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Hormonal, Targeted Therapy and Personalized Medicine

In the past, we thought of cancer as one size fits all. Now we understand there are many differences among breast cancer and each cancer has its own unique signature. One woman's breast cancer is not the same as another woman's breast cancer. Multiple studies have shown throughout the years that patients with the same type and stage of breast cancer may have a different prognosis.

 

 
The illustration on the left shows the way we understood breast cancer in the past. All breast cancers were the same. One size fits all. Every patient essentially was treated in a similar fashion. We understand now that all cancers are not the same and each one has its own characteristics. We have been able to identify molecular markers on each tumor that distinguish it from others. These tumor biomarkers are used to tailor specific therapies for each type of breast cancer.

 

In the past decade, our understanding of the molecular mechanisms that underlie breast cancer pathology and progression has dramatically improved. Significant progress has been made in the development of molecular markers that can predict response to anticancer drug therapy. By using this knowledge, we have identified additional targets and developed novel therapeutics interventions for breast cancer. The goal is to design a therapy that is effective, less toxic, and personalized for each individual. The goal is to find a therapy with a higher likelihood of curing the cancer and less secondary effects.

Research efforts are helping us to get into the era of personalized cancer treatment. Personalized medicine refers to the use of molecular tests performed on the patient to help better define therapies. These molecular tests include testing for variations in genes, gene expression, proteins, and metabolites, as well as new treatments that target molecular mechanisms. It means receiving a targeted therapy for a specific tumor type. Treatment based on a tumor and the patients own makeup can help to determine the best outcome. Personalized medicine is recognized as being a significant part of the solution for providing better healthcare outcomes.

Breast Cancer:
For breast cancer, we have a series of markers that classify tumors, which may look identical under the microscope, into completely different subgroups. This was not possible 15 years ago. Breast cancers have been divided into subgroups based on the biology of the disease:

  Estrogen (ER) positive or estrogen (ER) negative
  Progesterone (PR) positive or progesterone (PR) negative
  HER2-positive or HER2-negative

Each of these lead to specific treatment recommendations. Endocrine therapies only work for estrogen receptor and progesterone receptor positive tumors. Trastuzumab (Herceptin) therapy only works for human epidermal growth factor receptor 2 (HER2) positive tumors. On the other hand, chemotherapy is a hammer to hit every nail and has the potential benefit for all subsets of breast cancer including the so call triple negative tumors.

Chemotherapy
Chemotherapy is usually given as a combination of various drugs. Most chemotherapeutic regiments are given intravenously in an office setting. Chemotherapy is given in cycles. The cycle is divided into treatment and recovery periods. The chemotherapeutic drugs may damage rapidly dividing healthy cells, such as hair follicle cells and gastrointestinal tract cells. A recovery time is given to the healthy cells to repair themselves from the damage caused by the chemotherapeutic agent.

 

 
Triple Negative Breast Cancer
Triple negative tumors neither express hormone receptors (estrogen, progesterone) nor over-express the HER2-neu protein. They do not respond to either targeted hormonal or Herceptin therapy. These patients are treated with chemotherapy.

 

Hormone Therapy
Hormone therapy is effective in tumors that have either estrogen or progesterone receptors, or both. There are various hormone therapy drugs that have different mechanisms of action to block the effect of estrogen in the breast cancer cell. These include selective estrogen-receptor modulators (SERM's), aromatase inhibitors (AI's), and estrogen receptors downregulators. (see section of hormonal therapy for further information).

 

 
Hormone Positive Breast Cancer
Endocrine therapy works on hormone positive breast cancer. Tamoxifen is a selective estrogen modulator that acts by blocking the estrogen receptor in both normal breast cells and cancer cells. It prevents hormones from fueling the growth of breast cancer.

