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PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients
Open accessAbstract
To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy (P<0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR (P<0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.
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“PTEN inactivation (usually assessed as lack of protein expression) has been associated with nonresponsiveness to anti-EGFR moAbs in mCRC patients in several studies [19, 73, 75, 76]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [75]
In the citing paper
“Patients with PTEN-negative status showed a worse response rate and shorter progression-free survival (PFS) than those with PTEN-positive status [106, 108, 109].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [109]
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Cost-Effectiveness of Cetuximab for Advanced Esophageal Squamous Cell Carcinoma
Janmaat, V. T., Bruno, M. J., Polinder, S., Lorenzen, S., Lordick, F., Peppelenbosch, M. P., & Spaander, M. C. W. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153943 · Cited by 9
“Tumor specific EGFR downstream signaling mutations in KRAS, [8, 31] BRAF, [31, 32] PTEN, [33] and PIK3CA [31, 34] cause reduced benefit of cetuximab therapy in colon carcinoma patients.”
BackgroundPrice, T. J., Tebbutt, N. C., Karapetis, C. S., Segelov, E., Pavlakis, N., Cunningham, D., Sobrero, A. F., Haller, D. G., & Shapiro, J. D. (2010) · Clinical Colorectal Cancer · doi:10.3816/ccc.2010.n.001 · Cited by 9
Sesboüé, R., Pessot, F. L., Fiore, F. D., & Frébourg, T. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.570 · Cited by 10
“…several studies have shown that there is a clear association between EGFR amplification and clinical response, with percentages of responders varying from 10 up to 89% among patients displaying EGFR amplification (Moroni et al, 2005; Frattini et al, 2007; Cascinu et al, 2008; Razis et al, 2008).”
BackgroundIseki, Y., Shibutani, M., Maeda, K., Nagahara, H., Fukuoka, T., Ikeya, T., MATSUTANI, S., Kimura, K., Toyokawa, T., Amano, R., et al. (2016) · Anticancer Research · doi:10.21873/anticanres.11084 · Cited by 8
KRAS mutational analysis for colorectal cancerApplication: Pharmacogenomic
Wang, G., Kelley, R. K., & GAPPNet (2010) · PLoS Currents · doi:10.1371/currents.rrn1175 · Cited by 8
Ágoston, E. I., Micsík, T., Ács, B., Fekete, K., Hahn, O., Baranyai, Z., Dede, K., Bodoky, G., Bursics, A., Kulka, J., et al. (2016) · Diagnostic Pathology · doi:10.1186/s13000-016-0508-0 · Cited by 8
“A high concordance of PTEN expression levels in matched primary and metastatic CRCs was found and these expression levels significantly correlated with survival [27, 28].”
BackgroundInfluentialMolecular testing to optimize therapeutic decision making in advanced colorectal cancer.
Semrad, T. J., & Kim, E. J.-H. (2016) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2078-6891.2015.094 · Cited by 7
“In small retrospective series of 27 patients with CRC who received cetuximab as part of their therapy, 10 of 16 patients with intact PTEN had objective response in contrast to none of the 11 patients with loss of PTEN (68).”
BackgroundResultLoupakis, F., Cremolini, C., Fontanini, G., Stasi, I., Salvatore, L., & Falcone, A. (2009) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834009348984 · Cited by 8
“…anti-EGFRs has been suggested in a small series of 27 patients, treated with cetuximab alone or associated with chemotherapy, where none of 11 patients with loss of PTEN responded in comparison with 10 out of 16 patients in which the protein was normally expressed (p< 0.001) [Frattini et al. 2007].”
ResultInfluentialThe endothelin axis in the metastatic process of colon carcinoma.
Sørby, L. A., Kleiveland, C. R., Andersen, S. N., Bukholm, I., & Jacobsen, M. (2011) · PubMed · Cited by 8
Yu, A., Zhang, J., Mei, Y., Zhong, H., Chen, S., & Song, Q. (2020) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2019.0269 · Cited by 8
“Its disruption has been associated with the occurrence and development of human tumors (Myers et al. , 1998; Frattini et al. , 2007).”
