Clinical Oncology

[Molecular profi les in therapeutic strategy]

PETÁK István, SCHWAB Richárd

MAY 20, 2014

Clinical Oncology - 2014;1(02)

[In 2013, 10 years after the completion of the human genome, the cancer genome project has identifi ed almost all possible cancer genes, which could be responsible for the malignant transformation and progression. These genes are called „driver” genes, and the pathogenic mutations to be „driver” mutations. The census of „driver genes” in 2013 counted 138 genes and 1.5 million mutations. The situation is further complicated by the fact that up to 8 „driver” gene can be activated simultaneously in the same tumor, furthermore, the profi le may change during tumor growth and metastatization. 2013 was a turning point also because several targeted therapies were registered. Currently there are about 30 targeted drugs in clinical use and more than 200 targeted compounds in clinical development. This means that in 3-4 years the number of drugs will at least double. Most of the current patients can only access these compounds in clinical trials. But, patient already benefi t signifi cantly more even from phase I clinical trials, if they are selected based on the molecular profi le of the tumor. Fortunately, the advancements of next generation sequencing technologies provide the opportunity to identify all „driver” genes, - the whole molecular profi le, - in the patient’s tumor for the cost of one month targeted therapy. But the information generated can be only used in clinical practice if the results are processed by „molecular info-bionics”.]



Further articles in this publication

Clinical Oncology

[Management of prostate cancer today]

PETRÁNYI Ágota Eszter, BODROGI István

[Although metastatic prostate cancer remains an incurable disease, the past years witnessed an extraordinary progress in the management of patients with castration resistant prostate cancer (CRPC). Development of novel agents that modulate the androgen receptor pathway, growth factor signaling pathways, immune functions and bone targeting machinery has been the focus of therapeutic strategies because of its signifi cance in the biology of prostate cancer progression. The arrival of several new agents — cabazitaxel, abiraterone acetate, enzalutamide, sipuleucel-T, denosumab and radium-223 — is changing the options and management of patients with metastatic castration resistant prostate cancer (mCRPC). Prostate cancer is a heterogeneous disease, therefore, in treatment must be considered the clinical characteristics of the disease as it manifests in an individual patient. The aim of this review is to summarize the most important new fi ndings for metastatic prostate cancers according to the different molecular pathways and to discuss their potential role on the management of this disease.]

Clinical Oncology

[EGFR family and gynecologic cancers]


[The HER family of receptor tyrosine kinases may potentially play an important role in gynecologic malignancies. Amplifi cation and overexpression of various HER family members including epidermal growth factor receptor (EGFR/HER1) and HER2 have been reported in epithelial ovarian cancer and endometrial carcinoma as well as in cancer of the uterine cervix. High expression of EGFR has been associated with poor prognosis independent from histiotype while HER2 expression may be more histotype dependent. This review summarizes the clinical experience with anti EGFR/HER2 directed monoclonal antibody therapy in the three major gynecologic cancer types to date.]

Clinical Oncology

[Radiological response evaluation of targeted therapy]


[The objective assessment of the changes in the tumor burden along with cancer therapy has essential importance. Recently, the quantitative evaluation of the radiological tumor response was undergone several changes. For conventional chemotherapy of solid tumors the standard procedure has been RECIST since 2000. The targeted therapies trigger other pathophysiological changes in the cells than the cytotoxic agents, accordingly the morphological changes show a new picture. Therefore the targeted therapies require a new evaluation system, that takes into consideration not only the tumor size, but other changes as well, the changes of attenuation that corresponds with the proportion of the viable cells. In case of the targeted therapies in substantial clinical was experienced even without signifi cant morphological changes in the tumour size. As a consequence, the traditional, size-based criteria system can underestimate the effi ciency of the new types of treatments. To eliminate this problem new evaluation systems were created taking the tumortypes and treatment protocolls into consideration. The estimation of the early tumor response to targeted therapy also has high importance. In assessment of the response functional imaging methods are used more frequently. The role of PET has already been defi ned in numerous tumortypes, however the determination of the position of some promising functional examinations still require further studies.]

