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J Breast Cancer
J Breast Cancer
JBC
Journal of Breast Cancer
1738-6756
2092-9900
Korean Breast Cancer Society

39069780
10.4048/jbc.2024.0136
Commentary
Is Adjuvant Chemotherapy Preceding Cyclin-Dependent Kinase 4/6 Inhibitor Therapy Beneficial?
https://orcid.org/0000-0001-7408-0646
Sorscher Steven *
Correspondence to Steven Sorscher. 1821 Georgia Ave, Winston-Salem, NC 27104, USA. sorscher1@gmail.com
*Affiliation: Dr. Sorscher is a retired clinical oncologist. He is not currently affiliated with an institution or company.

8 2024
08 7 2024
27 4 289291
13 6 2024
26 6 2024
02 7 2024
© 2024 Korean Breast Cancer Society
2024
Korean Breast Cancer Society
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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pmcSince the 1980s, most patients with early-stage hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) invasive breast cancer (BC) have been offered adjuvant endocrine therapy possibly followed by extended endocrine therapy often preceded by adjuvant chemotherapy. Recently, the use of ovarian function suppression, bisphosphonates, poly- (ADP-ribose) polymerase (PARP) inhibitors and cyclin-dependent kinase (CDK) 4/6 inhibitors have each been associated with a statistically significant reduction in the absolute risk of distant recurrence (DR).

Researchers have discussed the benefits of these newer therapies but have generally not considered whether the absolute benefit of chemotherapy in the context of these newer systemic therapies is meaningful [1]. Can patients forego (neo) adjuvant chemotherapy if they choose, for example, to receive a CDK4/6 inhibitor? Here, whether the absolute benefit of chemotherapy in patients who afterwards receive what are probably the most heralded of these newer drugs, CDK4/6 inhibitors, is discussed.

Morrison et al. [2] described the use of CDK4/6 inhibitors as representing “a game-changing [revolutionary] era for breast cancer treatment.” The standard of care for patients who met eligibility criteria for participation in one of the landmark studies involving CDK4/6 inhibitor therapy involved the administration of chemotherapy which was followed by treatment with a CDK4/6 inhibitor, provided the patient was eligible for chemotherapy based on the high-risk features or quantitative mRNA genomic testing results.

The American Society of Clinical Oncology (ASCO) guidelines on BC recommend an adjuvant CDK4/6 inhibitor ribociclib or abemaciclib for patients with high-risk, early-stage HR+/HER2− BC [3]. In both the New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) and the monarchE landmark trials, the absolute DR risk was modestly lowered with a combination of CDK4/6 inhibitor, endocrine therapy, and chemotherapy compared with that of chemotherapy plus endocrine therapy alone [45]. This raised the question as to how much higher the absolute DR risk would be for patients choosing to forgo (neo) adjuvant chemotherapy but do receive an adjuvant CDK4/6 inhibitor with endocrine therapy [3].

For example, in the NATALEE trial, the absolute recurrence risks in patients who received chemotherapy plus endocrine therapy followed by the CDK4/6 inhibitor ribociclib and in those who received chemotherapy were 5.6% and 7.3%, respectively with no ribociclib (28% relative reduction in DR risk) (refer to Figure S.5 from Slamon et al. [4]).

In the Trial Assigning Individualized Options for Treatment (TAILORx) trial, patients with tumors having Oncotype DX Recurrence Scores of 26-–30 had 5-year DR risks with and without chemotherapy treatment of 5.4 and 10.4% respectively (51.4% relative reduction in DR risk) [6]. Given this this absolute difference of 6%, the benefit of chemotherapy is generally considered meaningful and outweighs the harms. Therefore, chemotherapy is recommended for these patients per standard of care guidelines [7].

However, whether the benefit of chemotherapy preceding treatment with the CDK4/6 inhibitor ribociclib is meaningful is unclear. The combined results from the NATALEE and TAILORx trials suggest that the absolute risk of recurrence is roughly 10.4 − (10.4 × 0.28) = 7.48% with endocrine therapies and ribociclib not preceded by chemotherapy. Therefore, if endocrine and CDK4/6 inhibitor therapies are administered along with chemotherapy, the recurrence risk is estimated as 7.48 − (0.514 × 7.48) =3.84%. The benefit derived from ribociclib raises the question of whether a 3.64% versus 6% difference in the risk of distant disease recurrence risk from chemotherapy versus no chemotherapy preceding ribociclib, respectively, should be considered clinically meaningful or only a minimal clinically important difference (MCID) in outcome.

