TAILORx Findings Augur Less-Toxic Treatment for Patients With Breast Cancer

Joyce A. O’Shaughnessy, MD

Results from the phase III TAILORx study will enable physicians to reduce the toxicity of treatment for many patients with early stage breast cancer, according to Joyce A. O’Shaughnessy, MD.

The findings will benefit those with disease that is hormone receptor (HR)—positive, HER2-negative, and axillary lymph node–negative, but changes will be fundamental, said O’Shaughnessy. “There will be less use of chemotherapy overall, but some continued use of it in the higher-risk, premenopausal patient population,” she told OncologyLive^®. O’Shaughnessy is chair of breast cancer research and the Celebrating Women Chair in Breast Cancer at Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas. She discussed the findings from the TAILORx and MINDACT trials and how the results will help clinicians select patients for more appropriate therapies.

TAILORx employed the Oncotype DX Breast Recurrence Score to investigate the relative value of hormone therapy plus chemotherapy versus hormone therapy alone in women with intermediate-risk breast cancer. The 21-gene Oncotype DX assay predicts the 10-year risk of distant recurrence in patients with early-stage, invasive breast cancer. The higher the score, the higher the risk of recurrence.¹ Patients with a high recurrence score benefit from chemotherapy, whereas patients with a low score respond better to endocrine therapy and would likely receive little or no benefit from chemotherapy.

The results of the TAILORx trial (NCT00310180), presented at the 2018 American Society of Clinical Oncology Annual Meeting in June, demonstrated that adjuvant endocrine therapy alone is noninferior to adjuvant chemoendocrine therapy in patients with early-stage HR-positive, HER2-negative, node-negative breast cancer (Table). The noninferiority of endocrine therapy alone compared with endocrine therapy plus chemotherapy met the trial’s primary endpoint of invasive disease-free survival (IDFS) (hazard ratio, 1.08; 95% CI, 0.94-1.24; P = .26).²

Trial Randomization

HR-positive, HER2-negative, node-negative breast cancer is one of the most common types of breast cancer, accounting for up to 50% of breast cancers, according to lead study author Joseph A. Sparano, MD, associate director for clinical research at the Albert Einstein Cancer Center in the Bronx, New York. Up to 30% of patients with these tumors typically have a recurrence by 10 years. Although adjuvant chemotherapy is recommended for these patients, the benefit is typically small, approximately 3% to 5%.²Of 6711 evaluable women with an intermediate recurrence score of 11 to 25, investigators randomized 3399 to receive endocrine therapy alone and 3312 to receive endocrine therapy plus chemotherapy. Randomization was based on these stratification factors: menopausal status, planned chemotherapy, planned radiation, and recurrence score groups.

After 5 years of treatment, the IDFS rate was 92.8% for those who had hormone therapy alone and 93.1% for those who also had chemotherapy. At 9 years, patients with intermediate recurrence scores receiving endocrine therapy alone and chemotherapy plus endocrine therapy showed similar IDFS rates (83.3% vs 84.3%). Also, distant recurrence-free interval (94.5% vs 95.0% with chemoendocrine therapy), recurrence-free interval (92.2% vs 92.9%, respectively), and overall survival (93.9% vs 93.8%) rates were similar between the 2 intermediate score arms at 9 years.

Among women with low-end recurrence scores (0 to 10), investigators noted a 3% distant recurrence rate with endocrine therapy alone at the 9-year mark, which confirmed findings from earlier studies; patients with high recurrence scores (26 to 100) had a distant recurrence rate of 13%, despite having received chemotherapy and hormone therapy. Investigators concluded that this indicates the need for therapies that are more effective for women at high risk of recurrence.

An exploratory analysis of patients in the 2 intermediate-range recurrence score arms considered factors that may determine which patients would benefit from added chemotherapy. Although there was no significant linkage between menopause, tumor size, or grade with recurrence score, there was a relationship between age and recurrence score.

In women 50 years or younger with a recurrence score of 16 to 20, there were 2% fewer distant recurrences; in those with a recurrence score of 21 to 25, 7% fewer. “The younger women who had a recurrence score of 16 to 25 had some chemotherapy benefit,” Sparano explained. “This was information that could drive some younger women who have a recurrence score in this range to accept chemotherapy.”

The TAILORx trial findings reconfirmed that patients of any age with low recurrence scores (0-10) would be recommended for endocrine therapy alone (16% of all patients), and all patients with high recurrence scores (26 to 100) (17%) would be recommended for chemotherapy.

