More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis that had a median follow-up of 5 years of the large-scale phase 3 RxPONDER trial, presented this week at the San Antonio Breast Cancer Symposium (SABCS) 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer in comparison to endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
"RxPonder: practice changing!!!" tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, North Carolina.
"Data from RxPonder are the most clinically important this year at @SABCSSanAntonio," tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, Massachusetts, who was not involved in the study.
"This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions," asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, Georgia, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That's because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy's cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression. "There are less toxic ways than chemo to suppress ovarian function," tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, Maryland, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
"I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy," summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, Texas, who is co-director of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women Had Limited Positive Nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2- breast cancer with involvement of one to three lymph nodes. The patients' recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of US women with nonmetastatic HR+, HER2- breast cancer present with involvement of one to three lymph nodes, added Kalinsky.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy, vs 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs 97.3%; P = .032).
Stratifying patients by recurrence score 0–13 vs 14–25 and by involvement of one vs two to three nodes did not have a major impact on the results, said lead author Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More About Endocrine Therapy in RxPONDER
Meeting co-director Osborne said that premenopausal women in RxPONDER were "nearly always" prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, "both of which have been shown to be superior to tamoxifen alone in this subgroup.
"Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients," he said, "these patients then in fact received ovarian suppression plus tamoxifen," rather than tamoxifen alone for the group that did not receive chemotherapy.
Osborne asked a question that came up again and again during the post-presentation discussion: "Is the difference in outcome in this subset due to the endocrine effects of chemotherapy?
"Unfortunately, we may never know the answer to this question," he added.
Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women "was a direct benefit, meaning that there's something about the biology difference" between tumors in premenopausal vs postmenopausal women, "or whether this was an indirect effect, meaning impacting rates of amenorrhea...is not specifically how this study was designed."
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Osborne said he is nevertheless "still skeptical that chemotherapy works differently in premenopausal women.
"Until we show that it's not an endocrine effect...I just can't imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy."
He added: "If I can think of a rationale...I would believe it, but right now, I'm a little bit skeptical."
Virginia Kaklamani, MD, of the UT Health San Antonio Cancer Center, San Antonio, Texas, who is a meeting co-director, said that she wanted to "second that.
"I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression vs not...showing that [it] can help as much as chemotherapy."
Kaklamani continued: "Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy."
The study was sponsored by the National Cancer Institute and in part by the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Kalinsky, Osborne, and Kaklamani report financial ties to multiple pharmaceutical companies.
San Antonio Breast Cancer Symposium (SABCS) 2020: Abstract GS3-00. Presented December 10, 2020.
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