Many cancer patients receive antiangiogenic agents as part of their treatment. However, the response to these agents varies. They are very effective in some cases but, in others, they can even be harmful. Consequently, it is important to identify each patient's situation as soon as possible. A randomised phase II clinical trial promoted by the Spanish National Cancer Research Centre (CNIO) in collaboration with the Spanish Breast Cancer Research Group (GEICAM) and 16 hospitals has demonstrated the effectiveness of a marker in identifying people for whom these drugs are ineffective.
The results of the study, the first randomised prospective study promoted by the CNIO, appear in the journal Clinical Cancer Research and confirm that 18F-fluoromisonidazole can detect, in the early stages of the treatment, patients who are not going to benefit from the use of nintedanib -an antiangiogenic agent of the TKI family-.
"We have been working on antiangiogenesis for years", says the lead author of the work, Miguel Quintela-Fandino, head of the Breast Cancer Clinical Research Unit at the CNIO. "There are two main issues: identify the patients for whom it is going to work or not; and what the resistance mechanisms are".
The bottom line is that antiangiogenic drugs can give rise to two reactions in the tumour tissue: normalise the typical tumour hypoxia (this is the desired effect) or increase it. Quintela-Fandino’s team demonstrated this dual response last year. On that occasion, they also showed that using PET scans to measure the presence of 18F-fluoromisonidazole in the tissue was an accurate marker to detect one situation or the other.
On this occasion, the goal was to check that what they had observed in mice also occurred in patients. This was the reason for launching this trial, which, in phase II, included 130 breast cancer patients.
The patients were divided into two groups. The first group was subjected to a first PET scan prior to two weeks of treatment with nintedanib, followed by another PET scan and 12 weeks of chemotherapy plus this antiangiogenic agent. The second group underwent one PET scan and 12 weeks of chemotherapy.
The goal was to determine whether PET scans could be used to monitor hypoxia in tumour tissue before and after treatment with antiangiogenic drugs. At this early stage we would, therefore, know their effectiveness to decide whether or not to continue with the drug regimen.
The results, obtained thanks to the work of the CNIO's Molecular Imaging Core Unit -lead by Francisca Mulero, coauthor of the paper-, indicated that they could. Those patients in whom the biomarker indicated that the tumour tissue remained hypoxic after the first two weeks of treatment, did not benefit from long-term treatment with nintedanib. Therefore, this early test can be used to personalise treatment based on these drugs.
"By using this marker, we can see that TKIs will not work in about 25% of patients and that, therefore, this drug should not be administered," says Quintela-Fandino.
"No drug is 100% effective,” says Quintela-Fandino. "Therefore, given the high cost of drugs of this kind and that they are not exempt of toxic effects, it is very important to stop administering them when we know that they are not going to have an effect. To date, we only realised that a drug of this type had failed when the disease progressed."
From a pre-clinical point of view, Quintela’s group had already described the differential mechanisms of resistance to antiangiogenic agents when they produce a hypoxic response as well as when they normalise hypoxia, published recently. Both mechanisms are radically different but reversible with different compounds.
At present, they are carrying out pilot studies on the tolerance and efficacy of combinations of antiangiogenic agents with mitochondrial inhibitors or modulators of the immune response, responsible for reversing the various adaptive responses of the tumour when treated with antiangiogenic drugs. "When these tests are completed, we shall launch a clinical trial in which we will finally be able to personalise antiangiogenic therapy by using misonidazole PET imaging to monitor the type of response that each patient experiences and add individualized drugs in each case to induce therapeutic synergy," concludes Quintela.
This research has been financed with funds from the Spanish Society of Medical Oncology (SEOM), the Spanish Association against Cancer (AECC), Avon Spain and Boehringer-Ingelheim.
18F-fluoromisonidazole PET and activity of neoadjuvant nintedanib in early HER2-negative breast cancer: a window-of-oppontunity randomized trial. Miguel Quintela-Fandino, Ana Lluch, Luis Manso, Isabel Calvo, Javier Cortes, José Angel García-Saenz, Miguel Gil-Gil, Noelia Martinez-Jánez, Antonio Gonzalez-Martin, Encarna Adrover, Raquel de Andres, Gemma Viñas, Antonio Llombart-Cussac, Emilio Alba, Juan Guerra, Begoña Bermejo, Esther Zamora, Fernando Moreno-Anton, Sonia pernas Simon, Alfredo Carrato, Antonio Lopez-Alonso, Francisca Mulero, Ramon Colomer. Clinical Cancer Research (2016). DOI: http://dx.doi.org/10.1158/1078-0432.CCR-16-0738