Patients older than 50 years with recurrence scores of 11 to 25 (45%) and 50 years or younger who have recurrence scores of 11 to 15 (8%) may avoid chemotherapy, according to the findings.

TAILORx Takeaways

Unless other factors strongly indicate the need for chemotherapy, postmenopausal women with recurrence scores between 11 and 25 “do not require chemotherapy and will not benefit from it,” O’Shaughnessy said. However, premenopausal patients with recurrence scores on the higher end of the intermediate range are still recommended to receive chemotherapy, she added. Factors that may weigh in favor of chemotherapy include a Ki-67 index value of 50%, grade 3 biology, and progesterone receptor—negative or estrogen receptor–positive disease, she said.Oncotype DX is among the genetic assays that have demonstrated value in discerning patients for whom chemotherapy would offer a clear advantage.

The lesson of the TAILORx trial is not only that endocrine therapy can be a noninferior choice to chemotherapy, but that it could be the better option for patients who have lower Oncotype DX scores. “These data confirm that using a 21-gene expression test to assess the risk of cancer recurrence can spare women unnecessary treatment if the test indicates that chemotherapy is unlikely to provide benefit,” Sparano said.

The TAILORx findings come with the caveat that premenopausal women and those younger than 50 years at the higher end of the intermediate risk range (16-25) may have a small benefit from chemotherapy and should consider it in discussion with their physicians. Investigators said it was unclear whether this benefit results from the effects of chemotherapy or the endocrine suppression that is caused by chemotherapy-induced menopause.

What is clear is that any woman 75 years and younger who has early stage breast cancer should have the Oncotype DX test, Sparano said.

“If patients [have a low recurrence score by Oncotype DX], 5 years of endocrine therapy should be adequate, because they have only a 1% risk of recurrence on 5 years of endocrine therapy, and you can’t improve on that,” O’Shaughnessy said. However, patients with recurrence scores ranging from 11 to 25 have an intermediate risk and are in a gray area.

At the low end of the intermediate-score range, the best course of action is to optimize endocrine therapy. For postmenopausal patients, the treatment will consist of either an aromatase inhibitor (AI) or tamoxifen followed by an AI, according to O’Shaughnessy. For premenopausal patients, treatment would include a luteinizing hormone-releasing hormone (LHRH) agonist with endocrine therapy, an AI alone, or treatment with tamoxifen followed by an AI.

Table. Little or no Chemotherapy Benefit With Low Oncotype DX Recurrence Scores

Personalized Therapy Improves

At the higher end, there is some benefit seen from chemotherapy in postmenopausal patients, but the reason for this effect is uncertain. “We don’t know whether [the effect is from] suboptimal endocrine therapy because only 15% of patients in the TAILORx study received an LHRH agonist to turn off their ovaries,” O’Shaughnessy said. “That means some patients were over- or undertreated with endocrine therapy, so the chemotherapy may have had an effect due to ovarian ablation.The findings from TAILORx confirm that physicians have another helpful tool for the personalization and improved targeting of therapy, improving their ability to deliver therapy as needed and not in excess amounts. “[The Oncotype DX assay] helps us fine tune our use of chemotherapy,” O’Shaughnessy said.

The test is incorporated into the National Comprehensive Cancer Network’s guidelines as the only multigene panel to help classify pathologic prognostic stage. Level 1 data support its use in this area for patients who have a recurrence score below than 11.³

An additional test that has shown value for determining chemotherapy benefit in early stage breast cancer is the MammaPrint 70-gene breast cancer recurrence assay, which assigns a binary low-risk or high-risk classification to patients, leaving out any intermediate category that may complicate treatment decisions. The TRANSBIG validation study found that patients classified as low risk by MammaPrint assessment had a 10% chance of distant recurrence without adjuvant treatment at 10 years and patients classified as high risk had a 29% chance of distant recurrence.⁴

Physicians are turning to such tests to determine whether patients can avoid chemotherapy.

The MammaPrint assay also has an ultra-low-risk group, according to O’Shaughnessy. Patients who fall within that range respond well with 2 years of endocrine therapy. Five years of endocrine therapy is still the standard treatment duration, but there are some patients who cannot tolerate that.

Patients who are low risk have no statistically significant benefit with chemotherapy, whereas patients who are high risk benefit from chemotherapy. The assay can also predict distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS).

