Sabato 27 ottobre 2012 - Pacini Editore

RElaziONi
“gold-standard panel”. Information regarding specific molecular
abnormalities of neoplastic cells is necessary in order
to assess the eligibility of Patients to specific “targeted” therapies.
New strategies are currently under evaluation to define
simplified diagnostic charts based on morpho-molecular techniques
useful to detect and quantify abnormalities in target
pathways. FISH analysis is the gold-standard technique for
evaluate the presence of gene translocations, amplifications,
gains and losses (e.g. FISH analysis for ALK translocation,
FGFR1 gene amplification). New antibodies can provide better
evaluation of target-protein expression (e.g. ALK). The
availability of mutation-specific monoclonal antibodies (e.g.
specific for BRAF V600E mutation) can represent a promising
tool in future studies. BRAF and C-MET genes are going
to be promising biomarkers, selected for new clinical trials.
Co-targeting more molecular pathways such as pi3k–Akt,
Ras–Erk, T790M, and c-Met, together with ErbB receptors,
may produce anticancer effects that are more optimal.
An extremely important key-point will be to understand the
driven receptor regulators involved in receptor degradation or
recycling. An ubiquitin lipase c-Cbl involved in internalization
and degradation of the epidermal growth factor receptor
(egfr) is frequently mutated or lost in lung cancer and stressactivated
kinases such as p38 have been implicated in egfr
recycling and endosomal accumulation. Those events may
contribute to resistance to antibody or tyrosine kinase inhibitors
in the treatment of NSCLC. Overall, co-targeting key
pathways involved in receptor recycling and receptor activity
may increase treatment efficacy and decrease the development
of tumour resistance.
Since the 1980s, chemotherapy for patients with non-smallcell
lung cancer has been shown to provide a small improvement
in survival. In the early 1990s, platinum-based regimens
became the treatment of choice. In 2002, the Eastern Cooperative
Oncology Group 1594 clinical trial showed that there was
no overall survival difference among four common chemotherapy
regimens used in non-small-cell lung cancer. It was
not until 2006 when the introduction of biologic agents into
the field of lung cancer improved, for the first time ever, median
overall survival beyond 1 year. Nowadays, we recognize
that there are differences between all histological subtypes
of non-small-cell lung cancer in terms of their response to
specific agents. All these plus the introduction of molecular
medicine have resulted in the identification of markers for
prognosis and prediction in lung cancer.
ALK
In a subset of patients with NSCLC, the anaplastic lymphoma
kinase (ALK) and echinoderm microtubule-associated protein
like 4 (EML4) gene have been recently found to undergo
fusion as a result of an inversion on the short arm of chromosome
2 resulting in the novel oncogene EML4-ALK. This
gene rearrangement occurs largely independent from EGFR or
K-Ras mutations. Patients with this fusion oncogene tend to be
younger, have adenocarcinoma with acinar histology, and be
never or light smokers. The overall incidence of EML4-ALK
rearrangement has been reported to be 4% - 7%. Patients
harboring the fusion oncogene were retrospectively studied
to examine its effect on both cytotoxic chemotherapy and
tyrosine kinase inhibitor therapy response. When comparing
those who did and did not harbor the EML4-ALK fusion oncogene,
there were no differences in response rates or time to
progression in those treated with platinum-based combination
therapy, whereas there was no clinical response and a time to
progression of 5 months for those treated with EGFR TKIs.
While these patients appear to be resistant to EGFR TKIs
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such as erlotinib and gefitinib, the small molecule tyrosine
kinase inhibitor crizotinib has shown activity against cell lines
containing the EML4-ALK fusion oncogene. A Phase II trial
of NSCLC patients who harbored EML4-ALK demonstrated
a radiographic response rate of 57% and a disease control rate
of 87% at eight weeks after receiving crizotinib 250 mg twice
daily. Progression free survival at six months had an estimated
probability of 72%. These results have led to a phase III trial
comparing crioztinib to standard, single-agent docetaxel or
pemetrexed in EML4-ALK positive NSCLC patients with
metastatic disease who have received one prior line of chemotherapy
(NCT00932893).
EGFR
Several studies have shown that EGFR over-expression, as
determined by immunohistochemistry, appears to confer
a poor prognosis in patients with NSCLC. However, these
results have not been confirmed in other studies. Given the
conflicting data that are currently available, EGFR does not
have a clear role as a prognostic marker in NSCLCs. With the
recent advances in the development of EGFR-targeted therapy,
however, it has become increasingly important to define
predictive markers that identify a subset of patients who are
most likely to benefit from EGFR-TKI therapy. Since particular
subtypes of NSCLC (squamous carcinomas, mucinous adenocarcinomas)
do not usually harbor EGFR mutations, these
histological subtypes can be defines as predictive, especially
when validated by refined immunohistochemical profiles.
FGFR1
Non-small cell lung carcinoma cell line harboring focal amplification
of FGFR1 is dependent on FGFR1 activity for
cell growth, as treatment of this cell line either with FGFR1specific
shRNAs or with FGFR small molecule enzymatic
inhibitors leads to cell growth inhibition. A significant subset
of squamous cell lung cancer usually show gains of FGFR-1.
3q
Squamous cell lung carcinoma usually show 3q gains and is
a sensitive marker of squamous cell differentiation. The locus
specific 3q region harbours several targeted genes and may
show promising value as predictiveness to new inhibitors.
Fattori predittivi morfo-molecolari nel
carcinoma renale
G. Martignoni, M. Brunelli, D. Segala
Università di Verona, Dipartimento di Patologia e Diagnostica, Verona
Renal cell carcinoma (RCC) accounts for about 3% of all new
cancer cases and the incidence rates for all stages have been
steadily rising over the last three decades. Approximately
one-third of patients present with metastatic disease at the
initial diagnosis and more than 40% of patients will eventually
die from their cancer. Despite the introduction of new treatment
regimens, surgical resection remains the only curative
therapy for RCC. However, up to 50% of patients undergoing
nephrectomy for clinically localized RCC will develop local
recurrence or distant metastasis.
RCC comprises a heterogeneous group of epithelial tumors
with various cytogenetic and molecular abnormalities and different
histological features. The taxonomy of renal epithelial
neoplasms has evolved greatly over the past two decades.
Landmark consensus conferences held in Heidelberg (1996)
and Rochester (1997) laid the foundations for our modern
classification system. Detailed morphological studies incorporating
contemporary immunohistochemical and molecular