Current+Testing

__ Genomic Tests Used __
In the past, clinics would only use microarray technologies to identify subtypes of breast cancer. Confusion in different prognoses could come from these tests. For example, Luminal A tumors have been found to have a better prognosis than any of the other subtypes, but it has similar characteristics to Luminal B tumor types (Zelnak, 2013). When only using microarrays the distinction between Luminal A or B was sometimes lost.

Another test used is the 21-gene recurrence score, a registered, multigene diagnostic test called Oncotype DX. This test helps determine a person’s individual risk of cancer recurrence in early-stage invasive breast cancer. It looks at the tumor biology to identify substantial benefits from treatment decisions (Zelnak, 2013). The patients receive a score that divides them into three risk groups: low, intermediate, and high. Higher scoring groups usually had Luminal B tumors and have been found to most likely to benefit from adjuvant chemotherapy (Zelnak, 2013).

The 70-gene prognosis signature test is also known as MammaPrint. It is a genomic test made by Agendia and analyzes certain genes in patients with early-stage breast cancer ([|http://www.breastcancer.org/symptoms/testing/types/mammaprint accessed 3/12/2016]). MammaPrint research suggests that it can be used to help determine the risk of cancer’s recurrence within ten years ([] accessed 3/12/2016).

The standard of care for Luminal A and B subtypes has been adjuvant anti-estrogen therapy with aromatase inhibitors with the addition of Tamoxifen (Zelnak, 2013). In addition to chemotherapy, adjuvant therapies include hormone therapy, radiation, immunotherapy, and targeted therapies (Zelnak, 2013). Aromatase inhibitors stop the production of estrogen in postmenopausal women, allowing less estrogen available to stimulate the growth of hormone receptor positive (HR+) breast cancer cells ([|http://www.breastcancer.org/treatment/hormonal/aromatase_inhibitors accessed 3/14/2016]). The most common aromatase inhibitors are anastrozole, exemestane, and letrozole.

Most Luminal B subtypes have been found to relapse due to a resistance to anti-estrogen therapy and also endocrine agents. By finding a better understanding of the different gene expressions in these subtypes, we can determine the mechanisms of resistance. Using MammaPrint, another genomic tool, we have found that cancers that are HR+ and have HER2 expression are driven by the HER2 pathway (Zelnak, 2013).

__ Receptors __
One of the first oncogenes (a gene that is mutated or can be overexpressed and has the potential to cause cancer) found was the erythroblast oncogene B (ERBB). Under the ERBB family, the human growth factor receptor (HER), HER2 and epidermal growth factor receptor (EGFR) have been shown to play important roles in the development and progression of breast cancer (Pouladi et al., 2014).

Basal-like subtypes have been found to have the worst clinical outcomes with clinical survival. This is due to the aggressiveness of basal-like subtype tumors coupled with the lack of targeted treatment therapies (Zelnak, 2013). Basal-like tumors are ER- and do not overexpress HER2, using anthracycline and taxane-b ased regimens (Zelnak, 2013). ERBB2+ (the protein biomarker for gene ERBB) with HER2+ demonstrate different responsiveness to chemo-sensitivity than luminal types (Donahue and Genetos, 2013). Anthracyclines are antibiotics used to treat cancer by damaging the DNA in cancer cells, causing them to die ([] accessed 3/12/2016). Common anthracyclines are daunorubicin, doxorubicin, and epirubicin. Taxane-based drugs block cell growth by stopping cell division. This kind of treatment is a mitotic inhibitor and an antimicrotubule agent. Microtubules are the structures that help move chromosomes during mitosis ([] accessed 3/12/2016).

HER2-enriched subtypes have been found due to the amplification of the HER2 gene. Two other genes, GRB7 and TOP2A are located next to the HER2 gene on chromosome 17 and have been found to be co-amplified (Zelnak, 2013). Patients with all of three of these gene expressions, had positive responses to anthracycline and taxane-based chemotherapy with or without trastuzumab. The patients that were HER2+ but did not have co-amplification of genes GRB7 and TOP2A had success with non-anthracycline regimen of docetaxel, carboplatin, and trastuzumeb (Zelnak, 2013). Trastuzumab is effective only in cancers where HER2 is over-expressed.

Over-expression of HER2 can also be suppressed by the amplification of other genes. It has been found that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K molecular pathway (Ping, Z. et al., 2014).



A view of gene TOP2A and its protein structure from RCSB's Proein Data Bank:



__ Pathway __
Phosphatidylinositol 3-kinase (PI3K pathway) has been observed in lung and breast cancers (Ping, Z., 2014). Increased activity in this pathway is associated with tumor progression and resistance to cancer therapies. Mutations in PI3K-alpha have been found in a variety of cancer types, since they increase kinase activity and oftentimes create transformations of certain genes. The gene that codes for PI3K-alpha is PIK3CA. Mutations on PIK3CA are widespread in a variety of cancer types, making it the most commonly mutated oncogene (Ping, Z., 2014).

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