Roxanne Nelson, BSN, RN
June 03, 2018
The results come from a federally funded study, the Trial Assigning IndividuaLized Options for TReatment (TAILORx), which involved more than 10,000 patients and tested the 21-tumor gene expression assay (Oncotype Dx, Genomic Health).
"This is the largest adjuvant breast cancer trial ever performed," said lead study author Joseph A. Sparano, MD, associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York City and vice-chair of the ECOG-ACRIN Cancer Research Group.
"What we were really trying to do with this trial was 'thread the needle,'" he said.
"In terms of the big picture and the impact on care, application of this test in clinical practice in this population will spare an estimated 70% [of patients] and limit chemotherapy to the 30% who may benefit from it," he added.
The results showed that about 70% of patients with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative early-stage breast cancer, who received a midrange (intermediate) score on the Oncotype Dx test, could be spared chemotherapy. The trial found no difference in the disease-free survival whether these women were treated with endocrine therapy alone or with the combination of endocrine therapy with chemotherapy.
The results were presented during the Plenary Session here at the American Society of Clinical Oncology (ASCO) 2018 and simultaneously published in the New England Journal of Medicine.
About half of all breast cancers are hormone receptor positive, HER2 negative, and axillary node negative (ie, like the trial population), but up to 30% of patients have incurable recurrences by 10 years, Sparano explained.
Adjuvant chemotherapy is typically recommended to reduce this risk for relapse, but the absolute benefit is small (3% to 5%). "This results in many women being overtreated, because endocrine therapy would be adequate," he explained.
Oncotype DX is a commercially available gene-expression assay that provides prognostic information in hormone receptor–positive breast cancer, with a recurrence score that ranges from 0 to 100.
Patients who obtain a high score (defined as 26 or higher, or sometimes as 39 or higher) are considered to be at high risk for relapse and so are considered to benefit from chemotherapy.
Patients who obtain a low score (0 to 10) are considered to have a very low rate of distant recurrence (2% at 10 years), and that recurrence is not likely to be affected with use of adjuvant chemotherapy. Thus, these women can skip it.
However, for the patients who score in the midrange between these two extremes — about two thirds who undergo testing — whether chemotherapy would reduce the risk for recurrence has been unclear.
So this is what the new trial set out to investigate.
No Benefit for Most Patients
The study enrolled 10,273 women with hormone receptor–positive, HER2-negative, axillary node–negative breast cancer, and of this group, 6711 had a midrange recurrence score of 11 to 25.
They were randomly assigned to receive endocrine therapy alone or endocrine therapy and chemotherapy.
At the final analysis, with a median follow-up of 90 months, there were 836 events of invasive disease recurrence, second primary cancer, or death. This included 338 (40.4%) recurrences of breast cancer as the first event, of which 199 (23.8% of the total events) were distant recurrences.
Overall, endocrine therapy was noninferior to chemotherapy plus endocrine therapy, with a hazard ratio (HR) for invasive disease recurrence, second primary cancer, or death of 1.08 (endocrine vs combination therapy; 95% confidence interval [CI], 0.94 - 1.24; P = .26).
Similarly, endocrine therapy alone was also noninferior for other endpoints that included freedom from recurrence of breast cancer at a distant site (HR for recurrence, 1.10; P = .48), freedom from recurrence of breast cancer at a distant or local-regional site (HR for recurrence, 1.11; P = .33), and overall survival (HR for death, 0.99; P = .89).
The 9-year rates were similar between both groups for disease-free survival (83.3% vs 84.3%), distant recurrence (94.5% vs 95.0%), and overall survival (93.9% vs 93.8%).
However, chemotherapy did appear to have some benefit in patients who were age 50 years or younger with a recurrence score of 16 to 25.
"A very important finding was that in an exploratory analysis in the randomized group, which we conducted to make sure that there weren't any subgroups who could derive some benefit from chemotherapy, we found an interaction between age and recurrence score," said Sparano.
Younger women (less than 50 years) with a recurrence score of 16 to 25 received some benefit from chemotherapy. There were 2% fewer distant recurrences for recurrence scores 16 to 20, and 7% fewer for recurrence scores of 21 to 25.
