“Nodal status remains the single most important prognostic marker in outcomes for women with estrogen receptor–positive, HER2-negative breast cancer. For that reason, it makes sense to think about optimizing adjuvant therapy, including endocrine treatments, chemotherapy, and targeted therapy,” Harold J. Burstein, MD, FASCO, PhD, told participants at the 2021 Lynn Sage Breast Cancer Symposium.1
“Over the years, I have become progressively more persuaded that using adjuvant bisphosphonate therapy can help reduce the risk of cancer recurrence and improve long-term outcomes.”— Harold J. Burstein, MD, FASCO, PhD
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Dr. Burstein is Professor of Medicine, Harvard Medical School, and medical oncologist at Dana-Farber Cancer Institute in Boston. The symposium was sponsored by Northwestern Medicine/Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
Two Fundamental Modalities
The two fundamental approaches to estrogen receptor–positive, early-stage breast cancer remain endocrine therapy and chemotherapy. Studies have looked at targeted treatment with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, but these agents have not yet been approved in the early-stage setting, and criteria for their use are undefined.
“Nearly all patients diagnosed with estrogen receptor–positive breast cancer will be offered endocrine therapy, particularly those with nodal involvement. As the stage of the cancer rises, we tend to escalate the intensity of the endocrine manipulations, including the addition of ovarian suppression to premenopausal women and longer durations of therapy,” Dr. Burstein said.
Chemotherapy requires “more of a nuanced discussion,” Dr. Burstein commented. “Many women will not need chemotherapy, including some women with node-positive breast cancer. For higher-stage cancers, particularly stage III, with higher-risk biologic features, chemotherapy remains an important treatment modality.”
Reducing the Risk of Recurrence
“We know from classic randomized trials—such as BIG 1-98—that incorporating an aromatase inhibitor can reduce the risk of recurrence and improve long-term disease endpoints for women who have estrogen receptor–positive, node-positive breast cancer,” Dr. Burstein stated. Data from a median follow-up of 12 years showed “modest but measurable benefits in terms of distant disease–free survival, breast cancer recurrence, and some trends favoring overall survival with the use of an aromatase inhibitor–based regimen instead of tamoxifen. I do prefer an aromatase inhibitor for most postmenopausal women who have node-positive breast cancer, assuming they tolerate the many side effects of these treatments,” Dr. Burstein remarked.
Subset analysis of BIG 1-98 revealed that “lobular breast cancers in particular seem to do less well with tamoxifen-based therapy, and that has been seen in retrospective analyses of other important clinical trials as well,” Dr. Burstein noted. “Based on that, when seeing a patient who has an obvious lobular breast cancer, my preference is to go with an aromatase inhibitor.”
“For a long time, we have known that women who experience chemotherapy-induced menopause could have a better outcome than women who did not have chemotherapy-induced menopause, suggesting that ovarian suppression might be important in the long-term management of these patients,” Dr. Burstein noted. But it took the results of the SOFT and TEXT trials “to clarify the role for higher-risk estrogen receptor–positive, node-positive breast cancer.”
Initial data suggested ovarian suppression had minimal benefit in low-risk patients—those with stage I, node-negative disease and “older in the premenopausal spectrum, with a median age in the early 40s,” Dr. Burstein reported. “By contrast, women who were typically given chemotherapy had higher-risk cancers—more often, node-positive and higher-grade—and tended to be younger, with a median age in the late 30s. In this group of patients, adding ovarian suppression and including the aromatase inhibitor exemestane substantially reduced the risk of recurrence.”
Women who were younger than 35 and received tamoxifen plus ovarian suppression and then an aromatase inhibitor had a 15% reduction in the risk of recurrence over the first 7 or 8 years, compared with tamoxifen alone.2 This is “a very dramatic benefit of ovarian suppression,” Dr. Burstein noted.
“With long-term follow-up, it is also apparent that there is a trending survival advantage in these higher-risk patient groups, and the fundamental question that has emerged is how much of this is because of the use of ovarian suppression and how much of it is simply because ovarian suppression enables the use of an aromatase inhibitor? The honest answer is we don’t know,” Dr. Burstein acknowledged. Both the therapeutic role of ovarian suppression itself and secondarily enabling the use of an aromatase inhibitor “is going to be important to patients who have higher-risk, estrogen receptor–positive, node-positive tumors.”
Duration of Treatment
“With remarkable consistency, studies looking at the duration of treatment with tamoxifen, aromatase inhibitors, or blended sequences have shown that longer durations of treatment do reduce recurrence risk, particularly in women who have node-positive, early-stage breast cancers,” Dr. Burstein said.
“For most women who have estrogen receptor–positive, node-positive disease, the minimum treatment duration is 5 years. But in regular practice, we are aiming for longer durations, probably closer to 7, 8, or even 10 years of therapy.”
A meta-analysis of 12 studies of extended therapy by nodal status found no major benefit for the treatment of node-negative patients beyond 5 years. But the data showed a 4% improvement in disease-free survival for patients with up to three positive nodes and a 7% or 8% improvement for those with four or more positive nodes.3
“The takeaway here is that nodal status is an important prognostic factor for late recurrence, and most women who have nodal involvement should anticipate considering at least extended therapy beyond 5 years,” Dr. Burstein stated.
Optimizing Endocrine Therapy
Recapping, Dr. Burstein listed the following recommendations for optimizing endocrine treatment:
For patients with estrogen receptor–positive, node-positive disease, “aim for treatment beyond 5 years,” Dr. Burstein said. For high-risk patients, therapy should probably continue for close to 10 years. “For average-risk, node-positive patients, 7 or 8 years is probably adequate therapy.”
