Understanding HER2 positive Breast Cancer and its Treatment

Discover what it means to have HER2‑positive or HER2‑low breast cancer, how testing is done, and how modern targeted drugs like trastuzumab, pertuzumab, Enhertu, and tucatinib can control the disease for many years in many women.

Charles H. Weaver, MD
6–8 minutes
Home » Breast Cancer » Understanding HER2 positive Breast Cancer and its Treatment

HER2 (human epidermal growth factor 2) is a receptor on the surface of breast cells. When HER2 is “turned on” it causes the cells to grow and reproduce. Normal breast cells have 2 copies of the gene that makes HER2. In contrast to normal breast cells some have more than two HER2 genes and/or produce too much HER2. This results in more HER2 receptors on breast cells – a condition doctors refer to as “over expression” Over expression of HER2 leads to increased breast cell production or cancer.

Doctors currently test for HER2 with two different tests.

  • IHC – measures the number of HER2 receptors on a scale of 1-3. 3 + means there are too many.
  • ISH – counts the number of HER2 genes.

Breast cancer is considered HER2-positive when there is evidence of HER2 over expression as shown by an immunohistochemistry (IHC) assay score of 3+ or gene amplification on an insitu hybridization (ISH) assay in at least 1 tumor sample.9,10

HER2 + “positive” breast cancers can be treated with precision cancer medicines that target the HER2 receptor. Approximately 20-25% of breast cancers are referred to as HER2-positive. There are several precision cancer medicines that target HER2 and the use of these medications improves the outcomes of women with both early-stage and advanced HER2-positive breast cancer. In fact HER2+ breast cancer can be controlled for many years in most women.

Medications for HER2 + Breast Cancer

Herceptin (trastuzumab)

Anti-HER2 Precision Cancer Medicines

  • Tykerb – small‑molecule TKI used in combination with capecitabine for certain patients with advanced or metastatic HER2‑positive breast cancer.​

  • Perjeta – monoclonal antibody that targets a different part of HER2 than trastuzumab; standard component of first‑line HER2‑positive metastatic regimens.​

  • Nerlynx – irreversible pan‑HER TKI approved for extended adjuvant treatment in high‑risk HER2‑positive early breast cancer.​

  • Kadcyla (T‑DM1) – antibody–drug conjugate that combines trastuzumab with emtansine, approved for residual disease after neoadjuvant therapy and for metastatic HER2‑positive breast cancer.​

  • Enhertu – high‑drug‑to‑antibody–ratio HER2‑targeted ADC FDA‑approved for unresectable or metastatic HER2‑positive, HER2‑low, and HER2‑ultralow breast cancer in multiple later‑line settings.​

  • Tucatinib – selective HER2 TKI, FDA‑approved with trastuzumab and capecitabine for unresectable or metastatic HER2‑positive breast cancer, including patients with brain metastases, after at least one prior anti‑HER2 regimen.​

  • Margetuximab – Fc‑engineered anti‑HER2 monoclonal antibody now FDA‑approved with chemotherapy for adults with metastatic HER2‑positive breast cancer after ≥2 prior anti‑HER2 regimens (≥1 in the metastatic setting).​

  • Pyrotinib – irreversible pan‑HER TKI with conditional approval and guideline‑listed use for HER2‑positive advanced breast cancer in China; not FDA‑approved but supported by growing real‑world and phase 3 data.

What is HER2 “low” Breast Cancer?

HER2‑low breast cancer describes tumors that have a small amount of HER2 on the cell surface but not enough to be considered HER2‑positive. Tumors with an IHC score of 0 are HER2‑negative, while tumors with IHC 1+ or 2+ and a negative ISH result are now classified as HER2‑low rather than simply HER2‑negative. HER2‑negative tumors can be hormone receptor–positive or triple‑negative; only HER2‑positive tumors (IHC 3+ or IHC 2+/ISH‑positive) clearly benefit from traditional anti‑HER2 therapies.​

Newer antibody–drug conjugates have changed treatment options for this group. Enhertu (fam‑trastuzumab deruxtecan‑nxki) is FDA‑approved for adults with unresectable or metastatic HER2‑low (IHC 1+ or IHC 2+/ISH‑) breast cancer after prior chemotherapy, and more recently for unresectable or metastatic HR‑positive HER2‑low or HER2‑ultralow disease that has progressed on endocrine therapy. Ongoing trials continue to evaluate additional agents and to refine which HER2‑low subgroups derive the greatest benefit from these targeted therapies.

What are the side effects of HER2 therapies?