Evolving role of cetuximab in the treatment of colorectal cancer.
Schuch, G., Kobold, S., & Bokemeyer, C. (2009) · PubMed Central · Cited by 8
Stücheli, S., Araya, S., Ercan, C., Moser, S. O., Gallon, J., Jenö, P., Piscuoglio, S., Terracciano, L., & Odermatt, A. (2022) · Cancers · doi:10.3390/cancers14133074 · Cited by 6
“In colorectal cancer, the response of EGFR to treatment with cetuximab is dependent on PTEN status, and in PC-3 cells, restoration of PTEN expression improved response to cetuximab-induced apoptosis and the inhibition of cell proliferation [48,49].”
BackgroundMolecular testing in colorectal cancer
Thomas, J. S., & Shi, C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-822824-1.00018-3 · Cited by 7
Predictive and prognostic biomarkers in gastrointestinal tract tumours
Nowak, K. M., & Chetty, R. (2024) · Pathology · doi:10.1016/j.pathol.2023.12.412 · Cited by 7
Lim, S. H., Lee, S.-Y., Hong, J. Y., Lee, J., & Kim, S. T. (2024) · Translational Cancer Research · doi:10.21037/tcr-24-20 · Cited by 8
“Concomitant occurrence of BRAF mutation and PTEN loss is considered a predictive marker for poor prognosis of cetuximab treatment (22-24).”
Lockhart, C. (2009) · OncoTargets and Therapy · doi:10.2147/ott.s3849 · Cited by 7
“In CRC, majority of the mutations (70%) occur in codon 12, with 30% occurring in codon 13.(59) Mutations of the KRAS gene may activate downstream signal transduction leading to resistance to upstream inhibition of the EGFR by monoclonal antibodies.”
Review: Medical treatment of advanced colorectal cancer in 2009
Grothey, A. (2009) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834009343302 · Cited by 7
“Further predictive biomarkers for the activity of EGFR antibodies in CRC have been identified in retrospective studies, in which the activity of cetuximab was correlated with the maintained expression of phosphatase and tensin homolog (PTEN) and higher levels of the EGFR ligands, amphiregulin and epiregulin [Loupakis…”
BackgroundIntegrating Biomarkers Into Clinical Decision Making for Colorectal Cancer
Wilson, P. M., & Lenz, H. (2010) · Clinical Colorectal Cancer · doi:10.3816/ccc.2010.s.003 · Cited by 7
New and potential clinical applications ofKRASas a cancer biomarker
Kriegshäuser, G., Auner, V., & Zeillinger, R. (2010) · Expert Opinion on Medical Diagnostics · doi:10.1517/17530059.2010.510512 · Cited by 7
Tsoukalas, N., Tzovaras, A. A., Tolia, M., Kostakis, I. D., Papakostidi, A., Pistamaltzian, N. F., & Ardavanis, A. (2012) · PubMed · Cited by 6
Ham-Karim, H. A., Negm, O. H., Ahmad, N., & Ilyas, M. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03020-7 · Cited by 6
Pfeiffer, P., Qvortrup, C., & Bjerregaard, J. K. (2009) · PubMed Central · Cited by 6
Prognostic markers in colorectal pathology: is morphology enough?
