ASCO-CAP Guideline Update Confirms Previous Recommendations for HER2 Testing in Breast Cancer

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In partnership with the College of American Pathologists (CAP), ASCO has affirmed findings from its 2018 practice guideline on the use of HER2 testing in breast cancer. Notably, the ASCO/CAP expert panel found there is currently no justification for a new designation of HER2 test results for patients with immunohistochemistry (IHC) findings that indicate low levels of HER2, such as an IHC score of 0 or 1+.

“The ASCO/CAP panel had concerns that it may be premature to create a new category, because the implication would be that tumors that test IHC 1+ or IHC 2+ without gene amplification and are called HER2-low behave differently or should be treated differently than tumors that test HER2 IHC 0. But we don’t know that yet,” said Antonio C. Wolff, MD, of Johns Hopkins University and Co-Chair of the Expert Panel. “Right now, there’s no evidence that HER2 IHC tests have sufficient clinical validity to define a new biologic entity that behaves differently as a prognostic marker from tumors that test HER2 IHC 0 or that such a category has clinical utility as a predictive marker to identify tumors that respond differently to specific therapies.”

The guideline update, “Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update,” was recently published in the Journal of Clinical Oncology.1

An Incomplete Story

HER2-targeted treatments, such as the monoclonal antibody trastuzumab, have only benefited patients whose tumors display a markedly high level of HER2 proteins (primarily because of HER2 gene amplification), that is, cancers classified by IHC or by in situ hybridization (ISH) testing as HER2-positive for protein overexpression or gene amplification and likely dependent on this growth receptor pathway. Although only about 10% to 20% of breast cancers are classified as HER2-positive by these criteria, breast cancers without HER2 protein overexpression/gene amplification still have some amount of HER2 protein present.

Cancers considered HER2-negative for protein overexpression have varying levels of protein expression by IHC, such that they can score 0, 1+, or 2+. However, it is not clear whether IHC testing is sensitive enough to consistently detect the lowest levels of the HER2 protein (ie, whether IHC 0 truly means no HER2 is present). In fact, the available tests were developed only to differentiate between tumors that are HER2-positive from those “not positive.”

Given the success of trastuzumab in improving survival among metastatic and early-stage breast cancers that are HER2-positive, antibody-drug conjugates that link a chemotherapy payload to this antibody were developed.2,3 One of them, fam-trastuzumab deruxtecan-nxki, was tested in the DESTINY-Breast-04 trial.3 In the trial, patients with tumors classified as IHC 1+ or IHC 2+/ISH-negative (but not HER2 IHC 0) were enrolled to determine whether they could also benefit from treatment that has traditionally benefited only HER2-positive tumors.

Trial investigators found significantly better overall survival (hazard ratio [HR] = 0.64, P = .003) and progression-free survival (HR = 0.51, P < .001) with trastuzumab deruxtecan vs physician’s choice of treatment.4 Investigators subsequently adopted the terminology “HER2-low” to describe IHC 1+ or 2+/ISH-negative tumors. However, these findings do not give a complete picture of the levels of HER2 IHC expression needed for treatment response because patients classified as IHC 0 were excluded from the study.

DESTINY-Breast-04 was the major impetus in ASCO/CAP revisiting the 2018 guideline, because pathologists and clinicians are now being asked to identify patients for treatment with this new drug. Based on the trial results and findings from a review of the available evidence, the panel was not persuaded to revise the existing HER2 classifications.

“While a terminology change was not recommended due to the lack of data [in IHC 0 tumors], the standard IHC result categories have a new clinical implication in the metastatic setting,” said Kimberly Allison, MD, of Stanford Medicine and Expert Panel Co-Chair. “Pathologists need to be aware that an IHC 0 vs IHC 1+ result may change treatment options for patients with metastatic breast cancer since patients with IHC 1+ and 2+/ISH-negative results are now eligible for treatment with trastuzumab deruxtecan. Previously, an IHC 0 vs IHC 1+ result made little clinical difference.”

Laying the Groundwork for the Future

DESTINY-Breast-04 did not lead to new testing recommendations, but it did create a pathway for future research that will hopefully answer the questions that DESTINY-Breast-04 could not. The DESTINY-Breast-06 trial ( identifier NCT04494425) is currently enrolling patients with IHC > 0 but < 1+ and should help provide some additional information about tumors that test in between IHC 0 and IHC 1+, which is something very difficult to define using available IHC assays.

Dr. Wolff noted the importance of looking for potential differential benefits of anti-HER2 therapies based on the specific levels of HER2 present. Such studies could help clarify whether the HER2 biomarker has any predictive value such that patients with more HER2 expression benefit more from HER2-targeted therapy than patients with low or very low levels of HER2.

“If DESTINY-Breast-04 had allowed patients with IHC 0 to enroll and the findings had been positive, it is possible that we would not be having this conversation,” Dr. Wolff said. “In a couple of years, we may learn that all patients without HER2 protein overexpression or gene amplification benefit from this new antibody-drug conjugate, perhaps except for a very small number of patients with tumors that may be truly HER2 IHC 0. Regardless, this new drug offers two very different ways to target HER2—one by disrupting a hyperactivated pathway and the other by more targeted delivery of chemotherapy.”

Dr. Allison also emphasized the importance of refining testing procedures going forward. Specifically, the HER2 IHC test was designed to detect high levels of protein overexpression that correlate with gene amplification. But another more sensitive and quantitative test methodology may be required if there is truly a clinical difference in the lowest levels of protein expression, she said.

“It is not a surprise that our 2018 recommendations were affirmed in this update. We knew the limitations of the DESTINY-Breast-04 trial population,” Dr. Allison added. “But this update is still important for maintaining standards of care and to avoid confusion and laboratories variably adopting nonstandard terminology. The guideline update makes it clear that laboratories do not need to change their current reporting but should be aware of the new clinical impact of HER2 IHC interpretations in the lower range of the test and do their best to maintain standards in HER2 test performance and interpretation.” 


1. Wolff AC, Somerfield MR, Dowsett M, et al: Human epidermal growth factor receptor 2 testing in breast cancer: ASCO–College of American Pathologists guideline update. J Clin Oncol. June 7, 2023 (early release online).

2. Martínez-Sáez O, Prat A: Current and future management of HER2-positive metastatic breast cancer. JCO Oncol Pract 17:594-604, 2021.

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Trastuzumab for early-stage, HER2-positive breast cancer: A meta-analysis of 13,864 women in seven randomised trials. Lancet 22:1139-1150, 2021.

4. Modi S, Jacot W, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9-20, 2022.

Originally published in ASCO Daily News © American Society of Clinical Oncology. ASCO Daily News, June 8, 2023. All rights reserved.