TAILORing the Decision to Have or Not Have Chemotherapy

Laura R. Bobolts, PharmD BCOP
Senior Vice President, Pharmacy at Oncology Analytics, Inc.
Plantation, FL
Clinical Affiliate Assistant Professor
Nova Southeastern University, College of Pharmacy Davie, FL

At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, the landmark clinical trial TAILORx found no efficacy advantage in adding adjuvant chemotherapy to endocrine therapy for hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, early breast cancer patients with a midrange Oncotype DX recurrence score of 11–25. The results indicate that nearly 70% of patients with the most common type of early breast cancer can forgo chemotherapy. However, an exploratory analysis did find benefit for chemotherapy in women 50 years of age or younger with a recurrence score of 16–25.¹

Trial Design Centered on Recurrence Score
TAILORx was a prospective phase 3 multinational study that enrolled 10,273 women with HR-positive, HER2-negative, axillary lymph node–negative breast cancer based on their Oncotype DX Breast Recurrence Score.¹

The 21-gene Oncotype DX breast cancer assay is a tool used in HR-positive, HER2-negative early breast cancer to help identify women who may benefit from the addition of adjuvant chemotherapy to endocrine therapy. This assay predicts the 10-year risk of distant recurrence, providing a recurrence score from 0 to 100 based on the patient’s genetic profile.² The higher the score, the higher the risk of recurrence and the greater potential for chemotherapy benefit.^3,4

Patients in TAILORx were assigned to one of four groups. Those with a recurrence score of 10 or less received endocrine therapy only, while those with a recurrence score of 26–100 received chemotherapy followed by endocrine (chemoendocrine) therapy. Women with a midrange recurrence score of 11–25 were randomized to receive either endocrine therapy alone or chemoendrocrine therapy. The purpose of this analysis, presented at ASCO 2018, was to use precision medicine to determine whether adjuvant chemotherapy is beneficial for those with a midrange recurrence score of 11–25.¹

Pivotal End Points Support Endocrine Therapy Alone
The primary end point of TAILORx was invasive disease-free survival (IDFS)—freedom from invasive disease recurrence, second primary cancer, and death. At 9 years, adjuvant endocrine therapy was noninferior to chemoendocrine therapy in women with a recurrence score of 11–25 with an IDFS of 83.3% versus 84.3%, respectively (hazard ratio, 1.08; 95% confidence interval [CI], 0.94–1.24; p = .26)¹.

Similar rates were seen with secondary end points. At 9 years, those with a midrange recurrence score of 11–25 had similar freedom from disease recurrence at a distant site (94.5% endocrine therapy and 95% chemoendocrine therapy), freedom from disease recurrence at distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). No detriment in survival was evident when chemotherapy was avoided.¹

Younger Patients with Scores 16–25 May Benefit from Chemotherapy
Of interest, an exploratory analysis of TAILORx highlighted the finding that patients age 50 years or younger with a recurrence score of 16–25 did benefit from adding chemotherapy to endocrine therapy, with a lower rate of distant recurrence over endocrine therapy alone (1.6% lower for recurrence score 16–20; 6.5% lower for recurrence score 21–25), although without a survival difference.¹ As a result, chemotherapy should be considered, but not mandated, in premenopausal patients age 50 or younger with a score of 16–25 (Table 1-see PDF).⁵  Yet the question remains whether chemotherapy is needed or whether similar reductions in disease recurrence can be achieved with the use of ovarian suppression and an aromatase inhibitor instead. Chemotherapy can induce menopause, creating a low estrogen environment that may be driving the benefit seen.

Ovarian suppression was not standardized in the design of TAILORx, which enrolled women between 2006 and 2010, although today it is considered standard for many in this population.¹ The SOFT/TEXT clinical trials paved the way for the addition of ovarian suppression (via luteinizing hormone-releasing hormone [LHRH] agonist, bilateral oophorectomy, or ovarian irradiation) to tamoxifen or an aromatase inhibitor in premenopausal women with operable breast cancer. The addition of ovarian suppression to tamoxifen increased 8-year disease-free and overall survival rates compared to tamoxifen alone, while the use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence.⁶ Given that only 13% of premenopausal patients in TAILORx received ovarian suppression, it is unknown whether similar benefits can be achieved with the addition of ovarian suppression to endocrine therapy instead of chemotherapy.¹

Results Not Applicable to Node-Positive Disease
It is important to remember that patients in TAILORx were axillary node negative. We are still awaiting prospective validation of this 21-gene assay in breast cancer patients with one to three lymph nodes from the RxPONDER trial.⁷ ASCO’s 2017 guideline on biomarker assays recommends against the use of this 21-gene assay to guide decisions on chemotherapy for node-positive patients who are HR-positive and HER2-negative, although clinical practice may differ.⁸

Final Word
The TAILORx results allow us to tell more breast cancer patients, “Your genetic makeup shows that you may not need chemotherapy.” Rare but serious risks of adjuvant breast cancer chemotherapy such as cardiotoxicity and secondary malignancies can now be avoided because applying the data from TAILORx will spare many patients from unnecessary chemotherapy. It is clear that we must consider the recurrence score from this genomic assay, in combination with the clinicopathological features of the patient’s individual disease, to help guide the patient through the difficult decision of whether or not to receive chemotherapy.

References

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018; 379:111-121.
2. About the Oncotype DX Breast Recurrence Score Test. Available at https://www.oncotypeiq.com/en-US/breast-cancer/healthcare-professionals/oncotype-dx-breast-recurrence-score/about-the-test. Accessed September 15, 2018.
3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer. J Clin Oncol 2006; 24: 3726-3734.
4. Stearns V. TAILORing adjuvant systemic therapy for breast cancer. N Engl J Med 2018; 379:191-192.
5. National Cancer Institute. TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy [press release]. Posted June 3, 2018. Available at https://www.cancer.gov/news-events/press-releases/2018/tailorx-breast-cancer-chemotherapy. Accessed September 15, 2018.
6. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 2018; 379:122-137.
7. A phase III, randomized clinical trial of standard adjuvant endocrine therapy +/- chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence score (RS) of 25 or less. RxPONDER: A clinical trial Rx for positive node, endocrine responsive breast cancer. ClinicalTrials.gov. Updated September 14, 2018. Available at https://clinicaltrials.gov/ct2/show/NCT01272037. Accessed September 16, 2018.
8. Krop I, Ismaila N, Andre F, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 2017; 35(24):2838-2847.