Certain factors are clearly associated with an increased risk of recurrence in patients with HR-positive/HER2 negative EBC. These include disease stage, as illustrated in this graph, which also shows how the risk of recurrence peaks within the first 2-3 years after primary therapy.⁷

Other risk factors include endocrine therapy resistance, larger tumor size, nodal positivity, higher grade, higher proliferation rate (ie, Ki-67 score), and lower estrogen receptor and progesterone receptor levels.^1-3 Patients with the luminal B, HER2-enriched, or basal-like molecular subtypes are also at increased risk.

Recall that our case patient had many of these high-risk features, including high-grade disease, nodal positivity, and a Ki-67 score of 25%. We will later discuss the challenges and limitations around testing for Ki-67, but I can briefly mention here that meta-analyses have reported Ki-67 cutoff values of 19% and 25% for identifying patients at higher risk of relapse and/or death.^8,9

Patients with these high-risk characteristics have a need for better curative therapies to reduce their risk of recurrence.

As I mentioned during our case discussion, adding CDK4/6 inhibition to adjuvant endocrine therapy has been demonstrated to significantly prolong iDFS.^4,6 But why target CDK4/6 in the first place?

In cancer cells, atypical cell cycle activity leads to uncontrolled proliferation.¹⁰ Proliferation and progression through the cell cycle depend on cyclin-dependent kinases (CDKs). Abnormal activation of CDKs is often observed in cancer cells, making CDK inhibition an attractive target for anticancer therapies.

Elements of the CDK4 and CDK6 pathway are frequently mutated in cancer. CDK4/6 inhibitors target these signaling pathways, thereby inducing cell-cycle arrest, reducing cell viability, and promoting tumor shrinkage.¹¹

Why combine CDK4/6 inhibition with endocrine therapy? Activation of the cyclin D–CDK4/6 complex—which promotes cell cycle progression—occurs downstream of estrogen signaling.¹⁰ Thus, endocrine therapy in combination with CDK4/6 inhibition acts synergistically against HR-positive breast cancer.

All FDA-approved CDK4/6 inhibitors have the same mechanism of action against cancer cells and generally similar safety profiles.¹² That said, some important differences in their pharmacologic characteristics affect dosing and safety. For example, ribociclib has greater selectivity for CDK4 and CDK6 than abemaciclib, which also inhibits other CDKs. In addition, ribociclib has a longer half-life than abemaciclib. This means that abemaciclib requires administration twice daily, whereas ribociclib is administered once daily, with weeklong breaks between treatment cycles to avoid drug accumulation.

We will now review the 2 positive phase III trials of adjuvant CDK4/6 inhibition combined with endocrine therapy for HR-positive/HER2-negative EBC, beginning with the monarchE trial.

monarchE compared the addition of abemaciclib to standard adjuvant endocrine therapy vs endocrine therapy alone in patients with high‑risk node‑positive, HR-positive/HER2‑negative EBC.^4,13 This was a large, international, randomized, open-label phase III trial. Eligible patients could have received prior neoadjuvant or adjuvant chemotherapy. Patients were randomized within 16 months of surgery and within 12 weeks of starting endocrine therapy.

This study enrolled 2 cohorts. Cohort 1 included patients who had ≥4 positive lymph nodes or 1‑3 positive lymph nodes plus grade 3 disease and/or tumor size ≥5 cm. Cohort 2 enrolled patients who had 1‑3 positive lymph nodes, Ki‑67 ≥20%, grade 1 or 2 disease, and a tumor size <5 cm.

As you can see, our case would have met the high-risk eligibility criteria for cohort 1 in monarchE, as long as she enrolled within 16 months of surgery and within 12 weeks of starting endocrine therapy. She had 2 positive lymph nodes and grade 3 disease.

Patients were randomized to receive either abemaciclib 150 mg twice daily for up to 2 years in conjunction with standard endocrine therapy for 5-10 years or endocrine therapy alone.

The primary endpoint was iDFS, with key secondary endpoints of iDFS in patients with a Ki‑67 ≥20%, distant relapse‒free survival, overall survival (OS), safety, and patient‑reported outcomes.

