Surgical staging is the first step in the management of patients with HR-positive/HER2-negative EBC.¹ For patients with a high risk of recurrence, it is important to determine whether the patient is a candidate for (neo)adjuvant chemotherapy. If neoadjuvant chemotherapy is received, after surgery, considerations should be made about the need for additional endocrine therapy (ET)–based options. For patients with a germline BRCA (gBRCA) mutation and residual disease postsurgery, the use of a PARP inhibitor–based adjuvant therapy should be considered. In practice, we sometimes encounter situations where the patient is eligible for (neo)adjuvant chemotherapy but may be frail or have preexisting comorbidities, causing concern that chemotherapy would be too aggressive. In such clinical scenarios, a single-agent neoadjuvant ET approach can be considered. Single-agent neoadjuvant ET may also be considered for patients who have a low likelihood of response to neoadjuvant chemotherapy based on gene expression–based assays. After surgery, adjuvant ET is routinely recommended for patients with HR-positive EBC. For patients with a high risk of recurrence, the combination of ET with a CDK4/6 inhibitor (either abemaciclib or ribociclib) may be considered as adjuvant therapy.

In general, adjuvant therapy should be personalized when making treatment decisions for patients with high-risk, HR-positive/HER2-negative EBC, particularly regarding factors such as menopausal status, presence or absence of nodal involvement, and preexisting comorbidities.

The RxPONDER study is a practice-changing study that investigated the role of chemotherapy in the EBC setting (NCT01272037). Patients aged 18 years or older with HR-positive/HER2-negative EBC and an Oncotype DX Recurrence Score (RS) of ≤25 without distant metastases were enrolled in the study.² To be eligible to participate in the study, patients would have undergone axillary staging by sentinel node biopsy or ALN dissection and have 1-3 positive lymph nodes. In total, 5015 patients were randomly assigned to receive either chemotherapy followed by ET (n = 2509) or ET alone (n = 2506). The primary endpoint was invasive disease–free survival (iDFS).

At the time of the prespecified third interim analysis, the benefit of chemotherapy differed based on menopausal status in terms of iDFS.³ Among postmenopausal women, there was no iDFS benefit at 5 years with the addition of chemotherapy to ET (hazard ratio: 0.97; 95% CI: 0.78-1.22; P = .82). However, among premenopausal women, the 5-year iDFS rate was 89.0% in the ET-only arm vs 94.2% in the chemotherapy plus ET arm (hazard ratio: 0.54; 95% CI: 0.38-0.76; P = .0004). Therefore, in the subgroup analysis of the RxPONDER trial, baseline serum anti-Müllerian hormone (AMH) levels were used to further categorize “premenopausal” women who stand to benefit from chemotherapy plus ET.

The subset analysis of the RxPONDER study used a clinical definition to categorize premenopausal vs postmenopausal status. Premenopausal status was defined as patients who had their last menstrual period within 6 months or patients aged younger than 50 years who had their last menstrual period within 6-12 months, whereas postmenopausal status was defined as women who had a low AMH level and their last menstrual period >12 months ago or who had undergone bilateral salpingo-oophorectomy. This definition is important because some patients might be considered as premenopausal but biologically are postmenopausal because they have a low ovarian reserve, which can be determined by measuring serum AMH levels and inhibin B levels. Of note, inhibin B levels decrease before menopause because of a reduced number of follicles and lower follicular function.

Also of note, a low serum AMH level and low inhibin B level suggest low ovarian reserve, and thus are consistent with a postmenopausal status. The objective of the subgroup analysis was to determine the benefit of chemotherapy in patients aged younger than 55 years using serum markers of ovarian reserve (AMH level) and follicular function (inhibin B level).

For this analysis, 1717 premenopausal women aged younger than 55 years were included. Of these patients, 1346 (78.4%) had pretreatment serum available for analysis; of those, 1032 were classified as premenopausal and 314 were classified as postmenopausal. In total, 1016 patients were included in the subset analysis.

Among women aged younger than 55 years, a low AMH level was categorized as <10 pg/mL at the time of final menstrual period (FMP) or later. Medium AMH level was classified as 10-99.9 pg/mL at <5 years after FMP, whereas a high AMH level was classified as ≥100 pg/mL at >5 years after FMP.

