Expert Point of View: Elizabeth Mittendorf, MD, PhD

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We really have no data to suggest any benefit from surgery. We also know that patients with estrogen receptor/progesterone receptor–positive or HER2-positive disease are more likely to benefit from targeted therapy….
— Elizabeth Mittendorf, MD, PhD

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The discussant of these studies was Elizabeth Mittendorf, MD, PhD, Associate Professor of Breast Surgical Oncology at the University of Texas MD Anderson Cancer Center, Houston. Dr. Mittendorf noted that approximately 3% of U.S. breast cancer patients present with de novo stage IV disease. For these patients, the role of surgery has remained undefined, and, because of design flaws, recent studies have not settled the issue.

A meta-analysis of 15 trials found a 30% reduced risk of death with surgery; however, its individual studies were plagued by selection bias.1 In the one prospective randomized trial to date, conducted in India on patients who responded to systemic treatment, surgery provided no additional benefit, although the study included 30% with HER2-positive breast cancer who did not receive anti-HER2 therapy.2

The Turkish study presented at ASCO showed a significant benefit after 40 months of follow-up, but the lack of stratification factors “makes it a bit difficult to interpret the data” due to potential imbalances between the arms, said Dr. Mittendorf. It is known that the surgical group was less likely to have triple-negative disease or visceral metastases and more likely to have solitary bone lesions or bone-only metastases, she noted.

The U.S. study sought to examine the “real-world management” of such patients. Its most informative finding was the substantial difference between responders and nonresponders to first-line therapy, with no benefit among the 40% of responders who went on to surgery, she said.

Why the Disparate Outcomes?

The strikingly different outcomes of these two studies may have a simple explanation, continued Dr. Mittendorf. The Translational Breast Cancer Research Consortium (TBCRC) reflects patients who responded to systemic therapy, and among these responders, median survival was 71 months with surgery and 65 months without surgery—a nonsignificant difference. The Turkish study randomized patients before any therapy and therefore probably included some nonresponders; overall, the median survival was 46 months with surgery and 37 months without—a significant difference. The longer survival in the TBCRC study vs the Turkish study may be attributable, in part, to the inclusion of nonresponders in the Turkish cohort.

Dr. Mittendorf further suggested that the differences in outcomes between these two trials and the Indian study may reflect differences among the countries in the rates of patients presenting with stage IV disease, diagnostic modalities (which affect the extent of metastatic disease at presentation), and systemic regimens utilized.

Findings ‘Confirm What We Know’

Dr. Mittendorf said that altogether, the findings “confirm what we know—Tumor biology is critical” and patients who do not respond to systemic therapy fare poorly. “It is not unwise to consider a ‘biologic stress test’ with initiation of first-line therapy, knowing that those who do not respond won’t benefit from surgery,” she maintained.

“We also know that patients with estrogen receptor/progesterone receptor–positive or HER2-positive disease are more likely to benefit from targeted therapy, and this will be even better with new targeted agents, such as pertuzumab [Perjeta] and palbociclib [Ibrance],” she added. Meanwhile, “we really have no data to suggest any benefit from surgery,” Dr. Mittendorf concluded.

Further Commentary

Steven Vogl, MD

Steven Vogl, MD

In an interview with The ASCO Post, Steven Vogl, MD, a medical oncologist from the Bronx, New York, also questioned some aspects of the studies. A key concern with the Turkish trial, he offered, was whether the diagnosis of bone metastases was accurate.

“The study should have excluded patients with solitary bone mets that were not biopsied,” he explained. “I’m afraid a lot of the difference may come from patients who did not have metastatic breast cancer. Instead of a bone met, they may have had trauma, a bone cyst, a hematoma, enchondroma—which was mistakenly called metastatic cancer. In a well-done study, you would biopsy these lesions.”

He added that the U.S. study, being observational and not prospective, also has inherent biases, but he tends to agree with its conclusion: Surgery provides no benefit in most cases. ■

Disclosure: Drs. Mittendorf and Vogl reported no potential conflicts of interest.


1. Petrelli F, Barni S: Surgery of primary tumors in stage IV breast cancer: An updated meta-analysis of published studies with meta-regression. Med Oncol 29:3282-3290, 2012.

2. Badwe R, Hawaldar R, Nair N, et al: Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: An open-label randomised controlled trial. Lancet Oncol 16:1380-1388, 2015.

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