ER/PgR guideline hones approach to ER-low positives

Anne Paxton

April 2020—The CAP and the American Society of Clinical Oncology released two years ago a focused update of their clinical practice guideline for HER2 testing for breast cancer, following an update in 2013. This year comes another update as the CAP and ASCO issue their latest guideline for estrogen receptor and progesterone receptor testing. The goal of the ER/PgR update: to continue improving the analytical performance, diagnostic accuracy, and clinical utility of hormone receptor testing.

“Things were changing in HER2 testing more rapidly than they were in ER testing,” says Kimberly Allison, MD, director of breast pathology at Stanford University Medical Center and co-chair of the multidisciplinary international expert panel in charge of the 2020 guideline update. “But when we were doing the 2018 HER2 update because there was new HER2 data emerging, we realized we needed to look at ER/PgR guideline updating as well.” In addition to a meta-analysis that had been published shortly after publication of the initial 2010 ER/PgR guideline, more data were emerging on the ER-low–positive group, she explains.

The expert panel Dr. Allison co-chaired, after several months of meetings, agreed to continue recommending ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy. But the new guideline contains three key changes: new reporting recommendations for low-positive ER results (one to 10 percent); recommendations that laboratories establish standard procedures to optimize performance, interpretation, and reporting of cases with low-positive or negative results; and a new testing recommendation for patients diagnosed with noninvasive ductal carcinoma in situ (Allison KH, et al. Arch Pathol Lab Med. Epub ahead of print Jan. 13, 2020. doi: 10.5858/arpa.​2019-0904-SA).

“The good news is that a lot hasn’t changed,” Dr. Allison says of the latest recommendations. “The 2010 guideline set several standards that are the same. So we’re really fine-tuning the grey zone a little bit here, just as we did in the HER2 guideline update in 2018, to make sure the more unusual results are as reproducible and clinically useful as possible.”

While the CAP/ASCO guidelines are focused on setting a threshold for ER positivity based on its ability to predict potential benefit from endocrine therapy, she says, ER testing is used for other purposes—determining overall treatment pathways, eligibility for clinical trials, predicting molecular subtype—where the same threshold for positive might not be the best discriminator. Gene expression data and clinical neoadjuvant treatment have shown that a significant proportion of the ER-low–positive cancers tend to profile and behave more like typical triple-negative cancers, Dr. Allison says. “In addition, the data on the benefit of endocrine therapy in this group is more limited and challenging to extrapolate from original ligand binding assay data to IHC percents.” For these reasons, a specific “low positive” reporting category was created, along with a recommended comment explaining the more limited data on this group, for cases with low ER expression—one percent to 10 percent.

The new recommendations respond to the more limited data on endocrine responsiveness in this low-positive group and the overlapping features with ER-negative cancers, says expert panel member David L. Rimm, MD, PhD, director of Yale Pathology Tissue Services, Yale School of Medicine. “The previous guideline set a conservative cutpoint to maximally treat patients with endocrine therapy.” Now, he says, new management strategies for cancer treatment have prompted a reexamination of what the cutpoint should be.

In 2010 there were fewer treatment options for patients with triple-negative results. “It was before the PARP inhibitors were available,” Dr. Rimm says, referring to the targeted breast cancer therapy poly (ADP-ribose) polymerase inhibitors. Thus, much of the focus of the guideline has changed, he says. “It’s become more important to not bias every diagnosis in favor of calling a result ER-positive.” If a patient is two percent positive and the tumor otherwise has features of a triple-negative cancer, “are we doing them an injustice by calling them an ER-positive? Because they aren’t going to get a PARP inhibitor from which they might benefit, we feel that if a patient is ER-negative, that needs to be recognized because there are now options for ER-negative patients.”

Many of the standard ideas about breast cancer treatment still rely, of necessity, on randomized double-blind endocrine therapy trials conducted in the 1970s, Dr. Allison says. A trial that assigned subjects to placebo rather than endocrine therapy would not be considered ethical now if the cancer has ER expression. “You’re not going to do a new trial where you say, ‘Let’s not give endocrine therapy to ER-positive cancers by IHC at different levels and see if there’s a better threshold.’ You’re kind of doing the best you can with the old data and translating it into today’s assay.”