The data showed that the AMH level varied by age. Among premenopausal women with a low AMH level, 2.9% were aged younger than 45 years; 14.6% were aged 45-49 years; and 52.2% were aged 50-54 years. Of interest, approximately 21% of women aged younger than 55 years who were classified as premenopausal had a serum AMH level in the postmenopausal range (<10 pg/mL). So, it appears that for patients aged 45 years or older, there are questions regarding whether a patient is truly premenopausal or postmenopausal; in this group of patients, the measurement of AMH levels can be helpful.

In terms of iDFS, pretreatment serum AMH level was found to be useful in predicting benefit from the addition of chemotherapy to ET vs ET alone (P <.019). Of note, AMH and inhibin B levels were strongly correlated (r = 0.74). Continuous age (50 years or older) was not predictive of benefit from chemotherapy. These results highlight AMH levels as a useful tool in clinical practice to predict which premenopausal women are likely to benefit from the addition of chemotherapy to ET.

In premenopausal women aged younger than 55 years with low AMH levels, there was no significant difference in 5-year iDFS rate with chemotherapy plus ET vs ET alone after adjustments for Oncotype DX RS (hazard ratio: 1.21; 95% CI: 0.60-2.43). On the other hand, among women with a medium/high AMH level, there was a 7.8% higher 5-year iDFS rate with the addition of chemotherapy to ET (hazard ratio: 0.48; 95% CI: 0.33-0.69). These results indicate that chemotherapy should be considered particularly for patients aged younger than 55 years with a medium/high AMH level.

In terms of distant recurrence–free survival (DRFS) at 5 years, the results were very similar to the iDFS results. After adjustments for Oncotype DX RS, there was no benefit of chemotherapy in women aged yonger than 55 years with a low AMH level, whereas a 4.4% higher 5-year DRFS rate was reported with chemotherapy plus ET among women with medium/high AMH levels (hazard ratio: 0.41; 95% CI: 0.24-0.68).

The subset analysis of the RxPONDER trial indicated that premenopausal women aged younger than 55 years with HR-positive/HER2-negative EBC and an Oncotype DX RS of ≤25 who have a low pretreatment AMH level of <10 pg/mL can safely forgo adjuvant chemotherapy.

As stated earlier, in the management of patients with HR-positive/HER2-negative EBC with a high risk of recurrence, adjuvant AI plus a CDK4/6 inhibitor (either abemaciclib or ribociclib) should be considered.^4,5 Abemaciclib and ribociclib are 2 CDK4/6 inhibitors with FDA approval in the HR-positive/HER2-negative EBC setting based on results from 2 pivotal, practice-changing trials (monarchE and NATALEE).

The phase III monarchE trial looked at abemaciclib plus ET vs ET alone as adjuvant therapy for patients with high-risk, node-positive, HR-positive/HER2-negative EBC.^6,7 In this trial, the majority of the patients (91%) had ≥4 positive ALNs regardless of any other criteria, or 1-3 positive ALNs plus histologic grade 3 disease and/or a tumor ≥5 cm in size (cohort 1). Patients in cohort 2 (9% of the patients) had 1-3 positive ALNs, and a tumor size of <5 cm, Ki-67 ≥20% and grade 1/2 disease. All patients in both cohorts (n = 5637) were randomly assigned to receive either ET alone (n = 2829) or ET in combination with abemaciclib (n = 2808). Patients continued to receive ET for 5-10 years.

Compared with the monarchE trial, the phase III NATALEE trial investigated adjuvant ribociclib plus an AI (either letrozole or anastrozole) in a broader patient population. NATALEE included premenopausal or postmenopausal patients with HR-positive/HER2-negative EBC who had previously received neoadjuvant or adjuvant chemotherapy.^8,9 Patients were required to be within 12 weeks of initiating ET to be eligible. The eligibility criteria included patients with any degree of ALN involvement, including those with stage IIA (N0 or N1), stage IIB (N0 or N1), and stage III (N0-N3) EBC. Those with node-negative, grade 2, stage IIA disease needed to have evidence of high-risk features including Ki-67 ≥20%, Oncotype DX RS ≥26, or high-risk disease assessed via genomic risk profiling. Patients with node-negative, grade 3, stage IIA disease were also eligible to participate in the study. In total, 5101 patients enrolled on the trial were randomly assigned to receive either a nonsteroidal AI (NSAI) alone (n = 2552) or the combination of an NSAI with ribociclib (n = 2549). In addition, premenopausal women and men received goserelin.