We have seen the results of multiple analyses of monarchE, with the most recent being the third interim analysis of OS performed after a median follow-up of 4.5 years.¹³ By now, all patients were off abemaciclib, with more than 80% followed for ≥2 years after completing abemaciclib.

By this point, the 60-month iDFS rate in the intention-to-treat population was 83.6% on the abemaciclib arm vs 76.0% on the comparator arm. This translates to a difference in iDFS rate of 7.6% (hazard ratio: 0.680; 95% CI: 0.599-0.772; nominal P <.001). As you can see here, the magnitude of benefit has grown over time.

Analyses indicate that the iDFS benefit is consistent across subgroups defined by patient and disease factors—including the Ki‑67 score.

The OS data remain immature, and longer follow-up is still needed.¹³ At this point in the natural history of EBC, we would not expect the OS data to be mature.

That said, there are numerically fewer deaths in patients who were treated with abemaciclib vs patients who were not. Specifically, there have been 154 deaths due to breast cancer in patients who received abemaciclib vs 187 deaths due to breast cancer in patients who did not. We also can see that there are fewer patients alive with metastatic disease on the abemaciclib arm vs the comparator arm (138 vs 269, respectively). Because metastatic disease is incurable, unfortunately, a higher rate of metastatic recurrence likely will translate into a higher rate of death due to breast cancer.

The positive data from this phase III trial show that adjuvant therapy with abemaciclib plus endocrine therapy reduces the risk of recurrence in patients with high-risk node-positive, HR-positive/HER2-negative EBC.¹³

Based on these data, the FDA approved adjuvant abemaciclib plus endocrine therapy for node‑positive, HR-positive/HER2-negative EBC at high risk of recurrence. The initial FDA approval included a requirement for a Ki‑67 score ≥20%, but that was ultimately dropped from the label in March 2023.⁵

The American Society of Clinical Oncology (ASCO) guidelines and the National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant abemaciclib plus endocrine therapy for patients who would have met the eligibility criteria for cohort 1 of the monarchE trial.^14,15 ASCO also recommends this treatment for patients with 1-3 positive lymph nodes and a Ki-67 ≥20%.

Our second positive phase III trial is the NATALEE study, which is comparing the addition of ribociclib to adjuvant endocrine therapy with a nonsteroidal aromatase inhibitor (NSAI) vs an NSAI alone in patients with intermediate- to high‑risk HR-positive/HER2-negative EBC.⁶ This was an international, randomized, open‑label phase III trial.

Eligible patients were pre- or postmenopausal women or men with HR-positive/HER2-negative EBC. Of note, this study included patients who had N0 status, whereas the monarchE trial did not. Patients with stage IIA disease were eligible if they had N0 disease that was grade 2 with a Ki‑67 ≥20%, had N0 disease that was grade 3, had N1 disease, or were high risk according to genomic risk profiling. Patients with stage IIB (N0 or N1) or stage III disease were eligible, as well. Prior (neo)adjuvant chemotherapy and up to 12 months of prior endocrine therapy were permitted.

In addition to meeting the criteria for monarchE, our case patient also would meet the eligibility criteria for NATALEE. She has stage IIB disease with 2 positive lymph nodes (N1).

Participants were randomized to receive either ribociclib for 3 years plus an NSAI—either letrozole or anastrozole—for ≥5 years or an NSAI alone for ≥5 years. Patients received ribociclib 400 mg daily on a schedule of 3 weeks on, 1 week off, rather than the 600-mg daily dose on that same schedule approved for the metastatic setting. The rationale for decreasing the dose was to reduce the risk of dose-dependent AEs, such as neutropenia and QT prolongation.¹⁹

As with monarchE, the primary endpoint was iDFS. Secondary endpoints included recurrence‑free survival, distant disease‒free survival, OS, quality of life, and safety.

