After definitive radiotherapy (RT) treatment (with or without chemotherapy), cervical and anal canal neoplasms frequently exhibit disease persistence or recurrence. Due to the local inflammatory process post-treatment, response assessment by imaging (current gold standard) is limited, often necessitating multiple follow-ups and repeated invasive biopsies. Conventional follow-up is complex and costly, requiring equipment from secondary and tertiary services, trained radiologists, and patient exposure to radiation and contrast.
In this context of human papillomavirus(HPV)-related neoplasms, recent studies have demonstrated the role of ctDNA (circulating tumor DNA) in assessing the risk of recurrence or disease progression, providing a rationale for using the tool in two fronts:
* Optimizing follow-up based on serial monitoring of ctDNA; * Selecting patients with positive ctDNA after RT, who are at high risk of recurrence, for treatment intensification.
Monitoring with ctDNA as a standalone follow-up tool in cases evolving with negative ctDNA after RT has the potential to replace imaging exams, being a minimally invasive test performed on a peripheral blood sample. Currently, ctDNA testing has expensive methodologies not available in the Unified Health System (SUS). This project aims to develop a methodology for ctDNA evaluation focused on HPV ctDNA research that is low-cost and executable in SUS, as well to assess the accuracy of this test in the population with HPV-related tumors.
Additionally, we will evaluate whether the early introduction of immunotherapy in patients with positive ctDNA after definitive treatment can increase cure rates. Immunotherapy already has a well-defined role in the treatment of metastatic HPV-related neoplasms. Recently, the use of anti-programmed death-1 (anti-PD1) has also shown benefits in patients with locally advanced cervical cancer with a high risk of recurrence who are candidates for chemoradiotherapy (CRT). Therefore, its use focused on HPV-related tumors, as well as a better understanding of which patients benefit from this strategy, warrants further investigation.
Histological diagnosis of anal canal or cervical cancer.
Documented presence of HPV.
Anal canal carcinoma stage I to III, according to American Joint Committee on Cancer (AJCC) 8th edition;
Cervical carcinoma stage I B2 to IV A, according to AJCC 8th edition.
Patients with unequivocal distant metastasis at diagnosis.
For participants with positive ctDNA after treatment, those candidates for participation in Phase II will be excluded if there is unequivocal radiological progression in the first imaging exam after the completion of radiotherapy (with or without chemotherapy) or routine indication for salvage surgery immediately after the conclusion of definitive treatment.
Need for recurrent blood transfusions, such as weekly frequency.
Another uncontrolled disease representing a life risk, as determined by medical judgment.
Sequential
ctDNA test
Diagnostic testctDNA involves the collection of peripheral blood samples for the analysis of circulating tumor DNA (ctDNA). The samples are processed using next-generation sequencing (NGS) and/or digital polymerase chain reaction (PCR) techniques to detect specific genetic alterations related to the tumor. The objective is to assess the presence and quantity of ctDNA, providing information on tumor burden and treatment response.
Pembrolizumab
DrugParticipants will receive the institution's standard treatment during Phase I. If ctDNA remains positive between 8 and 12 weeks after the standard treatment, the participant will be invited to proceed to Phase II, which will consist of intravenous immunotherapy for up to 12 months, or until disease progression or unacceptable toxicity occurs. Continuous monitoring with ctDNA testing will be performed during Phase II.
General Objective
The objective of this study is to develop and validate a low-cost ctDNA test focused on detecting HPV-associated ctDNA for use in patients within the Brazilian Unified Health System (SUS). The test will be evaluated for its effectiveness in improving traditional monitoring methods and guiding the intensification of adjuvant treatment for anogenital neoplasms, including anal canal and cervical cancer. The impact of the test will be measured by correlating ctDNA detection with clinical outcomes of patients over time.
Number of HPV-focused ctDNA tests developed and validated
Measure the number of HPV-related ctDNA tests developed and validated for detecting HPV ctDNA in patients with anogenital neoplasms.
Performance of the validated HPV-related ctDNA test
Measure the accuracy and specificity of the validated HPV-related ctDNA test, including the assessment of HPV typing, ctDNA, and HPV E6\*I messenger ribonucleic acid (mRNA) levels in the study population.
Comparison of accuracy between standard ctDNA and HPV-focused ctDNA
valuate the accuracy of standard ctDNA compared to HPV-focused ctDNA and in relation to standard radiological control, based on routine imaging, through serial testing of ctDNA and HPV ctDNA after completion of treatment with definitive radiotherapy or chemoradiotherapy.
Comparison with Commercially Available HPV ctDNA Tests
Compare the diagnostic accuracy of standard ctDNA with HPV-focused ctDNA and standard radiological control, using routine imaging and serial ctDNA tests after definitive treatment with radiotherapy or chemoradiotherapy.
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Instituto do Cancer do Estado de São Paulo
Lead sponsor
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Collaborator
