Reference Article: Cancer – The Missing Point
Gene expression profiling (GEP) can be a potent tool to determine genes and pathways that are abnormally expressed during carcinogenesis. Though these discoveries improve our understanding of molecular pathogenesis, they are able to also recommend novel therapeutic targets, present information about drug resistance pathways, and refine prognostic classifications.
A important problem in clinical oncology could be the heterogeneous response of histologically related tumors to treatment options just like cytotoxic chemotherapy. Using the exception of estrogen/progesterone receptor, and HER2 (c-erbB-2) expression in breast cancer (for hormonal therapy and trastuzumab, respectively) Cancer Research in Biotechnology Component II – Genetic Analysis , EGFR kinase domain mutations and genomic amplification in lung cancer (in EGFR targeted inhibitors gefitinib or erlotinib), and K-ras mutations in colon cancer (lack of response to EGFR-targeted antagonists), you’ll find no other single molecules which are clinically beneficial predictors of response validated for any kind of anticancer therapy.
Encouraging emerging data suggest that prediction of response to chemotherapy or biologically targeted agents might be feasible by analyzing gene expression profiles (GEPs). With rapid advances inside the DNA microarray technologies and additional sophisticated scientific studies, microarray analysis has started to produce strategies into clinical trials and practices in oncology.
Several examples in the prospective application of GEPs in clinical oncology are described here to illustrate the utility of this technology in popular solid tumors and hematologic malignancies.
Acute leukemia – The first report to show that GEPs could be utilised to classify tumors analyzed a group of acute leukemias Cancer Analysis in Biotechnology Element II – Genetic Analysis . Based upon gene expression patterns, acute myeloid leukemia (AML) may be distinguished from acute lymphoblastic leukemia (ALL) with out standard histology information. Similarly, B-cell versus T-cell ALL may be separated according to GEP. This study served as proof of principle that clinically beneficial classifications may very well be made merely by gene expression patterns. In one more report Cancer Analysis in Biotechnology Element II – Genetic Analysis , a case with equivocal histology by typical criteria was accurately classified by gene analysis, demonstrating the prospective utility of GEP beyond normal histologic and immunocytochemical approaches.
Others have shown that GEP can distinguish among prognostically necessary subgroups of young children with ALL and adults with AML, in some circumstances identifying individuals who eventually fail therapy. If these findings are confirmed by others, the logical subsequent step is to apply a a lot more intense initial treatment strategy to such patients, selected on the basis of their GEP.
It may possibly also be possible to screen for agents capable of inducing leukemic cell differentiation by means of adjustments in their GEP. A important caveat is the fact that gene expression profiles of clinical samples could differ significantly from those observed in cell lines representing the corresponding leukemia.
Prostate cancer – A prospective application of GEP in guys at threat for prostate cancer may be the identification of biomarkers which will aid select males with a borderline elevation in serum prostate particular antigen (PSA) for biopsy. Furthermore, GEP may be applied to determine males whose early stage tumors are destined to recur and thus would benefit from alot more aggressive therapy.
GEP has been put to use to identify various genes (e.g., hepsin and pim-1) which can be upregulated in prostate cancer compared to benign prostatic hyperplasia and typical prostate tissue, and some are extremely correlated with clinical outcome [25-30]. Investigators have discovered a ≥3-fold distinction in expression in over 3000 genes when nonrecurrent prostate cancers were compared to metastatic tumors.
Colon cancer – The serine phosphatase PRL-3 is consistently upregulated in metastatic as in comparison to non-metastatic colorectal cancers [31]. The obtaining that metastatic prospective appears to be encoded in the main has challenged the notion that metastases arise from rare cells which have acquired the capacity to metastasize.
GEP is under study as a strategy to enhance prognostication, and perhaps, individualize adjuvant therapy recommendations. An location of intense study would be the use of GEP to predict which patients with node-negative resected colon cancer are at a somewhat greater risk of relapse, and thus, might possibly benefit from adjuvant chemotherapy, as is typically advised for patients with node-positive disease.
Breast cancer – A molecular classification for breast cancer has been proposed based upon GEP
symptoms of ovarian cancer
. Luminal (mainly estrogen receptor [ER] positive), basal-like (mostly ER-negative), normal-like, and erbB2+ (mostly HER-2 overexpressing, ER-negative) subgroups happen to be identified, and have different prognoses.
A key area of investigation will be the use of such molecular profiling to predict response to therapy. The GEPs of breast cancers that respond best to neoadjuvant (preoperative) chemotherapy (ie, basal-like, erbB2+) differ from those of nonresponding or resistant tumors.
Analysis of GEP may also distinguish sporadic breast cancers from those associated with BRCA mutations
stages of cervical cancer
. Perhaps far more importantly, GEP may also permit stratification of defined subgroups (ie, those with axillary lymph node-negative breast cancer or grade 2 tumors) into prognostically separate categories
stages of cervical cancer
. In at the least some reports, outcome prediction by GEP outperforms existing prognostic classifications. This topic is discussed in detail elsewhere.
GEP analysis by DNA microarray is obtainable in patients with breast cancer (the 21-gene recurrence score assay, like Oncotype DX) to quantify the likelihood of a breast cancer recurrence in ladies with newly diagnosed, node-negative hormone receptor-positive early stage breast cancer
test for ovarian cancer
. The assay is created to identify those ladies whose danger of recurrence is low enough to justify the omission of chemotherapy and use of tamoxifen alone as systemic adjuvant therapy.
Although commercially available, the benefit of applying 21-gene recurrence score assays (e.g, Oncotype DX) to select the adjuvant therapy strategy has not been tested inside a prospective trial. Such an approach is getting evaluated within the phase III Trial Assigning IndividuaLized Solutions for Treatment (Rx) (the TAILORx clinical trial), sponsored by the National Cancer Institute and led by the Eastern Cooperative Oncology Group (ECOG).