Do we need biopsies of metastases for colorectal cancer patients?
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SIR We read with great interest the paper by Molinari et al (2009), recently published in the _British Journal of Cancer_. The study compares findings in primary colorectal cancer and paired
metastases in 38 patients, showing differences with respect to EGFR pathway deregulation, which may imply a different response to anti-EGFR monoclonal antibodies. As a consequence, the
authors suggest that the analysis of metastatic lesions should be considered both for patient management and when planning clinical trials with anti-EGFR drugs. Although this statement can
be considered as a hypothesis tenable in principle, it seems not to be supported by the results provided by the study itself, for the following reasons: * 1) Statistical analysis is lacking
in terms of study question definition and sample size calculation and therefore all the considerations made are not supported by a formal hypothesis verification; * 2) Comparisons are made
in terms of concordance, using the kappa index, instead of exploiting discrepancies between the two paired sets of data. However, even looking at concordance indexes, kappa values were equal
to 0.83, 1, 0.73, 1, 0.49 for _KRAS_ mutational status, _BRAF_ mutational status, PTEN protein expression, EGFR protein expression and _EGFR_ gene status, respectively, showing that only
for _EGFR_ gene status the concordance did not reach a ‘good’ value. As no intra-sample concordance results are available, the question whether these differences are because of a true
discordance between primary tumour and metastases or rather due to an intra-sample variability (i.e., variability (a) between different areas within the same sample because of biological
heterogeneity (Al-Mulla et al, 1998) or (b) to technical reproducibility) remains unanswered. * 3) Looking at Table 2, * 1) for _KRAS_ the data show two patients mutated in primary tumour
whose result became wild type in distant metastatic sites, whereas one patient wild type in primary tumour became mutated; * 2) only for three patients with PTEN-negative metastases but
positive primary tumours, the finding of non-response is consistent with biological hypothesis and other retrospective proof of principles (Loupakis et al, 2009); * 3) for _BRAF_ no
modification was seen; * 4) full concordance was detected for EGFR IHC analysis, whereas for _EGFR_ gene status the problems related to the reproducibility are well known. Even looking at
these data in a ‘qualitative’ way, the overall picture does not seem to suggest a clear trend towards a negative predictive effect of metastases, and only for PTEN there is some evidence
towards a negative effect. In the clinical practice, the biopsy of the metastatic lesion could be an invasive procedure, not free from risks and causes delays in treatment start, other than
understandable anxiety for the patient. Therefore, costs and advantages should be well balanced. Moreover, it should be considered (1) that the only universally accepted determinant of
resistance to anti-EGFR MoAbs are _KRAS_ mutations, (2) that _post hoc_ analyses of randomised studies, which led to the regulatory restriction for anti-EGFR MoAbs to _KRAS_ wild-type
patients were conducted almost exclusively on primary tumours (Amado et al, 2008; Karapetis et al, 2008) and (3) that other series greater than the present found a degree of correlation
between primary tumours and related metastases in terms of _KRAS_ mutational status that does not justify, at present, the clinical need for biopsies of metastases (Artale et al, 2008;
Santini et al, 2008; Loupakis et al, 2009). Given the retrospective nature of the study, which exposes the results to selection and verification biases, and given the small sample size, we
do think that no definitive clinical implication can be driven from this study. Rather, it is important to stress the need for prospective, properly powered studies, aimed to evaluate the
importance of tumoral sampling at time of treatment's start for the molecular prediction of benefit from anti-EGFR MoAbs, but, at the same time, there are no data for supporting the
need for biopsies of metastases in the routinary practice. CHANGE HISTORY * _ 16 NOVEMBER 2011 This paper was modified 12 months after initial publication to switch to Creative Commons
licence terms, as noted at publication _ REFERENCES * Al-Mulla F, Going JJ, Sowden ET, Winter A, Pickford IR, Birnie GD (1998) Heterogeneity of mutant versus wild-type Ki-ras in primary and
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Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
_J Clin Oncol_ 26: 1626–1634 Article CAS Google Scholar * Artale S, Sartore-Bianchi A, Veronese SM, Gambi V, Sarnataro CS, Gambacorta M, Lauricella C, Siena S (2008) Mutations of KRAS
and BRAF in primary and matched metastatic sites of colorectal cancer. _J Clin Oncol_ 26: 4217–4219 Article Google Scholar * Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ,
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colorectal cancer. _N Engl J Med_ 359: 1757–1765 Article CAS Google Scholar * Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E,
Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A (2009) PTEN expression and KRAS mutations on primary tumors and metastases in
the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. _J Clin Oncol_ [E-pub ahead of print] * Molinari F, Martin V, Saletti P, De Dosso S,
Spitale A, Camponovo A, Bordoni A, Crippa S, Mazzucchelli L, Frattini M (2009) Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic
sites may be clinically relevant. _Br J Cancer_ 100: 1087–1094 Article CAS Google Scholar * Santini D, Loupakis F, Vincenzi B, Floriani I, Stasi I, Canestrari E, Rulli E, Maltese PE,
Andreoni F, Masi G, Graziano F, Baldi GG, Salvatore L, Russo A, Perrone G, Tommasino MR, Magnani M, Falcone A, Tonini G, Ruzzo A (2008) High concordance of KRAS status between primary
colorectal tumors and related metastatic sites: implications for clinical practice. _Oncologist_ 13: 1270–1275 Article CAS Google Scholar Download references AUTHOR INFORMATION AUTHORS
AND AFFILIATIONS * Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano, Italy I Floriani & V Torri * U.O. Oncologia Medica, Università Campus Biomedico,
Roma, Italy D Santini * U.O. Oncologia 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy C Cremolini, A Falcone & F Loupakis Authors * I Floriani View author
publications You can also search for this author inPubMed Google Scholar * D Santini View author publications You can also search for this author inPubMed Google Scholar * V Torri View
author publications You can also search for this author inPubMed Google Scholar * C Cremolini View author publications You can also search for this author inPubMed Google Scholar * A Falcone
View author publications You can also search for this author inPubMed Google Scholar * F Loupakis View author publications You can also search for this author inPubMed Google Scholar
CORRESPONDING AUTHOR Correspondence to F Loupakis. RIGHTS AND PERMISSIONS From twelve months after its original publication, this work is licensed under the Creative Commons
Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Reprints and permissions ABOUT THIS
ARTICLE CITE THIS ARTICLE Floriani, I., Santini, D., Torri, V. _et al._ Do we need biopsies of metastases for colorectal cancer patients?. _Br J Cancer_ 101, 374–375 (2009).
https://doi.org/10.1038/sj.bjc.6605131 Download citation * Published: 07 July 2009 * Issue Date: 21 July 2009 * DOI: https://doi.org/10.1038/sj.bjc.6605131 SHARE THIS ARTICLE Anyone you
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