'Ultralow-Risk' Breast Cancers Can Skip Endocrine Therapy

Nick Mulcahy

July 06, 2017

Postmenopausal patients with "ultralow-risk" breast cancers may be able to forgo standard endocrine treatment with tamoxifen, which is routinely prescribed after surgery for many patients.

The new findings come from a long-term follow-up of patients who were retrospectively tested with the Mammaprint 70-gene panel. The findings were published online June 29 in JAMA Oncology.

In the study, patients whose tumors scored under the ultralow-risk threshold on the Mammaprint panel and who did not receive tamoxifen had an "exceedingly low" risk for death from breast cancer during 20 years of follow-up, report the investigators, led by Laura Esserman, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco (UCSF).

"This is an exciting advance because approximately 20% to 25% of tumors diagnosed today may be ultralow risk," said Dr Esserman in a press statement.

The ability to identify patients with ultralow-risk disease can allow clinicians to make bold recommendations, suggested Dr Esserman.

"You can really say to someone, 'You're not going to die of this disease. And we don't have to be aggressive up front and treat you with everything," she said in an article posted on the npr.org website.

Dr Esserman provided Medscape Medical News with an example of how she uses the Mammaprint test in her practice. An older patient with a number of comorbidities was "very afraid to stop her hormone therapy that was also causing her significant difficulty walking up stairs. Her tumor was ultralow. I was able to reassure her that she could safely stop the hormone therapy," she said.

The concept of ultralow-risk breast cancer has been talked about for the past decade or so, said Dr Esserman, but this is the first evidence that it is possible to run a diagnostic test at the time of diagnosis to identify a breast cancer as being associated with ultralow risk.

The new study from Dr Esserman and colleagues is a secondary analysis of the Stockholm Tamoxifen clinical trial (STO-3), which enrolled patients from 1976 to 1990 in Sweden.

The trial included patients with small (≤3 cm), hormone-receptor-positive early-stage breast cancers. Such patients are typically treated with endocrine therapy, such as tamoxifen, after the tumor is surgically removed.

In the trial, after first undergoing surgery, half of the patients were treated with tamoxifen, and the other half received no antiestrogen therapy. Most of the women (79%) received mastectomies. For all participants, tumors were detected clinically, because the trial took place before screening mammography was widely used in Sweden.

In the new analysis, Dr Esserman and coinvestigators used the Swedish trial's archived tumor blocks to perform retrospective risk assessments with the Mammaprint assay among 652 participants with node-negative disease.

The Mammaprint panel identified 377 women (58%) as being at low risk and 275 (42%) as being at high risk. Such binary information is typically used by clinicians to help decide about using adjuvant chemotherapy. Indeed, a huge European trial has shown that use of the Mammaprint test results in de-escalation of chemotherapy for patients with early-stage breast cancer.

In the current analysis, Dr Esserman and colleagues also found that 98 patients (15%) were at ultralow risk. (It is likely that the percentage would have been higher had the study been conducted in the era of screening mammography.)

The follow-up results for these ultralow-risk patients suggest that Mammaprint is helpful in making decisions about adjuvant endocrine therapy.

Specifically, for the ultralow-risk patients who received tamoxifen (n = 54), the 20-year disease-specific survival rate was 97%. For the ultralow-risk patients who received no tamoxifen (n = 44), the 20-year survival rate was 94%.

That additional 3% risk for death over 20 years is "minimal," say the study authors.

"Women who have a tumor that is an ultralow-risk tumor by 70-gene signature can be reassured that their long-term outcome is expected to be excellent, with or without endocrine therapy," they write.

Why Mammaprint?

Dr Esserman described the potential utility of Mammaprint in the setting of early-stage breast cancer with respect to any would-be endocrine therapy.

"This now provides another potential way to use the test," she said. "If a woman has a screen-detected tumor, which we know is more likely to be ultralow risk, this may be a good test to order to get more information to see if a less aggressive treatment approach is warranted. We know that low grade alone is not sufficient. Only 25% of tumors with low-risk features were ultralow risk in our Stockholm study."

Dr Esserman also explained why the 21-gene panel, Oncotype DX, which is a more commonly used multigene assay, is not appropriate for identifying ultralow-risk disease. "The data set where Mammaprint was developed did not have any systemic treatment. This allowed us to set the threshold for ultralow at a point where there were no recurrences over 15 to 20 years. This kind of data was simply not available for Oncotype Dx," she said.

The new study's relevance is partly rooted in the fact that mammography screening has resulted in an increase in the detection of cancers with "indolent behavior," the study authors say.

The net effect of screening has been both a mortality benefit (a relative risk reduction of 20% in breast cancer–specific mortality) and an increase in the detection of low-risk lesions (and thus an increase in overtreatment).

The study's relevance also relates to the fact that the American Society of Clinical Oncology recently recommended that patients with hormone receptor–positive breast cancers undergo 10 years of adjuvant endocrine therapy. The recommendation is based on the results from the MA.17R trial.

"A test that accurately identifies a population of women who have very little risk [for metastasis and disease-specific death] to begin with should be welcomed by patients and clinicians alike," they study authors say.

Vexingly, breast cancer can recur years after diagnosis; the majority of recurrences of low-grade tumors are after 5 years.

Oncologists need tools that can provide strong assurance for specific patients that late recurrence can be avoided, say the study authors.

They point out that cancer type, histologic grade, proliferative index, and stage are all associated with lower early metastatic disease risk. However, none of these measures "reliably" identify those breast cancers with "sufficiently low long-term (20 years) risk of recurrence to avoid or further reduce therapy," they also say.

A clinician not involved with the study was cautious about the study's implications and about the use of the Mammaprint test in this context.

"This is not something we are routinely discussing or offering to patients," said Harold Burstein, MD, a medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was also quoted in the story that appeared on the npr.org website.

Ultralow risk has not been extensively reported on before, he also said.

Indeed, a PubMed search for the term only resulted in five hits, the oldest of which was a 2011 study from the same team of investigators, who include Laura Van't Veer, MD, one of the creators of Mammaprint, who is also a UCSF faculty member.

"This study suggests we may be able to get more information out of MammaPrint, which is exciting, but it needs to be looked at in more studies," concluded Dr Burstein.

This study was supported by grants from the California Breast Cancer Research Program, the Swedish Research Council, the Gösta Milton Donation Fund, and the Breast Cancer Research Foundation. Various test results used in the study were provided by Agendia, the makers of Mammaprint. Dr Esserman and Dr Burstein have disclosed no relevant financial relationships.

JAMA Oncol. Published online June 29, 2017. Abstract

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