Clinical Oncology

[Neoadjuvant therapy in breast cancer – an update]

KAHÁN Zsuzsanna, RUSZ Orsolya, UHERCSÁK Gabriella, NIKOLÉNYI Alíz

[Traditionally, neoadjuvant systemic therapy (NST) serves as treatment of advanced breast cancer to achieve technical operability by resulting in tumor regression. Nowadays, NST is advantageous in all cases if adjuvant systemic therapy is needed, since the in vivo study of its effect provides possibility for the estimation of prognosis, the treatment may be modifi ed according to the therapeutic response, the systemic therapy starts earlier as compared to adjuvant therapy, and fi nally, it may result in the reduction of surgical and radiotherapeutical radicality. The type of NST should be selected on the basis of tumor features refl ecting treatment sensitivity. In case of chemosensitive cancers, chemotherapy is taxane- and anthracycline-based, and the planned dose should be delivered prior to surgery. In HER2-positive cancers, the addition of an anti-HER2 agent doubles the rate of pathological complete regressions. In hormone-sensitive tumors, the standard neoadjuvant endocrine therapy consists of an aromatase inhibitor (postmenopause), or tamoxifen or an aromatase inhibitor combined with an LHRH analog (premenopause) for 4-8 months that is continued following the surgery in the adjuvant setting. For the early evaluation of the effect of NST, serial tumor biopsy or imaging studies (MRI, PET) seem promising. Sentinel lymph node biopsy around the NST should be practiced with prudence; it may warrant the avoidance of axillary blockdissection in some cases. For the design of radiotherapy, the initial stage and the degree of regression are considered.]

Clinical Oncology

[Complex medical treatment of non small cell lung cancer - new challenges, new possibilities]


[Previously, it was suffi cient to differentiate small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC) in the decision making process for the therapeutic strategy of lung cancer. Recently, the situation has changed signifi cantly. There are only few new cytotoxic agents, and platinum based chemotherapy remains the standard combination in the treatment of NSCLC. In the last decade no further development has been discovered in the treatment of SCLC. However, the new molecular diagnostic and therapeutic possibilities have altered dramatically the management of NSCLC. NSCLC could not be considered as a separate entity anymore. The complex medical treatment of advanced NSCLC includes the molecular target driven therapies the histopathological subtype based chemotherapies and the immunotherapy. Immunotherapy is a new challenge in the treatment of lung cancer. Tumor-vaccines, inhibition of immune checkpoint pathways are investigated in clinical trials. Ongoing studies will defi ne the true effi cacy of these drugs. The complex combination of genes, proteins, different molecular pathways and patients characteristics, called “panomics”, are all parts of the treatment of lung cancer in the daily clinical practice.]

All articles in the issue

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Clinical Oncology

[Management of renal cancer]

MARÁZ Anikó, SZŰCS Miklós

[Targeted anti-cancer agents are used as standard therapies in case of advanced or metastatic clear cell renal carcinoma. Neovascularisation plays an important role in the progression of hypervascularized cancers. Vascular endothelial growth factor (VEGF) is the key molecule in this mechanism. Most of the registered agents inhibit the angiogenesis by blocking the VEGF signalling pathway. It can occur if an antibody binds to the VEGF, so the linkage to the receptor is blocked. This happens in case of bevacizumab. Another mechanism is the inhibition of the intracellular compound of VEGF receptor by tyrosine kinase inhibitors (TKI). Sorafenib, sunitinib, pazopanib and axitinib belong to this group. Other well-known mechanism of action is the inhibition of mammalian target of rapamycin (mTOR) receptor, like temsirolimus and everolimus. Based on randomised controlled trials sunitinib, pazopanib or IFNα-bevacizumab combination is recommended fi rst-line according to the international recommendations in case of good and moderate prognosis. For patients with poor prognosis temsirolimus is the standard therapy. In second-line, after ineffective cytokine therapy, sorafenib, pazopanib and axitinib are the supported options. If TKI is ineffective, everolimus or axitinib can be administered. In the latest recommendations sorafenib is another possible option (off label). After two TKIs, only everolimus is registered for third-line therapy. Life expectancy of patients can further be improved as the number of targeted drugs increases, more effective agents appear and as appropriate sequences and their benefi cial effects are recognised.]