Although, theoretically, anyone who is ER-positive is a candidate for endocrine treatment, Dr. Rimm says, the placebo studies showed that many patients didn’t need that treatment because even if they got the placebo they did well. “However, the patients who got the endocrine therapy did better than the placebo patients. So we had a reason to treat them in both the adjuvant setting and in the metastatic setting.”

In the course of his career, Dr. Rimm says, ER cutpoints have shifted substantially. “When I was a resident, the ER-positive cutpoint was an H-score of 75”—intensity times percentage of cells positive at intensity of 1+, 2+, or 3+. “So that would have meant more than 10 percent positive cells at 3+ intensity would be negative [H-score = 30]. Then they switched it down to 10 percent positive, and then down to one percent positive. So clearly we were always erring toward increasing the number of ER-positive patients because we had a therapy for those patients. But if they were ER-negative, until recently we didn’t have a therapy. We wanted to perhaps officially bias our cutpoint toward making sure that no patient missed the opportunity to benefit from therapy if they had even a whiff of ER presence.”

Now there are new therapies for triple-negative breast cancer and new trials underway that give more options to ER-negative patients than they used to have, Dr. Rimm says. “So we don’t want to be so quick to treat by ER-positive algorithms if the patient might actually be best treated as an ER-negative cancer. There is a grey zone near the threshold.” Among the expert panel members, “There was a lot of discussion about that,” he adds. “In the whole first recommendation and throughout the guideline document, there are nods to the fact that we need to be identifying patients who are ER-low but positive. Even though there are not a lot of patients in that category, clinicians should be aware of them.”

The guideline also recommends that the status of internal controls be reported for cases with zero percent to 10 percent staining, with a special comment included for those lacking internal controls.

Another concern the panel talked about was the possibility of assay drift, with increases in the numbers of ER-positive cancers over time, Dr. Rimm says. “In the 1980s, they used to do the dextran-coated charcoal assay, which was a biochemical assay that might have been pretty strict, and you needed a big chunk of tissue to do it. In the late 1990s, the standard was an ER greater than 10 percent or an H-score of about 75, so that was even more strict. We might have only had 70 percent or 75 percent of patients test ER-positive.”

“Then after we moved the cutpoint down to one percent,” he continues, “many labs switched antibodies. They went from the antibody clone 1D5 to the antibody clone SP1, which is more sensitive, so we then got even more patients who were in the ER-positive group because we kept changing the definition of what was ER-positive. We don’t really know how much assay drift may have occurred with these changes.” The recommendations therefore emphasize the importance of low-positive negative control tissue, such as tonsil, as well as good negative controls to ensure that assay drift is not occurring in the laboratory.

Fortunately, Dr. Allison says, it’s rare to get an ER result in the one percent to 10 percent range. No more than two to four percent of cases tend to fall in that range. “So it’s not as if suddenly a lot of patients will be having a challenging conversation with their oncologists on the pros and cons of endocrine therapy.” The 2020 guideline update continues the 2010 guideline recommendation on such a discussion. “But we’re bringing it more to the forefront as a bigger bullet point with a standardized comment and so on. Any time you have a really low result that is close to a threshold,” she says, “more conversation is needed because the data is more limited.”

Left unchanged in the guideline is the recommendation to continue using validated immunohistochemistry for primary screening for ER expression. “IHC is still the gold standard,” Dr. Allison notes. “The big benefit of IHC is that you can visualize it. Because normal background breast expresses some hormone receptor, you can make sure you are looking at the invasive cancer and not hormone-expressing cells in the background. Ductal carcinoma in situ can also express hormone receptor and kind of mix in with your invasive cancer if you are grinding up tissue and running an assay. And that’s how the old ligand-binding assay used to work, so you had those potential confounders. So IHC has an advantage in that you can look at it as an in situ assay, and visually know what you’re scoring your assay for.”

IHC does have drawbacks. “You have to have well-preserved tissue and consistency in staining, and your observers who are interpreting the assay have to be well trained and know how to score so that everybody scores the same,” Dr. Allison notes. But while the expert panel considered other assay types, such as RNA-based tests like Oncotype DX and the Prosigna gene signature assay, and many RNA companies were listening carefully to see if RNA was going to be acceptable, Dr. Rimm says, “the committee didn’t feel there was sufficient evidence to put one of those in a guideline.”