ASCO 2010-TUMOR BIOLOGY CHANGES WHEN BREAST CANCER METASTASIZES

June 10, 2010 (Chicago, Illinois) — For breast cancer patients whose disease has metastasized, tumor biology often changes between primary and metastatic lesions.

According to the results of a retrospective study presented here at the American Society of Clinical Oncology 2010 Annual Meeting, a proportion of women with metastatic breast cancer required a change in therapy after rebiopsy revealed discordance in receptor status between the primary tumor and liver metastasis.

The authors found that estrogen-receptor (ER), progesterone-receptor (PgR), or HER2-receptor status of liver metastases differed from that of the primary breast tumor, necessitating a change in endocrine therapy or targeted treatment in 12.1% of the study cohort.

"There is emerging evidence that tumor receptor status may change dynamically during the natural history of the disease," said lead author Marzia Locatelli, MD, during her presentation.

Dr. Locatelli, who is from the European Institute of Oncology in Milan, Italy, added that when it is "safe and easy to perform, a biopsy of the metastatic lesion should be considered in all patients, particularly if there is a long interval from diagnosis to biopsy."

Possible Reasons and Questions for the Future

There are any number of reasons for the discordance seen in the primary tumor and metastatic lesions, said Andrea L. Richardson, MD, PhD, who served as a discussant of the paper.

Errors in assay methodology is one possible reason, although that would not explain the majority of discordances, said Dr. Richardson, who is assistant professor of pathology at Harvard Medical School in Boston, Massachusetts.

Sampling size is another possibility; liver biopsies provide a much smaller sample of tissue for evaluation of ER and PgR status, but Dr. Richardson pointed out that discordance rates for loss of ER or gain of ER are roughly the same, or even a little higher for ER gain in liver metastases. "This suggests that the smaller sample size of recurrences is not the major reason for discordance," she said.

A third possibility is delayed fixation and false negative results for the primary tumor, which could explain some of the gain of ER in recurrence. "I think we should be aware of this when thinking about the use of adjuvant therapy, and reducing false negatives on primary tumors as well," Dr. Richardson explained.

There might also be biologic reasons for discordance; genomic studies have shown that there is heterogeneity within most tumors. She noted that receptor studies are generally performed only on a single block of the primary breast tumor or limited to a core biopsy of the tumor.

"The failure to detect a significant subpopulation with different receptor expression within a large primary tumor may explain discordances," she said, and questioned whether there is an association between tumor size and the likelihood of discordance.

"Should we, as pathologists, be evaluating more areas of the primary tumors to rule out a subpopulation with a different phenotype?" she asked.

All things considered, the reason for discordance might not be important. "Therapy is determined by receptor status, and we need to treat the tumor that is present now, not the tumor that used to be there years before," Dr. Richardson said.

Biopsy of presumed metastatic disease will detect some benign lesions, new primaries, and metastases of a second cancer — all of which require different considerations for treatment and prognosis, Dr. Richardson noted.

But this does pose questions for the future, she told the audience. "Is there a subgroup with a low enough rate of discordance to suggest that rebiopsy is not necessary?"

"How do ER discordance rates vary based on expression of HER2?" she asked. "Are most of the cases with unstable expression of ER, either gains or losses, occurring in patients with HER2-positive primary tumors?"

Discordance Noted, Therapy Changed

During a press conference at which the results were highlighted, study coauthor Giuseppe Curigliano, MD, PhD, also from the European Institute of Oncology, pointed out that the premise of this study was very simple: Should liver metastasis or any metastatic site in breast cancer be biopsied to improve treatment choice?

"Determination of ER, PgR, and HER2 status is clinically relevant for the treatment choice and for breast cancer subtype determination," he said. "But despite this evidence, it is not routine practice to perform biopsies on metastatic deposits of disease. So when we choose treatments for patients with metastatic disease, we choose the treatment according to the biologic features of the primary tumor."

In this study, the authors analyzed a database of ultrasound-guided liver biopsies performed from 1995 to 2008, and identified 255 breast cancer patients with matched primary and liver tissue samples. The median time from primary diagnosis to liver biopsy was 3.4 years (range, 0 to 18.3 years).

The overall discordance rate for ER status between the primary tumor and liver metastases was 14.5%. The status of 15 patients (25.9%) changed from ER negative to ER positive, and of 22 patients (11.2%) changed from ER positive to ER negative.

For HER2, the authors observed an overall discordance rate of 13.9%. There were 7 patients (5.9%) in whom status switched from HER2 negative to HER2 positive, and 17 patients (31.5%) in whom it changed from HER2 positive to HER2 negative.

Progesterone status changed in 48.6% of the patients, and changes in therapy were made in 12.1% of patients on the basis of the results of their liver biopsy.

Biopsy More Necessary in Era of Targeted Therapy

Other studies have already shown that tumor biology can change. One study, for example, showed that half of cancers change when they spread to the sentinel node.

Biopsy of metastases is becoming increasingly more common in the United States, and is being done more and more frequently, said Eric P. Winer, MD, professor of medicine at Harvard Medical School.

Dr. Winer, who moderated the press briefing, noted that with a whole new generation of targeted therapies becoming available over the next decade, "I think that it will be that much more necessary to obtain tissue, not just when a woman first has metastatic breast cancer, but potentially over the course of her illness."

"There is the potential that the cancer can evolve over time; it may not actually change, but certain features of the cancer may be more prominently expressed," he added.

The authors have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract CRA1008. Presented June 5, 2010.