Clinical Oncology

[The use of NGS in oncology in diagnostic setting]


[Today the information could be the basis of further development by collecting, saving, structuring and analyzing them. Inside the living organism and inside viruses the biochemical storage system was evolved. The linear coding inside macromolecular structures could create and store a series of building block combinations along the chain structure. Those chemical structures are the so called information coding macromolecules, for example, the polypeptides and nucleic acids. Analysis of the genetically coded functionalities of tumor cells has a great impact in the oncological setting. The connected functions of inherited or acquired alterations inside the tumor cell clones are the main contributors of tumor evolution and surviving, although provide a way to target possible mechanism and touch points. Today the oncodiagnostic use of next generation sequencing technology focus on tumor evolution and tumor surviving connected gene set analysis. This kind of gene panel analysis connected to NGS technology is enough enforced - enforced enough - to reach the diagnostic level, but one still need to take care about the quality and standardization to meet the IVD conditions.]

Clinical Oncology

[Cell cycle as therapeutic target – CDK4/6 inhibition]


[One of the most important decision of a cell: to live or die. If survival is the choice, there are three options: proliferate, to stay in sleeping state for a while, or differentiate in order to perform its specifi c function. These decisions are under a very strict molecular regulation infl uenced by internal and external factors. Tumor cells more and more disregard the regulations, and move into independency for a continuous proliferation, which has a very similar program in normal and tumor cells. The main route towards mitosis is the cell cycle, under the supervision of positive and negative regulators, forming checkpoints, telling to the cell - under the infl uence of mitogenic signals - to go or to stop. The most critical checkpoint is at the border of G1 and S phases where the main players are cyclinD, CDK4/6 and RB1. It turned out that the best targets to inhibit cell proliferation are the CDKs, but this approach, when used unselected targets, was unsuccessful due to the toxicity. To improve the clinical results, the selection of CDK4/6 as a therapeutic target seems to fulfi l most of the hopes. Today three drugs are the most promising: palbociclib (with an acceptance by FDA and EMA to treat breast cancer patients), abemaciclib and ribociclib (underclinical trials). Now, most of the data concern breast cancer, especially the combinations of CDK4/6 inhibitors and endocrine therapy, but many other malignancies are studied (e.g. liposarcoma, mantel cell lymphoma, melanoma, renal cancer, lung cancer, pancreatic cancer, ovarian cancer, teratomas etc.). The key points are the side-effects, the most frequently observed is neutropenia, but so far it is managed without serious toxicity.]

Clinical Oncology

[MEK and ERK - against RAS and RAF ]


[In most cases, the targeted therapy is able to produce clinical response, but after a certain interval it turns to be ineffective due to secondary resistance against the therapy. One of the most demanding challenge in treatment of cancer is to prevent or inhibit such resistance, which could have several forms, e.g. appearance of new driver activating mutations in the treated tumor, clon(s) existed in minority with different mutations (targets) can grow and replace the temporarely sensitive tumor cells (on the basis of tumor heterogeneity); another pathway takes over the role in cancer progression, etc. Such problems are very common in the RAS-RAF-MEK-ERK pathway. These are very important proteins to collect extracellular signals in order to regular different cell functions, especially proliferation. With activating mutations make the RAS-pathway independent from the normal .regulation. To inhibit the consequence of the mutations is largely still an unsolved problem, with few exceptions (e.g. inhibition of BRAF mutations). Theoretically, the inhibition of the next steps of the pathway, MEK and ERK, may stop the pathologically activated signals, partly due to their inhibition, and party to effi ciently decrease the feedback inside the pathway. This review discusses aspects of this possibilities, especially to overcome resistance and prolong the effectiveness of therapy.]

Clinical Oncology

[Oncogene-targeted therapy of non-small cell lung cancer]


[Lung cancer is the leading cause of cancer related deaths thus presenting one of the main public health related issues globally. Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. Historically, platinum-based chemotherapy was the mainstay of systemic therapy for NSCLC, leading to median survival rates of only 8 to 10 months. Major improvement in the treatment of NSCLC was made through the identifi cation of key genetic aberrations (oncogene drivers) that drive tumor initiation, maintenance and progression and development of highly effective oncogene- directed therapies. Oncogene-directed therapies against epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in conjunction with well-validated methods for the detection of their targets already represent a standard care of advanced NSCLC patients. Encouragingly, in the recent years a number of additional genetic aberrations have emerged as novel molecular targets with potential therapeutic implications in lung cancer. In this review a comprehensive overview of standard oncogene-directed therapies of advanced NSCLC is provided, challenges in overcoming resistance to those therapies are discussed and novel oncogene-directed therapies under development are briefl y presented.]