Notably, all premenopausal patients in the NATALEE trial received ovarian function suppression and, for certain high-risk patients, PARP inhibitors, bisphosphonates and extended endocrine therapies are now routinely recommended [47]. However, the absolute benefits of ribociclib treatment for patients who received those therapies in the NATALEE has not been reported. Thus, with one or more of these new therapies and ribociclib, the absolute benefit of chemotherapy would be further reduced.

Several uncertainties are associated with the hypothesis that the absolute benefit of chemotherapy might not be meaningful or carry only an MCID in patients who receive treatment with a CDK4/6 inhibitor. As chemotherapy precedes CDK4/6 inhibitor treatment, the potential impact of adherence to 2–3 years of planned CDK4/6 inhibitor therapy must be stressed to patients who do not receive chemotherapy. In addition, the estimates of DR effects are uncertain because the absolute and relative benefits in the TAILORx and NATALEE trials were obtained from 5- and 3-year follow up reports, respectively. [45] Equally long follow-up results from the TAILORx and NATALEE trials are needed to ensure the reliability of the calculations regarding the impact of omitting chemotherapy on DR risk reduction.

Additionally, the effectiveness of CDK4/6 inhibitor therapy may depend on the patient receiving chemotherapy. For instance, the optimal benefit of adjuvant trastuzumab for patients with HER2+ disease appears to depend on them receiving concurrent chemotherapy [7]. Finally, as absolute risks cited are averages from the TAILORx and NATALEE trials, patients with higher-risk disease (e.g. Oncotype Recurrences Score greater than 30), would likely experience a greater absolute benefit from the chemotherapy component. Therefore, a more meaningful benefit might be achieved from the chemotherapy in these patients.

Chemotherapy is among the most concerning consequences of a cancer diagnosis for patients and is associated with both acute and chronic adverse effects. If a patient could be assured that their absolute benefit from chemotherapy would not be meaningful, considering the harms associated with chemotherapy, or only provide an MCID in outcome, many would likely choose to forgo chemotherapy [8]. For now neither ASCO nor National Comprehensive Cancer Network guidelines discuss the possibility of omitting chemotherapy for patients who plan to receive one or more of the new therapeutic agents [37].

Prospective, randomized de-escalation trials in which patients with HR+/HER2− BC are randomly assigned to receive CDK4/6 inhibitors with or without chemotherapy, are needed to establish whether the absolute benefit of adjuvant chemotherapy is clinically meaningful in these patients who receive CDK4/6 inhibitors or one or more of the other recently endorsed therapies. However, enrolling patients in trials that randomly assign them to not receive chemotherapy may be challenging because patients at high risk according to clinicopathologic features or those who have genomic profiling suggesting a chemotherapy benefit have long been considered for such treatment.

Conflict of Interest: The author declares that he has no competing interests.

Data Availability: In accordance with the ICMJE data sharing policy, the authors have agreed to make the data available upon request.
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1 Conforti F Pala L De Pas T Zattarin E Catania C Cocorocchio E Fine-tuning adjuvant endocrine therapy for early-stage breast cancer” An expert consensus on open issues for future research Clin Cancer Res 2024 30 1093 1103 37906083
2 Morrison L Loibl S Turner NC The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment Nat Rev Clin Oncol 2024 21 89 105 38082107
3 Freedman RA Caswell-Jin JL Hassett M Somerfield MR Giordano SH Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer Guideline Expert Panel Optimal adjuvant chemotherapy and targeted therapy for early breast cancer-cyclin-dependent kinase 4 and 6 inhibitors: ASCO guideline rapid recommendation update J Clin Oncol 2024 42 2233 2235 38768407
4 Slamon D Lipatov O Nowecki Z McAndrew N Kukielka-Budny B Stroyakovskiy D Ribociclib plus endocrine therapy in early breast cancer N Engl J Med 2024 390 1080 1091 38507751
5 Rastogi P O’Shaughnessy J Martin M Boyle F Cortes J Rugo HS Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes J Clin Oncol 2024 42 987 993 38194616
6 Sparano JA Gray RJ Makower DF Albain KS Saphner TJ Badve SS Clinical outcomes in early breast cancer with a high 21-Gene Recurrence Score of 26-100 assigned to adjuvant chemotherapy plus endocrine therapy JAMA Oncol 2020 6 367 374 31566680
7 Gradishar WJ Moran MS Abraham J Aft R Agnese D Allison KH NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Version 2.0.2024 - March 11, 2024 2024 Accessed May 2nd, 2024 www.nccn.org
8 Weinfurt KP Clarifying the meaning of clinically meaningful benefit in clinical research JAMA 2019 322 2381 2382 31790549
