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HER2-low breast tumors may be a distinct breast cancer subtype

Kaiser Permanente study adds to the evidence that HER2-low breast cancer may have unique biological characteristics

New research from Kaiser Permanente adds to a growing body of evidence that suggests breast tumors that produce low levels of a protein called HER2 may be a distinct subtype of breast cancer.

The study, published March 22 in JAMA Network Open, is believed to be the first to comprehensively evaluate associations between HER2-low tumors and breast cancer risk factors and other aspects of tumor pathology.

Lawrence Kushi, ScD

“There has been interest in the breast cancer field as to whether HER2-low expressing tumors are different from HER2-negative tumors and, if so, in what ways,” said senior author Lawrence Kushi, ScD, a research scientist at the Kaiser Permanente Division of Research. “Our study findings suggest that these tumors not only have a small amount of the HER2 protein but have other unique characteristics.”

For decades, breast tumors have been tested by pathologists to see if they are hormone receptor-positive or receptor-negative. Those that are hormone receptor-positive are treated with anti-estrogen therapies.

Pathologists also test all breast cancer tumors for the HER2 (also known as ERBB2) protein, with the result scored on a scale from 0 to 3+. A 3+ tumor would be categorized as HER2-positive, while tumors that score 0 to 2+ would be categorized as HER2-negative. Cancer therapies that block the HER2 protein are typically only used to treat HER2-positive tumors.

More recently, some studies have suggested that tumors that scored HER2 1+ or HER2 2+  — now called HER2-low — could also potentially respond to HER2-targeted therapies and might be a distinct type of breast cancer. Even so, the 2023 American Society of Clinical Oncology-College of American Pathologists’ guidelines noted there is currently not enough evidence to conclude that HER2-low is a distinct breast cancer subtype with prognostic significance. The new study adds to this evidence base by investigating distinct risk factors or tumor features in women with HER2-low tumors.

Our study findings suggest that these tumors not only have a small amount of the HER2 protein but have other unique characteristics.

— Lawrence Kushi, ScD

The research team studied 2,200 women with breast cancer enrolled in The Pathways Study, an ongoing prospective study of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013. They first looked at whether there were differences based on hormone receptor type. About 20% of the women had hormone receptor-negative tumors. The study showed that within this group, those who had HER2-low tumors had better overall and breast cancer-specific survival than those with HER2-negative tumors.

For the study, the researchers also looked at the presence of tumor infiltrating lymphocytes (TILs), the white blood cells that can kill cancer cells, in the breast tumors. Previous studies have suggested that in some types of breast cancer, women whose tumors have TILs have better survival.

The new study found that among the women with hormone receptor-positive breast cancer, patients who had HER2-low expressing and high-TIL tumors were less likely to have a recurrence and had better survival than those who had HER2-negative and low-TIL tumors.

The researchers also looked at known breast cancer risk factors, such as family history, menopausal status, number of births, smoking history, breast feeding, and body mass index.

They found that patients with HER2-low tumors were less likely than those with HER2-negative tumors to have a family history of breast cancer. None of the other variables the researchers looked at showed any associations. They also found that Asian women had a higher incidence of HER2-low tumors than women of other racial and ethnic groups.

“Overall, our study suggests that HER2-low tumors might be a distinct biologic and clinical entity,” said Kushi. “We believe our findings will help other researchers who are also currently studying HER2-low tumors as well as medical oncologists who must identify the best personalized treatment plans for patients with this type of breast cancer.”

The study was funded by the National Cancer Institute.

Co-authors include Thaer Khoury, MD, Lucas Mendicino, BA, Rochelle Payne Ondracek, PhD, Song Yao, MD, PhD, Warren Davis, PhD, Angela R. Omillian, PhD, MPH, Alfredo V. Chua Jr, MD, and Christine Ambrosone, PhD, of the Roswell Park Comprehensive Cancer Center; and Marilyn Kwan, PhD, Janise M. Roh, MSW, MPH, Lia D’Addario, MPH, Emily Valice, MPH, Daniel Fernandez, BS, and Isaac J. Ergas, PhD, MPH, MFA, of the Division of Research.

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About the Kaiser Permanente Division of Research

The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and society at large. It seeks to understand the determinants of illness and well-being, and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 600-plus staff is working on more than 450 epidemiological and health services research projects. For more information, visit or follow us @KPDOR.


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