The interim analysis of iDFS, which was published in 2024, reported that adding ribociclib to adjuvant NSAI therapy significantly improved iDFS vs an NSAI alone.⁶ The final iDFS analysis shown here was presented at the 2023 San Antonio Breast Cancer Symposium and confirmed the findings of the interim analysis.²⁰

At a median follow-up of 33.3 months for the final iDFS analysis, investigators reported an iDFS rate of 90.7% with adjuvant ribociclib plus an NSAI vs 87.6% with an NSAI alone, yielding an absolute difference of 3.1% in favor of ribociclib. Adding ribociclib to adjuvant NSAI therapy significantly reduced the risk of invasive disease by 25.1% vs treatment with an NSAI alone (hazard ratio: 0.749; 95% CI: 0.628-0.892; nominal 1-sided P = .0006).

As with the monarchE trial, the OS data remain immature because HR-positive/HER2-negative breast cancer can recur late, and patients can live a number of years after they have had a metastatic relapse. After a median follow-up of 30 months, 2.4% of patients treated with ribociclib plus an NSAI vs 3.0% of patients treated with an NSAI alone had died (hazard ratio for OS: 0.76; 95% CI: 0.54-1.07).⁶

The investigators reported consistent iDFS benefit with ribociclib plus an NSAI across the prespecified subgroups, including those defined by stage (II vs III) and nodal status (N0 vs N1-N3).²⁰

Recall that our case patient had stage IIB disease. The subgroup with stage II disease had a 3-year iDFS rate of 94.2% with ribociclib plus an NSAI vs 92.6% with an NSAI alone (hazard ratio: 0.700; 95% CI: 0.496-0.986). For those with stage III disease, the rates were 88.1% vs 83.8%, respectively (hazard ratio: 0.755; 95% CI: 0.616-0.926). She also had a high Ki-67 score of 25%. However, the benefit from ribociclib was maintained regardless of Ki-67 score. The subgroup with a Ki-67 ≤20% had a hazard ratio of 0.794 (95% CI: 0.605-1.042), whereas those with a Ki-67 >20% had a hazard ratio of 0.743 (95% CI: 0.570-0.988).

Altogether, these results provide evidence supporting consideration of adjuvant ribociclib for select patients although this agent does not currently have FDA approval in the adjuvant setting.

Both adjuvant abemaciclib in the monarchE trial and adjuvant ribociclib in the NATALEE trial were well tolerated.^20,21 Looking specifically at grade ≥3 AEs, we see that the safety profiles for both agents share a risk for high-grade neutropenia, although this was more common among NATALEE participants receiving ribociclib.

A noteworthy AE associated with abemaciclib is diarrhea. Diarrhea is quite common with abemaciclib and, for many patients, improves within a few months of starting the drug. Grade ≥3 diarrhea occurred in 7.8% of monarchE participants receiving abemaciclib and 0.6% of NATALEE participants receiving ribociclib.

In the NATALEE study, noteworthy AEs included neutropenia, hepatotoxicity, and QT interval prolongation. Ribociclib was associated with grade ≥3 neutropenia in 44.3% of patients and grade ≥3 hepatotoxicity in 8.6% of patients. Similar to what was observed in the metastatic setting, ribociclib was associated with grade ≥3 QTc interval prolongation in 1.0% of patients.

That said, quality-of-life scores were maintained over time on treatment for both trials, although a limitation of this analysis was the lack of early data; the first quality-of-life assessment was at 3 months post study initiation.^22,23

To wrap up our discussion here, recall that our case patient has preexisting Crohn’s disease and frequent diarrhea at baseline. Given this bowel comorbidity, I would prefer to not increase her risk of diarrhea by administering adjuvant abemaciclib. Instead, I would prefer to start her on adjuvant ribociclib to reduce her risk of recurrence.

CDK4/6 inhibitors exert their antiproliferative effects on both cancer cells and the rapidly proliferating gastrointestinal epithelium.²⁴ As we discussed earlier, diarrhea is quite common in patients receiving CDK4/6 inhibitors, occurring in 83.5% of monarchE participants receiving abemaciclib and 14.5% of NATALEE participants receiving ribociclib.^20,21 In monarchE, 18.5% of patients discontinued abemaciclib because of AEs, with diarrhea being the most common (5.3%). Fortunately, for many patients, the risk of abemaciclib-induced diarrhea will decrease within the first few months of starting therapy.

