Breast Cancer Changes When it Spreads to Nodes in Nearly Half of Patients

Zosia Chustecka

November 12, 2009

November 12, 2009 — A new study in breast cancer patients with nodal disease has found that the expression of key receptors in nodal tumor tissue and in primary breast cancer differsin nearly half the patients, a much higher proportion than has been reported previously.

The difference between the receptors found in the primary tumor and those found in metastatic disease "might be an important reason for treatment failure," the researchers explain.

The study was published online November 3 in the Annals of Oncology, and was carried out by researchers from the Breakthrough Breast Cancer Research Unit at the University of Edinburgh in Scotland.

The team analyzed the expression of 3 receptors: estrogen receptor (ER), progesterone receptor, and human epidermal growth-factor receptor 2 (HER2). The expression of these are used to guide decisions about adjuvant therapy for breast cancer; ER-positive patients are offered hormonal therapy (tamoxifen and/or aromatase inhibitors) and HER2-positive patients are offered trastuzumab (Herceptin).

Those treatment decisions are made on the basis of the receptor status in the primary tumor, obtained from a diagnostic core biopsy or resection specimen. But as the breast cancer spreads, its characteristics can change. Several studies have documented this phenomenon, but have found changes in receptors in only a small proportion of patients (<20%).

This latest study showed a change in nearly half of the patients studied (46.9%).

In addition, many of the differences in expression between the primary tumor and the node were "large-magnitude (>5-fold) changes," the team reports.

"We were surprised that such a high proportion of tumors change form when they spread beyond the breast," lead researcher Dana Faratian, MD, said in a statement. "This suggests there is a need to test which type of disease a woman has in the lymph nodes, because it could radically alter the course of the treatment she receives. We are now trying to set up a clinical trial to see how these results could benefit patients."

"This is a very interesting paper," says Paul E. Goss MD, PhD, director of breast cancer research at Massachusetts General Hospital in Boston, who was approached for an independent comment.

"These findings could go on to be confirmed in larger patient subsets, and prospectively, and could turn out to be very useful for guiding treatment decisions in the future," Dr. Goss told Medscape Oncology.

However, he adds, "at the moment the results cannot be used in the clinic."

Another breast cancer experts agrees. Kathy Miller, MD, from the Indiana University School of Medicine in Indianapolis, who has a new videoblog on Medscape Oncology, said: "While the data lead to a fascinating hypothesis, they shouldn't change treatment at this point."

Largest Study to Date

The researchers say that their finding of a higher proportion of disparate cases might stem from a number of factors. They note that this study is the largest of its kind to scrutinize all 3 receptors, pointing out that analysis was performed on 385 primary tumor and 211 nodal cancer samples.

This study also used a method of measuring the receptors that is more sensitive than traditional methods (high-throughput quantitative immunofluorescence [AQUA HistoRx technology] vs manual immunohistochemistry).

In addition, this study population was "biased toward patients with large or high-grade invasive breast carcinomas, while other studies included a broader population of patients," the researchers note. Previous studies have shown that patients with distant metastases have lower concordance between breast and metastases than patients who had only local lymph node involvement, which indicates that in advanced disease there is more likely to be a receptor-status change, they add.

Reason for Treatment Failure?

Although the proportion of disparate cases was higher, the nature of the changes seen in receptor expression was similar to those seen in previous studies, the researchers explain.

For instance, 35 cases (18%) changed from ER-positive breast to ER-negative node disease, which is similar to what has been reported in 2 other studies. Another 20 cases (10%) changed from ER-negative breast to ER-positive node disease. "This is in keeping with previous studies where it has been shown that discordant cases more commonly shift from positive breast to negative node than vice versa," they write.

It is possible that such patients — with ER-positive breast and ER-negative node disease — are being "inappropriately treated with endocrine therapy and might, therefore, be spared unnecessary therapy and unpleasant side effects," the researchers note.

But the consequences could also be the exact opposite. In this study, 9.9% of patients displayed disparity in HER2 status, and the majority of the changes went from HER2-negative breast to HER2-positive node disease. These patients would be considered HER2-negative and would be "denied trastuzumab, despite the potential to manage their systemic disease," the researchers say.

"Our data show that there may be added benefit to molecular testing on nodal metastases as well as the primary tumor in order to guide adjuvant therapy," the researchers conclude.

"While this might incur additional financial costs for specimen processing and molecular analysis, savings could be made by avoiding overtreatment. This would reduce morbidity for patients and ultimately has the potential to produce more favorable outcomes," they add.

However, they emphasize that a prospective phase 3 clinical trial will be needed to assess whether or not the clinical outcome is altered by taking into account the nodal tissue results for receptor expression when making the decision on adjuvant therapy.

This is a point that was also made by Dr. Goss when he was discussing a similar study at last year's annual meeting of the American Society of Clinical Oncology. He emphasized that biologic findings need to be prospectively correlated with subsequent response to therapy.

The study that Dr. Goss was discussing covered the same subject — variation in key receptors that guide clinical management of primary and metastatic tissue. However, that previous study focused on "distant metastatic tissue that is difficult to access and comes from a variety of sites, which complicates the analyses and interpretation," he told Medscape Oncology.

This latest study compares the key markers in the primary and "the regional lymph node metastases, a tissue more routinely accessed and more homogenous to interpret," he stated.

Both of the experts approached for comment highlighted the fact that this study used more sensitive technology to measure receptors. "With that they found a much greater range of expression than we are able to distinguish with IHC," Dr. Miller said, but she questioned whether this was useful.

"The more sensitive technique may be the equivalent of 'splitting hairs' and further subdividing the categories in a way that isn't clinically relevant," Dr. Miller told Medscape Oncology.

"For instance, if your tumor is ER-negative with IHC but ER-positive at low levels with the more sensitive technique, the level of ER may be too low to expect any benefit from hormone therapy." she said.

"We don't know if making decisions based on the nodal population would improve outcome," Dr. Miller explained. She also cautioned that it has the potential to deny patients effective therapy (e.g., if the primary tumor is ER-positive but the node is ER-negative, hormone therapy is not used) and/or to expose patients to potentially harmful and costly therapy without benefit.

Funding came from the Breakthrough Breast Cancer charity and the Scottish Funding Council. The researchers and Dr. Goss have disclosed no relevant financial relationships. Dr. Miller reports serving as an advisor or consultant for Genentech, Roche, and Research to Practice, and has served as a speaker for Genentech.

Ann Oncol. Published online November 3, 2009. Abstract

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