The probability of obtaining a HER2-low test result increases with the number of biopsies performed, according to a study of more than 500 biopsy samples in patients with triple-negative breast cancer. For patients originally labeled as having no HER2 expression (HER2 0), each successive biopsy rendered one-third of these patients HER2-low, potentially qualifying them for treatment with fam-trastuzumab deruxtecan-nxki (T-DXd).1
“Our findings show that HER2 status is dynamic in patients with triple-negative breast cancer and support the idea that HER2-low is a spectrum, not a specific entity.”— YAEL BAR, MD, PhD
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“Our findings show that HER2 status is dynamic in patients with triple-negative breast cancer and support the idea that HER2-low is a spectrum, not a specific entity. We further report the novel finding that for patients without a prior HER2-low result, repeat biopsies at disease progression can increase the chance of obtaining a HER2-low result and provide clinically impactful information,” said Yael Bar, MD, PhD, a research fellow at the Massachusetts General Hospital, Boston, who presented the study at the 2023 ASCO Annual Meeting.
Importance of Testing
In the DESTINY-Breast04 study, T-DXd led to improvements in progression-free survival and overall survival for patients with metastatic breast cancer with HER2-low tumors, defined as HER2 1+ or 2+ and nonamplified in situ hybridization (ISH), including the triple-negative subgroup. This led to the approval of T-DXd for HER2-low but not HER2 0 metastatic triple-negative breast cancer, making the detection of HER2-low status of particular clinical significance, she said.
“While HER2-low status is detected in about 30% to 50% of patients with triple-negative breast cancer, several studies have shown that HER2 expression is heterogeneous and also dynamic over time. However, the additive value of repeat biopsies in the detection of a new HER2-low result for patients with triple-negative disease is currently unknown,” Dr. Bar noted.
To inform this issue, Dr. Bar and colleagues conducted a two-part study in 512 patients (median age = 52 years) with triple-negative breast cancer (estrogen/progesterone < 10% and HER2-negative) retrospectively identified from a single institutional database (2000–2022) who had at least one biopsy with known HER2 status. Almost half (48%) were diagnosed with stage II disease, and 8% with diagnosed with stage IV disease; 13% had estrogen receptor–low disease (1%–10%) at first diagnostic biopsy, and about half (54%) had received neoadjuvant therapy.
In part 1 of the study, investigators evaluated the correlation between the number of biopsies performed and the probability of a HER2-low result as well as the additive value of each successive biopsy in detecting a new HER2-low result in patients with prior HER2 0 status. In the second part, they studied the dynamics of HER2 status by comparing matched biopsies from different time points throughout the disease course of patients with triple-negative breast cancer.
More Biopsies, More HER2-Low Tumors Found
The probability of a HER2-low result increased with the total number of biopsies. Among patients who underwent only one biopsy, 59% were found to have HER2-low tumors. This percentage increased to 73% with two biopsies, further reaching 83% for those who had three or four biopsies, and finally reaching 100% among the small subset with at least five biopsies, Dr. Bar reported.
Regarding the detection of HER2-low results with each successive serial biopsy, the investigators found that among the 512 patients who had at least one biopsy, 60% had their first HER2-low result in their initial biopsy. Thirteen percent of the patients who had two biopsies or more had their first HER2-low result on their second biopsy, with a total of 73% demonstrating a known HER2-low status by the second biopsy. Similarly, 9% of the patients with three or more biopsies and 8% of the patients with four or more biopsies had their first HER2-low result in their third or their fourth biopsies, respectively. All patients with five biopsies or more had their first HER2-low result in an earlier biopsy. “New HER2-low results continued to be detected with repeat biopsies,” she said.
Investigators then questioned the additive value of each successive biopsy in detecting a new HER2-low result for patients with prior HER2 0 status, who are ineligible for treatment with T-DXd. Among the 207 patients who had a HER2 0 result in their first biopsy, 127 underwent a second biopsy, which for 32% of patients revealed a new HER2-low result. Out of the 86 patients whose result remained HER2 0 in the second biopsy, 24 patients underwent a third biopsy, and 33% of those had a new HER2-low result on the third biopsy. Similarly, three (38%) of eight patients with prior HER2 0 results only who underwent a fourth biopsy obtained a new HER2-low result. “So, with each successive biopsy, a new HER2-low result was detected for a third of the patients with prior HER2 0 results only,” she said.