Besides the inclusion of a broader patient population in NATALEE compared with monarchE, there are other notable clinically important differences in the designs of the 2 trials. The duration of treatment with the CDK4/6 inhibitor is different in the NATALEE and monarchE trials.^6-9 Abemaciclib was given for up to 2 years in monarchE whereas ribociclib was given for up to 3 years in NATALEE. In addition, the abemaciclib dosage in monarchE was 150 mg twice daily whereas the ribociclib dosage was 400 mg daily on a 3-weeks-on/1-week-off schedule. For both trials, however, the primary endpoint was iDFS. Key secondary endpoints included overall survival (OS), distant disease–free survival (DDFS), DRFS, and safety.

Between the 2 treatment arms of the monarchE trial, there was an absolute difference in the 5-year iDFS rate of 7.6% improvement with the addition of abemaciclib to ET (hazard ratio: 0.680; 95% CI: 0.599-0.772; P <.001).⁶ This is a statistically significant and clinically meaningful benefit with abemaciclib. The 5-year iDFS benefit was consistent across all evaluated subgroups, regardless of the number of positive ALNs, histologic grade, primary tumor size, menopausal status, and receipt of previous chemotherapy.

In terms of the 5-year DRFS in the monarchE trial, there was an absolute difference of 4.7% in favor of abemaciclib (hazard ratio: 0.675; 95% CI: 0.588-0.774; P <.001). Although the OS data are still immature, fewer deaths were reported on the abemaciclib arm (hazard ratio: 0.903; P = .284).

The main adverse event (AE) associated with abemaciclib was diarrhea, which was reported in 83.5% of patients who received abemaciclib (grade ≥3: 7.8%). Other common all-grade AEs associated with abemaciclib included neutropenia (45.9%), fatigue (40.9%), leukopenia (37.7%), abdominal pain (35.7%), nausea (29.6%), arthralgia (26.5%), and anemia (24.4%).^10,11 

Venous thromboembolism (VTE) is an AE of special interest that is associated with abemaciclib. Of note, the incidence of VTE is higher when used in combination with tamoxifen (4.3%) compared with an AI (1.8%). Thus, for premenopausal patients, abemaciclib, in general, is combined with an AI and ovarian suppression rather than with tamoxifen and ovarian suppression. It is also important to be aware that abemaciclib is associated with interstitial lung disease (ILD), which was reported in 3.3% of patients in the monarchE trial.

Based on the results of the monarchE trial, abemaciclib 150 mg twice daily for 2 years was granted FDA approval in combination with ET (tamoxifen or an AI) for the adjuvant treatment of adult patients with node-positive, HR-positive/HER2-negative EBC at high risk of recurrence.⁴

Recently, updated results from the NATALEE trial demonstrated an absolute difference in 4-year iDFS rate of 4.9% improvement with the addition of ribociclib to ET (hazard ratio: 0.715; 95% CI: 0.609-0.840; P <.0001).⁹ In terms of the key patient subgroups, benefit with ribociclib was consistent regardless of lymph node positivity status and stage II vs stage III disease. In all these subgroups, the benefit with ribociclib was maintained.

At 4 years, the DDFS results in the NATALEE trial favored ribociclib (hazard ratio: 0.715; 95% CI: 0.604-0.847; P <.0001).⁹ Although the OS results are not yet mature, a trend in favor of ribociclib was reported (hazard ratio: 0.827; 95% CI: 0.636-1.074; P = .0766).

With ribociclib, the most common AE was neutropenia, which was reported in 62.8% of patients (grade ≥3: 44.4%), including 0.3% with grade ≥3 febrile neutropenia in the NATALEE trial. Other AEs of special interest included elevations in liver enzyme levels, QT interval prolongation, and ILD/pneumonitis, a rare but notable ribociclib-related AE. Based on these results, the FDA approved ribociclib in combination with an AI for the adjuvant treatment of adults with HR-positive/HER2-negative, stage II or stage III EBC at high risk of recurrence.⁵

The monarchE and NATALEE trials have shown that both agents (abemaciclib and ribociclib) have manageable tolerability profiles. With these agents, the quality-of-life (QoL) scores were maintained over time.^12,13 However, the QoL tools used did not capture early events, with the first QoL event seen at Month 3.