“Over the years, I have become progressively more persuaded that using adjuvant bisphosphonate therapy can help reduce the risk of cancer recurrence and improve long-term outcomes,” Dr. Burstein stated.
In postmenopausal women in particular, he said, including bisphosphonate therapy has been shown to reduce bone metastases and improve overall breast cancer mortality rates. “The secondary benefit is reducing the risk of osteopenia or osteoporosis among patients who are postmenopausal getting adjuvant endocrine treatments.”
Who Needs Chemotherapy?
Chemotherapy has been transitioning from an important part of treatment for estrogen receptor–positive, node-positive breast cancer to providing “rather modest” benefits, Dr. Burstein noted.
“RxPONDER is an important study because it says what the contemporary outcomes would be for women who have one, two, or three positive lymph nodes, and it also allows us to tease out the value of chemotherapy in this cohort with lower recurrence scores,” Dr. Burstein commented.
“There was a 1% difference overall in disease-free survival with the addition of chemotherapy to endocrine therapy in the whole study cohort. It is hard to think that there is a real clinical benefit when you weigh the side effects of chemotherapy and this relatively modest disease-free survival benefit,” he said.
Among postmenopausal patients with breast cancer, “there was absolutely no suggestion of clinical benefit with the use of chemotherapy in addition to endocrine therapy for women who have one, two, or three positive nodes and a recurrence score less than or equal to 25. This means that the majority of our patients with estrogen receptor–positive N1 breast cancers probably don’t need chemotherapy if they have a successful recurrence score less than 25.”
“Intriguingly, premenopausal women actually did seem to have a robust benefit from the use of chemotherapy [in RxPONDER],” Dr. Burstein noted. “The question that arises from this study and the related TAILORx trial is: how much of the benefit is due to the ovarian suppression effects of chemotherapy? The answer has to be a lot of it, but we don’t necessarily know for sure whether all of it.”
TAILORx included women aged ≤ 50 with Oncotype DX recurrence scores ≤ 25; it found a relative increase in the benefit of chemotherapy as women in their 40s got closer to natural menopause and were more likely to go into chemotherapy-induced menopause. “The greatest benefit of chemotherapy was in women aged 46 to 50,” Dr. Burstein said. “If the patient was already postmenopausal but young, there was no benefit for chemotherapy when the endocrine effects are neutral. The only explanation that accounts for these data is the idea that nearly all the benefit of chemotherapy in premenopausal women with recurrence scores < 25 is because of the onset of treatment-induced menopause.”
Among premenopausal patients in the RxPONDER study, the benefit from chemotherapy “is more pronounced, relatively speaking, in the group with a recurrence score between 0 and 13,” Dr. Burstein noted. “The only explanation that fits with that is the idea that chemotherapy is causing ovarian suppression, which is contributing to the benefit.”
“The key point is that you don’t have to give chemotherapy to put a patient into menopause,” Dr. Burstein said. “More and more when I have a patient who is premenopausal, with limited node-positive breast cancer and a recurrence score < 25, I use ovarian suppression instead of chemotherapy. Chemotherapy is more or less restricted to stage III tumors with higher Oncotype DX scores.”
The CDK4/6 inhibitors abemaciclib and palbociclib have been tested in clinical trials as targeted therapies for estrogen receptor–positive, node-positive breast cancer. In the monarchE study, more than 5,500 patients received endocrine therapy with or without abemaciclib.
“These women were a relatively high-risk group. They had four or more positive nodes, or at least one, two, or three positive nodes and some other feature, such as a high Ki67 score, high grade, or large tumor size,” Dr. Burstein explained.
In early follow-up, “there was about a 25% relative risk reduction favoring abemaciclib,” Dr. Burstein reported. “Women who had tumors with high Ki67 expression were at greater risk of recurrence. Not surprisingly, they saw a greater absolute benefit with the inclusion of abemaciclib—up to a 4% or 5 % difference through 2 years of follow-up. Women who had a lower Ki67 score had the same relative risk reduction, but because of the better overall prognosis, that translated into a somewhat smaller 2% to 3% benefit,” Dr. Burstein noted. “These kinds of data are going to be really important when thinking about how to optimally use drugs like abemaciclib in the early-stage setting as a partner to endocrine therapy.”
In the Penelope-B study, women with residual cancer after receiving neoadjuvant chemotherapy were stratified to endocrine therapy alone or with palbociclib. “One of the intriguing things seen in this study is that there was an apparent benefit for palbociclib at the 2-year landmark,” Dr. Burstein reported, “but by years 3 to 4, the curves were coming together again.”
These results highlight “the importance of longer follow-up” before CDK4/6 inhibitors are used in routine management of stage II and early stage III, node-positive, estrogen receptor–positive breast cancer, Dr. Burstein said. “We are waiting for ongoing data and regulatory review to decide how best to use these drugs.”
Disclosure: Dr. Burstein reported no conflicts of interest.
1. Burstein A: Adjuvant therapy for ER+ node positive breast cancer. 2021 Lynn Sage Breast Cancer Symposium. Presented October 25, 2021.
2. Francis PA, Pagani O, Fleming GF, et al: Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 379:122-137, 2018.
3. Gray R, Early Breast Cancer Trialists’ Collaborative Group: Effects of prolonging adjuvant aromatase inhibitor therapy beyond 5 years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 6, 2018.