In a study that investigated the predictive value of MammaPrint, 252 patients were classified as low risk and 289 as high risk.⁵ In the low-risk group, BCSS at 5 years was 97% for patients who received endocrine therapy alone and 99% for those who received endocrine therapy plus chemotherapy (hazard ratio, 0.58; 95% CI, 0.07-4.98; P = .62). In the high-risk group, BCSS at 5 years was 81% for patients who received endocrine therapy and 94% for patients who received endocrine therapy plus chemotherapy (hazard ratio, 0.21; 95% CI, 0.07-0.59; P < .01).⁵

MINDACT

DDFS was 93% in the low-risk endocrine therapy group and 99% in the endocrine therapy plus chemotherapy group (hazard ratio, 0.26; 95% CI, 0.03-2.02; P = .20). In the high-risk endocrine therapy group, DDFS was 76% versus 88% in the endocrine therapy plus chemotherapy group (hazard ratio, 0.35; 95% CI, 0.17-0.71; P <.01).⁵“The MINDACT trial identified MammaPrint as a clinically useful tool in high-risk patients with larger cancer, nodes positive, grade 3 disease. Any of those would fall into the highrisk category, but not all those patients will benefit from chemotherapy,” O’Shaughnessy said. “The low-risk MammaPrint group will have either no or very little benefit from chemotherapy, and those in the high-risk group have substantial benefit.”

In the phase I II MINDACT study (NCT00433589), patients deemed high risk clinically but low risk by the gene signature had a similar 5-year rate of distant metastasis- free survival (DMFS) whether randomized to adjuvant chemotherapy or not.

The rate of 5-year DMFS in women who were clinically high risk/genomically low risk and randomized to no chemotherapy was the primary statistical test for MINDACT. In this group, in which 48% of the women had positive nodes, the 5-year DMFS rate was 94.7% (95% CI, 92.5%-96.2%).^6,7

MINDACT enrolled 6693 patients with early-stage breast cancer from 112 centers in 9 European countries who had their risk of tumor recurrence following surgery assessed in 2 ways: genetically, through use of MammaPrint, performed on frozen tumor tissue, and clinically, with Adjuvant! Online. Overall, 2745 women were categorized as low risk using both methods, 1806 were categorized as having a genetically and clinically high risk of recurrence, 592 were categorized as having a genetically high risk of recurrence and low clinical risk of recurrence, and 1550 were categorized as genetically low risk and clinically high risk.

Patients characterized by both assessments as low risk did not receive adjuvant chemotherapy. Chemotherapy was recommended for those characterized as high risk by both methods. Those with discordant results, meaning low by one measure and high by another, were randomized to adjuvant chemotherapy or no adjuvant chemotherapy.

Five-year DMFS was 97.6% among the women who were low risk by both assessment methods, but 90.6% among the women who were high risk by both methods and received adjuvant chemotherapy.

The discordant groups had a DMFS rate in between that of the “concordant” groups (low-low and high-high). The 5-year DMFS rates were 94.8% and 95.1% in the patients who were clinically low risk/genomically high risk and clinically high risk/genomically low risk, respectively.

“I think we will see more of these assays used over time,” O’Shaughnessy said. “Both to find the most favorable risk group, as well as to help us to find what to do with chemotherapy in the intermediate risk group.”

References

1. What is the Oncotype DX Breast Cancer Test? Genomic Health website. oncotypeiq.com/en-GB/breast-cancer/healthcare-professionals/oncotype- dx-breast-recurrence-score/about-the-test. Accessed July 6, 2018.
2. Sparano JA, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 2018;36(suppl, abstr LBA1) meetinglibrary.asco.org/record/161490/abstract.
3. Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN guidelines version 1.2018: breast cancer. NCCN website. nccn.org/professionals/physician_ gls/pdf/breast.pdf. Published March 20, 2018. Accessed July 6, 2018.
4. MammaPrint 70-Gene breast cancer recurrence assay. Agendia website. agendia.com/healthcare-professionals/breast-cancer/mammaprint/. Accessed July 6, 2018.
5. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661. doi: 10.1007/s10549-010-0814-2.
6. Piccart M, Rutgers E, van’t Veer L, et al. Primary analysis of the EORTC 10041/ BIG 3-04 MINDACT study: a prospective, randomized study evaluating the clinical utility of the 70-gene signature (MammaPrint) combined with common clinical-pathological criteria for selection of patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes. Presented at: AACR Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. Abstract CT-039. cancerres.aacrjournals.org/content/76/14_Supplement/CT039.
7. Kuznar W. 70-Gene signature identifies breast cancer subgroup unlikely to benefit from adjuvant chemo. OncLive. April 18, 2016. onclive. com/conference-coverage/aacr-2016/70-gene-signature-identifies- breast-cancer-subgroup-unlikely-to-benefit-from-adjuvant-chemo. Accessed July 24, 2018.