Wang, L. M., & Sheahan, K. D. (2011) · Diagnostic histopathology · doi:10.1016/j.mpdhp.2011.06.016 · Cited by 6
Resistance--the true face of biological defiance
Emami-Shahri, N., & Hagemann, T. (2011) · Rheumatology · doi:10.1093/rheumatology/ker326 · Cited by 6
Cho, B. C., Kim, J. H., Soo, R. A., & Yang, C.-H. (2009) · Yonsei Medical Journal · doi:10.3349/ymj.2010.51.1.1 · Cited by 6
Deyati, A., Bagewadi, S., Senger, P., Hofmann‐Apitius, M., & Novac, N. (2015) · Scientific Reports · doi:10.1038/srep08013 · Cited by 6
Advances in the Treatment of Metastatic Colorectal Cancer
Kurkjian, C. D., & Kummar, S. (2010) · Disease-a-Month · doi:10.1016/j.disamonth.2009.12.005 · Cited by 6
Picker, A., & Jackson, D. (2011) · Expert Review of Molecular Diagnostics · doi:10.1586/erm.11.45 · Cited by 6
Mishra, R. K., Ahmad, A., Vyawahare, A., Kumar, A., & Khan, R. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200616133814 · Cited by 6
Integration of Anti-Epidermal Growth Factor Receptor Therapies With Cytotoxic Chemotherapy
Serrano, C., Markman, B., & Tabernero, J. M. (2010) · The Cancer Journal · doi:10.1097/ppo.0b013e3181e07670 · Cited by 5
miRNAs as Modulators of EGFR Therapy in Colorectal Cancer
Pereira, D. M., & Rodrigues, C. M. P. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-02771-1_9 · Cited by 5
de Bruin, L. B., Wachters, J. E., Schrijvers, M. L., Slagter‐Menkema, L., Mastik, M. F., Langendijk, J. A., van der Wal, J. E., Schuuring, E. M. D., & van der Laan, B. F. A. M. (2019) · Laryngoscope Investigative Otolaryngology · doi:10.1002/lio2.272 · Cited by 5
“Frattini et al showed in a series of colorectal cancer patients that loss of PTEN expression by immunohistochemistry distinguished responder from nonresponder patients to cetuximab.(43) Studies in prostate cancer cells showed a comparable relation and PTEN reintroduction restored the cell response to cetuximab.”
ResultMolecular Testing in Colorectal Cancer
Thomas, J. S., & Shi, C. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800886-7.00024-8 · Cited by 5
Han, C., Ma, J.-T., Li, F., & Zou, H. (2011) · Journal of Cancer Therapy · doi:10.4236/jct.2011.25090 · Cited by 6
Laurent‐Puig, P., Lièvre, A., & Blons, H. (2009) · European Journal of Cancer · doi:10.1016/s0959-8049(09)70063-2 · Cited by 6
Metadata
- Authors
- Frattini, M., Saletti, P., Romagnani, E., Martin, V, Molinari, F., Ghisletta, M., Camponovo, A., Etienne, L. L., Cavalli, F., & Mazzucchelli, L.
- Affiliations
- Istituto Cantonale di Patologia (CH)
- Ospedale San Giovanni Bellinzona (CH)
- Corresponding author
- Frattini, M
- Venue
- British Journal of Cancer
- Published
- 2007-10
- Volume
- 97
- Issue
- 8
- Pages
- 1139-1145
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2360431
- OpenAlex
- W2100589633
- Cited by
- 540
- References
- 31
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 14 · 2020: 16 · 2019: 14 · 2018: 9 · 2017: 15 · 2016: 20 · 2015: 30 · 2014: 38 · 2013: 38 · 2012: 63
- FWCI
- 33.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Oncosuisse
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- PTEN loss, cetuximab, metastatic colorectal cancer, EGFR overexpression, EGFR amplification, KRAS mutation, chromosome 7 polysomy, drug response prediction, predictive biomarkers
- MeSH terms
- Cetuximab, Adult, Aged, Algorithms, Antibodies, Monoclonal, Antineoplastic Agents, Chromosomes, Human, Pair 7, Female, Gene Amplification, Humans, Immunohistochemistry, Male, Middle Aged, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression, Proto-Oncogene Proteins p21(ras), In Situ Hybridization, Fluorescence, ras Proteins, Drug Resistance, Neoplasm, PTEN Phosphohydrolase, Antibodies, Monoclonal, Humanized, ErbB Receptors
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