The screening with the liquid biopsy for the rechallenge with anti-epidermal growth factor receptor antibodies in metastatic colorectal cancer
A perspective based on pharmacological costs

Jacopo Giuliani1, Beatrice Mantoan2, Maria Viviana Candela4, Giuseppe Napoli1, Marco Muraro1, Daniela Mangiola1, Marta Mandara1

1Department of Oncology, Az. Ulss 9 Scaligera, Legnago (Verona), Italy; 2Department of Diagnostic Imaging, Az. Ulss 9 Scaligera, Legnago (Verona), Italy; 3Centre for Health Economics, Social and Health Care Management, Università Carlo Cattaneo - Liuc, Castellanza (Varese), Italy; 4Istituto tecnico Bachelet, Ferrara, Italy.

Received on March 2, 2023. Accepted on March 27, 2023.

Dear Editor,

the use of anti-epidermal growth factor receptor antibodies (EGFRs) can be considered the standard of care in the first-line of therapy in patients with left-sided RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC). Re-using anti-EGFRs in mCRC patients who previously achieved benefit from a first-line anti-EGFR-based treatment seem to benefit in terms of activity, as showed in retrospective analyses and phase II single-arm trials1,2. In daily clinical practice, rechallenge with anti-EGFR monoclonal antibodies is often empirically, used with some benefit as late-line therapy. Recently, the CHRONOS Trial3, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA), showed that the detection of RAS mutations in ct-DNA at the time of re-treatment may be useful to identify resistant patients. The liquid biopsy was used for driving anti-EGFR rechallenge therapy in mCRC. The introduction of the rechallenge with active new agent is associated with a relevant increase of costs and it is important to make a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as PFS. It is also important to find a predictor of response that can drive therapy (and reduce potentially only toxic and consequently only expensive therapy) and this factor could be represented by liquid biopsy. The aim of this paper was to assess the gain in economic terms (pharmacological costs) derived from the rechallenge with panitunumab in RAS/BRAF wt mCRC based on the screening of liquid biopsy. We referred exclusively to the data relating to direct pharmacological costs to provide a quick estimate of the costs and potential savings deriving from the introduction of the screening with the liquid biopsy rechallenge with panitunumab in RAS/BRAF wt mCRC. We have considered CHRONOS Trial3. We have considered a standard patient of 70 kg with BSA= 1.8. We have assumed the following costs (VAT excluded): panitunumab (ex-factory) 1 vial of 5 ml (20 mg/ml)= 425 € (= 100 mg)4, liquid biopsy for the screening of ctDNA for RAS/BRAF/EGFR mutations= from 400 € to 500 €.

Twenty-seven patients were included. Median progression free survival (PFS) was 3.68 months3. The pharmacological cost of each month of treatment is 4250 € per patient, which added to the costs of the liquid biopsy (from 400 € to 500 €), with entire costs that range from 4650 € to 4750 € per patient. It means a total cost from 360,850 € to 360,900 € every 100 mCRC patients (from 40,000 € to 50,000 € for the screening with liquid biopsy in the entire population and 320,850 € for each month of treatment with panitunumab in the 69% of population3) (table 1).

Based on the data of CHRONOS Trial3, 31% more patients would have ineffective treatment (with potentially only toxicity) with panitunumab without the screening with liquid biopsy and it means that the screening with liquid biopsy for the detecting of ctDNA for RAS/BRAF/EGFR mutations of the entire population of mCRC patients potentially candidates for rechallenge with panitunumab allows us a total saving on pharmacological costs alone of 1042 € for each month of therapy for each mCRC patient treated).

The relation between efficacy of treatment (strictly related to the patient’s inclusion criteria in randomized controlled trials (RTCs)) and pharmacological costs is the main bias. In turn, the price of drugs could reflect differences in pharmacy costs within different European Countries (in Italy there are no significant pharmacy cost differences between the different regional realities). Third, the consideration of only the pharmacological costs of drugs (the data would undoubtedly be greater if we also considered the treatments toxicities) could represent another bias (even knowing that it account for about 55% of total medical expenses). This new type of resistance can be called “costs resistance” and in several Countries this could results in precluding new oncological treatments4. Actually, in our Country, the rechallenge with anti-EGFR monoclonal antibodies in mCRC patients is empirically, due to the fact that the registered indications by the Regulatory Authorities do not include the liquid biopsy for the screening of ctDNA for RAS/BRAF/EGFR mutations.

In conclusion, the introduction of the screening with the liquid biopsy for the detecting of ctDNA for RAS/BRAF/EGFR mutations would save money in terms of unnecessary treatments with anti-EGFRs rechallenge in mCRC.

Authorship: all authors contributed equally to (1) conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article and revising it critically for important intellectual content; and (3) final approval of the version to be published.

Conflict of interests: the authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Disclosure: no founds were received to support this article.

Research involving human participants and/or animals: no human participants and/or animals were involved.

Informed consent: not needed (no human participants were involved).


1. Santini D, Vincenzi B, Addeo R, et al. Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Ann Oncol 2012; 23: 2313-8.

2. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486: 532-6.

3. Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial. J Clin Oncol 2021; 39: astr.3506.

4. Determina n. 374/2022. GU Serie Generale n.125 del 30-05-2022.

5. Bonetti A, Giuliani J. Implications of drugs with rebate in Europe. Lancet Reg Health Eur 2021; 3: 100060.