Enhertu: A Promising New Treatment for Patients with HER2-Low Breast Cancer

In the coming months, pathologists will be hearing a lot more about Enhertu, a promising new treatment for patients with some forms of HER2-negative breast cancer, referred to as “HER2-low.”

Approved this spring by the Food and Drug Administration, Enhertu can be used in patients with metastatic or inoperable breast cancer to delay disease progression. The drug has been found to reduce the risk of progression of the disease or death by 50 percent versus chemotherapy in patients with HER2-low metastatic breast cancer with both HR-positive and HR-negative disease.

“Pathologists need to know about Enhertu and its indications, as well as how patients are determined eligible to receive this drug,” says Ali Brown, MD, FASCP, ASCP Chief Officer, Medical Quality. “This is another exciting development that further emphasizes the vital role that pathologists play in the care of our patients with breast cancer.” 

For decades, the drug Herceptin has been used to target tumor cells with HER2 overexpression and has been very effective in treating patients with breast cancers that have HER2 amplification.  

“Pathologists have assessed HER2 status for patients with breast cancer for decades,” Dr. Brown explains. “Patients with tumors showing HER2 overexpression were then eligible to receive Herceptin. Fast forward to today. This more recent drug, Enhertu, is different from Herceptin. It not only targets cells with HER2 overexpression, but it also has a mechanism to deliver chemotherapy selectively to the tumor cells. It takes this tailored therapy and marries it to a more typical cytotoxic chemotherapeutic drug. Additionally, studies found that patients who did not meet the current criteria for HER2 positivity actually benefited from Enhertu as well.”

In recent studies, patients with a low-level of HER2 expression (1+ or 2+ by immunohistochemistry with no amplification by in situ hybridization), though not enough to be considered positive—or eligible to receive Herceptin—those patients still showed a benefit. Since approximately 50 percent of all breast cancers fall into the 1+ or 2+ categories, this drug opens the door for so many more patients to receive  effective treatment in the clinically advanced setting, where it was shown to significantly delay tumor progression.^1-4 

Going forward, Dr. Brown adds, pathologists will hear more of an emphasis from their oncology colleagues on reporting negative HER2 immunohistochemistry results as either 0 or 1+, since patients with a 1+ result are eligible for Enhertu treatment. For patients with a HER2 2+ result, in situ hybridization is required to ensure that patients do not have HER2 gene amplification 

For pathologists, Enhertu is adding a new caveat to guideline recommendations for HER2 testing. “It’s an important time for many of our patients with advanced breast cancer who previously were not eligible for this treatment,” Dr. Brown says. “As pathologists we are on the front lines, ensuring our patients are afforded this new opportunity.”  

References
1.  Ahn S, et al. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020; 54(1): 34-44.
2. Schalper K, et al. A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas. Arch Pathol Lab Med. 2014; 138:213-219.
3. Schettini F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. npj Breast Cancer. 2021; 7:1; https://doi.org/10.1038/s41523-020-00208-2.
4. Denkert C, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. 2021. Lancet Oncol; 22: 1151–61.