Nonetheless, given the risk of diarrhea with abemaciclib, it is critical to guide patients on how to manage this AE. At the first sign of loose stools, I counsel patients to initiate antidiarrheals with loperamide and increase their oral fluid intake.^5,21,25

If patients have grade 1 diarrhea, defined as <4 stools per day above their baseline, I advise them to continue abemaciclib without modifying their dose.

If patients have grade 2 diarrhea, defined as 4‑6 stools per day above their baseline, I advise them to hold the medication until they see improvement to grade 1 or better. If patients have a rapid resolution to their symptoms, dose modification is not necessarily required. However, if their symptoms do not resolve expediently or are recurrent, then the dose of abemaciclib may be reduced to the next dose level.

For patients who have grade 3 or worse diarrhea, I recommend holding the medication until symptoms resolve to grade 1 or better and subsequently reducing the dose when restarting the medication. Recall that this was the approach taken with the second case patient when she experienced grade 3 diarrhea after starting adjuvant abemaciclib.

The approved starting dose of adjuvant abemaciclib is 150 mg twice daily. The next dose level is 100 mg twice daily, and the lowest dose is 50 mg twice daily. If a patient is unable to tolerate the medication at 50 mg twice daily, I advise discontinuing abemaciclib altogether.

Dietary modifications, such as a diet lower in fiber and fat, as well as smaller, more frequent meals, also may help mitigate diarrhea.

The safety profiles for all approved CDK4/6 inhibitors include neutropenia because these agents inhibit proliferation of hematopoietic stem cells by halting cell cycle progression.²⁶ However, CDK4/6 inhibitor–related neutropenia is readily reversible because the affected stem cells can resume cell cycle progression after dose interruption and/or reduction. This mechanism is distinct from chemotherapy-induced neutropenia, in which chemotherapy suppresses bone marrow by inducing apoptosis.

To monitor for abemaciclib‑induced neutropenia, I advise checking a CBC prior to starting therapy, then every 2 weeks for the first 2 months, followed by every month for the next 2 months, and then as clinically indicated.^5,21,25

In patients with grade 1 or 2 neutropenia, where the ANC is ≥1000/mm³, I advise continuing abemaciclib with no dose modification.

In patients with grade 3 neutropenia, where the ANC is <1000 to 500/mm³, I advise holding abemaciclib until the neutropenia has resolved to grade 2 or better. At the first occurrence of grade 3 neutropenia, no dose reduction is required. This was the approach we took with our second case patient, who was experiencing her first occurrence of grade 3 neutropenia while receiving abemaciclib.

In patients who experience either grade 4 neutropenia or recurrent grade 3 neutropenia, I recommend holding abemaciclib until the neutropenia resolves to grade 2 or better and then doing a dose reduction of 50 mg at a time.

Similar to the recommendations for management of abemaciclib-induced diarrhea, if a patient is still experiencing neutropenia at the lowest dose level of 50 mg twice daily, I recommend discontinuing abemaciclib altogether.

An important AE related to ribociclib is hepatotoxicity, which does not appear to be dose dependent and can recur after dose reduction. The mechanism is unknown but may relate to an immunogenic or toxic metabolite generated during CYP3A4 metabolism of ribociclib.²⁷ In the NATALEE trial, hepatotoxicity was the most common cause of AE-related treatment discontinuations, with 8.9% of patients on the ribociclib arm discontinuing treatment due to hepatotoxicity vs 0.1% of patients on the comparator arm.⁶

In the curative setting for early-stage disease, I advise managing hepatotoxicity more conservatively than the prescribing information recommendations for use of ribociclib in advanced disease. Furthermore, it can be more concerning if a patient experiences transaminitis at the lower 400-mg dose used in the adjuvant setting.

To monitor for hepatotoxicity, I recommend obtaining liver function tests prior to starting therapy, then every 2 weeks for the first 2 cycles, then at the beginning of every cycle for the next 4 cycles, followed by testing as clinically indicated.²⁶ In patients who develop hepatotoxicity, I advise even more frequent monitoring.

