Bisphosphonates: Breast Cancer Julia Foldi SABCS 2022 Cohort Study
How can BMAs (zoledronic acid) help oncology patients with early-stage breast cancer in the United States and not in other countries? I’m talking about our study looking at patterns of adjuvant bone modifying use in patients with early stage breast cancers. Bone modifying agents, particularly bisphosphonates, not only help preserve bone density (or bone material loss) in postmenopausal women receiving endocrine therapy for treatment of breast cancer, but we also know that they reduce the risk of breast cancer recurrence as well as reduce the risk of breast cancer specific deaths. While these reductions in risk are small and very dependent on the underlying risk factor of breast cancer recurrence, they are very well documented in multiple prospective randomized clinical trials and also in a large meta-analysis of multiple trials combined.
And so in, in 2017, the ESCO and Cancer Care Ontario published clinical practice guidelines which recommend that clinicians discuss. Adjuvant bisphosphonate therapy with all postmenopausal patients receiving any kind of systemic therapy for early stage breast cancer, regardless of the subtype of breast cancer, however, based on surveys of clinicians, we know that the actual prescribing of adjuvant bisphosphonates was lower than what we would expect based on these recommendations. So the goal of our study really was to evaluate the prescribing patterns of bone modifying agents, including bisphosphonates and others, such as denosumab.
In the period immediately following breast cancer diagnosis and definitive surgery. So the way we defined the adjuvant timeframe was to. Look at prescribing within the first 2 years after a breast cancer diagnosis. And our hypothesis was that the overall prescribing of bone modifying agents is low and that it may have increased after the publication of the 2017 ASCO CO guidelines.
So we used a Flatiron Health EMR based data set of early stage breast cancer patients. So these include stage 1, 2, 3 breast cancer patients of any subtype. This included over 11,000 women diagnosed from 2012 to 2019, and we analyzed data on the use of bone modifying agents, including all bisphosphonate (therapy) categories and denosumab.
Within the first 24 months after diagnosis of breast cancer, what we found was that only 7 0.4% of patients who were diagnosed before the publication of the ESCO CCO guidelines. So before 2017 received any bone modifying agent within the first 24 months after diagnosis, and this increased slightly to 9% after the publication of the guidelines so after 2017. We found that only 7.4% of all patients were prescribed any bone modifying agents in the pre 2017 period, so before the publication of the clinical practice guidelines. And this increased to 9% post 2017, so after the publication of the guidelines, this change in the percent of patients receiving bone modifying agents was statistically significant with an odds ratio of 1.23.
When we looked specifically in patients over the age of 50. So these would, for the most part, represent postmenopausal patients. The percent of patients receiving bone modifying agents was slightly higher, 8.7% pre 2017, and 9.9% post 2017. This change, while numerically higher, was not statistically significantly higher. We also looked at the factors that are associated with prescribing of bone modifying agents in this population, and we found that age over 50 years being postmenopausal, having a primary tumor that was at least T2 or higher, and having adjuvant endocrine therapy as well as a coexisting diagnosis of bone loss. So osteopenia (bone pain) or osteoporosis (bone disease) were all associated with the receipt of adjuvant bone modifying agents. Now, one of the most interesting findings in my mind is that out of the 935 patients who received any bone modifying agents in the adjuvant setting, 65% of them received denosumab only, while only 32 and 32.5% received bisphosphonate therapy, with 1.4% of them receiving both a bisphosphonate and denosumab at some point in their course.
This is to me very interesting because the guidelines specifically recommend the use of bisphosphonates in the adjuvant setting and recommend against denosumab because of the lack of clear evidence that denosumab decreases recurrence of breast cancer as well as breast cancer related. Now one of the major limitations of our study, it is retrospective, looking at an EMR based data set, and there is no detailed information on the rationale for prescribing these bone modifying agents. So we don’t know what the intent of use for these drugs was in in these patients. We did define the adjuvant period as being within the first 24 months of diagnosis, but we know that many clinicians prescribe these bone modifying agents, not only to reduce the risk of breast cancer recurrence, but also for coexisting bone loss diagnoses (loss of bone cells) in patients who have osteopenia or osteoporosis. And we based, just looking at this database, we unfortunately cannot tell which patients got these drugs purely for their bone loss diagnosis versus really for the breast cancer to reduce risk of recurrence.
And I think one of the interesting things that this study brings up is that we need to look more closely at why the prescribing of bone modifying agents is so low. Even in our postmenopausal patients, post 2017, only about 10% of them are getting any of these drugs, and much less for bisphosphonates specifically.
So what are the barriers to prescribing? How can we better implement and disseminate the guidelines? I think these are some of the interesting questions that I see as the next steps to answer.
What are the most common questions you’re asked by your colleagues about this study?
So, people have asked me what is my practice in prescribing adjuvant bisphosphonates or adjuvant bone modifying agents and what. But agents I tend to use, so I try very hard in my practice to discuss. This topic is discussed with patients early on in their course of treatment. So as soon as I see them in the clinic to discuss adjuvant treatment for breast cancer, especially on the, in those women who are going to be receiving adjuvant endocrine therapy for a hormone receptor positive breast cancer, because as we know, aromatase inhibitors can over time lead to a decrease in bone density (or bone material loss).
