Targeted Options Explained: HER2-Low to PARP Inhibitors

Targeted therapies are reshaping breast cancer care by linking each treatment decision to the biology of the tumor and a person’s medical history. For many in the United States, comprehensive testing now goes beyond hormone receptors and classic HER2 status to include HER2‑low categorization, germline BRCA1/2 status, PIK3CA alterations, ESR1 mutations, and more. Understanding how these results inform choices—from antibody–drug conjugates to PARP inhibitors—can clarify discussions with your oncology team and local services in your area.

This article is for informational purposes only and should not be considered medical advice. Please consult a qualified healthcare professional for personalized guidance and treatment.

Which targeted breast cancer treatment options?

Targeted options depend first on tumor subtype. In hormone receptor–positive, HER2‑negative disease, endocrine therapy remains foundational. It is often paired with CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) to help delay progression. If a PIK3CA mutation is present, a PI3K inhibitor such as alpelisib may be added with endocrine therapy. For certain pathway alterations (for example, ESR1), oral selective estrogen receptor degraders like elacestrant can be considered after prior endocrine therapy. In HER2‑positive cancers, regimens built on trastuzumab and pertuzumab, followed by antibody–drug conjugates such as ado‑trastuzumab emtansine (T‑DM1), are standard components.

A notable advance is the recognition of HER2‑low tumors (immunohistochemistry 1+ or 2+ with negative in situ hybridization). These cancers are not HER2‑positive by traditional criteria but can respond to specific antibody–drug conjugates. Trastuzumab deruxtecan (T‑DXd) delivers chemotherapy payloads directly to cells expressing low levels of HER2, offering an option after prior treatments. As with any therapy, benefits must be weighed against side effects; with T‑DXd, clinicians monitor for interstitial lung disease/pneumonitis and manage promptly if suspected.

How do metastatic breast cancer therapies fit in?

In metastatic settings, the goals are prolonging survival, controlling symptoms, maintaining quality of life, and sequencing treatments strategically. For hormone receptor–positive, HER2‑negative metastatic disease, many begin with endocrine therapy plus a CDK4/6 inhibitor. If progression occurs and a PIK3CA mutation is present, a PI3K inhibitor may be used; otherwise, options include everolimus with endocrine therapy, chemotherapy, or an antibody–drug conjugate such as sacituzumab govitecan.

HER2‑positive metastatic breast cancer typically starts with a trastuzumab/pertuzumab‑based combination with chemotherapy. After progression, T‑DM1 and other HER2‑targeted options can follow. Tucatinib, combined with trastuzumab and capecitabine, is often considered for patients who have previously received HER2‑targeted therapy, including those with treated or active brain metastases. For HER2‑low metastatic disease after prior lines, T‑DXd has emerged as a targeted option that can extend control in appropriately selected patients.

Where does immunotherapy for breast cancer help?

Immunotherapy for breast cancer is most established in triple‑negative disease. Pembrolizumab, an immune checkpoint inhibitor, can be combined with chemotherapy for people with metastatic triple‑negative tumors that express PD‑L1 above a defined threshold, determined by a test called the combined positive score. In early‑stage, high‑risk triple‑negative disease, immunotherapy may be part of pre‑ and post‑surgery treatment plans.

Because activating the immune system can affect healthy tissues, clinicians monitor for immune‑related effects like thyroid changes, skin reactions, colitis, hepatitis, or pneumonitis. Prompt reporting of new symptoms is important. Outside triple‑negative disease, immunotherapy may be considered for rare biomarker situations (for example, microsatellite instability–high or high tumor mutational burden), but these are uncommon in breast cancer.

Current triple negative breast cancer treatment paths

Triple negative breast cancer treatment often starts with chemotherapy; however, targeted additions can make a difference. If PD‑L1 is positive, pembrolizumab plus chemotherapy is a common consideration in the metastatic setting. For people with a germline BRCA1 or BRCA2 mutation and HER2‑negative disease, PARP inhibitors such as olaparib or talazoparib may be used in the metastatic setting and, in certain circumstances, after surgery for high‑risk early disease. Sacituzumab govitecan, an antibody–drug conjugate targeting Trop‑2, is another option after prior therapies and is used for both triple‑negative and hormone receptor–positive, HER2‑negative metastatic disease.

Platinum chemotherapies (such as carboplatin) are frequently used in triple‑negative disease, particularly when BRCA mutations are present. Clinical trials continue to explore combinations and sequencing—for example, pairing immunotherapy with targeted agents or novel antibody–drug conjugates—to improve durability of response.

From HER2‑low to PARP inhibitors: who benefits?

HER2‑low categorization is determined by pathology testing (IHC 1+ or 2+ and ISH‑negative). For patients with metastatic HER2‑low tumors who have received prior therapy, T‑DXd has shown clinically meaningful activity. Patient selection accounts for prior treatments, lung health, and monitoring capability. Discuss with your oncology team how HER2 testing was performed and whether the result supports HER2‑low–directed therapy.

PARP inhibitors target a DNA repair vulnerability in tumors with germline BRCA1/2 mutations. By blocking the PARP pathway, these drugs can selectively harm cancer cells that already have impaired DNA repair. Genetic counseling and testing are essential to confirm eligibility. In practice, PARP inhibitors may delay disease progression and sometimes reduce the need for immediate chemotherapy. Side effects can include anemia, fatigue, nausea, and, less commonly, changes in platelets or white blood cells—regular labs help ensure safe use.

Making sense of testing and sequencing

Precise treatment depends on accurate, up‑to‑date testing. Discuss with your care team whether your pathology includes HER2‑low scoring and whether germline testing for BRCA1/2 was performed. For hormone receptor–positive disease, ask about PIK3CA and ESR1 testing, which can open doors to PI3K inhibitors or oral SERDs. Sequencing often follows a principle of using the least toxic effective option first, reserving chemotherapy for when targeted approaches are exhausted or when rapid disease control is needed. Accessing multidisciplinary input through comprehensive cancer centers or local services in your area can help align treatment with personal goals and preferences.

In summary, targeted therapies now span the spectrum from HER2‑positive and HER2‑low antibody–drug conjugates to DNA repair–focused PARP inhibitors, with immunotherapy primarily benefiting PD‑L1–positive triple‑negative disease. The most effective plan emerges from careful biomarker testing, thoughtful sequencing, and proactive side‑effect monitoring within a care team you trust.