As reported by Kalinsky et al and summarized in this issue of The ASCO Post, an interim analysis of the phase III RxPONDER trial showed that the addition of adjuvant chemotherapy to endocrine therapy improved invasive disease–free survival among premenopausal—but not postmenopausal—women with hormone receptor–positive, HER2-negative, node-positive breast cancer and a 21-gene assay recurrence score up to 25.1
The results of the RxPONDER trial are a strong step forward in trying to define which patients with hormone receptor–positive breast cancer can be spared adjuvant cytotoxic chemotherapy.1 Clearly, for postmenopausal women with 21-gene recurrence scores ranging from 0 to 25 who have one to three positive axillary nodes (n = 3,353), there is no benefit to the use of chemotherapy. Invasive disease–free survival (the primary trial endpoint) at 5 years was 91.9% with endocrine therapy alone and 91.3% with chemoendocrine therapy. However, like all good trials, RxPONDER leaves us with many unanswered questions, both for future research and for day-to-day practice.
Gini F. Fleming, MD, FASCO
Questions in Need of Answers
First, what about women with more than three positive nodes? Are their tumors biologically different in some way so they may benefit from chemotherapy even with a recurrence score of up to 25? Or can we look to expand our biologic predictors of chemotherapy sensitivity to those at much higher clinical/anatomic risk?
Second, although a concern affecting a minority of patients, what about postmenopausal women with a recurrence score slightly above 25? For women with a recurrence score up to 25 and N1 breast cancer, the recurrence score value did not significantly predict the relative benefit of chemotherapy. The authors commented that, among markers contributing to the recurrence score (which include Ki67), it is the proliferation markers that are likely to be implicated in chemotherapy sensitivity. However, the proliferation markers have a threshold of a single default value when the overall recurrence score is below a certain value.
Is 26 the appropriate cutoff recurrence score at which there is—or starts being—a meaningful benefit from chemotherapy for postmenopausal women? In the retrospective assessment of the SWOG S8814 trial, benefit from adjuvant chemotherapy for postmenopausal women was reported with a recurrence score of at least 31. Alternately, might a molecular profiling score that is more driven by proliferation in the lower range provide a useful predictor of chemotherapy benefit?2
For postmenopausal women with 21-gene recurrence scores ranging from 0 to 25 who have one to three positive axillary nodes, there is no benefit to the use of chemotherapy.— Gini F. Fleming, MD, FASCO
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If the recurrence score does not operate as a predictive marker of chemotherapy benefit in the lower score range, might some small group of postmenopausal women who may potentially benefit from chemotherapy be missed—eg, much as the benefit for premenopausal women is obscured when the overall RxPONDER trial results (5-year invasive disease–free survival of 91% with endocrine therapy and 92.2% with chemoendocrine therapy, P = not significant) are seen without consideration for menopausal status?
What About Premenopausal Women?
Most pressingly, what are the practice implications of the RxPONDER results in premenopausal women, who made up a substantial proportion of subjects in the trial (n = 1,665)? Among premenopausal women, there was a definite benefit of chemotherapy. The hazard ratio for 5-year invasive disease–free survival with the addition of chemotherapy was 0.60. Benefit for distant relapse–free survival was similar. Interestingly, for premenopausal women aged 50 or older (n = 511), no benefit of chemotherapy was seen. When analysis was limited to women younger than age 50, the hazard ratio for 5-year invasive disease–free survival was an impressive 0.48 (95% confidence interval [CI] = 0.32–0.72; hazard ratio = 0.60, 95% CI = 0.43–0.83, after adjustment for known prognostic factors such as tumor size).
As previously described, relative benefit did not increase with an increase in recurrence score: for women younger than age 50 who had a recurrence score of up to 10, 5-year invasive disease–free survival improved from 91% to 98% with the addition of chemotherapy; for those with a recurrence score between 21 and 25, 5-year invasive disease–free survival improved from 80% to 90%.
Similar results were seen in the TAILORx trial, in which women with node-negative breast cancer were randomly assigned to receive endocrine therapy alone or endocrine therapy plus chemotherapy. In TAILORx, women aged 50 or younger with node-negative disease and a recurrence score between 16 and 25 had a decrease in distant recurrence with adjuvant chemotherapy added to endocrine therapy, whereas women older than age 50 did not.
In TAILORx, unlike in RxPONDER, the recurrence score did appear to help identify which younger women would benefit from chemotherapy: those with a score between 11 and 15 had no apparent benefit from the addition of chemotherapy (women with scores up to 11 did not undergo randomization).3 Although results from different tumor molecular profiling assays are not necessarily concordant, it is noteworthy that similar results have been observed using the 70-gene signature in the MINDACT trial. Women who were premenopausal or aged 50 or younger and at clinical high risk reaped a benefit in terms of distant metastasis–free survival at 8 years—hazard ratio was 0.54 for the addition of chemotherapy; however, there was no significant benefit for older/postmenopausal women.4
Why do younger women with tumors that appear to be low risk on genomic scores benefit from chemotherapy, whereas older women do not?
