Adjuvant chemotherapy plus endocrine therapy fails to increase OS in breast cancer subset
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CHICAGO — The addition of chemotherapy to endocrine therapy did not extend OS after surgery among older patients with ER-positive, HER2-negative breast cancer with a high tumor genomic grade index.
Researchers presented the results of the Unicancer ASTER 70s trial at ASCO Annual Meeting.
Rationale and methods
“[We sought] to identify with a modern prognosticator/gene expression profile a population of older patients with ER-positive breast cancer in whom the addition of adjuvant chemotherapy to endocrine treatment is meaningfully beneficial,” Etienne Brain, MD, PhD, oncologist in the department of medical oncology at Institut Curie — Hospital Rene Huguenin, told Healio. “After the age of 70 years, there is such high competition between cancer and comorbidities for prognosis that it really makes it a much harder challenge to identify the few patients in whom adjuvant chemotherapy could be useful without harm — such as side effects, loss of autonomy, downfall after chemotherapy due to unveiling some level of frailty — beyond what can be already provided by adjuvant endocrine therapy, especially with optimized endocrine therapy with the combination with CDK 4/6 inhibitors.”
This population of patients deserves more attention and constant adjustments of “recipes’ used in younger adults, he added.
“Of note, this is totally different for ER-negative disease, where the magnitude of the benefit provided by chemotherapy is potentially important without lifting the caveats on the marks of aging,” Brain said.
Investigators assessed tumor genomic grade index among 1,089 patients (median age, 75 years) and randomly assigned patients with high index to either chemotherapy plus endocrine therapy (n = 541) or endocrine therapy alone (n = 548).
OS benefit of chemotherapy in the intent-to-treat population served as the primary objective. Secondary endpoints included breast cancer-specific survival, invasive DFS, EFS, competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimensions, and quality of life.
Key findings
Median follow-up was 5.94 years, with 214 OS events observed.
Researchers reported no significant OS differences between the chemotherapy-plus-endocrine therapy vs. endocrine therapy alone groups in the intent-to-treat population (HR = 0.79; 95% CI, 0.6-1.03).
Four-year OS was 90.6% (95% CI, 87.7-92.9) with chemotherapy plus endocrine therapy vs. 89.4% (95% CI, 86.3-91.7) with endocrine therapy alone in the intent-to-treat group, and 91% (95% CI, 87.8-93.4) vs. 89.3% (95% CI, 86.2-91.7) in the per-protocol group (HR = 0.73; 95% CI, 0.55-0.98).
“If there is any benefit for chemotherapy in such a large 70 years-and-older population, it remains nonsignificant on OS and/or marginal on other secondary and exploratory endpoints,” Brain said.
Looking ahead
Endocrine therapy should remain the reference treatment in the adjuvant setting for this population of patients, irrespective of other standard prognostic factors, Brain said. He added that even with a modern prognostic tool to select patients potentially more at risk for breast cancer relapse, it is necessary to factor in other essential health aspects beyond tumor aggressiveness, Brain added.
“We have collected a vast amount of data and we plan to look at interactions between items describing geriatric/health status in this patient population,” Brain said. “The major point to investigate in the future is the change in the official rules of development of strategies in oncology, address the concept of stepwise and cautious dose-escalation to avoid toxicity instead of the classical ‘more concept,’ and better matching the most important segment of our patients to give a real service that is highly needed.”
These patients need constant adjustments and top-quality research, he added.
“Trials should provide answers, not real-world data as suggested by some, with all their selection biases increased by the heterogeneity of aging,” Brain said. “ASTER 70s is also proof that with long persistence and public support, it is possible to run a research question in a timely fashion in an adequate and relevant patient population who are usually not invited to a trial.”
Work also is needed on the best endpoints to use in trials for older patients, he added.
“In ASTER 70s, we used OS because in the context of an older person with a decreasing lifespan, OS is more global, more inclusive and counts much more than the classical oncologic endpoints,” he said. “Because the burden of treatment is hard to take as chemotherapy may create a downfall of unveiling frailty, the older patient may never recover from it, with a very well-described prognostic impact.”
For more information:
Etienne Brain, MD, PhD, can be reached at etienne.brain@curie.fr.
Reference:
Partridge AH. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.4671.
Perspective
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Seth A. Wander, MD, PhD
This effort addresses an important unmet need in clinical oncology: how to best approach our patients aged older than 70 years with early-stage breast cancer. To understand the current effort, it is important to look at the CALGB 49907 study, which evaluated use of standard combination chemotherapy regimens compared with capecitabine in patients aged older than 65 years with early-stage breast cancer, including patients with hormone receptor-positive and -negative disease. That effort demonstrated benefits with standard chemotherapy regimens, including multiple different agents such as anthracyclines, methotrexate and cyclophosphamide. With longer follow-up in that study, superior outcomes were noted in the patients with hormone receptor-negative disease.
The findings are borne out in this study. For those patients with hormone receptor-positive disease and higher genomic grade index, there was no significant OS benefit with the inclusion of conventional cytotoxic chemotherapy.
Of course, it is critical to emphasize that for every patient, the approach to adjuvant therapy, including the use of chemotherapy, is a personalized decision that should take into account a multitude of factors and should be discussed carefully with the medical oncologist. This discussion will involve not simply the patient’s age, but also other medical issues, functional status and goals of care, as well as a number of different features related to the tumor phenotype. In addition, regardless of the approach to cytotoxic chemotherapy, these results underscore the importance of endocrine therapy for patients with early-stage. hormone receptor-positive disease in reducing the long-term risk for both local and distant recurrence.
This effort also highlights the importance of conducting these types of studies, looking at specific subgroups of patients who may not be adequately represented by larger prospective trials. As the authors highlight here, there are a number of other competing survival risks as patients become older. This work will hopefully prompt new discussions related to the benefit of cytotoxic chemotherapy in this patient population, while fostering additional efforts to address this important question.
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Brain E, et al. Abstract 500. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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