ASCO and CAP Release Updated Guideline on Estrogen and Progesterone Testing in Breast Cancer

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ASCO and the College of American Pathologists (CAP) have jointly published an update to a clinical practice guideline on estrogen receptor and progesterone receptor testing in breast cancer.1 The guideline for immunohistochemistry testing of estrogen receptor and progesterone receptors in patients with breast cancer was first released by ASCO/CAP in 2010. This guideline provided the first consensus-based recommendations for hormone receptor predictive testing in this patient population.

Kimberly H. Allison, MD

Kimberly H. Allison, MD

A multidisciplinary expert panel conducted a systematic review of the literature. For the update, Kimberly H. Allison, MD, of Stanford University School of Medicine and Guideline Co-Chair, said that she and colleagues were particularly interested in examining more recent data that might support a modification to the 1% threshold originally recommended for identifying patient eligibility for endocrine therapy. She also said that they were interested in making new recommendations that are specific to uncommon yet challenging low estrogen receptor–expressing cancer.

“While most estrogen receptor–positive breast cancers are strongly estrogen receptor–positive, between 2% and 3% of cancers have only 1% to 10% estrogen receptor expression by immunohistochemistry,” she said. “These cases often present a clinical challenge because they frequently have other characteristics that are more similar to estrogen receptor–negative cancer, such as higher grade, younger age, ‘basal-like’ gene-expression profiles, and good responses to neoadjuvant chemotherapy.”

New Recommendations

Although the guideline continues to recommend that cases with 1% to 100% estrogen receptor expression should be considered estrogen receptor–positive and be eligible for endocrine therapy, the new guideline builds upon the previous version by now recommending a new estrogen receptor–low-positive reporting category. This category can be used with a specific recommended comment for tumors that are estrogen receptor 1% to 10% by immunohistochemistry.

“The comment emphasizes that although the data are more limited and the benefit appears modest, they continue to support a recommendation for endocrine therapy,” said Antonio C. Wolff, MD, FACP, FASCO, of Johns Hopkins University and Guideline Co-Chair. “However, breast cancers with low levels of estrogen receptor expression by immunohistochemistry often have gene-expression profiles that are more similar to estrogen receptor–negative cancers.”

“Breast cancers with low levels of estrogen receptor expression by immunohistochemistry often have gene-expression profiles that are more similar to estrogen receptor–negative cancers.”
— Antonio C. Wolff, MD, FACP, FASCO

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The low-positive reporting category and comment does not apply to progesterone receptor testing, explained Drs. Allison and Wolff. “While progesterone receptor testing is still recommended as routine in invasive breast cancers,” they jointly said, “it is considered optional in cases of ductal carcinoma in situ, but estrogen receptor testing of ductal carcinoma in situ is recommended to determine potential benefit of endocrine therapies to reduce [the] risk of future breast cancer.”

There is also a new recommendation that establishes lab-specific standard operating procedures for patients with 0% to 10% estrogen receptor expression as a means of confirming or adjudicating preliminary results in this range, Dr. Wolff said. The recommendation was added to ensure against the occurrence of false-negatives and to encourage the reproducibility of results that are close to the positive threshold.

The standard operating procedures “should include evaluation and reporting of internal and external controls and should also include correlation with histology,” Dr. Wolff said. Additionally, consideration should be given to additional steps, such as second reviews, to ensure reproducible results in the laboratory by any pathologist.

Practical Implications and Future Need

Dr. Allison concluded that “clinicians should be aware and able to discuss the limited data on estrogen receptor–low-positive cases of invasive breast cancer and potential issues with test results close to a threshold.”

According to Dr. Wolff, challenges exist in validating newer assays or methodologies that are superior to the current standard of immunohistochemistry-based testing. These challenges are predominantly due to the unlikelihood of the original endocrine therapy trials being repeated.

“It would be useful to have an alternative predictive assay to use in cases with estrogen receptor–low-positive immunohistochemistry results,” he said. “It is currently not recommended to use mRNA assays for this purpose due to the lack of clinically validated concordance data in this group, most of which support that mRNA is more often negative in this group than immunohistochemistry.”

Although strategies consisting of artificial intelligence or digital pathology-based “second reads” or response predictors are exciting, Drs. Allison and Wolff agree that these methods are still in very early phases of development. “There is currently a need for well-calibrated, standardized, tissue-based controls that can serve as assay calibrators and ensure that there is not assay drift, such as stronger antibodies creating more positive cases,” Dr. Allison said. “The ideal standardized control tissue would be clinically validated, quantified, and include samples in the lower levels of estrogen receptor expression—not just strong positive—to ensure appropriate limits of detection.” 

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1. Allison KH, Hammond MEH, Dowsett M, et al: Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol. January 13, 2020 (early release online).

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, January 14, 2020. All rights reserved.