Blog September 19, 2022

ASCO 2022 – Part 1: Redefining Breast Cancer Classification and Treatment

Each June, the American Society for Clinical Oncology (ASCO) Annual Meeting spotlights the latest and most exciting clinical research and related news in the field of cancer therapy and diagnosis. This year’s meeting was no exception, marked by several advances that we found noteworthy. In this first of two ASCO posts, we look at an important new development in breast cancer that greatly expands the number of patients who might benefit from HER2-targeting treatment.  

Redefining Breast Cancer Treatment with Enhertu

Exciting data presented at ASCO showed for the first time that many breast cancer patients who have been previously considered ineligible for a HER2-targeted therapy due to low expression of the marker (HER2-low) may benefit from treatment with Enhertu, AstraZeneca and Daiichi’s antibody-drug conjugate (trastuzumab-deruxtecan). Results of the Phase 3 Destiny-Breast04 trial showed that Enhertu reduced the risk of disease progression or death by 50% and the risk of death by 36% in patients with previously treated HER2-low metastatic breast cancer. At a median follow-up period of 18.4 months, Enhertu extended the median time to disease progression to 9.9 months versus 5.1 months for patients treated with chemotherapy. Overall survival was also extended for the Enhertu-treated patients to a median of 23.4 months versus 16.8 months for chemotherapy.

ENHERTU is a specifically engineered HER2-directed antibody-drug
conjugate (ADC)
HER2-directed mAb3

HER2 expression is currently determined through two tests: an immunohistochemical (IHC) stain that allows semi-quantitative measure of the amount of HER2 protein in cancer cells, and a test that detects amplification of the HER2 gene via in situ hybridization (ISH). Today, tumors with an IHC rating of at least 3+ or an IHC rating of 2+ and a positive ISH test are considered HER2 positive. The results of Destiny-Breast04 suggest that breast cancer classification should be revised to include the new category of HER2-low, encompassing those patients with IHC score of 1+ or 2+, but with a negative ISH result. Such a reclassification would greatly expand the number of breast cancer patients who can benefit from HER2 targeted therapy, and the FDA granted Breakthrough Therapy designation to Enhertu in HER2-low metastatic breast cancer in April of this year. The drug is also being studied in other HER2-expressing tumor types such as gastric, lung, and colorectal cancers. Other companies, including Seagen and RemeGen, are also developing HER2-targeted antibody-drug conjugates for patients expressing low HER2 levels.

The relatively high response by HER2-low patients to Enhertu in the Destiny-Breast04 trial raises the question of whether there is an ultra-low HER2 population that might also achieve some response to treatment. What is the threshold of HER2 expression below which a patient is truly HER2 negative? Could newer, more sensitive, and more accurate diagnostic methods aid in better identifying patients who might benefit from HER2-targeted therapies? In light of these issues, recent advances have already started to uncover answers and produce solutions.

Currently, it is difficult to distinguish between IHC 0 and IHC 1+ patients, with only about 26% diagnostic agreement between expert pathologists. Moreover, some health providers are only using ISH tests to identify clearly HER2 positive patients and considering all others to be HER2 negative. However, researchers at Yale have recently published findings on a new reproducible and tumor-agnostic quantitative assay that measures HER2 protein by mass spectrometry. The new assay is sensitive at the attomole/mm2 levels, and the researchers have determined that the low HER2 range is between 2-20 attomole/mm2.

Based on these findings, how many more patients stand to gain from such changes in breast cancer classifications and treatment? Will the benefits of Enhertu and potentially, similar drugs in HER2-low breast cancer extend to HER2-low patients with other cancers as well?

In our next post, we will discuss two other noteworthy pieces of ASCO news: startling, although early, positive news in colorectal cancer; and new research that has identified easily measured markers for predicting the risk of severe cytokine release syndrome, the potentially life-threatening adverse reaction associated with CAR-T and other immuno-oncology therapies.