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ABSTRACT: Personalized medicine emphasizes the practice of considering individual patient characteristics as opposed to that centered on standards derived from epidemiological studies which, by definition, do not take into account the variability of individuals within a given population. When applied to oncology, personalized medicine is an even more complex concept because it extends the variability beyond the individual patient to the individual tumor. Indeed, the great genotypic and phenotypic variability (both in primary and metastatic sites of cancer) the development of targeted therapies, and the growing availability of biological assays complicate the scenario of personalized medicine in the oncological field. In this paper we review the results of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy in metastatic colorectal cancer (mCRC) in the context of tumor biology, delineating the future prospects of patient-tailored medicine in this area. In particular, we deal with EGFR inhibition by Cetuximab, a chimeric mouse human IgG1 mAb, and panitumumab, a fully human IgG2 mAb. We discuss the clinical impact of anti-EGFR mAbs on wild-type (WT) KRAS mCRC, also taking into account the feasibility of novel multi-marker approaches to treatment decision-making, aimed at increasing the predictive power of pre-therapy biomarkers. Experimental topics and fields of ongoing research, such as targeting microRNAs (miRNAs) with novel anticancer drugs and epigenetics in CRC are also addressed.
Current cancer drug targets 03/2012; 12(4):316-28. · 5.13 Impact Factor
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G. Zoppoli,
E. Moran,
D. Soncini,
M. Cea,
A. Garuti, I. Rocco,
G. Cirmena,
V. Grillo,
L. Bagnasco,
G. Icardi,
F. Ansaldi,
S. Parodi,
F. Patrone,
A. Ballestrero,
A. Nencioni
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ABSTRACT: Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what is observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.
Current Cancer Drug Targets 02/2010; 10(2):168-175. · 4.33 Impact Factor
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A Ballestrero,
G Cirmena,
A Dominietto,
A Garuti, I Rocco,
M Cea,
E Moran,
A Nencioni,
M Miglino,
A M Raiola,
A Bacigalupo,
F Patrone
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ABSTRACT: Molecular monitoring of the BCR-ABL1 transcript in chronic myelogenous leukemia (CML) using quantitative real-time PCR (RQ-PCR) can be performed using either bone marrow (BM) or peripheral blood (PB). However, a recent report by Stock et al. [International Journal of Oncology 28 (2006) 1099] questioned the reliability of PB samples for BCR-ABL1 detection as performed by RQ-PCR. We report a study on 114 CML patients who received allogeneic stem cell transplantation (ASCT), and who were monitored by RQ-PCR using paired samples of BM and PB: the total number of determinations was 428, with a median follow-up after transplant of 8 years. BCR-ABL1 transcript was undetectable or <0.1%, in 106 (49.57%) and 62 (29%) paired determinations, respectively. BCR-ABL1 was >0.1% in 36 (16.8%) paired determinations and was discordant in 10 (4.7%). Agreement between PB and BM results was quantified by the kappa test (k = 0.85; 95% CI 0.76-0.94). This study shows that BCR-ABL1 RQ-PCR monitoring of CML patients after ASCT with PB is concordant with BM in 95.3% of cases, and thus may be used to monitor the disease. This may be relevant when discussing both quality of life issues and the need for post-transplant monitoring with the patient.
International journal of laboratory hematology 11/2009; 32(4):387-91. · 1.30 Impact Factor
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EUROPEAN JOURNAL OF HUMAN GENETICS. 01/2009; 17/supplement 2.
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ABSTRACT: In cancer patients, the ability to detect disseminated tumour cells in peripheral blood or bone marrow could improve prognosis and consent both early detection of metastatic disease and monitoring of the efficacy of systemic therapy. These objectives remain elusive mainly due to the lack of specific genetic markers for solid tumours. The use of surrogate tissue-specific markers can reduce the specificity of the assays and give rise to a clinically unacceptable false-positive rate. Mammaglobin (MAM) and maspin are two putative breast tissue-specific markers frequently used for detection of occult tumour cells in the peripheral blood, bone marrow and lymph nodes of breast cancer patients. In this study, it was evaluated whether MAM and maspin gene expression may be induced in the normal blood and bone marrow cells exposed to a panel of cytokines, including chemotactic factors (C5a, interleukin (IL)-8), LPS, proinflammatory cytokines (TNF-alpha, IL-1beta) and growth factors (IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor). The experimental data show that all cytokines included in the panel, except for IL-8, were able to induce maspin expression; on the contrary, MAM gene was never induced. These results suggest that MAM is more specific than maspin and that the possible interference of cytokines should be taken into account in interpreting molecular assays for detection of isolated tumour cells.
British Journal of Cancer 06/2005; 92(10):1948-52. · 5.04 Impact Factor
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ABSTRACT: Maspin is a molecular marker used for the detection of contaminating breast carcinoma (BC) cells in peripheral blood and lymph nodes. However, its specificity has been questioned recently. The objective of this study was to verify the specificity of this marker and to determine the incidence of positive bone marrow results in patients with BC who are eligible for high-dose chemotherapy (HDT) both in early and advanced disease stages and before and after treatment.
Bone marrow specimens from 41 patients with BC as well as from 35 normal volunteers and 17 patients with hematologic tumors were examined for maspin transcript expression by a modified nested reverse transcriptase-polymerase chain reaction technique.
Maspin transcript was found in all normal and neoplastic breast tissues and in none of the 35 normal bone marrow specimens (specificity, 100%; 95% confidence interval, 90-100%). However, the transcript was found in 40% of the bone marrow samples from patients with hematologic malignancies. Thus, this marker appears very specific for discriminating between normal controls and patients with BC, but it cannot be considered disease specific. Among patients with BC, bone marrow was positive for the maspin transcript in 32% of patients with early-stage disease and in 75% of patients with metastatic disease before chemotherapy. After treatment, in 75% of patients with early-stage disease and in 50% of patients with metastatic disease, the bone marrow results became maspin negative.
On the basis of the current data, although it is not disease specific, maspin is a reliable marker for detecting bone marrow molecular disease in patients with BC and should be considered for prospective studies as a prognostic indicator and as an assay for monitoring residual disease.
Cancer 11/2001; 92(8):2030-5. · 4.77 Impact Factor
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ABSTRACT: The current treatment of chronic myelogenous leukemia (CML) is one of the most successful examples of molecularly targeted therapy in cancer. The identification of the fusion oncogene BCR-ABL allowed the discovery of small molecule inhibitors of its tyrosine kinase activity which, in turn, have literally revolutionized the treatment of this disease. However, large part of a successful clinical management of CML relies on appropriate diagnosis, molecular monitoring and identification of mutations potentially leading to drug resistance. These issues are discussed here together with an overview on how patients treated with tyrosine kinase inhibitors should be monitored.
Journal of B.U.ON.: official journal of the Balkan Union of Oncology 14(4):565-73. · 0.61 Impact Factor