Both abemaciclib and ribociclib are associated with diarrhea, hepatobiliary toxicity, neutropenia, and ILD/pneumonitis.^4,5 Whereas VTE is associated with abemaciclib, QT interval prolongation is associated with ribociclib. Diarrhea can be appropriately managed with the use of antidiarrheals, increased oral hydration, and with dietary modifications. Before the initiation of either of these CDK4/6 inhibitors, liver function tests and blood work for the determination of complete blood cell counts should be performed. Based on the findings, appropriate treatment schedule modifications may be integrated into the treatment plan. These measures will help to manage CDK4/6 inhibitor–related toxicities. Patients receiving abemaciclib or ribociclib should be carefully monitored for pulmonary symptoms indicative of ILD/pneumonitis. Of note, the risk of developing VTE is significantly increased when abemaciclib is used in combination with tamoxifen. The integration of these AE management measures into the patient’s treatment plan will help to maximize adherence among patients receiving treatment with abemaciclib or ribociclib.

An important question that often comes up is whether the use of dose reductions to manage AEs associated with abemaciclib or ribociclib can compromise efficacy. Data from the monarchE and NATALEE trials have demonstrated that dose reduction of either of these agents does not appear to affect the iDFS benefit.^14-16 It is better for patients to remain on treatment than to permanently discontinue CDK4/6 inhibitor. Dose reductions/modifications should be used if necessary and as indicated for the management of the specific AE being experienced by the patient.

The phase II TRADE trial is evaluating whether a dose-escalation strategy for abemaciclib will reduce the associated drug discontinuations and dose modifications among patients with HR-positive/HER2-negative EBC who are about to initiate treatment with abemaciclib plus ET in the adjuvant setting (NCT06001762). This trial has the potential to shed critical light on whether a dose-escalation approach for abemaciclib will improve its tolerability. This trial is still active but no longer recruiting.

OlympiA is a pivotal phase III trial for patients with high-risk, HER2-negative EBC harboring a gBRCA1/2 mutation who have undergone definitive local therapy and neo(adjuvant) chemotherapy.^17-19 Patients with HR-positive or triple-negative breast cancer were eligible to participate in the OlympiA study. In total, 1836 patients were randomly assigned to receive either olaparib (300 mg twice daily) for 1 year or placebo. The primary endpoint was iDFS. The secondary endpoints included DDFS, OS, and safety.

After a median follow-up of 6.1 years, olaparib continued to demonstrate higher rates of iDFS, DDFS, and OS vs placebo.¹⁹ In the intent-to-treat (ITT) population, the 6-year iDFS rate was 79.6% with olaparib vs 70.3% with placebo, showing a 9.3% improvement with olaparib (hazard ratio: 0.65; 95% CI: 0.53-0.78). Similarly, in the subgroup of patients with high-risk, HR-positive/HER2-negative EBC, the 6-year iDFS rate was 77.5% with olaparib vs 67.7% with placebo (hazard ratio: 0.681; 95%CI: 0.437-1.051). In the ITT population, the 6-year DDFS rate was 83.5% with olaparib vs 75.7% with placebo, demonstrating a 7.8% DDFS improvement with olaparib (hazard ratio: 0.65; 95% CI: 0.53-0.81). There was also a 4.4% improvement in the 6-year OS rate with olaparib (87.5%) vs placebo (83.2%) in the ITT population (hazard ratio: 0.72; 95% CI: 0.56-0.93). We are waiting to see the final OS results of the OlympiA trial.

Common AEs reported in >10% of patients who received olaparib in the OlympiA trial included nausea, fatigue, anemia, vomiting, headache, diarrhea, decreased neutrophil and white blood cell counts, decreased appetite, dysgeusia, and dizziness.¹⁷ Even though olaparib interacts with the DNA and has the potential to cause mutations in the DNA and hematologic malignant conditions, the risk of myelodysplastic syndromes/acute myeloid leukemia or any other new primary malignancies was <5% even after an extended follow-up period.¹⁹

The results from the OlympiA study were practice changing. Based on these results, olaparib received FDA approval for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated, HER2-negative, high-risk EBC who have been treated with (neo)adjuvant chemotherapy.²⁰ In the management of patients with a gBRCA mutation and residual disease after surgery, a PARP inhibitor–based adjuvant treatment approach should be considered.

The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines now recommend that BRCA1/2 mutations be tested at any age in patients with breast cancer, constituting a major change from previous recommendations.^21,22 This will aid with making optimal adjuvant treatment decisions regarding the use of olaparib for all patients with high-risk, HER2-negative EBC harboring a gBRCA mutation.