Conference Update

Adjuvant endocrine therapy for premenopausal breast cancer: Tailor according to the risk of recurrence

Oncology
4 months ago, OP Editor

TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial), led by the International Breast Cancer Study Group (IBCSG), randomized nearly 6,000 premenopausal women with hormone receptor [HR]-positive early breast cancer (eBC) to receive 5 years of adjuvant endocrine therapy.1,2 Presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, an updated result from the two trials suggested a potential benefit in escalating endocrine therapy in high-risk patients.1,2 The findings were concurrently published in The New England Journal of Medicine.3

Choosing the optimal adjuvant therapy for premenopausal patients

There has always been a debate regarding the optimal adjuvant endocrine therapy for premenopausal women with HR-positive eBC. The complementary SOFT and TEXT trials, specifically designed to explore the clinical benefits of different endocrine therapies (Figure 1), have tried to provide an evidence that it is better to tailor adjuvant endocrine therapy according to individual disease characteristics.4,5

In 2014, a joint analysis of both trials (median follow-up of ~5.7 years) found that exemestane plus ovarian function suppression (OFS) was superior to tamoxifen plus OFS in 5-year disease-free survival rates (91.1% vs. 87.3%; p<0.001).5 However, the overall survival (OS) rates were high in the two groups and not significantly different, presumably because it was premature to determine survival due to the low event rate.4,5 “Several features still need to be clarified before a definitive picture can be drawn,” the researchers wrote at that time.4,5

“While this result supporting the use of [OFS] and [aromatase inhibitors] in premenopausal women with hormone-sensitive eBC, we still need to see the results of the tamoxifen-alone arm to complete the picture,” said Dr. Clifford A. Hudis, ASCO Immediate Past President, at a press conference during the 2014 ASCO Annual Meeting.5

 

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Longer follow-up of SOFT and TEXT: Is escalating endocrine therapy worth it?

The updated analysis, presented at the 2018 ASCO Annual Meeting by Dr. Meredith M. Regan of the Dana-Farber Cancer Institute in Boston, US, was based on a longer follow-up of the SOFT and TEXT populations. “These new results may help women and their physicians decide whether the potential benefits of treatment with aromatase inhibitors plus OFS are worth the potential side effects,” she said.1,2

Updates on SOFT analysis

The first set of data came from an 8-year median follow-up of the population in the SOFT trial.3 In the previous report of SOFT (median follow-up of 5.6 years), similar rates of disease-free survival with adjuvant tamoxifen was reported regardless of the addition of OFS (86.6% vs. 84.7% with tamoxifen-OFS and tamoxifen alone, respectively).4 However, the present analysis found a 4.2% absolute benefit of disease-free survival rate with the addition of OFS to tamoxifen vs. tamoxifen alone (HR=0.76; 95% CI: 0.62-0.93; p=0.009).3 A greater benefit from the addition of OFS to tamoxifen was observed among women with human epidermal growth factor receptor 2 (HER2)-positive tumors (HR=0.83 vs. tamoxifen alone; 95% CI: 0.67-1.04; p=0.04).3

As seen in Figure 2, an even higher rate of disease-free survival was observed with exemestane plus OFS.3 A larger absolute benefit with tamoxifen-OFS (5.3% vs. tamoxifen alone) and exemestane-OFS (9.0% vs. tamoxifen alone) was found in women who remained premenopausal after receiving chemotherapy before starting OFS.3

 

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At 8 years, an overall survival (OS) benefit was seen in the OFS treatment arms as compared to tamoxifen alone.3 The 8-year survival rate was 93.3% with tamoxifen-OFS (p=0.01 vs. tamoxifen alone), 92.1% with exemestane-OFS, and 91.5% with tamoxifen alone.3

In addition, the 8-year rate of freedom from distant recurrence was 89.4% with tamoxifen-OFS (p=0.28 vs. tamoxifen alone), 91.2% with exemestane-OFS, and 88.4% with tamoxifen alone.3 Most distant recurrences occurred in patients who had received chemotherapy, and a greater benefit was observed with the addition of OFS to tamoxifen or exemestane.3

Consistent with the guidelines’ recommendations for the use of OFS in women diagnosed with HR-positive BC before the age of 35 years (deemed at a higher risk for recurrence),6-8 the 8-year results of SOFT found a higher rate of freedom from distant recurrence in this age group.3 The absolute benefit was 8.6% with exemestane-OFS and 3.7% with tamoxifen-OFS, when compared to tamoxifen alone.3

Updates on TEXT-SOFT joint analysis

The second set of data came from a 9-year median follow-up of the combined population in TEXT and SOFT trials.3 Exemestane-OFS maintained superiority over tamoxifen-OFS in the 8-year disease-free survival rate (Figure 3), but the OS rate remained similar between the two groups (93.4% vs. 93.3%).3 “Given the long natural history of breast cancer with HR positivity, conclusions regarding OS remain premature,” the authors wrote in the published paper.3