Total bilirubin levels are an important indicator for when hepatic injury is so extensive that the liver is unable to clear bilirubin from plasma.²⁸ Assuming the patient has not experienced a total bilirubin increase >2x the upper limit of normal (ULN), then the hepatotoxicity is graded and managed based on aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevations.

For patients with grade 1 transaminitis, defined as an AST/ALT elevation up to 3x ULN, I recommend holding ribociclib until the transaminitis resolves to baseline and then resuming treatment at the same dose.

For patients with grade 2 or 3 transaminitis—where grade 2 is >3-5x ULN and grade 3 is >5-20x ULN—I advise holding ribociclib until hepatotoxicity resolves to baseline. Ribociclib then should be resumed at the next lowest dose; assuming the patient started at 400 mg for EBC, the next lowest dose would be 200 mg.

In the event of recurrent grade 2/3 or any instance of grade 4 hepatotoxicity (>20x ULN), I recommend permanently discontinuing ribociclib. I also recommend permanently discontinuing ribociclib if a patient has total bilirubin >2x ULN along with AST and/or ALT >3x ULN. There have been case reports of drug-induced liver injury occurring in patients being treated with ribociclib.²⁹

Given how central dose reductions are to managing CDK4/6 inhibitor–related AEs, it is important to review an important analysis of the relationship between dose reductions and efficacy of adjuvant abemaciclib using monarchE data.³⁰

This analysis reported that dose reductions—which reduce the relative dose intensity—were not associated with decreased benefit of abemaciclib. Instead, efficacy was similar between patients who received the full dose compared with patients who received reduced doses, when accounting for the timing of the dose reductions. For the considerable proportion of patients who will require dose reductions of adjuvant abemaciclib for tolerability, these are very reassuring data.

The relationship between dose holds and efficacy has not specifically been studied. That said, dose holds are very common; 61.7% of patients on monarchE had dose holds to manage AEs, and abemaciclib still was associated with robust iDFS benefit.²¹ Healthcare professionals (HCPs) should feel comfortable doing dose holds as warranted.

In the adjuvant setting, abemaciclib typically is given at a starting dose of 150 mg by mouth twice daily, and ribociclib is given at a starting dose of 400 mg by mouth once daily.^4,5,19,31 Abemaciclib is taken continuously, but ribociclib has a longer mean half-life, necessitating a dosing schedule of 3 weeks on, 1 week off to prevent drug accumulation and toxicity.

When should patients start an adjuvant CDK4/6 inhibitor? In the monarchE trial evaluating abemaciclib, patients were randomized within 16 months of surgery. In the NATALEE trial evaluating ribociclib, patients were randomized within 12 months of starting endocrine therapy. These windows of time have important implications for patient eligibility and uncommon scenarios involving treatment sequencing. Although not a studied approach, HCPs might consider sequencing adjuvant olaparib for 1 year followed by adjuvant abemaciclib on a case-by-case basis for patients with very high–risk HR-positive/HER2-negative EBC harboring a germline BRCA mutation.

How long should patients receive an adjuvant CDK4/6 inhibitor? The duration differed between monarchE and NATALEE. Abemaciclib was given for 2 years in monarchE, and ribociclib was given for 3 years in NATALEE.

What adjuvant endocrine therapies can be paired with abemaciclib or ribociclib? The choice of endocrine therapy also was slightly different between these studies. In monarchE, endocrine therapy could be any of 3 AIs or tamoxifen. In NATALEE, the choice of endocrine therapy was letrozole or anastrozole. In practice, I tend to avoid combining tamoxifen with abemaciclib due to the increased risk of venous thromboembolism.

Returning to the starting dose, I want to note that for patients aged 75 years and older, HCPs may consider starting at a lower dose of abemaciclib 100 mg twice daily, given that older patients have a greater risk for abemaciclib-related AEs. If treatment is well tolerated at this dose, HCPs can consider increasing the dose to 150 mg twice daily.