"This information can drive some women with recurrence scores in this range to accept chemotherapy," he explained.
"Definitely Practice Changing"
Approached by Medscape Medical News for an independent comment, Charles L. Shapiro, MD, professor of medicine and director of translational breast cancer research and cancer survivorship at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, emphasized that "this is definitely practice changing."
"We knew about the low-risk patients and could pretty much select those out as they didn't need chemotherapy," he said. "And we knew that the high-risk patients did need chemotherapy."
However, the situation was quite different with intermediate-risk patients, and there was always a question as to whether they needed chemotherapy. "Many of us were uncertain about what to do," said Shapiro.
"But this answers definitively that chemotherapy doesn't benefit patients with recurrence scores of 11 to 25," he continued. "Many physicians were afraid not to give chemotherapy to patients in that group as they didn't want to take a chance of just treating with endocrine therapy alone when the benefit of chemotherapy wasn't known."
Now the situation has changed, and the results of this trial have "shut the coffin on chemotherapy."
"What this means is that 70% of patients do not need chemotherapy if they are ER [estrogen receptor] positive and node negative, and this is a definitive trial and it says no," he explained. "Many of us were torn and some of us were giving chemotherapy, but now we're not going to."
The next step is to see how well these data might extrapolate to patients with node-positive disease, he said. A prospective randomized trial has just finished enrolling for women with one to three positive nodes and a recurrence score of less than 25. He said that he believes the results will be similar to those of the TAILORx trial.
This study really gives a "plug for doing large trials, which NCI [National Cancer Institute] really doesn't do much of anymore," he commented. "The money isn't there and it cost millions to these trials and do the follow-up," he said.
"But a study this size is powered to provide definitive answers to questions."
Elias Obeid, MD, director of the Breast, Ovarian and Prostate Cancer Risk Assessment program at Fox Chase Cancer Center, Philadelphia, Pennsylvania, echoed that these data are indeed practice changing and will "save thousands of women from getting unnecessary chemotherapy."
"Up until now we have been offering women chemo because we didn't know whether there was any benefit or lack thereof in this group of patients with intermediate-risk breast cancer by the 21-gene assay," he said. "However, now we can, with an evidence-based recommendation, de-escalate treatment, avoid chemotherapy, treat only with hormonal therapy, and still have a great survivorship rate with early-stage breast cancer.
ASCO expert Harold Burstein, MD, PhD, also weighed in on the results.
"The most challenging decision we have to make with these patients is whether to recommend adjuvant chemotherapy, with all of its side effects and its potential benefits," he said.
Burstein, who is also clinician and clinical investigator in the Breast Oncology Center at the Dana Farber Cancer Institute in Boston, Massachusetts, pointed out that if "you've ever been a clinician, or a patient in a consultation room, there's a big difference between saying, 'You may benefit a little bit or you won't benefit at all.'"
With these data, most women who have this test performed can be told that they don't need chemotherapy, and that can be said with tremendous confidence and reassurance.
However, Burstein also pointed out that because this test has already been available for 12 years, a question arises: "Why did we need this study to validate this experience?"
The study is important for several reasons, he noted. First, the original data on the Oncotype assay were based on chemotherapy regimens that are now 25 years old. "So there was the question [of whether] the results would be different with the use of modern chemotherapy agents," he said.
"Second, the endocrine therapy approaches have changed, which also could have affected these results.
"Third, we now have a prospective validation of the data."
He also emphasized that this study is not really about de-escalation because its goal was not just to use less treatment. "The goal was to tailor treatment and they chose the title [TAILORx] very applicably," he added.
"This allows us to individualize treatment based on extraordinary science and validation," he added.
This study received funding primarily from the National Cancer Institute, part of the National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp. The ECOG-ACRIN Cancer Research Group designed and conducted the study. Sparano has disclosed the following: consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; stock and other ownership interests with Metastat; and research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Several coauthors have disclosed relationships with industry. Shapiro and Burstein have disclsoed no relevant financial relationships.
American Society of Clinical Oncology (ASCO) 2018. Presented June 3, 2018. Abstract LBA1
N Engl J Med. Published June 3, 2018. Abstract