Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR-based therapy in patients with metastatic colorectal cancer.

UNLABELLED: Half of patients with KRAS wild-type colorectal cancer do not benefit from adding anti-epithelial growth factor receptor (EGFR) to standard chemotherapy regimens. This retrospective study was performed in 94 patients with metastatic colorectal cancer (mCRC) treated in the second line with cetuximab and chemotherapy. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in tumor cells was correlated with decreased median progression-free survival and overall survival (OS). These results highlight the potential role of STAT3 as a molecular target to optimize anti-EGFR therapies. BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in epithelial growth factor receptor (EGFR) signaling in a KRAS-independent manner. Phosphorylated STAT3 (pSTAT3) expression in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR-containing salvage chemotherapy has never been investigated. PATIENTS AND METHODS: : The first endpoint of this retrospective study was to evaluate the impact of pSTAT3 on the time to progression (TTP) in 94 patients with mCRC treated with anti-EGFR-based therapies in the second- or third-line setting between July 2004 and November 2009. The influence of pSTAT3 on objective response rate and overall survival (OS) was also reported. Nuclear expression of pSTAT3 status was evaluated by immunohistochemical tests on formalin-fixed and paraffin-embedded tumor samples obtained before therapy. RESULTS: Positive expression of pSTAT3 was observed in 24.5% of the tumor samples. The probability of achieving an objective response was 13% among patients with positive nuclear expression of pSTAT3 compared with 41% for patients displaying pSTAT3-negative tumors (P = .02). In a multivariate logistic regression model, high-grade skin rash, wild-type KRAS status, and negative pSTAT3 status significantly improved TTP and OS. CONCLUSION: These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker.

Discordance in early breast cancer for tumour grade, estrogen receptor, progesteron receptors and human epidermal receptor-2 status between core needle biopsy and surgical excisional primary tumour.

The aim of the present study was to compare the tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) status in the core needle biopsy (CNB) with those observed in the subsequent excisional primary tumour (EPT). All patients diagnosed with an early breast cancer in our University Hospital Center between January 1, 2005 and December 31, 2006 were included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy and cases with more than one tumour (multicentricity/multifocality tumours). Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed twice in CNB and in EPT. A total of 175 patients were assessed. The concordance between CNB and EPT for Grade, ER, PgR and HER2 status were 75.4% (p > 0.00001), 84% (p > 0.00002), 78.3% (p = 0.002) and 98.3% (p = 0.486) respectively. In conclusion CNB can be used with confidence for HER2 determination. For grade, PgR and ER due to substantial discordance results from CNB should be used with caution.

Response rates: a valuable signal of promising activity?

A main criterion to identify activity in phase II studies is the response rates achieved in a well-defined subset of patients. The response could be defined as a measure of tumor shrinkage. For 30 years, metric methods have been used to assess this response. The World Health Organization was the first organization to propose a unified definition for response status. Over time, the latter evolved and 10 years ago an international consensus panel proposed the Response Evaluation Criteria in Solid Tumors criteria. Although these guidelines for response assessment have limitations and biases, they have nevertheless been proven useful and advantageous. This article reviews those criteria and describes their use.

[Pemetrexed development in oncology]. / Perspectives de développement du pemetrexed en oncologie.

The pemetrexed disodium (Alimta), LY231514) is the first antifolate able to inhibit at the same time the synthesis of purins and pyrimidins. Many therapeutic tests were carried out in clinical situations where the methotrexate and the fluorouracil had been the proof of their effectiveness. It then showed an interesting activity in a great number of tumours but with very different profiles of tolerance according to the studies and pathologies. The explanation will come in 2001 by the description from the relation between the vitamin deficiencies among treated patients and occurred from toxicities. The two randomized studies carried out in the malignant pleural mesothelioma and the non small cell lung cancer made it possible to establish its utility and to record the pemetrexed in these clinical situations. Others axes of development remain possible, but the results are stanby or to confirm as in squamous-cell cancer in the head and neck and breast, digestive or urinary tracts cancer. In all the cases, the optimization of the pemetrexed in terms of amount/methods of administration and associations possible because of its profile of tolerance makes of it a molecule of chemotherapy with a future.