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What are gene signatures?

Gene signature is an examination performed on tumor tissue, which indicates the benefit of each patient to chemotherapy treatment and the chance of disease recurrence, when in early stages. It aims to help doctors select the best treatment for invasive breast tumors, in a fully individualized way, for their patient

Hormone therapy is standard treatment for hormone receptor-positive breast cancer, but it is not always clear when to combine chemotherapy. These tests can help guide that decision. Studies show that the results of these tests collaborate for decision making about treatments after surgery, especially the indication of chemotherapy (adjuvant). But it is necessary to clarify that these signatures do not replace the assessment of the medical team. This is one more possibility for planning the treatment of each case of breast cancer.

They are indicated in hormone receptor positive, HER-2 negative tumors with compromised or non-compromised lymph nodes. They are important decision tools for evaluating the benefit of adjuvant chemotherapy. These tests are currently being analyzed in large clinical trials to understand when is the best time to use them.

See below the most used gene signatures:

Oncotype DX is used to estimate the risk of recurrent disease. It should normally be ordered when the disease is at an early stage, hormone receptor positive and HER2 negative, to assess the need for chemotherapy. The test evaluates 21 genes to determine breast cancer behavior and then calculates a recurrence score number between 0 and 100. The higher the score, the greater the risk of recurrence of invasive breast cancer. The risk is divided as low, intermediate or high for relapse. The Taylor X randomized trial evaluated this test and the result showed that patients with low genomic risk do very well without chemotherapy.

Mammaprint analyzes 70 genes to understand disease behavior and calculate recurrence risk as high or low. It can be used in patients with high clinical risk, that is, who would have a high possibility of undergoing chemotherapy in order to assess distant recurrence (metastasis). This is because if the risk is low, chemotherapy would not be beneficial.

Breast cancer index is the test that analyzes the behavior of seven genes to predict the risk of hormone-positive and HER2-negative breast cancer relapse after five years. It may also help to decide whether hormone therapy or hormone therapy needs to be extended for another five years, making a total of 10 years.

Endopredict is used to predict the risk of distant recurrence of hormone-positive and HER2-negative breast cancer. EndoPredict analyzes 12 genes to assess tumor behavior and then combines it with clinical cancer risk (cancer size and armpit lymph node status) to calculate a score that categorizes cancer as high or low risk for distant recurrence ( metastasis).

Prosigna analyzes the behavior of 58 genes and calculates the risk of recurrence score (low, intermediate or high). Some studies suggest that Prosigna may eventually be used to make treatment decisions, based on the risk of distant recurrence, within 10 years of initial diagnosis, in hormone-positive, HER2-negative breast cancer.

The FoundationOne® CDx  presents the result of the analysis of 324 genes relevant to cancer, including the biomarkers recommended by medical guidelines for the use of target therapies, in addition to the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI), parameters that help the oncologist in deciding on the use of immunotherapies. In addition, the report provides information on tumor fraction, an indication of the probability of detecting genomic alterations in the liquid biopsy sample, as well as relevant clinical studies according to the patient's molecular profile.

Pharmacogenomics studies how inherited genes affect the way the human body processes and responds to drugs, which makes these drugs more or less effective and more or less toxic. A drug may act differently in two patients, even if it was given for the same condition. For example, some patients may experience significant side effects with a particular drug, while others may not, even when receiving comparable doses of the drug.

Pharmacogenomics offers important benefits, such as:

Improve patient safety: Severe drug reactions lead to numerous hospitalizations annually. Pharmacogenomics can prevent them by identifying patients at risk.

Improve healthcare costs and efficiency: Pharmacogenomics can help you find the right drugs and doses faster.

How is locally advanced breast cancer treated?

Locally advanced breast cancer (LAMC) can be defined in two ways: The first is if the tumor size is not large, however, the cancer has spread to axillary lymph nodes or lymph nodes close to the sternum and skin. The second is if the tumor is large, and there is little lymph node spread. CMLA is best treated using systemic and locoregional therapy.

Neoadjuvant chemotherapy is the performance of systemic treatment before locoregional treatment: surgery and radiotherapy. The advantages of neoadjuvant chemotherapy are: the possibility of turning inoperable tumors into operable ones; tumor reduction and consequent reduction in the radicality of the initial surgery, converting mastectomies into conservative surgeries; possible control of micrometastases; predictive and prognostic information, when the tumor presents a complete pathological response; possible post-surgical growth inhibition, as identified in some animal models; in addition to being the only possibility to assess the in vivo response to systemic treatment in patients.

Most patients with locally advanced breast cancer and some with early-stage disease, particularly if the HER2+ or triple negative tumor are treated with systemic neoadjuvant therapy.

● For patients with HER2 positive breast cancer, a HER2-targeted agent (eg, trastuzumab with or without pertuzumab) should be added to the chemotherapy regimen.

● For patients with HER2 negative disease and negative hormone receptors (Triple negative tumor), neoadjuvant therapy consists of polychemotherapy only

● For most patients with hormone receptor-positive disease, we recommend chemotherapy in the neoadjuvant setting rather than neoadjuvant endocrine therapy. Chemotherapy is associated with higher response rates in a shorter period. For selected patients with hormone-positive disease, neoadjuvant endocrine therapy may be an appropriate option if there are severe comorbidities or other factors (eg, patient preference) that require this strategy.

How to assess tumor response to neoadjuvant therapy?

The complete pathological response (PCR), that is, the anatomopathological analysis of the tumor in the surgical specimen,  it is considered the best criterion for long-term evaluation of clinical benefit, since patients who obtained CPR had longer global and disease-free survival, with greater prognostic value in aggressive tumor subtypes (triple negative and HER2).

Assessment of response to neoadjuvant chemotherapy (NTQ) is typically done using a combination of clinical examination and imaging techniques. Magnetic resonance imaging (MRI) has been shown to be the most sensitive imaging modality to follow a patient's response to QTN. Contrast uptake on MRI (magnetic resonance imaging) with dynamic evaluation using the contrast can detect tumor angiogenesis, associated changes in tumor microcirculation, and even increased permeability of the newly formed vessels. Thus, it provides an insight into the pathophysiology of tumor response to QTN, allowing an earlier and more accurate assessment of the response to QTN than the only anatomical assessment performed in mammography and ultrasonography.

Patients, during neoadjuvant treatment, must be periodically evaluated in order to verify the therapeutic response and ensure the non-progression of the disease. There is no standard protocol for this follow-up, but there are some recommendations for this scenario: - Carry out a clinical examination every 2 to 4 weeks, evaluating breasts and armpits before each cycle. - For patients on hormone therapy, this assessment can be done every 4 to 8 weeks considering that the response is slower.

Imaging exams can be performed when progression is suspected. In that case, RM may add some benefit to the USG. An MRI before treatment and another at the end is mandatory.

Even though it is an excellent test, the RM is not perfect. Discrepancies between MRI findings and surgical pathology are well documented. Overestimation of residual disease may result in greater surgery than is actually necessary (larger conservative surgery, wider margins, and mastectomy) and underestimation may result in insufficient surgery, resulting in positive margins and re-excisions. Therefore, it is important to compare the MRI findings, particularly the complete radiological responses (CRRs), with the anatomopathology.

The most adequate criterion to assess the response to treatment is the pathological evaluation of the surgical specimen. The pathological response is divided into:

class 0 - Complete Pathological Response - Absence of residual tumor or presence of carcinoma in situ or axillary micrometastasis

class I (minimal residual disease);

  class II (moderate residual disease);

class III (extensive residual disease).

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