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MIAMI BEACH -- Accumulating evidence on HER2-low breast cancer has revealed a heterogeneous hormone receptor (HR) status, no distinctive mutation pattern, and changing expression levels over time, which collectively challenge current detection methods, a breast pathologist said here.

About half of all breast cancers exhibit low HER2 expression, which accounts for . Recognition of the clinical relevance of this expression category has forced breast cancer specialists to rethink the historical approach to diagnosis and treatment of HER2-positive disease, said Jorge S. Reis-Filho, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, during the Miami Breast Cancer Conference (MBCC).

"The distinction that we sought to achieve was HER2 3+ and 2+ amplified, not at the very low end between 0 and 1+," said Reis-Filho. "Multiple clinical trials demonstrated the benefits of the humanized monoclonal antibody trastuzumab for HER2-positive disease. Use of HER2 agents has consistently improved outcomes. Not surprisingly, we have seen a proliferation of therapies targeting HER2."

Therapeutic expansion for HER2-positive breast cancer included antibody-drug conjugates (ADCs), which showed considerable promise in HER2-amplified disease. Recognition that ADCs also are effective in HER2-low breast cancer created even more excitement about the therapeutic class, he added.

"The concept here is different," Reis-Filho continued. "We are not trying to silence the pathways activated by HER2. We're just using HER2 as a homing device [that leads to] internalization of the toxic payload. That has led to a new requirement for us in HER2 testing. Rather than finding HER2 2+ or 3+ breast cancers -- the ones that are HER2-amplified -- we have to identify all cancers that express HER2."

The enthusiasm for ADCs in breast cancer reached new heights last year with the results of the DESTINY-Breast 04 trial, which showed that trastuzumab deruxtecan (T-DXd, Enhertu) significantly improved survival versus chemotherapy for patients with metastatic HER2-low breast cancer, irrespective of HR status.

It's Complicated

Information about the biology of HER2-low breast cancer continues to accumulate. Defining HER2-low as 1+ or 2+ and lack of ERBB2 amplification, showed that the vast majority of HER2-low breast cancers are estrogen receptor (ER)-positive. A majority of the tumors are luminal A or B subtype, 10-15% are basal-like, and a "teeny tiny minority" are HER2 enriched.

HER2-low breast tumors exhibit no distinct clinical behavior, said Reis-Filho. A recent analysis of more than 1 million patients with breast cancer presented at the 2022 San Antonio Breast Cancer Symposium showed no consistently significant differences in outcomes for patients with HER2-low and HER2 0 breast cancer. Other recent abstract presentations have shown that occurs independent of PAM50 subtype, and the incidence of oncogenic mutations does not differ between patients with ER-positive and ER-negative tumors, said Reis-Filho.

HER2-low status changes throughout the course of the disease. Studies have shown that HER2 expression status can change from and . Another recent study showed that changes in HER2 expression occur .

Defining HER2-low by mRNA expression also has proved challenging, Reis-Filho continued. Considerable overlap exists between expression levels included in the definition of HER2-low. Molecular subtyping of HER2-low breast cancers has multiple distinct subtypes.

The clinical picture for HER2-low breast cancer and ADCs were further complicated by results of of 177 patients with ER-positive breast cancer and varying levels of HER2 expression, including HER2 0 in about a third of the cohort. The data showed that 30% of the HERR2 0 subgroup responded to T-DXd.

"I hope I have demonstrated that HER2-low breast cancers are an incredibly heterogeneous group of tumors," said Reis-Filho. "They are not a discrete entity, at the pathological levels, at the molecular level, or particularly at the clinical level. They seem not to have a distinct repertoire of somatic genetic alterations, and we are facing real challenges in terms of identification in the clinic."

'Prescient Statement'

During the opening session of MBCC, program chair Patrick Borgen, MD, of Maimonides Medical Center in New York City, showed video clips of some memorable moments in the conference's 40-year history. In one segment from about 20 years ago, Larry Norton, MD, also of Memorial Sloan Kettering, expressed reservations about discounting the clinical significance of tumors with HER2 expression in the range of what is now called HER2-low, which Borgen called a "prescient statement."

Contacted for comment by MedPage Today, Norton said, "I think we limited our creativity somewhat by sticking with arbitrary classifications like 0, 1+, 2+, 3+ -- or, even worse, HER2-negative and HER2-positive. Paraphrasing Mark Twain, 'It is not what you don't know that gets you into trouble, it is what you know for sure that turns out to be wrong.'"

"HER2 protein in cells is a continuous variable, from very low amounts (never completely absent) to amounts orders of magnitude higher," Norton continued. "Furthermore, by focusing on it as a signalling molecule amenable to disruption by antibodies we could have missed the ability of these same antibodies to deliver medicines. Fortunately, the success of antibody-drug conjugates regardless of the level of HER2 expression is putting us back on track. In this regard, I wouldn't discount what we now erroneously call HER2-zero, which is a work in progress."

Calling ADCs "some of the brightest stars in our panoply of emerging anticancer medicines," Norton predicted that "we are just at the dawn of what we will be able to achieve with anatomically targeted therapies like the ADCs."

Summarizing his thoughts, Norton added, "My point is that classifications like 0 to 3+ express a certain level of understanding, but we mustn't allow them to stunt our growth in understanding. And, fortunately, they have not in the case of HER2 -- even if it has taken a couple of decades since my quote shown at the Miami meeting!"

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