  • Side effects are unique to each drug used to target HER2.
  • Nausea, diarrhea, skin rash can occur with Herceptin and other anti HER2 treatments.
  • Herceptin and side effects to the heart.
  • Enhertu is associated with a significant “late” toxicity to the lungs known as Interstitial Pneumonitis.

Should all HER2 + breast cancers be treated?

All invasive and metastatic HER 2 positive breast cancers benefit from HER2 directed therapy. Even very small cancers appear to benefit. A U.S. study evaluated the records of 965 women with small cancers that had not been treated with HER2-targeted therapy or chemotherapy. By the end of five years, 6% of women with HER2-negative breast cancer had a recurrence compared with 23% of women with HER2-positive breast cancer.

Standard HER2 Treatment Regimens

Early Stage Breast Cancer

The standard treatment regimen for early stage HER2-positive breast cancer uses Herceptin.

Advanced Breast Cancer

Advanced HER2‑positive breast cancer is now treated with several effective targeted regimens that are sequenced to maximize disease control and account for HER2 expression level, hormone receptor status, CNS involvement, and prior therapies.​

Evolving first-line options

  • THP (trastuzumab + pertuzumab + taxane) remains an established standard first‑line regimen for metastatic HER2‑positive breast cancer, typically followed by maintenance trastuzumab + pertuzumab.​

  • Recent phase 3 DESTINY‑Breast09 data show a robust progression‑free survival benefit with first‑line trastuzumab deruxtecan (Enhertu)–based regimens, and FDA has now approved Enhertu with pertuzumab for unresectable or metastatic HER2‑positive breast cancer in the first‑line setting.​

Second-line focus on Enhertu

  • Current guidelines and regulatory updates position Enhertu as the preferred second‑line therapy after THP for most patients with metastatic HER2‑positive disease, based on superiority over T‑DM1 in DESTINY‑Breast03.​

  • Enhertu is also approved in earlier metastatic lines for HR‑positive HER2‑low or HER2‑ultralow disease after progression on endocrine therapy, broadening its role beyond classic HER2‑positive tumors.​

Later-line and CNS-directed therapy

  • The tucatinib + trastuzumab + capecitabine triplet (HER2CLIMB regimen) is a preferred later‑line option, particularly valuable for patients with active or stable brain metastases given its demonstrated intracranial activity and survival benefit.​

  • In practice, many algorithms now sequence:

    • 1st line: THP or Enhertu‑based regimen (per new approval and patient factors).

    • 2nd line: Enhertu (if not used first line) or T‑DM1 in select cases.

    • 3rd line and beyond: tucatinib + trastuzumab + capecitabine and other TKIs/ADCs, with tucatinib prioritized for CNS disease.​

Toxicity considerations

  • Enhertu carries a boxed warning for interstitial lung disease/pneumonitis, so baseline lung status, symptoms, and imaging are critical when considering or sequencing this agent.​

  • Tucatinib‑based regimens are associated with manageable GI and hepatic toxicities and have become a key strategy for controlling brain metastases in HER2‑positive metastatic breast cancer.

What is the role of HER 2 in DCIS?

Compared with invasive breast cancer, DCIS more often expresses HER2, however current research does not support the use of human HER2 – directed therapy in DCIS.

References:

  1. nccn.org/patients/guidelines/breast-invasive/22/
  2. Roses RE, Paulson EC, Sharma A et al. HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiology, Biomarkers & Prevention. 2009 18: 1386-1389.
  3. Gonzalez AM, Litton JK, Broglio KR et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. Journal of Clinical Oncology[early online publication]. November 2, 2009.
  4. Curigliano G, Viale G, Bagnardi V et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. Journal of Clinical Oncology [early online publication]. November 2, 2009.
  5. Burstein HJ, Winer EP. Refining therapy for human epidermal growth factor receptor 2-positive breast cancer: T stands for trastuzumab, tumor size, and treatment strategy. Journal of Clinical Oncology [early online publication]. November 2, 2009.​
  6. nccn.org/patients/guidelines/stage_iv_breast/30/
  7. NCCN Guidelines Version 3.2013 Ductal Carcinoma in Situ (Accessed on August 07, 2013).
  8. Allred DC, Clark GM, Molina R, et al. Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 1992; 23:974.
  9. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-1962. doi:10.1200/JCO.19.02488
  10. Schettini F, Prat A. Dissecting the biological heterogeneity of HER2-positive breast cancer. Breast. 2021;59:339-350. doi:10.1016/j.breast.2021.07.019
  11. Agostinetto E, Rediti M, Fimereli D, et al. HER2-low breast cancer: molecular characteristics and prognosis. Cancers (Basel). 2021;13:2824. doi:10.3390/cancers13112824
  12. Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. doi:10.1200/JCO.2018.77.8738
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