This dose-escalation strategy is under investigation in the ongoing TRADE trial, a prospective, open-label, single-arm phase II study (NCT06001762). This trial is enrolling 90 patients eligible for adjuvant abemaciclib—specifically, those with stage II/III node-positive, HR-positive/HER2-negative breast cancer who have not received any prior CDK4/6 inhibitors. Participants will step up their abemaciclib dose as tolerated.

The primary endpoint is the composite AE rate at 3 months, and investigators also will look at the rate of patients reaching vs not reaching the full dose intensity. This study is currently recruiting, with an estimated primary completion date in 2026.

Now that we have reviewed key efficacy and safety data behind adjuvant CDK4/6 inhibitors, I would like to discuss an overarching algorithm for approaching treatment of patients with node‑positive, HR-positive/HER2-negative EBC.³⁷

In patients with 1‑3 positive lymph nodes who are premenopausal, the current standard of care is to treat with adjuvant chemotherapy followed by endocrine therapy based on data from the RxPONDER trial.³⁸ Patients also may consider the ongoing OFSET study (NRG‑BR009), which is enrolling premenopausal women with HR-positive/HER2-negative EBC, 0-1 positive lymph nodes, and a 21-gene recurrence score ≤25 (NCT05879926). OFSET is evaluating ovarian function suppression plus adjuvant endocrine therapy with vs without adjuvant chemotherapy.

In postmenopausal women with 1‑3 positive lymph nodes, genomic profiling tests such as Oncotype DX help guide whether chemotherapy may reduce the risk of recurrence.³⁹ In patients deemed to be at low risk of recurrence, only adjuvant endocrine therapy is given. Patients at high risk of recurrence are treated with adjuvant chemotherapy followed by endocrine therapy.

Regardless of menopausal status, a patient with 1-3 positive lymph nodes and a germline BRCA mutation should be considered for adjuvant olaparib based on the positive phase III OlympiA study.⁴⁰ For those without a germline BRCA mutation and who have high-risk features (ie, grade 3 status, tumor ≥5 cm), abemaciclib should be added to their adjuvant treatment.

In select cases, adjuvant ribociclib may be considered, despite the agent not currently having an indication for the adjuvant setting. For example, ribociclib may be appropriate for patients who do not have grade 3 status and/or who have a smaller tumor (≤5 cm). As with our first case patient, adjuvant ribociclib also may be more appropriate for patients who have a bowel comorbidity that increases their risk of diarrhea with abemaciclib.^5,6,20

We should note that the NATALEE trial allowed enrollment of patients with node-negative disease, who are not included in this algorithm. Recall that subgroup analyses found benefit with adjuvant ribociclib regardless of nodal status.

Returning to the algorithm, the current standard of care for patients who have ≥4 positive lymph nodes is adjuvant chemotherapy. If they have a germline BRCA mutation, then chemotherapy is followed by 1 year of olaparib plus endocrine therapy. If they are wild-type for BRCA and otherwise eligible for abemaciclib, then adjuvant chemotherapy is followed by abemaciclib plus endocrine therapy.

This algorithm does not address an interesting clinical scenario: How should we treat a patient eligible for both adjuvant olaparib and abemaciclib? Should these agents be administered concurrently or sequentially?

When I have a patient with a germline BRCA mutation who would be eligible for both olaparib and abemaciclib, I favor olaparib. The OlympiA study demonstrated a significant OS benefit with adjuvant olaparib, whereas the OS data for adjuvant abemaciclib are not yet mature. Although it is certainly possible that abemaciclib will demonstrate an OS benefit, as we discussed earlier, the data currently available point me toward choosing olaparib.

I would not concurrently administer olaparib and abemaciclib. There are no robust safety data on coadministration, and I would be concerned about overlapping safety profiles, particularly cytopenias.

HCPs sometimes may consider administering these agents sequentially in particularly high‑risk patients. In such cases, olaparib is often given first for 1 year, followed by abemaciclib, which can be initiated up to 16 months after surgery per monarchE eligibility criteria.¹³ Further data are needed to know whether sequential administration helps reduce the overall risk of recurrence, as opposed to just using one of these agents alone. However, this is an approach that can be considered on a case-by-case basis for patients who are particularly high risk.