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Breast Cancer Biologic Subtype Does Not Predict Radiotherapy Benefit

Goodwin, Peter M.

doi: 10.1097/01.COT.0000558227.52108.74
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VIENNA—Subgroups of patients who can safely choose to omit whole breast irradiation from their treatment for early breast cancer cannot yet be identified by biologic subtype, according to a Canadian breast oncologist reporting at the 2019 St. Gallen International Breast Cancer Conference.

“Today, I don't think we can use genetic factors to select patients for omission of radiotherapy,” said Timothy Whelan, MSc, FRCPC, from the Juravinski Cancer Centre Supportive Cancer Care Research Unit in Hamilton, Ontario, who is Canada Research Chair in Health Services Research in Cancer at the Department of Clinical Epidemiology and Biostatistics of McMaster University.

From his assessment of recently published data, he concluded that only clinical factors could currently help oncologists advise patients about avoiding radiation, though he acknowledged this could change in the future pending further studies in progress.

Whelan reported no clear signals currently about using genomic tests of “intrinsic subtype”—such as PAM50 and the Oncotype DX recurrence score—as predictors of radiotherapy benefit.

He said there had been a lack of randomized controlled studies looking at biomarkers as determinants of benefit from radiation treatment (compared with no radiotherapy). It was important to establish if there was a group of patients at very low risk for local recurrence. And there was also a need to test whether there were patients who were less responsive to radiation therapy.

Whelan discussed the relevance of subtype to breast cancer recurrence by quoting findings from several recent studies that collectively indicated that genetic tests were not yet ready for prime time in deciding whether or not to use radiotherapy in patients with low-risk early breast cancer.

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Canadian Trial

The Toronto-British Columbia Trial identified 501 women (out of a study total of 769 post-menopausal patients) with node-negative T 1-2 tumors who were randomized to tamoxifen endocrine therapy with or without radiation—after having breast-conserving therapy—whose tumors had been subtyped for luminal A, luminal B, HER-2 enriched, and basal biomarkers by immunohistochemistry (IHC) (J Clin Oncol 2015;33(18):2035-2040).

The researchers wanted to determine the prognostic and predictive value of subtyping with these biomarkers for ipsilateral breast relapse.

Radiotherapy reduced the 10-year local recurrence rate overall from 13.8 percent in patients on endocrine therapy alone compared to 5.3 percent in those also receiving radiotherapy. There was also benefit from radiation in terms of lower recurrence rates within groups of patients who had luminal A, luminal B, or HER2-enriched/basal subtypes. But the study found that, although IHC subtyping had been prognostic for recurrence, it had not predicted benefit from radiation.

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Swedish Study

Whelan also quoted findings from the randomized Swedish Breast Cancer Group Trial 91 on response to adjuvant radiotherapy after breast-conserving surgery in different breast cancer subtypes among 1,175 patients not treated with endocrine therapy (J Clin Oncol 2017;35(28):3222-3229).

The investigators concluded that genomic subtype had not been predictive of response to radiotherapy. But they noted that HER2-positive tumors seemed to be the most resistant to radiation benefit. They also found that the effect of radiotherapy in the “presumed low-risk luminal A-like” tumors had been “excellent.”

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U.S. Clinical Trial

Whelan said findings from the Cancer Intervention and Surveillance Modeling Network (CISNET) and NCI Breast Oncology Local Disease (BOLD) Task Force Meta-Analysis—looking at the effects of radiotherapy on early-stage low-recurrence risk, hormone-sensitive breast cancer among 1,778 women from seven trials—had also failed to link genetic factors with benefit from radiotherapy.

The effects of radiotherapy varied across subgroups—with lower recurrence-free interval rates in older women whose small HER2-positive tumors had Oncotype scores less than 11. The investigators concluded that omission of radiotherapy in hormone-sensitive patients with low recurrence risk had been associated with a modest increase in “loco-regional recurrence event rates,” but did not appear to increase the rate of distant recurrence or death (J Natl Cancer Inst 2018;110(12):1370-1379).

Whelan concluded that genetic risk signatures were not predictive of radiotherapy benefit and that oncologists should continue to use clinical factors when having discussions about omitting radiation with older patients who had small, endocrine-sensitive, low-grade tumors.

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Review Outcomes

“The conclusion from this brief review is that subtypes—or the current commonly used genomic risk signatures—predict the risk of local recurrence. They are prognostic. But they definitely don't appear to be predictive of the response to radiotherapy,” Whelan explained.

Philip Poortmans, MD, PhD, Head of Radiation Oncology at the Institut Curie in Paris and President of the European CanCer Organisation, agreed with Whelan, but he said that molecular profiling was useful as an aid towards predicting which patients were at high risk for local and regional recurrences, distant metastasis, overall survival, and breast cancer-related survival and that there was likely a link with survival.

“When we can identify patients with a low risk for recurrence, [these] are the same patients who benefit relatively less from radiation therapy,” he told Oncology Times.

Poortmans said that, although radiation could reduce recurrence risk by about 85 percent, the absolute benefit was small in the context of recurrence rates that were already low after standard breast-conserving therapy. And in the lowest risk patients, the additional risk reduction from adding radiation was even smaller. “If [patients] have only 5 percent of recurrence risk, the benefit [of adding radiation] melts down to maybe 3 or 4 percent [overall].”

But he suggested genomic and clinical factors had the potential to be combined to assess potential benefit from radiation therapy and perhaps could eventually help identify patients who could do without it.

“Radiation therapy is currently a standard after breast-conserving surgery. If you have a patient who has low risk—based on clinical factors confirmed [by] a molecular profile—especially when the patient is old and has limited life expectancy—then speak with the patient and consider omitting radiation therapy. For all other patients, radiation therapy is still the gold standard,” he said.

Poortmans said he was looking forward to results from current prospective randomized trials and cohort registration studies looking at the contribution of genetic testing for predicting recurrence risk and survival after radiation therapy in early breast cancer. “[In] a couple of years, we'll have the answer to this question. Not now,” he concluded.

Peter M. Goodwin is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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