Subject Ph. D.

Upper aerodigestive tract (UADT) squamous cell carcinomas are the seventh leading cause of cancer and affect approximately 600,000 patients per year worldwide (1). The majority of UADT cancers are diagnosed at an advanced stage (70.3% at stage III and IV) and less than 60% of these patients are disease-free at 3 years, despite aggressive multimodal local treatment by surgery and/or radiochemotherapy (1-3). The mean progression-free survival at 2 years varies between 45 and 60% depending on the study (4-8). Tumor recurrence is most often incurable. The two main etiologies are represented by alcohol and tobacco poisoning and the human papillomavirus (HPV), with very different prognoses for the latter (9). Recent randomized trials of treatment intensification with immunotherapy or tyrosine kinase inhibitors in head and neck squamous cell carcinomas have not met their primary endpoint of improving PFS at 24 months (2,3). These results may be partly explained by the lack of a marker capable of identifying minimal residual disease (MRD) after curative treatment. Such markers could improve the selection of patients who would benefit from therapeutic escalation. MRD can be measured by the amount of tumor DNA found in the blood after treatment, corresponding to circulating tumor DNA (ctDNA) (10). This emerging technique, performed from a simple blood test, is called liquid biopsy and provides a wealth of information on the tumor, such as genomic or epigenomic signatures (10,12-14). It therefore seems interesting to use this liquid biopsy approach in patients with stage III or IV head and neck cancer to identify patients at high risk of early relapse after curative treatment. The work carried out to date, for diagnostic and prognostic purposes, mainly concerns patients with HPV-positive status (15-17). The available data are limited for patients with non-HPV-induced tumors (HPV negative), because monitoring of ctDNA requires the identification and detection of genomic alterations specific to each tumor, mainly at the level of tumor suppressor genes such as TP53, PIK3CA, CDKN2A, NOTCH1 (18, 19). ctDNA can be measured in different ways: Either by measuring viral DNA sequences by the number of copies carrying a tumor mutation or by studying the methylation patterns of genes involved in the tumor process or p16. Studies are therefore needed to identify genomic variations (SNVs, indels, SCNA), as well as epigenetics, in particular ctDNA methylation in squamous cell carcinomas of the head and neck and to validate their incorporation into future prognostic and therapeutic tools. Studies on different types of cancer have demonstrated that ctDNA can identify patients likely to recur with high specificity and sensitivity (25-27). Honoré et al. recently showed on 41 patients treated with radiochemotherapy for squamous cell carcinomas of the head and neck that the detectability of ctDNA within 12 weeks after the end of treatment made it possible to identify patients likely to recur with high sensitivity and specificity (7). These promising results need to be supported by other larger clinical studies with consistent monitoring and blood collection in order to be able to offer liquid biopsy routinely in the monitoring of patients with head and neck cancers. To our knowledge, no study has demonstrated the value of early assessment of the rate of decrease in ctDNA at 1 month after the end of radiotherapy alone or combined with concomitant treatment, as a predictive factor for PFS in head and neck squamous cell carcinomas regardless of their HPV status.

PROJECT AND SCIENTIFIC OBJECTIVES: The study of ctDNA seems to be a good alternative to tissue biopsies which are more invasive and more restrictive for the patient. The ctDNA isolated from a simple blood sample allows an evaluation of both tumor genomic alterations representative of the quantity of the present and residual disease, but has the advantage of adding a notion of temporality and iterativity, that is to say the measurement of the evaluation of the disease over time. The measurement of ctDNA therefore allows a qualitative, quantitative and temporal evaluation of the disease. The studies cited above have provided data on the interest of ctDNA as prognostic biomarkers in VADS cancers, however it seems essential to carry out other more rigorous prospective trials and on a larger number of patients before being able to offer liquid biopsy routinely. We hypothesize that a detectable ctDNA level at 1 month after curative radiotherapy alone or associated with concomitant treatment can predict recurrence and the presence of residual disease. To answer this question, ctDNA will be measured by the methylation of genes specifically methylated in VADS cancers and unmethylated in healthy tissues. If our study is positive, we will consider a randomized clinical trial with treatment intensification for patients with detectable ctDNA after 1 month post-treatment. Clinical studies are ongoing or closed to inclusion and propose to add Xevinapant or Avelumab in addition to treatment with radiotherapy or radiochemotherapy (RAVINA (NCT05724602), TrilynX (NCT04459715) and REACH (NCT02999087)). However, there is little data to date evaluating the benefit of adjuvant treatment for existing tumors. In the longer term, measuring ctDNA by liquid biopsy could revolutionize the therapeutic pathway for patients with head and neck cancer. By providing predictive and prognostic data more quickly than the imaging currently used, this complementary tool will save time in diagnosing relapse and provide patients with early therapeutic intervention to prevent recurrence before it becomes visible on imaging. This new management should have a beneficial impact on patient survival and quality of life.