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RxPONDER Update Yields No Clear Guidance on Chemo Decisions for Younger Breast Cancer Patients


NEW YORK – Updated analysis from the RxPONDER trial did not yield definitive answers to oncologists' questions as to whether all premenopausal women with early-stage lymph node-positive hormone receptor-positive breast cancer should receive chemotherapy with endocrine therapy if they have Oncotype DX recurrence scores between 0 and 25, or if they can do just as well with ovarian suppression instead of chemo.

At the San Antonio Breast Cancer Symposium on Wednesday, Kevin Kalinsky, principal investigator of the SWOG Cancer Research Network-supported study, presented his team's exploratory efforts to tease out which premenopausal breast cancer patients with node-positive disease and scores of 25 or lower on Exact Sciences' multi-gene expression Oncotype DX may benefit from chemo. The analysis involved small subgroups, however, and did not provide a clear answer to oncologists' main question: is the benefit seen in RxPONDER in premenopausal women due to the anti-tumor or the ovarian suppression effects of chemo?

Oncologists at SABCS further debated this question in a session entitled "RxPONDER: Was it all ovarian function suppression?" Harold Burstein, medical oncologist at Dana-Farber Cancer Institute who moderated the debate, noted that "if this was a compelling question last week in the clinic, it has become red hot" since Kalinsky's presentation at the meeting.

The answer is important because amenorrhea lowers estrogen levels and staves off cancer recurrence. If the benefit reported last year at SABCS in premenopausal women with 0 to 25 Oncotype DX recurrence scores is largely due to the ovarian suppression effects of chemo, then some oncologists would prefer to use other less toxic ways to stop women's menses, including combining hormone therapies with aromatase inhibitors and surgical removal of ovaries for women who are not planning to have children. Other oncologists, at this point, aren't ready to entirely forgo chemotherapy in all younger breast cancer patients with recurrence scores of 0 to 25, recognizing that gene expression testing with Oncotype DX may not fully capture the biological differences that make some premenopausal tumors more likely to relapse.

Unfortunately, RxPONDER wasn't designed to provide the type of guidance doctors are looking for. "RxPONDER was not powered for subgroup differences, and interpretation of these data can be challenging in the pre-menopausal subgroup given that confounding factors can change over time," Kalinsky, who is also director of the Glenn Family Breast Center at the Winship Cancer Institute, said at the meeting.

He proposed that a large, randomized study is needed to definitively determine which premenopausal women in the 0 to 25 Oncotype DX recurrence risk score category should receive chemo and endocrine therapy, and which can do well with ovarian suppression by other means and endocrine therapy. Such a trial is under discussion among breast cancer researchers, which Exact Sciences indicated it will support.

Updated analysis

Kalinsky reported last year at SABCS that in the 5,000-patient Phase III RxPONDER trial, post-menopausal women with lymph node-positive, HR-positive, HER2-negative breast cancer did not have better invasive disease-free survival or distant relapse-free survival with chemotherapy followed by endocrine therapy if they had Oncotype DX recurrence scores of 25 or lower. However, the five-year invasive disease-free survival rate in premenopausal women with recurrence scores in the same range was 94 percent for those receiving chemo-endocrine therapy, and 89 percent for those in the endocrine therapy-only arm.

These findings left oncologists wondering what the biological basis may be for premenopausal women's tumors benefitting from chemotherapy and postmenopausal women's tumors not, despite having the same recurrence scores. Some questioned whether the invasive disease-free survival benefit seen in premenopausal women was entirely due to chemotherapy stopping younger women's menses, and if so, if the same outcomes may be achieved by combining endocrine therapy and other means of ovarian function suppression.

In the New England Journal of Medicine last week, Kalinsky and colleagues published earlier results from RxPONDER based on 5.3 years of follow-up and 481 patients having invasive disease-free survival events — a broad endpoint that includes local-regional invasive recurrence, second invasive primary cancers, distant recurrence, and death from breast cancer or other causes.

At SABCS yesterday, Kalinsky provided updated results based on six years of follow-up and 553 invasive disease-free survival events and showed that postmenopausal women continue to derive no benefit from chemo-endocrine therapy. Distant relapse-free survival rates — calculated based on the number of patients who have distant recurrence or die from breast cancer and other causes — were also similar in postmenopausal women in the chemo-endocrine therapy and endocrine therapy-only arms.

Similarly, the updated data didn't change the finding overall that node-positive premenopausal women in RxPONDER derived benefit from adding chemo. The five-year distant relapse-free survival rate was 96 percent and 93 percent in the chemo-endocrine therapy and endocrine therapy-only arms, respectively.

In terms of five-year distant recurrence-free interval — which Kalinsky said is the narrowest and more clinically relevant outcome since it tracks only distant recurrence and death specifically from breast cancer — there was no statistically significant difference between treatment arms in postmenopausal women. In premenopausal women, however, 3.7 percent had such events over five years on chemo-endocrine therapy, while 6.1 percent of patients had these events on just endocrine therapy — translating to a five-year absolute chemo benefit of 2.4 percent.

"Recurrence score was a stratification factor" in premenopausal women, Kalinsky noted. In women with Oncotype DX recurrence scores of 0 to 13, there was a 2.3 percent absolute benefit from adjuvant chemo in terms of five-year distant recurrence-free internal, while the chemo benefit was 2.8 percent in those with recurrence scores between 14 and 25.

Ongoing debate

The updated analysis only fueled further debate at SABCS, as oncologists tried to interpret how the findings might impact their practice. "Chemotherapy is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine non-responsive disease," said Michael Gnant, director of the surgery department at the University of Vienna, who argued that the benefit with adjuvant chemo seen in RxPONDER in premenopausal women is all due to ovarian function suppression.

