Clinical risk factors add prognostic information that complements the 21-gene recurrence score, according to a new analysis from the landmark TAILORx trial.^1,2

The integration of clinical risk with the recurrence score provides greater precision in determining recurrence risk and guiding the use of adjuvant therapy than relying solely on the recurrence score. Moreover, using all this information together may help identify

It stands to reason that the integration of clinical and genomic risk offers the potential for greater precision in prognosis and ultimately guiding the use of adjuvant therapy.

— Joseph A. Sparano, MD

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premenopausal patients who could derive benefit from more effective hormonal therapy as an alternative to chemotherapy, said Joseph A. Sparano, MD, Associate Director for Clinical Research at the Albert Einstein Cancer Center and Montefiore Health System, and Vice Chair of the ECOCG-ACRIN Cancer Research Group, who was the lead author of TAILORx.

“The prognostic precision afforded by the integrated-risk model is superior to that by the use of clinical or genomic features alone,” Dr. Sparano said at the 2019 ASCO Annual Meeting.¹ The findings were simultaneously published in The New England Journal of Medicine.²

Aim of Secondary Analysis

“It stands to reason,” Dr. Sparano said, “that the integration of clinical and genomic risk offers the potential for greater precision in prognosis and ultimately guiding the use of adjuvant therapy.” The objective of the prespecified secondary analysis, therefore, was to evaluate whether the addition of clinical risk (as determined by the binary clinical risk categorization employed in the MINDACT trial and Adjuvant! Online) provides more prognostic or predictive information than the recurrence score result alone.

Of 9,427 women in TAILORx with recurrence score and clinical risk information, 70% were determined to have low clinical risk (tumor ≤ 3 cm and low grade; ≤ 2 cm and intermediate grade; or ≤ 1 cm and high grade) and 30% were at high clinical risk (not meeting low clinical risk criteria). The new findings complement the study’s original conclusion that 70% of women with hormone receptor–positive, HER2-negative, axillary lymph node–negative breast cancer can forgo chemotherapy when guided by their recurrence score.

With this new analysis, it is clear that women aged 50 or younger with a recurrence score between 16 and 20 and at low clinical risk do not need chemotherapy.

— Joseph A. Sparano, MD

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“Last year’s TAILORx results gave clinicians high-quality data to inform personalized treatment recommendations for women,” said Dr. Sparano. “With this new analysis, it is clear that women aged 50 or younger with a recurrence score between 16 and 20 and at low clinical risk do not need chemotherapy.”

He added: “Furthermore, the integration of the recurrence score with clinical risk information could identify premenopausal women with high integrated risk who may benefit from more effective antiestrogen therapy including ovarian function suppression plus an aromatase inhibitor rather than tamoxifen, which most younger women in TAILORx received as their endocrine therapy.”

Fine-Tuning Recommendations

For the group with a recurrence score of 11 to 25, there was a 2.5- to 3-fold higher relative risk and 5% higher absolute distant recurrence risk for the high vs low clinical risk group. For patients in the recurrence score ≥ 26 group, who were treated with chemotherapy plus endocrine therapy, there was a threefold higher relative risk and a 10% higher absolute difference for high vs low clinical risk.

Clinical risk did not provide predictive information for chemotherapy benefit for those with a recurrence score from 11 to 25. “Thus, the primary trial results remain unchanged and were not impacted by the integration of clinical risk,” he added. “However, for women aged ≤ 50 years and a recurrence score of 16 to 25, integrated risk distinguished the 50% who derived no chemotherapy benefit from the 50% who derived an absolute benefit of 6% to 9%—a level that is higher than an unselected population.”

For women ≤ 50, under the new framework, 68% of TAILORx subjects fell into the low–integrated-risk group (with < 5% distant recurrence risk), including all those with a recurrence score of 0 to 10, irrespective of clinical risk, and those with a recurrence score from 11 to 20 and low clinical risk. In contrast, 25% fell into the high–integrated-risk group (> 10% distant recurrence risk), including those with a recurrence score of 21 to 25 irrespective of clinical risk and recurrence score 16 to 20 and high clinical risk treated with endocrine therapy alone, and a recurrence score of 26 to 100 and a high clinical risk who received both chemotherapy and endocrine therapy. The remaining 7% had a distant recurrence risk of about 6% to 7% and thus were at intermediate integrated risk.

Among women who were ≤ 50 who had received endocrine therapy alone, the estimated rate of distant recurrence at 9 years was < 5% in the low integrated risk groups,including 1.8% with arecurrence score 0 to 10 irrespective of clinical risk, and 3.2% with an recurrence score 11 to 20 and low clinical risk. It exceeded 10% among women with a high integrated risk, including 14.7% for those with a recurrence score of 16 to 25 and high clinical risk and 11.4% for recurrence score of 21 to 25 and low clinical risk who received endocrine therapy alone, and 15.2% and among those with a high recurrence score of 26 to 100 and high clinical risk who received chemoendocrine therapy.

What Results Suggest for Younger Patients

Importantly, the study showed that the absolute chemotherapy benefit was greatest for premenopausal women aged 45 to 50 with a recurrence score of 16 to 25. “This suggests that the absolute chemotherapy benefit observed in younger women in TAILORx may be due to an endocrine effect,” Dr. Sparano said.

Based on findings from TAILORx, for the low–integrated-risk group, tamoxifen alone should be adequate. For the high–integrated-risk group, ovarian function suppression plus an aromatase inhibitor could be considered as an alternative to chemotherapy in those with a recurrence score of 16 to 25, or in addition to chemotherapy in those with a recurrence score of 26 to 100 who have not developed chemotherapy-induced menopause, he said. ■

DISCLOSURE: Dr. Sparano has held consulting or advisory roles for Adgero Biopharmaceuticals, AstraZeneca, Cardinal Health, Celgene, Celldex, Genentech/Roche, Juno Therapeutics, Lilly, Merrimack, Novartis, Pfizer, and Prescient Therapeutics; has received travel expenses from Adgero Biopharmaceuticals, AstraZeneca, Menarini Silicon Biosystems, Myriad Genetics, Pfizer, and Roche/Genentech; has ownership interest or stock in MetaStat; and has received institutional research funding from Deciphera, Genentech/Roche, Merck, Merrimack, Novartis, Prescient Therapeutics, and Radius Health.

REFERENCES

1. Sparano JA, Gray RJ, Makower DF, et al: Impact of clinical risk category on prognosis and prediction of chemotherapy benefit in early breast cancer by age and the 21-gene recurrence score in TAILORx. 2019 ASCO Annual Meeting. Abstract 503. Presented June 3, 2019.

2. Sparano JA, Gray RJ, Ravdin PM, et al: Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. N Engl J Med 380:2395-2405, 2019.