Targeted therapy for breast cancer. What are the molecular targets of drugs? 1

Targeted therapy for breast cancer. What are the molecular targets of drugs? 1

Targeted therapy for breast cancer. What are the molecular targets of drugs? 1

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You're a director of the new drug development for innovative therapies at the European Institute of Oncology where we are. It is a beautiful institution. You specialize in solid tumor treatments, especially in breast cancer. Breast cancer treatment has entered the precision medicine era. Targeted therapy for breast cancer has improved the prognosis for patients with breast cancer. What are the major molecular targets of new breast cancer medications today?

So, thanks a lot, first, for coming here late in the evening. In my institution, of course, we have new molecular targets for breast cancer according to the subtype. Let us consider estrogen receptor-positive and HER2-negative diseases. The most important targets, of course, are CDK4/6 inhibitors. They are specific medications that are combined with endocrine therapy. CDK4/6 inhibitors can improve progression-free survival, response rate, and overall survival. Recently, during the ESMO meeting in Paris two weeks ago, there have been presented new data of Ribociclib in combination with an aromatase inhibitor in ER-positive disease. There was a clear improvement in overall survival that was never previously observed in this population (ER+ HER2- breast cancer). So those are unprecedented data. If we move to HER2-positive breast cancer, we have, of course, the new data on trastuzumab deruxtecan. In the context of a clinical trial, the DESTINY-Breast03, trastuzumab deruxtecan is being compared with T-DM1.

There was a dramatic improvement in progression-free survival from seven months to 24 months. This is an antibody-drug conjugate. It targets specifically HER2 in the context of second-line patients with HER2-positive metastatic breast cancer. For triple-negative breast cancer, I would like to mention the data on PARP inhibitors for BRCA-mutant breast cancer. Olaparib and talazoparib in the metastatic setting demonstrated the progression-free survival benefit. Specifically, olaparib was also used in the adjuvant chemotherapy setting for high-risk breast cancer patients. Olaparib improved invasive disease-free survival, with positivity in overall survival. Another target, of course, is the population of PD-L1-positive triple-negative breast cancer. For this population, we improve both progression-free survival and overall survival from the combination of immunotherapy plus chemotherapy. Immunotherapy, in this case, was atezolizumab and pembrolizumab. Another target in the triple-negative breast cancer patient population can be Trop-2. We have a new class of antibody-drug conjugated. The name is sacituzumab govitecan. It can improve overall survival in later lines of treatment.

Cancer diagnosis typically reflects the origin and the type of tissue where cancer originated. But precision medicine offers a new paradigm in cancer classification. This new cancer diagnosis classification is based on specific mutations in the tumor. It is irrespective of cancer origin in the organ or the tissue. What kind of opportunities and challenges such biomarker-based cancer diagnosis and treatment bring to patients with breast cancer?

This is an agnostic approach to cancer therapy. In the past, we led a lot of cancer medications clinical trials that were organ-oriented. So to do a registration of a drug for metastatic breast cancer, you should select the population according to the organ or the anatomical region and randomize the standard of care regimen versus the new treatment. The agnostic approach is completely different. So you select patients not according to the organ of origin but according to a specific molecular alteration. Let us say RET amplification, NTRK amplification. These types of alterations can also be common in breast cancer. Gene alterations are not as high as a general incidence of breast cancer, but 1% to 2%. All metastatic breast cancer may express RET alteration or NTRK alteration, for whom you can select a targeted therapy with the Pralsetinib or Larotrectinib. So I must say that in the context of the agnostic mutation-based medications approval, also breast cancer patients may benefit.

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