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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.

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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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