For patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer, treatment often begins with hormone therapy combined with a CDK 4/6 inhibitor. However, when this initial approach stops working, a range of second-line and emerging options exist to extend survival and improve quality of life. Understanding these alternatives—and how genomic testing can guide the best choice—is crucial for effective management.
When to Consider Switching Treatment
Doctors typically recommend a change when cancer begins to grow despite treatment, symptoms return, or imaging scans reveal disease progression. Another key indicator is the presence of specific gene mutations, such as ESR1 or PIK3CA, which can signal resistance to current therapies.
Genomic testing, using either a liquid or tissue biopsy, is essential. Liquid biopsies (blood tests) detect cancer DNA, while tissue biopsies require a sample from the tumor itself. Both provide insights into mutations that can inform treatment decisions.
Your doctor will also consider your overall goals and preferences. Some treatments are oral, while others require intravenous administration; different drugs also carry different side effect profiles. Selecting the option best suited to your individual needs is paramount.
Second-Line Treatments: Targeted Approaches
Several targeted therapies are available when initial treatment fails. These include:
- Selective Estrogen Receptor Degraders (SERDs): These drugs block estrogen receptors on cancer cells, hindering growth. Fulvestrant (Faslodex) is a standard SERD, administered via injection. Newer options, elacestrant (Orserdu) and imlunestrant (Inluriyo), are specifically approved for patients with an ESR1 mutation, which affects up to 40% of those who develop resistance to hormone therapy. Giredestrant, while not yet FDA-approved, shows promising results in trials.
- PIK3CA Inhibitors: About 40% of HR+/HER2- breast cancers have a PIK3CA mutation. Drugs like alpelisib (Vijoice), capivasertib (Truqap), and inavolisib (Itovebi) block the protein produced by this gene, inhibiting cancer cell growth. Capivasertib also treats cancers with AKT1 or PTEN mutations. Note: PIK3CA inhibitors are not recommended for patients with diabetes due to potential blood sugar side effects.
- mTOR Inhibitors: For patients without ESR1 or PIK3CA mutations, everolimus (Afinitor) remains a viable option, often combined with fulvestrant.
- PARP Inhibitors: If BRCA1 or BRCA2 mutations are present, olaparib (Lynparza) or talazoparib (Talzenna) can be effective. These drugs exploit the cancer’s inability to repair DNA damage, leading to cell death.
Emerging Therapies: Immunotherapy and Antibody-Drug Conjugates
Beyond these established options, new strategies are under investigation:
- Antibody-Drug Conjugates (ADCs): These “biological missiles” deliver chemotherapy directly to cancer cells. Fam-trastuzumab deruxtecan (Enhertu) is approved for HER2-low breast cancers, while sacituzumab govitecan (Trodelvy) and datopotamab deruxtecan (Datroway) are used after hormone therapy and chemotherapy fail.
- Immunotherapy: While initially ineffective against HR+/HER2- breast cancer, researchers are exploring combinations with chemotherapy, hormone therapy, or AKT inhibitors to enhance the immune system’s attack on cancer cells. PD-1/PD-L1 inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), are being studied.
Clinical Trials: Accessing Cutting-Edge Treatment
Joining a clinical trial can provide access to experimental therapies before they are widely available. Resources like ClinicalTrials.gov can help you find relevant studies.
The decision of what comes next in treatment is highly individualized. Genomic testing, patient preferences, and the availability of clinical trials all play a role in determining the most effective course of action.
Ultimately, the goal is to extend survival while maintaining quality of life. By understanding the evolving landscape of breast cancer treatment, patients and their doctors can make informed decisions.