Gnant cited a number of older studies that have found that chemotherapy and ovarian ablation yield similar outcomes in patients. "This is clear because both interventions do the same: they suppress ovarian function," Gnant said. "We're in danger of heavily overtreating these patients if we give them treatments that basically do the same [thing]."

Sibylle Loibl, CEO and chair of the German Breast Group, argued in opposition and showed data that premenopausal women with certain high-risk breast cancer subtypes do benefit from chemotherapy. In Loibl's view both the cytotoxic and ovarian suppression effects of chemo are important for younger women with breast cancer, because the biology of their tumors differ based on age. Even a 30-year-old woman's breast tumor may be different from a 40-year-old's tumor, and in Loibl's view, these biological differences aren't necessarily being captured by gene expression profiling tests like Oncotype DX and others.

Burstein observed that if it's not just ovarian suppression that's causing the benefits seen in premenopausal women in RxPONDER, then it has to be tumor biology that's driving the outcomes seen in younger patients' tumors. "We've gotten used to the idea that with a [Oncotype DX] recurrence score and other gene expression profiling assays we're accounting for the vast majority of biologic heterogeneity," he said. "Are we mistaken in that assumption?"

Loibl reflected that breast cancer gene expression profiling tests doctors use today were initially developed in postmenopausal patients and retrospectively used in premenopausal women. The tests likely don't assess the expression of the genes that best capture young women's tumor biology, she said, highlighting a study under review for publication, which found that younger women with higher immune gene expression may be more sensitive to chemo, while lower expression of estrogen receptor genes may make them less sensitive to endocrine therapy. Tests like these as well as measurement of estrogen and progesterone receptors, and Ki-67 and tumor infiltrating lymphocytes, along with consideration of women's age, Loibl said, could help more accurately identify which premenopausal breast cancer patients to give chemo to.

Questions remain

Recognizing there are still many outstanding questions among oncologists as to how to integrate the RxPONDER findings for premenopausal women in the clinic, Kalinsky's group conducted exploratory analysis, looking at invasive disease-free survival in patients with micro-metastatic lesions; two-year invasive disease-free survival in women treated only with endocrine therapy who had ovarian function suppression and those who didn't; and two-year invasive disease-free survival in women with and without regular menstrual periods in both treatment arms.

In around 200 premenopausal women with micro-metastases there were 22 invasive disease-free survival events over five years: seven in the chemo-endocrine therapy arm and 15 in the endocrine therapy only arm. This translated to a 7.3 percent five-year invasive disease-free survival benefit with adjuvant chemotherapy. In around 1,400 premenopausal women who had macro-metastases, the chemo benefit was around 4.8 percent. 

Kalinsky said that these data should be interpreted with caution since there are so few invasive disease-free survival events in the subgroup of premenopausal women with micro-metastasis.

RxPONDER researchers also looked at the impact of ovarian function suppression — either using medicine or surgery — over the first two years in RxPONDER among those receiving just endocrine therapy. The aim of this exploratory analysis was to tease out if the combination of ovarian function suppression and endocrine therapy would yield comparable results to the chemo plus endocrine therapy arm, particularly since some oncologists have wondered if comparable outcomes could be achieved with the non-chemo strategies in young women with recurrence scores of between 0 and 25.

Kalinsky showed at the meeting that ovarian suppression didn't seem to make much difference in invasive disease-free survival rates for patients receiving only endocrine therapy. Again, he cautioned that this finding came out of a small, exploratory analysis.

Since chemotherapy can also stop menses, which in turn can lower cancer recurrence risk, researchers also considered how premenopausal women in both treatment arms fared based on if they were having regular menstrual periods or not. Although more women in the chemotherapy arm stopped having regular periods, the rate of regular menses decreased over the first two years among women receiving chemo-endocrine therapy and just endocrine therapy. And Kalinsky reported "a numerical improvement in invasive disease-free survival" in both treatment arms among premenopausal women no longer having periods compared to those still having regular periods.

Specifically, around 59 percent of women in the endocrine therapy-only arm and 81 percent in the chemo-endocrine therapy arm stopped having regular periods in the first two years in the study and had numerically better invasive-disease free survival compared to those still having regular menses. This raises the question, "Is the benefit from chemotherapy actually from ovarian suppression or the chemotherapy itself?" wondered Anne Blaes, director of cancer survivorship services and translational research within the University of Minnesota's Masonic Cancer Center, while reviewing the updated RxPONDER data at the meeting. "This question still remains."

While it's clear that the RxPONDER data shows that some premenopausal women with an Oncotype DX recurrence score of between 0 and 25 derive benefit from chemotherapy followed by endocrine therapy, Kalinsky cautioned oncologists at the meeting from drawing definitive conclusions based on the exploratory analysis he presented. "It remains unclear if ovarian function suppression can replace chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative, node-positive breast cancer," he said. "We conclude that a future randomized trial should be considered to address this important clinical question in a genomically defined population."

Rick Baehner, chief medical officer of precision oncology at Exact Sciences, indicated the company is committed to supporting future clinical trials that will improve the utility of Oncotype DX recurrence scores and help oncologists personalize the use of chemotherapy, endocrine therapy, and ovarian function suppression in premenopausal breast cancer patients. "The breast [cancer] community is discussing a randomized clinical trial to assess whether premenopausal patients with recurrence scores of 0 to 25 benefit from endocrine therapy plus chemotherapy; endocrine therapy plus ovarian function suppression; or endocrine therapy plus ovarian function suppression plus chemotherapy," Baehner said.