (cTF) was not evaluable for 47% (n=15/32) while 53% had ≥ 10% cTF. The median Tumor Mutational Burden (TMB) was 7.6 mutations (mut) per megabase (Mb) (range: 0-21.49) and was not correlated to cTF (p=0.37). All the samples were micro satellite stable (MSS). At least one molecular alteration (MA) was identified in a proportion of 81% (n=26/32) pts. Out of the 154 MA identified, the most frequently affected genes were PIK3CA (13.2%), KMT2D (8.3%), FBXW7 (4.9%) and TP53 (4.2%). Targetable molecular alterations (MA) were found in 30% (n=10 )pts. The presence of ctDNA could not be certified for 22% of pts (n=7/32) due to the absence of MA or to the presence of mutations occurring only in clonal hematopoiesis genes.HPV serotypes 6, 11, 16 or 18 were detectable by NGS in 88% of pts (n=28/32). Level of detection of HPV was highly correlated to the cTF. 82% (n=14/17) of the samples with more than 100 reads/million of HPV had an evaluable cTF. Tissue molecular profiling from archival tissue was available in 26% (n=10/38). The median TMB was 4.41 mut/Mb. Out of the 44 MA identified, the most frequently affected genes were PIK3CA (11.4%), KMT2D (6.8%), PTEN (6.8%) and FBXW7 (4.5%). All sample were MSS.

Molecular profiling can identify several druggable genes and could have an interest in AC. Because it is a rare disease, larger national and international cohorts are needed for a better characterization.

The authors.

Has not received any funding.

A. Hollebecque: Honoraria (Institution): AstraZeneca, Roche; Advisory / Consultancy: Abbvie, Amgen, Basilea, BMS, Incyte, Servier, QED therapeutics, Relay Therapeutics, Seagen, Taiho; Research grant / Funding (self): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. A. Bayle: Advisory / Consultancy: Sanofi, Roche; Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.