HER2-Low Breast Cancer Is NOT a Separate Clinical Entity: Study

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER-2 targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%–60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argue that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online February 23 in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the US National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers comment.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they add.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concludes.

Not necessarily, Giuseppe Curigliano, MD, PhD, director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Curigliano was approached by Medscape Medical News for reactions to this latest analysis. He said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”

Analysis Quoted by Both Sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology–oncology in the Department of Medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he told Medscape Medical News. It’s a matter of “the eye of the beholder,” he suggested.

Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Howard agreed with Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in five years.

Renewed Interest in This Subgroup

In their paper, Howard and colleagues point out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor positive and triple negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan (T-DXd, Enhertu) doubled progression-free survival vs chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers note.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million US patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010 through 2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until November 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor-positive than triple negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor (PR)-positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio [aOR] of 1.15 for each 10% increase (P < .001).

Non-Hispanic black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple negative breast cancer, at hazard ratios of 0.92 and 0.91, respectively, although the researchers note that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program.

Howard reports no relevant financial relationships. Other authors report numerous relationships with pharmaceutical companies, as listed in the original article. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Meyers Squibb, Scientific Affairs Group, and Ellipsis.

JAMA Oncol. Published online February 23, 2023. Full text

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