Understanding Breast Cancer Through Genetics: How Next-Generation Sequencing Is Changing Treatment Choices

By: Dr. Peng-Yu Chen, Senior Attending Physician, Department of Medical Oncology

Breast cancer remains one of the most important women’s health issues. According to Taiwan’s National Health Administration, breast cancer has the highest incidence among cancers in Taiwanese women. As medicine and molecular biology have advanced rapidly, breast cancer diagnosis and treatment are no longer based only on tumor size or stage. We have entered a “gene-driven” era, where the biology of the tumor increasingly shapes clinical decisions.

In recent years, next-generation sequencing (Next-Generation Sequencing, NGS) has been reshaping how we think about breast cancer diagnosis and treatment. By revealing actionable genetic changes within a tumor, NGS can help patients access treatment options that are more personalized and more precise.

What Is Next-Generation Sequencing?

In simple terms, NGS is a technology that can rapidly and comprehensively analyze DNA or RNA. Traditional genetic testing often examines only a small number of genes at a time. That approach is like using a magnifying glass to look for a single mistake. NGS is more like a high-resolution scanner. It can evaluate dozens to hundreds of genes at once and identify key variants that may influence tumor growth and behavior.

NGS works by breaking DNA or RNA into many small fragments and sequencing them in parallel, often generating data from thousands to millions of fragments at the same time. These fragments produce large volumes of sequencing data through chemical reactions, and computer algorithms then assemble and analyze the data to reconstruct genetic sequences and identify meaningful variants. The core strengths of NGS are high throughput and parallel processing, which allow large-scale sequencing to be completed in a relatively short time. Clinically, this provides an unprecedented amount of genetic information and helps map a patient’s “genetic blueprint.”

Why NGS Matters in Cancer Care

The clinical value of NGS can be understood in three main ways. First, it helps physicians understand tumor biology with much greater precision. Every tumor has its own pattern of genetic changes, like a fingerprint. With NGS, we can see the tumor’s “genetic fingerprint” and better understand what is actually driving its growth.

For example, among patients whose breast cancer is hormone receptor-positive, some may carry an ESR1 mutation, while others may carry a PIK3CA mutation. These differences can meaningfully affect how a tumor responds to treatment and may signal that medication adjustments should be made earlier. In this way, NGS functions like a highly precise compass that helps guide the most appropriate treatment direction.

Second, NGS can help predict how a tumor may respond to therapy. Certain mutations can make tumors more sensitive to targeted therapies or immunotherapy, essentially revealing a vulnerability. Other mutations may be associated with drug resistance. If physicians understand this genetic information upfront, they can reduce “trial-and-error” treatment and choose a regimen that is more likely to be effective.

Third, NGS can help estimate recurrence risk. Some genetic alterations act like an “accelerator,” suggesting a tumor may progress faster or be more likely to recur, while other alterations may indicate a less aggressive course. With this information, physicians can adjust treatment intensity more precisely. Higher-risk patients may benefit from earlier, more aggressive strategies, while lower-risk patients may avoid overtreatment and unnecessary physical and emotional burden.

How NGS Is Changing Breast Cancer Treatment Choices

Breast cancer treatment has always involved multiple approaches, including surgery, radiation therapy, chemotherapy, targeted therapy, and hormone therapy. In the past, physicians often based treatment decisions primarily on standard tumor subtypes, such as whether hormone receptors are positive and whether HER2 is overexpressed. With the rapid growth of NGS, we can now look deeper into the mutations that drive cancer cell growth and design more individualized strategies based on molecular features.

1) More precise use of targeted therapy

NGS can help identify the most suitable “key” for treatment. Research has found that about 30% to 40% of patients with hormone receptor-positive breast cancer carry PIK3CA mutations. For these patients, targeted drugs against PIK3CA, also called PI3K inhibitors, may work well by blocking the growth signals driven by the mutation and improving treatment effectiveness.

In addition, about 5% to 10% of breast cancer patients carry BRCA mutations. In these cases, PARP inhibitors can block cancer cells’ DNA repair pathways, reducing the tumor’s ability to repair itself. This enables a more precise approach that can delay disease progression and, for some patients, may help avoid moving directly to traditional chemotherapy. These developments reflect how NGS is helping redefine breast cancer subtypes and expanding the boundaries of treatment.