Assessing HER2 Discordance
Matched biopsies are two biopsies taken from the same patient at two different time points. In part two of the study, they were used to assess for HER2 status discordance throughout the disease course of patients with triple-negative breast cancer. Among the 242 patients with matched core and surgical -biopsies, HER2 status was changed for 26%, with approximately half changing from HER2 0 to HER2-low, and half from HER2-low to HER2 0. No differences were seen between patients who received neoadjuvant therapy and had residual disease vs patients who had primary surgery.
Among the 71 patients with matched early and metastatic biopsies, HER2 status was changed for 44% of the patients. Thisproportion was significantly higher than that observed in the matched core/surgical biopsies analysis (44% vs 26%). Among patients with matched early and metastatic biopsies discordance, a higher proportion changed from HER2-low to HER2 0 than from HER2 0 to HER2-low (68% vs 26%). Finally, among the 50 patients with two matched metastatic biopsies, HER2 status was changed for 33% of the patients, with 63% changing from HER2 0 to HER2-low.
“When looking at 35 patients with matched early, surgical and metastatic biopsies, overall HER2 status was changed for half the patients (49%) throughout the disease course,” Dr. Bar said. “Most of the change was happening between the early and metastatic phases of the disease.”
Dr. Bar said the findings lead to more questions: Does the dynamic course of HER2 represent the underlying biology of the disease or analytic variation? Considering that repeat biopsies can identify new HER2-low results in patients previously ineligible for T-DXd, should rebiopsy be considered? (The investigators claim that in the absence of a prior HER2-low result, rebiopsy can be considered if “feasible and safe,” especially during metastatic recurrence.) Finally, since emerging data hint at the potential for T-DXd’s efficacy in HER2 0 or “HER2–ultra-low” tumors, she said, “efforts should be made to ensure that potential candidates with triple-negative metastatic breast cancer are not deprived of this potentially life-prolonging medication.”
During the discussion period, several interesting points were raised. One listener questioned whether “we need to do all those biopsies, since every patient had HER2-low status anyway,” to which Dr. Bar responded: “This is a valid point…. However, the administration of T-DXd involves some toxicity. We don’t want to give it outside of its approved indications. In the future, when we have better quantification methods or broader indications, we may not need those repeat biopsies anymore.”
Lajos Pusztai, MD, DPhil
Lajos Pusztai, MD, DPhil, Professor of Medicine at Yale University, Scientific Co-Director of the Breast Center, and Co-Director of the Cancer Center Genomics, Genetics, and Epigenetics Program, congratulated the investigators on the large amount of work that was put into the study but shared these thoughts: “What you have found is consistent with random error in the assay. A 30% misclassification rate would produce a similar close-to-30% discordance rate in repeat testing. Several studies have documented low reproducibility ofdistinguishing a HER2 immunohistochemistry (IHC) 0 from an IHC 1+ signal.2 The problems that arise from multiple testing, when a test is less than 100% accurate, have long been recognized in statistics. If you repeat the biopsies enough, you are guaranteed by chance alone to find a HER2-low result.”
Dr. Bar responded that “this is a possibility” but noted there are other possibilities for obtaining a new HER2-low result with repeat biopsies as “[there is] huge heterogeneity, dynamic changes over time, and some analytic variation … and regardless of the underlining cause of HER2 status dynamics, the detection of a new HER2-low result has meaningful effects for our patients who are ineligible for T-DXd. Additionally, we know from the DAISY3 trial that T-DXd is effective in patients with a very low HER2 expression (ie, HER2 IHC 0), so we think it is reasonable to offer [the treatment] to those patients, based on other options and clinical judgment,” she said.
DISCLOSURE: Dr. Bar reported no conflicts of interest. Dr. Pusztai has received consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Genentech, Personalis, Daiichi, Natera, Exact Sciences, and Foundation Medicine; and has received research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb.
1. Bar Y, Dedeoglu A, Fell G, et al: Dynamic HER2-low status among patients with triple negative breast cancer: The impact of repeat biopsies. 2023 ASCO Annual Meeting. Abstract 1005. Presented June 5, 2023.
2. Fernandez AI, Liu M, Bellizzi A, et al: Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol 8:1-4, 2022.
3. Dieras V, Deluche E, Lusque A, et al: Trastuzumab deruxtecan for advanced breast cancer patients, regardless HER2 status: A phase II study with biomarkers analysis (DAISY). 2021 San Antonio Breast Cancer Symposium. Abstract PD8-02. Presented December 8, 2021.
The invited discussant of the study by Bar et al, Barbara Pistilli, MD, Head of the Breast Cancer Unit at Gustave Roussy Cancer Center, Villejuif, France, noted that third-generation antibody-drug conjugates, such as fam-trastuzumab deruxtecan-nxki (T-DXd), are showing activity across a wide range ...