Primary Breast Tumors Often Switch HER2 Status on Relapse

Pam Harrison

May 11, 2021

A substantial proportion of primary breast tumors that are HER2 negative (HER2-0) switch to showing HER2-low expression upon relapse, a first-of-its-kind study suggests.

This switch may allow patients to be treated with HER2-targeted therapies, giving a treatment option where there may be few available, inasmuch as HER2-negative tumors are also hormone negative (so-called triple-negative tumors) and are thus difficult to treat.

The new study followed 547 such patients and found that in nearly 30% of cases, tumors converted from — or to — HER2-low status during the disease course, investigators report.

Results also showed that among 14% of patients with triple-negative breast cancer, the cancer converted from HER2-0 to HER2-low expression on recurrence.

"HER2-low expression is highly unstable during disease evolution," commented lead author Federica Miglietta, MD, the University of Padua, Padua, Italy.

"Our findings stress the importance of re-testing HER2 expression on tumor relapse since it might provide the option of new therapeutic opportunities — currently in the context of clinical trials and hopefully in the future in clinical practice — for patients whose tumors convert to HER2-low status," Miglietta added in a statement.

The study was presented at the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress 2021.

Regarding the findings, Aleix Prat, MD, head of medical oncology, Hospital Clinic of Barcelona, Barcelona, Spain, agreed with the authors that the observed changes in HER2-low levels of expression between the primary tumor and samples taken after relapse are "substantial."

However, he also pointed out that "there could be a biological rationale for this — or a technical one — given that there is currently no standardization of how to determine levels of the HER2 biomarker in metastatic biopsies, which could be biopsied from skin, liver, or bone and give different results." (Asked about this, Miglietta said that in their study, the evaluation of HER2-low expression did not differ across different metastatic sites.)

"We need to work out how the HER2 status determines response to therapies — is it the HER2 status in the primary tumor or in the metastatic biopsy that is important?" Prat commented.

If some patients have HER2-low expression in metastatic tumors and now respond to different treatments when they did not respond previously, Prat felt that this, too, might change over time with further relapses. "This all speaks to a much greater need to biopsy metastatic tumors," he emphasized.

"Importantly, we need to determine who will benefit from treatments for HER2-low tumors, because patients will be asking about this in clinic soon if trial results are positive," he added

Primary Tumor Phenotype

In the overall study cohort, 61% of patients had luminal-like, hormone receptor–positive (HR+)/HER2- primary tumors; 25% had HER2+ tumors; and 14% had triple-negative tumors.

On diagnosis, 34% of primary tumors had HER2-low expression; after relapse, 38% had HER2-low expression.

"However, 15% of the total cases switched from HER2-0 (HER2-) primary breast cancer to HER2-low breast cancer at relapse — thus widening the number of patients who can benefit from new investigational agents such as novel antibody-drug conjugate therapies," Miglietta emphasized in an email to Medscape Medical News.

Examples of novel anti-HER2 antibody drug conjugates include trastuzumab deruxtecan (Enhertu) and trastuzumab duocarmazine (SYD985), which showed promising activity in early-phase clinical trials in heavily pretreated advanced breast cancer patients with HER2-low expression, she noted.

In the cohort of patients with HR+/HER2- tumors, 47% of breast cancer cases showed HER2-low expression on the primary tumor.

However, in 21% of these patients, the cancer converted from HER2-negative on the primary tumor to HER2-low on recurrence, Maglietta observed.

The study also showed that HER2-low expression was more frequent in HR+/HER2- tumors compared to triple-negative tumors, at 47% vs 36% on primary tumor samples and 54% vs 36 on relapse samples.

The investigators also calculated the overall rate of HER2 discordance between primary tumors and relapse samples. By the overall rate of HER2 discordance, "we mean the percentage of cases showing conversion in HER2 status when considering the three categories of HER2: HER2-0, HER2-low, and HER2+," Miglietta explained.

Overall, the investigators observed a modification in the HER2 status in 39% of breast cancer cases. This was mostly driven by cases that switched either to or from HER2-low expression. HER2+ breast cancer was, as expected, the most stable, with 10% of the total cases either gaining or losing HER2 positivity, she noted. "We have to think about HER2 expression where HER2- breast cancer encompasses a wide spectrum of HER2 expression levels," Miglietta said.

Indeed, as with the simple distinction between HER2+ vs HER2- status, "the discordance in HER2-low expression during disease evolution may reflect both a true biological shift in HER2 expression as well as technical issues." Although so far, investigators have focused solely on the distinction between HER2+ vs HER2- tumors, "our results support the inclusion of HER2-low [status] in this evaluation," she noted.

In short, the study highlights the great instability of HER2-low expression during disease evolution and as such emphasizes the importance of retesting HER2 expression levels during disease evolution, both on first relapse and on subsequent progression, she added.

The study received no funding. Miglietta and Prat have disclosed no relevant financial relationships.

European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress 2021: Abstract 4MO. Presented May 8, 2021

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