2) New opportunities for immunotherapy

Triple-negative breast cancer (TNBC) is a subtype that lacks hormone receptors (ER, PR) and does not overexpress HER2. It accounts for roughly 10% to 15% of breast cancers and tends to have a higher risk of recurrence and metastasis. Because TNBC lacks many established targets, patients historically relied heavily on repeated courses of chemotherapy.

With advances in genetic testing and immune profiling, researchers have found that some TNBC tumors show higher immune activation and higher expression of PD-L1, making immunotherapy a promising direction. For some patients, chemotherapy can be combined with immune checkpoint inhibitors. These drugs are designed to release the immune system’s “brakes.” Cancer cells can evade immune attack by expressing PD-L1, which binds to PD-1 receptors on immune cells and weakens T-cell activity. Immune checkpoint inhibitors can disrupt this suppression, allowing T cells to become active again and recognize and attack cancer cells.

Clinical trials have shown that for PD-L1-positive TNBC, immunotherapy combined with chemotherapy can significantly improve tumor response rates and progression-free survival (PFS). Some patients may even achieve long-term disease control. This has reshaped the TNBC treatment landscape and signals that breast cancer care is moving into an era of “immune precision medicine.” As more immune therapies and biomarkers are identified, immunotherapy may benefit broader breast cancer populations in the future.

3) Hereditary genetics and family risk assessment

NGS is not only used to detect tumor mutations. It can also evaluate inherited genetic variants. According to Taiwan’s Ministry of Health and Welfare, approximately 5% to 10% of breast and ovarian cancers are related to BRCA gene defects, most commonly BRCA1 and BRCA2 mutations. These inherited variants influence not only a patient’s treatment strategy, but also prevention and screening decisions for family members. A widely known example is actress Angelina Jolie, who chose preventive mastectomy after learning she carried a BRCA1 mutation.

NGS Costs in Taiwan and How Doctors Decide Whether Testing Is Needed

Starting May 1, 2024, NGS testing has been officially included in Taiwan’s National Health Insurance (NHI) coverage. According to Ministry of Health and Welfare announcements, there are 14 major categories of solid tumors for which clinicians can use single-gene testing or NGS to help select the most appropriate targeted therapies. Because test methods, the number of genes evaluated, and patient needs vary, the NHI system uses a model of fixed reimbursement with patient payment for any remaining balance.

The three fixed reimbursement tiers are: BRCA gene testing at 10,000 points, a small panel test (up to 100 genes) at 20,000 points, and a large panel test (more than 100 genes) at 30,000 points. As a result, patients may still need to pay an additional balance depending on the hospital and the specific test used. Even so, this policy reduces financial burden and allows more people to access precision medicine.

Who Should Consider BRCA Genetic Testing?

BRCA testing is generally recommended for patients who have already been diagnosed with breast cancer, especially those with one or more of the following features. This includes patients diagnosed before age 50 who also have a family history of breast or ovarian cancer, patients with cancer in both breasts, patients with triple-negative breast cancer, and patients with certain pathological subtypes such as lobular carcinoma. It also includes patients with both breast and ovarian cancer in their medical history, as well as male breast cancer patients.

How Physicians Decide Whether to Order NGS

Not every patient needs NGS, and not every case will benefit from it. Clinicians weigh multiple factors. Physicians consider whether a given tumor type has meaningful targeted or immunotherapy options linked to specific genetic findings. When a tumor responds poorly to standard treatment, or when recurrence or metastasis risk is high, NGS may help identify additional therapeutic targets. If a patient has a family history of breast or ovarian cancer, or develops cancer at a young age, physicians may recommend testing for BRCA1/2 or other inherited cancer-related genes. Finally, physicians and patients should discuss cost-effectiveness and clinical relevance carefully, so that the results can realistically translate into a treatment advantage rather than remaining only “interesting information.”

NGS is advancing at an extraordinary pace. Its impact is not limited to breast cancer. It is increasingly being applied across many cancers, including lung cancer, colorectal cancer, ovarian cancer, cholangiocarcinoma, and more, helping precision medicine become a practical part of everyday clinical care.