A clinical benefit of 2.1% in 8-year freedom from distant recurrence rate was also noted for exemestane-OFS group, as compared to tamoxifen-OFS group (91.8% vs. 89.7%; p=0.02).3 Among patients with HER2-negative tumors, a clinical benefit of 3.5% in 8-year rate of freedom from distant recurrence was observed in patients assigned to receive exemestane-OFS compared to tamoxifen-OFS.3

 

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Adverse events and treatment discontinuation

In the combined population of SOFT and TEXT, targeted adverse events of grade 3 or higher were reported in 31% and 32.3% of patients receiving tamoxifen-OFS and exemestane-OFS groups, respectively.3 Early discontinuation of the assigned oral endocrine therapy was greater in the exemestane-OFS group (23.7% vs. 19.3% in the tamoxifen-OFS group), mainly because of therapy-related side effects.3,9 “The toxicity profiles of exemestane plus OFS as compared with tamoxifen plus OFS remain similar to those seen in postmenopausal women,” the authors wrote.3

Incidence of thrombosis or embolism of any grade was greater in the tamoxifen-OFS group (2.3% vs. 1.2% in the exemestane-OFS group), but musculoskeletal symptoms of grade 3 or 4 were more common in those receiving exemestane-OFS (11.4% vs. 5.7% in the tamoxifen-OFS group).3 Similarly, osteoporosis (defined as T score <-2.5) was reported in 14.8% of those receiving exemestane-OFS, as compared to 7.2% in the tamoxifen-OFS group.3

Interpretation of the latest SOFT and TEXT data

Based on the findings of the new analysis, Dr. Regan noted that the therapies reduce recurrences, “but the question now is, is it worth in terms of side effects and menopausal symptoms for an individual woman,” she said.1

Indeed, the potential benefits of escalating endocrine therapy in premenopausal women with the highest-risk of recurrence may be higher (e.g. younger women with multiple positive lymph nodes, large tumors, high tumor grade), as the use of exemestane plus OFS may increase 10% to 15% of freedom from distant recurrence, Dr. Regan said.1,2

For women at low-risk of recurrence, the benefits seem to apply regardless of the endocrine therapy chosen, but “then there are those who are in the middle in terms of risk where the improvement was 4 to 5 percentage points—that’s where the decision-making becomes more of a challenge and may depend upon the individual patient’s preference and tolerance of treatment,” she said.1,2

In an accompanying editorial of the new analysis, Dr. Marc E. Lippman of the University of Miami Miller School of Medicine, Miami, US, also noted that the use of bone-strengthening agents (e.g., bisphosphonates) or inhibitors of receptor activator of nuclear factor-κB ligand (RANKL) in the trials was not permitted unless such use was medically indicated.9 He believed that “the data strongly favor adding either a bisphosphonate or RANKL inhibitor administered at 6-month intervals for 3 years to help prevent problems with loss of bone density and increase survival in such patients.”9

Nevertheless, the data for survival and late adverse events are still immature, and longer follow-up is planned for SOFT and TEXT.3 Maximal separation of Kaplan-Meier curves for OS typically occurred late in the randomized trials of adjuvant endocrine therapy, reaching more than 10 years after randomization.3 “Very long-term follow-up of these 5,700 young women remains critical,” Dr. Regan said.1,2

 

  1. 2018 ASCO: Aromatase Inhibitor Plus Ovarian Suppression Yields Benefit in High-Risk Premenopausal Patients With Breast Cancer. The ASCO Post. 2018 (Accessed June 19, 2018, at http://www.ascopost.com/News/58912).
  2. TEXT & SOFT Press Release ASCO 2018. IBCSG. 2018 (Accessed June 19, 2018, at http://www.ibcsg.org/News/Pages/TEXTSOFTPressReleaseASCO2018.aspx).
  3. Francis PA, Pagani O, Fleming GF, et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med. 2018 [Epub ahead of print].
  4. Pagani O, Regan MM, Francis PA. Are SOFT and TEXT results practice changing and how? Breast. 2016;27:122-5.
  5. Exemestane/Ovarian Suppression Reduces Recurrence vs Tamoxifen/Ovarian Suppression in Premenopausal Breast Cancer. The ASCO Post. 2014 (Accessed June 19, 2018, at http://www.ascopost.com/issues/june-25-2014/exemestaneovarian-suppression-reduces-recurrence-vs-tamoxifenovarian-suppression-in-premenopausal-breast-cancer/).
  6. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016;34:1689-701.
  7. Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies — improving the management of early breast cancer: St. Gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 2015; 26: 1533-46.
  8. Paluch-Shimon S, Pagani O, Partridge AH, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017; 35: 203-17.
  9. Lippman ME. Endocrine Adjuvant Therapy for Localized Breast Cancer. N Engl J Med. 2018 [Epub ahead of print].

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