Study data presented at the 2024 ASCO Congress demonstrate that CDK4/6 inhibitors and other therapies are effective in treating early breast cancer within specific subgroups. New biomarker data can also refine treatment algorithms.
In patients with hormone receptor (HR)-positive/HER2-negative early breast cancer, the phase III NATALEE trial showed the benefit of combining the CDK4/6 inhibitor ribociclib with non-steroidal aromatase inhibitor (NSAI) therapy compared to NSAI alone (1). The monarchE study also investigated the use of a CDK4/6 inhibitor in addition to endocrine therapy for early breast cancer. Unlike monarchE, NATALEE included patients with node-negative disease; further high-risk characteristics were required in stage IIA but not in stages IIB and III (3).
Risk Reduction in Node-Negative Early Breast Cancer (EBC)
At the ASCO Congress, Yardley et al. presented results from NATALEE on patients with node-negative disease. This group included 285 patients in the test arm and 328 in the control arm. About half of the cases were grade 2 or grade 3, and 74% were in stage IIA. Prior to study inclusion, 71% had received (neo)adjuvant chemotherapy.
After three years, the combination of ribociclib and NSAI provided an absolute benefit of 2.6% (93.2% vs. 90.6%) in invasive disease-free survival (IDFS; HR: 0.72) compared to NSAI alone. This risk reduction is comparable to that observed in the node-positive subgroups of the NATALEE and monarchE studies after three years (2, 3).
Overall, both arms showed favorable survival outcomes due to the lack of lymph node involvement. However, despite the relatively short observation period, a significant difference in favor of the ribociclib combination was already evident, which could potentially increase with longer follow-up.
These results support the use of ribociclib even in low-risk patients without lymph node involvement, although the modest benefit must be weighed against the potential toxicities and cost. Nevertheless, ribociclib should be considered for at least some node-negative patients. NATALEE does not address whether CDK4/6 inhibition could replace adjuvant chemotherapy, but this is a consideration in the clinical setting. The possibility of shortening the duration of therapy will also be a topic of future discussion.
Anti-Müllerian Hormone as a Predictor
In the setting of node-positive breast cancer, the RxPONDER study (SWOG S1007) compared the sequential strategy of adjuvant chemotherapy followed by endocrine therapy (ET) versus ET alone (4). Patients with HR-positive/HER2-negative breast cancer and one to three positive lymph nodes with an Oncotype score of 0-25 participated in the study.
In the premenopausal group, those treated with sequential therapy had better outcomes in terms of IDFS and survival without distant metastasis compared to those who received ET alone. In contrast, there was no difference in the postmenopausal group.
An analysis of the RxPONDER study presented at ASCO identified anti-Müllerian hormone (AMH) as the strongest predictor of chemotherapy benefit within the premenopausal cohort (5). Patients with the lowest AMH levels (< 10 pg/mL) did not experience an IDFS benefit from the sequential strategy. These low levels were primarily found in the 50-54 age group and are considered postmenopausal. However, some patients with significantly reduced AMH levels were also found in the 45-50 age group. In contrast, medium (10-99.9 pg/ml) and high (≥ 100 pg/ml) AMH levels resulted in a 7.8% increase in IDFS after five years compared to the control arm (95.2% vs. 87.4%; HR: 0.48).
These findings suggest a treatment algorithm for patients with one to three positive lymph nodes and an Oncotype score < 26 (Fig. 1). Women over 55 or postmenopausal women can be treated with ET alone, as can younger women with AMH levels < 10 pg/ml. Those under 45, who almost always had high AMH levels, or those with higher AMH levels, benefit from sequential therapy. The longstanding debate on whether the adjuvant benefit is due to the castration effect of chemotherapy or its cytotoxicity is addressed here, with data suggesting an advantage from endocrine suppression at high AMH levels, indicating a stronger ovarian reserve.
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Fig 1. Treatment recommendations for HR-positive/HER2-negative early breast cancer with 1-3 lymph nodes and oncotype < 26. Adapted from Universimed.
Very Low ER Expression: To Endocrine Therapy (ET) or Not?
Another analysis presented at the ASCO Congress focused on early breast cancer with very low estrogen receptor expression (1-10%). Choong et al. sought to determine whether adjuvant ET could be omitted in this group (6). The results argued against this: three years after definitive resection, patients without adjuvant ET had significantly reduced overall survival compared to those who received endocrine treatment (92.3% vs. 89.1%; HR: 1.25; p = 0.01).
Factors such as low ER expression, progesterone receptor negativity, Ki67 ≥ 20%, higher histologic grading, lack of lymph node involvement, and prior neoadjuvant chemotherapy often led to the omission of ET. A subgroup analysis showed that omitting ET after failing to achieve pathological complete remission (pCR) resulted in shorter overall survival compared to those who achieved pCR with neoadjuvant chemotherapy. Thus, under certain circumstances, ET might be omitted in patients who achieve pCR at the time of surgery.
Correlation of ctDNA and IDFS
Finally, a pre-planned biomarker analysis investigated the prognostic value of circulating tumor DNA (ctDNA) in the monarchE study (7). MonarchE compared the addition of the CDK4/6 inhibitor abemaciclib to ET with ET alone in early, HR-positive/HER2-negative high-risk breast cancer with lymph node involvement. Measurements were taken before randomization and at 3, 6, and 24 months post-randomization.
Patients who were ctDNA-positive before the study had a markedly lower IDFS rate than the ctDNA-negative group, with four-year IDFS rates of 20.0% vs. 79.1%. ctDNA dynamics during treatment also played a significant role. The group that remained ctDNA-negative from the start had the best IDFS outcome (4-year IDFS rate: 87.5%), followed by those who converted from positive to negative (58.3%). In cases of reverse conversion or persistent ctDNA positivity, the IDFS rate was much lower (11.0% or not ascertainable).
In summary, ctDNA is a strong prognostic biomarker. However, as therapeutic implications are currently lacking, no practical benefits from early changes in ctDNA levels can yet be derived for clinical routine. Its use in timing PET scans for the detection of distant metastases could be considered.
To learn more on breast cancer, catch up on our roundtable with Drs. Jens Huober, Isabell Witzel and Konstantin Dedes.
References:
- Slamon D et al.: Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med 2024; 390: 1080-91
- Johnston SRD et al.: Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 2020; 38(34): 3987-98
- Yardley DA et al.: Baseline characteristics and efficacy endpoints for patients with node-negative HR+/HER2- early breast cancer in NATALEE. J Clin Oncol 2024; 42(Suppl. 16): Abstr. #512
- Kalinsky K et al.: 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 2021; 385(25): 2336-47
- Kalinsky K et al.: Serum anti-Mullerian hormone levels refine identification of premenopausal patients with HR+, HER2-, node-positive breast cancer most likely to benefit from adjuvant chemotherapy in SWOG S1007 (RxPONDER). J Clin Oncol 2024; 42(Suppl. 16): Abstr. #505
- Choong GM et al.: The impact of adjuvant endocrine therapy omission in ER-low (1-10 %) early-stage breast cancer. J Clin Oncol 2024; 42(Suppl. 16): Abstr. #513
- Loi S et al: Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer. J Clin Oncol 2024; 42(Suppl. 17): Abstr. #LBA507
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