Advanced Targeted Therapy for Breast Cancer: Key Molecular Targets and Treatments

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• CDK4/6 Inhibitors for ER-Positive Breast Cancer
• Antibody-Drug Conjugates for HER2-Positive Disease
• PARP Inhibitors for BRCA-Mutant Breast Cancer
• Immunotherapy for Triple-Negative Breast Cancer
• Trop-2 Targeted Therapy with Sacituzumab Govitecan
• Agnostic, Biomarker-Based Cancer Treatment
• The Future of Precision Medicine in Breast Cancer

CDK4/6 Inhibitors for ER-Positive Breast Cancer

For patients with estrogen receptor-positive (ER+), HER2-negative breast cancer, CDK4/6 inhibitors represent a major advancement in targeted therapy. Dr. Giuseppe Curigliano, MD, explains that these medications are combined with endocrine therapy to block cancer cell division. This combination has proven to significantly improve key patient outcomes, including progression-free survival, response rate, and overall survival.

Dr. Giuseppe Curigliano, MD, highlights recent groundbreaking data from the ESMO meeting on the CDK4/6 inhibitor ribociclib. When combined with an aromatase inhibitor, it demonstrated a clear improvement in overall survival for patients with ER+ HER2- metastatic breast cancer. He describes these results as unprecedented, marking a new era of hope for this large patient population.

Antibody-Drug Conjugates for HER2-Positive Disease

Targeted therapy for HER2-positive breast cancer has been transformed by a new generation of antibody-drug conjugates (ADCs). Dr. Giuseppe Curigliano, MD, discusses the dramatic results from the DESTINY-Breast03 clinical trial. The ADC trastuzumab deruxtecan was compared to the standard T-DM1 in the second-line metastatic setting.

The data showed a remarkable improvement in progression-free survival, increasing from a median of 7 months to 24 months. This powerful therapy works by specifically targeting the HER2 protein on cancer cells and delivering a potent chemotherapy payload directly to the tumor, maximizing efficacy while aiming to minimize systemic side effects.

PARP Inhibitors for BRCA-Mutant Breast Cancer

For breast cancer patients with a BRCA gene mutation, PARP inhibitors offer a highly effective targeted treatment strategy. Dr. Curigliano identifies olaparib and talazoparib as key medications that have demonstrated a clear progression-free survival benefit in the metastatic setting. These drugs exploit a specific weakness in BRCA-mutant cancer cells, a concept known as synthetic lethality.

The utility of PARP inhibitors is expanding. Dr. Giuseppe Curigliano, MD, notes that olaparib is now also used in the adjuvant setting after initial chemotherapy for high-risk, early-stage breast cancer patients with a BRCA mutation. In this context, treatment with olaparib improved invasive disease-free survival and showed a positive trend in overall survival, helping to prevent cancer recurrence.

Immunotherapy for Triple-Negative Breast Cancer

Immunotherapy has emerged as a critical targeted treatment for a subset of patients with triple-negative breast cancer (TNBC). Dr. Giuseppe Curigliano, MD, explains that for patients whose tumors express the PD-L1 biomarker, combining immunotherapy with chemotherapy yields superior outcomes. The checkpoint inhibitors atezolizumab and pembrolizumab are used in this context.

This combination strategy leverages the patient's own immune system to recognize and attack cancer cells. Clinical trials have shown that adding immunotherapy to chemotherapy improves both progression-free survival and overall survival for PD-L1-positive metastatic triple-negative breast cancer, offering a new lifeline for this aggressive disease.

Trop-2 Targeted Therapy with Sacituzumab Govitecan

A novel target in triple-negative breast cancer is Trop-2, a protein highly expressed on many cancer cells. Dr. Giuseppe Curigliano, MD, describes a new class of antibody-drug conjugate designed to attack this target: sacituzumab govitecan. This ADC binds to Trop-2 and delivers its chemotherapy payload directly into the tumor.

This targeted therapy has shown significant efficacy in later lines of treatment for metastatic TNBC. Clinical data confirms that sacituzumab govitecan can improve overall survival, providing a valuable new option for patients who have progressed on other therapies.

Agnostic, Biomarker-Based Cancer Treatment

Precision medicine is evolving toward a tumor-agnostic approach to cancer diagnosis and treatment. Dr. Giuseppe Curigliano, MD, explains this paradigm shift to Dr. Anton Titov, MD. Instead of selecting treatments based on the organ where the cancer originated (e.g., breast), therapies are chosen based on specific molecular alterations within the tumor, regardless of its source.

These alterations, such as RET or NTRK gene fusions, may occur in only 1-2% of metastatic breast cancer cases. For these patients, highly effective targeted therapies like pralsetinib (for RET) or larotrectinib (for NTRK) are available. This agnostic approach ensures that every patient has the opportunity to receive a treatment matched to their tumor's unique biology.

The Future of Precision Medicine in Breast Cancer

The landscape of breast cancer therapy is now fundamentally defined by its molecular targets. As Dr. Curigliano outlines, the future lies in continued biomarker discovery and the development of increasingly sophisticated targeted agents like antibody-drug conjugates. The conversation with Dr. Anton Titov, MD, underscores that comprehensive genomic testing is essential to identify these targets and match every patient with the most effective, personalized treatment strategy available.

Full Transcript

Dr. Anton Titov, MD: 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. What are the major molecular targets of new breast cancer medications today?

Dr. Giuseppe Curigliano, MD: Thanks a lot for coming here late in the evening. In my institution, 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 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, new data on ribociclib in combination with an aromatase inhibitor in ER-positive disease were presented. There was a clear improvement in overall survival that was never previously observed in this population. So those are unprecedented data.

If we move to HER2-positive breast cancer, we have the new data on trastuzumab deruxtecan. In the context of the clinical trial DESTINY-Breast03, trastuzumab deruxtecan was 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 that targets HER2 specifically in 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 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 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 conjugates called sacituzumab govitecan. It can improve overall survival in later lines of treatment.

Dr. Anton Titov, MD: 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, irrespective of cancer origin in the organ or the tissue. What kind of opportunities and challenges does such biomarker-based cancer diagnosis and treatment bring to patients with breast cancer?

Dr. Giuseppe Curigliano, MD: This is an agnostic approach to cancer therapy. In the past, we led many cancer medication clinical trials that were organ-oriented. To register a drug for metastatic breast cancer, you should select the population according to the organ or anatomical region and randomize the standard of care regimen versus the new treatment. The agnostic approach is completely different.

You select patients not according to the organ of origin but according to a specific molecular alteration. Let us say RET amplification or NTRK amplification. These types of alterations can also be common in breast cancer. Gene alterations are not as high in general incidence of breast cancer, but 1% to 2% of all metastatic breast cancer may express RET alteration or NTRK alteration, for whom you can select a targeted therapy with pralsetinib or larotrectinib.

So I must say that in the context of the agnostic mutation-based medication approval, breast cancer patients may also benefit.