Here are two primary possibilities:
- Younger women have some biologic feature making their tumors more sensitive to chemotherapy than tumors in older women with similar genomic scores.
- A substantial portion of the benefit of chemotherapy is the result of ovarian function suppression—in which case, similar results could be achieved by enhanced endocrine therapy without the need for chemotherapy.
In all three trials, the use of ovarian function suppression for premenopausal women was quite low: in the RxPONDER trial, just 6.3% of premenopausal women who received endocrine therapy plus chemotherapy and 19% of those who received endocrine therapy alone were prescribed ovarian function suppression.
In similar recurrence score ranges in RxPONDER, the outcomes for younger women assigned to endocrine therapy alone were modestly worse than those for older women who received endocrine therapy alone: for recurrence scores between 21 and 25, 5-year invasive disease–free survival for those receiving endocrine therapy alone was 80.0% for those aged 50 or younger and 86.9% for those aged 50 or older; for recurrence scores ≤ 10, the values were 91.0% and 93.1%, respectively. It is possible there could be a difference in the composition of recurrence scores (the same sum total but some systemic difference in which components make up that total) or some other unmeasured “chemosensitivity factor” that may account for a greater chemotherapy benefit in younger women, but the explanation is not obvious.
Difficulty in Comparing Different Trials With Different Populations
In TAILORx, unlike in RxPONDER, the recurrence score did appear to help identify which younger women would benefit from chemotherapy.— Gini F. Fleming, MD, FASCO
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On the other hand, ovarian function suppression has a clearly proven benefit in the adjuvant therapy for young women. In the SOFT trial, which tested the addition of ovarian function suppression to tamoxifen (regardless of chemotherapy use) in premenopausal women with hormone receptor–positive breast cancer, the hazard ratio for 5-year invasive disease–free survival with the addition of ovarian function suppression to tamoxifen was 0.83; in multivariable analysis including known prognostic factors, the hazard ratio was 0.78.5 This may seem less striking than the hazard ratio of 0.60 observed with the addition of chemotherapy to premenopausal women in RxPONDER; however, comparison across these very different trials with different populations is difficult.
For example, the SOFT premenopausal population was younger, as patients had to remain premenopausal after chemotherapy if it was given: the average age on the SOFT chemotherapy cohort was 40 years, whereas just 8.5% of premenopausal patients (premenopausal prior to any therapy) on RxPONDER were younger than 40. It has been suggested that the fact that women up to age 40 appeared not to benefit from chemotherapy in the TAILORx trial6 is supportive evidence that the benefit of chemotherapy is related to ovarian function suppression (since women younger than age 40 years are less likely to have ovarian function suppression due to chemotherapy), but there were just 203 women in that age group (with 35 events). It could be hypothesized that the lack of benefit of chemotherapy for premenopausal women older than age 50 is due to the beneficial effects of naturally occurring menopause regardless of chemotherapy. Of course, it also could be the result of the fact that their tumors are missing the chemosensitivity factor seen in tumors of younger women.
Closing Thoughts
Only a randomized prospective trial is likely to be able to answer the question of which, if any, premenopausal women younger than age 50 with node-positive hormone receptor–positive breast cancer and low genomic risk scores truly need chemotherapy in addition to ovarian function suppression. At this point, given that even the groups with the lowest risk score in RxPONDER seem to have substantial benefit from chemotherapy, most node-positive premenopausal women will likely receive chemotherapy regardless of their recurrence score. There seems little benefit to obtaining a genomic signature for this group of women other than to refine prognosis. Those who remain premenopausal after chemotherapy should consider ovarian function suppression. Perhaps in the future, treatment de-escalation will be possible for these women.
Dr. Fleming is Medical Director, Gynecologic Oncology, UChicago Medicine, Comprehensive Cancer Center, Chicago.
DISCLOSURE: Dr. Fleming has received funds for serving on the advisory board of GSK, a planned presentation from OncLive, and Corcept Therapeutics.
REFERENCES
1. Kalinsky K, Barlow WE, Gralow JR, et al: 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 385:2336-2347, 2021.
2. Buus R, Sestak I, Kronenwett R, et al: Molecular drivers of Oncotype DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC study. J Clin Oncol 39:126-135, 2021.
3. Sparano JA, Gray RJ, Makower DF, et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018.
4. Piccart MJ, Kalinsky K, Gray R, et al: Gene expression signatures for tailoring adjuvant chemotherapy of luminal breast cancer: Stronger evidence, greater trust. Ann Oncol 32:1077-1082, 2021.
5. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.
6. 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.