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And I think it’s extremely important not only for the risk reduction for breast cancer recurrence, but also to protect the bones for these patients. And so I generally will discuss with them the use of zoledronic acid or zometa (zoledronic acid) every 6 months dosing for two to three years. I think based on the SUCCESS A trial, we now have an idea that, after 2 years versus 5 years, there’s really no difference in terms of the risk of breast cancer recurrence. And so, 2 years of zoledronic acid seems to be sufficient. And we know that the risk of side effects is less with a shorter duration of treatment. One of the other questions that I get asked, is something I briefly touched upon what, what are the implications of our study, what are the next steps, and how can we improve the uptake of these agents in clinical practice? I think the answer to that question is complicated and it’s a little bit unclear to me, but the next concrete steps could be, as I mentioned, that we need to understand better the barriers to prescribing are clinicians not trusting the data? I think it’s one of the issues in this area; there have been some conflicting studies, especially looking at the efficacy of denosumab in the reduction of breast cancer recurrences, where we have 2 major trials with contradicting results, with the larger of the 2 trials actually being negative.
The 2 trials use different dosing regimens and different durations, and so there might be some in terms of dosing in how efficacious the drug may be. I think some clinicians tend to also not trust the data on cancer bisphosphonates as the reduction in risk of breast cancer recurrence and breast cancer specific death tends to be small, especially for those patients with a low risk disease to begin with.
And so, I think, especially in those patients with a low clinical risk factors of breast cancer, most clinicians may not want to discuss using bisphosphonate therapy with their patients because they don’t believe that there would be much benefit. I think what’s really clear is even beyond reducing the risk of breast cancer recurrence that these agents do protect.
From bone loss, reduce the risk of bone fractures, and so those are all important considerations. I think we do need to do a better job disseminating and implementing the guidelines. There was an update to the 2017 ASCO CO guidelines that was published just last year. The 2021 Guidelines are largely unchanged in terms of the main recommendations, they continue to recommend that clinicians discuss the use of adjuvant bisphosphonates with all patients who are postmenopausal, either by natural menopause or chemical menopause. So even those premenopausal patients who are on ovarian function suppression, regardless of subtype of breast cancer, if they’re getting any kind of adjuvant systemic therapy.
They also continue to endorse the use of bisphosphonates, including zoledronic acid as well as two oral bisphosphonates, which unfortunately are not available in the United States at this time, at the dosing that’s recommended. So we’re really stuck with zometa (zoledronic acid) for the most part, which, as we know some patients do not tolerate very well.
And then they, the guidelines, continue to recommend against the use of denosumab and adjuvant settings specifically for breast cancer risk reduction because the data is insufficient. However, based on our study, we know that many clinicians are using denosumab. In fact, most people are prescribed denosumab in the first 24 months after their breast cancer diagnosis.
And I think this shows that denosumab, is a popular drug, it is, what’s thought of by more clinicians than bisphosphonates when they think about treating osteopenia or osteoporosis. I think it should be noted that denosumab is much more expensive than bisphosphonates, and there are some potential increased side effects (or adverse side effects), including the risk of bone fractures in the immediate period after discontinuing denosumab.
So I think this needs to be studied more, especially in this particular population. So I think overall, our study just highlights some of the practice patterns that are currently ongoing in the United States and opens up some new avenues for investigation in this area.
Will this data affect clinicians today?
I don’t think this data will change anybody’s practice per se. I hope that it makes clinicians think about the guidelines and put them in the front of their minds. When they are meeting their individual patients who are starting adjuvant therapy, that they would be more likely to at least discuss with those patients the use of these bone modifying agents.
But I do not think that this study will directly change anybody’s practice. I do hope that people prescribing these medications consider the recommendations and look at (oral) bisphosphonates in addition to denosumab when they start patients on these bone modifying and bone protective agents.
What are the key takeaways from this research and data from the clinical trial on early stage breast cancer?
So I think the key takeaways are that prescribing of adjuvant bone modifying agents across the board is very low and well under 10% even in postmenopausal women with early stage breast cancer where these, the use of these agents is specifically recommended. And the other interesting finding is that denosumab is the most commonly used agent of the one, ones that are available. And so I think one of the questions is why is denosumab being used more often? And that again is one of the one of the areas to explore in the future.
Julia Foldi, MD, PhD – About The Author, Credentials, and Affiliations
Dr. Julie Foldi, a health care professional, specializes in the treatment of breast cancer patients as a medical oncologist. She sees patients at UPMC’s Magee-Cancer Women’s Hospital’s Women’s Center. Her goal is to deliver interdisciplinary, evidence-based, and individualized care to each breast cancer patient.
She is a researcher who focuses on enhancing breast cancer treatments by combining clinical care with rigorous clinical inquiry and translational research. Her primary interest is designing clinical trials for the treatment of both early-stage and metastatic breast cancer using innovative medicines such as immunotherapy and targeted therapies, based on solid scientific reasoning. She also intends to utilize patient data, such as patient-reported outcomes, blood and tissue samples, to pose fundamental questions regarding tumor biology and host-tumor interactions.