Study design with clearly defined demographics and outcomes facilitates decision making
James Fleck, MD, PhD: Anticancerweb 18 (03), 2022
Most advanced breast cancer patients are diagnosed as a postmenopausal disease, being predominantly of HR-positive Her2-negative (HR+Her2-) luminal subtype. Historically, these patients have been managed with endocrine therapy, like letrozole or fulvestrant. Recently, cyclin-dependent kinases 4 and 6 (CDK4/CDK6) inhibitors have been used to overcome endocrine resistance in HR+HER2- postmenopausal metastatic breast cancer. Increased expression of CDK4 has been associated to breast cancer cells endocrine resistance. All these are important prognostic and predictive factors that must be considered when defining eligibility criteria for any prospective randomized clinical trial. Three phase III prospective randomized trials have been published evaluating the impact of adding CDK4/CDK6 inhibitors to palliative endocrine first-line treatments in postmenopausal HR+Her2- advanced breast cancer patients. Data, shown in the table 1, revealed an increase in progression-free survival with combined therapy, when compared to endocrine treatment alone. However, most of these patients express low-aggressive disease, requiring a longer follow-up to assess the impact on overall survival.
In March 10th, 2022 the New England Journal of Medicine published mature results of the MONALEESA-2 prospective randomized trial, after a median follow-up of 6.6 years. First-line treatment of HR+Her2- postmenopausal women with letrozole + ribociclib resulted in significant overall survival benefit when compared to letrozole + placebo. This is the first prospective randomized trial to show an overall survival benefit for this specific first-line treatment in postmenopausal population. Increase in overall survival has been described with endocrine therapy + CDK4/CDK6 inhibitors in different scenarios, as shown in table 2. For instance, MONALEESA-7 also showed a first-line overall survival benefit with the same combined therapy, but it included both premenopausal and postmenopausal women, leading to natural limitation in subset analysis. MONALEESA-3, using fulvestrant and ribociclib addressed both first- and second-line treatments, creating a decision-making deadlock about what strategy was responsible for the positive results. This impasse is even greater in the MONARCH-2, since the accrual included patients in any menopausal status receiving fulvestrant and abemaciclib as first- and second-line combined treatments. Expected methodologic limitations emerged as a consequence of a broader inclusion criteria or double treatment intention (first- and second-line).
In conclusion, two prospective randomized trials have already published mature results, showing benefit of combined approach (endocrine therapy + CDK4/CK6 inhibitors) in specific populations. These trials are very useful for clinical oncology decision-making. The PALOMA-3 prospective randomized trial is very assertive, since the combination of fulvestrant + palbociclib led to a significant increase in overall survival, when the combined approach was used as a second-line treatment in HR+Her2- postmenopausal patients. Mature results of the MONALEESA-2 prospective randomized trial also defined letrozole + ribociclib as the new first-line standard treatment for HR+Her2- postmenopausal women.
References:
1. Gabriel N. Hortobagyi, Salomon M. Stemmer, Howard A. Burris, et al: Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer, N Engl J Med 386: 942-50, 2022
2. S.-A. Im, Y.-S. Lu, A. Bardia, et al: Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer, N Engl J Med 381: 307-316, 2019
3. Richard S. Finn, Miguel Martin, Hope S. Rugo, et al: Palbociclib and Letrozole in Advanced Breast Cancer, N Engl J Med 375:1925-36, 2016
4. Stephen Johnston, Joyce O’Shaughnessy, Miguel Martin, et al: Abemaciclib as initial therapy for advanced breast cancer: MONARCH 3 updated results in prognostic subgroups, Breast Cancer 7:80, 2021
5. Dennis J. Slamon, Patrick Neven, Stephen Chia, et al: Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer, N Engl J Med 382:514-24, 2020
6. Jason Harris: Palbociclib Plus Fulvestrant Combo Maintains Long-Term OS Benefit, ASCO Annual Meeting – Breast cancer, June 5, 2021
7. George W. Sledge, Jr., Masakazu Toi, Patrick Neven, et al: MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy, J Clin Oncol 35:2875-2884, 2017
Breast cancer is undoubtedly the most feared tumor by women in recent years. HER 2+ are those with the worst prognosis due to their aggressiveness. Therefore, studies like this are increasingly essential.
Breast cancer therapy based on immunophenotype analysis has been established with each scientific research in recent years and more and more predictive factors (which are those that include a patient in a certain treatment group or not) associated with prognostic factors have been of vital importance for the decision making. New clinical trials testing combined therapeutic approaches in an attempt to gain survival in these women have shown promising results, including the association of CDk4/CDK6 tyrosine kinase inhibitors in the treatment of luminal hormone receptor A positive and HEr-2 negative luminal immunophenotype women, winning resistance to hormone inhibitors in the long term with survival gain in these women regardless of menopausal status, that is, the combined approach (endocrine therapy plus tyrosine kinase inhibitors in specific populations) being an individualized therapy and very important works in clinical decision making in oncology.
Targeted therapy is a newer approach to treating breast cancer and is designed to target specific proteins that promote the growth of cancer cells. Examples of targeted therapies for HER2-negative breast cancer include CDK4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors. Ultimately, the treatment approach for advanced HR-positive, HER2-negative breast cancer will depend on a variety of factors, including the extent of disease, patient characteristics, and potential side effects of the various treatments.
The results of these studies evidence the most updated therapeutic alternatives for the management of breast cancer patients. However, although Oncology is a rapidly growing study field, its results take a relatively long time to become a reality in clinical practice, especially in Brazil. I recently got in contact with an advanced breast cancer patient whose initial treatment plan was letrozole + ribociclib (such as evaluated in MONALEESA-2). Nevertheless, as ribociclib is not insured by the Brazilian health system and the judicial process of obtaining it is quite complex, that patient could not benefit from the favorable outcome of the combined therapy on overall survival. It is frustrating to see how much knowledge has been acquired in treating cancer in just over a few decades and how it can all be restained by bureaucratic barriers. I hope our health system can overcome them in the foreseeable future.
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