 

Targeted Therapy
The classification of breast cancers into subtypes is of paramount importance to determine the best treatment for a specific tumor. This has been possible with recent advances in molecular and genetic profiling. Estrogen and progesterone receptors and the expression of the HER2 protein are the main tumor biomarkers to sub-classify breast cancers. Target therapy refers to the treatment against specific genes or proteins that promote the growth of a cancer cell. Target therapy blocks the signals produced by these substances and inhibits the growth of the tumor. The best known targeted therapy agents are the anti-HER2 agents. These include trastuzumab (Herceptin) and lapatinib (Tykerb). The third agent is called bevacizumab (Avastin). It inhibits a protein that helps tumors form new blood vessels. These vessels are necessary for the growth of the cancer cell. Other targeted agents under investigation include the PARP inhibitors. PARP inhibitors block an enzyme which cancer cells use to repair their damaged DNA. Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.

 

 
HER2 neu Positive Breast Cancer
HER2 neu positive tumors overexpress the HER2 protein. Herceptin attaches to the breast cancer cell. The patient's own immune system targets the cancer cell and prevents it from growing.

 

Goal:
The ultimate goal is to personalized treatment for all cancer patients, identify the molecular abnormalities in each patient's cancer, and then prescribe the appropriate therapy that will target those abnormalities. As genetic understanding progresses, we will continue to change the classification of breast cancers and individualize each tumor based on its unique characteristics, including its response to different treatments. As a result, improve the outcome by personalizing medicine.

 

Oncotype

The Oncotype DX is a test that looks at a group of genes within a woman's breast tumor to determine the presence and activity. This test uses a technology known as gene expression profiling. This technology allows for several genes in a tumor to be studied at the same time. This test provides information on the activity of genes that affect the growth of cancer cells. The genetic profile of a tumor is associated to its behavior. This group of genes is studied using a research tool called quantitative RT-PCR on fixed paraffin embedded tissue specimen. The test will quantify RNA for 21 different genes (16 cancer genes and 5 control genes) that are highly relevant and correlated with the likelihood of breast recurrence. The study of multiple genes, their functions, and their interaction is known as genomics.

 

  Oncotype DX:
The tumor specimen is analyzed using RT-PCR. The test evaluates the activity of 21 genes. The activity is calculated as a Recurrence Score of 0 to 100 points. A low score indicates a low risk of recurrence and a high score indicates a high risk of recurrence within 10 years after diagnosis. The treatment can be tailored to the specific risks for each individual.

 

Hormone Positive, HER2 Negative and Lymph Node Negative:
The main application of this tool is to help identify patients with node-negative, hormone receptor positive, and HER-2-negative breast cancer, which may be at a higher risk of developing postoperative distant recurrence. It helps the patients and doctors to make decisions of whether or not to include chemotherapy in their adjuvant treatment plan. There is ongoing research to apply this test to some women with positive lymph nodes. The results of the test are reported as a recurrence score between 0 and 100. The report includes a "recurrence score" likelihood of experiencing a distant recurrence (metastasis) within 10 years of diagnosis. It also corresponds to the likelihood that a patient's cancer will respond to chemotherapy in addition to hormonal therapy. New data also shows prediction in local recurrence.

Predictive and Prognostic Test:
The Oncotype DX is both a prognostic and predictive test. Prognosis refers to the likelihood a cancer will return or spread outside of the primary site. Predictive indicates the relative sensitivity or resistance to specific treatments, such as chemotherapy or hormonal therapy, and the likelihood that a cancer will respond to a particular type of treatment. Oncotype DX predicts the magnitude of chemotherapy benefit for the patient and the likelihood that a patient's breast cancer will spread or return.

Goal:
We need continue finding new ways to help individualize treatment planning for patients based on the genomic activity within their tumors. Genomics provide greater individualization of treatment decisions and targeted therapies based on individual disease. Future research should continue focusing on how these molecular tools can enhance the predictive utility of drug selection, on defining which patients would benefit the most from these tests, and on establishing practical guidelines on how to apply therapeutic decisions based on test results.