Community Practice Perspectives: Exploring Treatment Intensification with CDK4/6 Inhibitors in Adjuvant HR+, HER2−, High-Risk Early Breast Cancer

Section 1: What Constitutes High-risk in HR+/HER2− Early Breast Cancer?

Early breast cancer: Introduction and rationale for determining risk of recurrence as early as possible

Early breast cancer (EBC) refers to disease confined within the breast and/or neighboring lymph nodes (National Cancer Institute). Approximately 90% of breast cancer diagnoses are EBC, with about 70% of EBC patients having hormone receptor (HR)-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HER2−) disease (Howlander et al, 2014). Around 20% of EBC patients experience disease recurrence within 10 years after diagnosis, often with incurable distant metastases (Early Breast Cancer Trialists' Collaborative Group, 2015).  The risk of recurrence is highest in the first 2 years following diagnosis. Patients with high-risk clinical and/or pathologic features are more likely to experience recurrence or distant metastases, particularly in the initial years of adjuvant endocrine therapy (Mamounas, 2018). Patients who experience disease recurrence have poorer prognosis and worse overall outcomes (Sheffield, 2021).

The goal of HR+, HER2− EBC treatment is to eradicate cancer and prevent disease recurrence (Gradishar et al, 2024). The standard of care for HR+, HER2− EBC includes locoregional therapies (surgery, radiation therapy) and adjuvant/neoadjuvant systemic therapies (chemotherapy, endocrine therapy, and targeted therapy; Gradishar et al, 2024). Unmet needs include understanding who does/does not need adjuvant chemotherapy, identifying those with primary endocrine resistant HR+ BC, and preventing or delaying recurrence with additional therapy. Preventing early recurrence and metastasis is crucial. Novel therapies have been shown to reduce the risk of distant relapse in patients with HR+/HER2− EBC, improving overall outcomes. CDK4/6 (cyclin-dependent kinases 4 and 6) inhibitors represent a major breakthrough in the treatment of HR+/HER2− advanced breast cancer. These agents markedly improve outcomes in the metastatic setting and have demonstrated significant benefits in progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) (Gil-Gil, 2021) They  are now standard-of-care in the advanced breast cancer treatment. Naturally, these same agents have and continue to be explored in the adjuvant setting for EBC. The purpose of this review is to look at CDK4/6 inhibitors in the adjuvant treatment of early-stage HR+/ HER2− breast cancer.

Risk assessment: When, and in whom is treatment intensification needed to reduce the risk of recurrence? 

Various factors contribute to the risk of breast cancer recurrence, including age at diagnosis, tumor size, nodal status, lymphovascular invasion, histologic tumor grade, ER/HER2 status, and proliferation rate as measured by Ki-67 protein levels (Gyorffy, 2015; Sheffield, 2021). Factors that affect risk of recurrence in patients with EBC are summarized in Figure 1. Understanding and recognizing these factors allows for personalized treatment plans and improved outcomes for patients with early-stage breast cancer in the community setting.

Figure 1. Risk of Early Breast Cancer Recurrence

Community-based clinicians play a vital role in identifying patients at high risk of recurrence, based on clinicopathologic features.There are several ways to determine which patients with EBC are at high risk of recurrence. One prognostic factor is tumor grade. When examining the relationship between histological grade and breast cancer-specific survival, it is evident that patients with high-grade tumors are at greater risk of early recurrence, metastasis, and death, while low-grade tumors tend to be associated with very good outcomes with few, if any, events occurring (Rakha et al, 2010).

Another prognostic factor in identifying high-risk EBC recurrence is Ki-67 expression, a marker of cellular proliferation (Viale et al, 2008; Fasching et al, 2019). Ki-67 is a nuclear protein expressed in proliferative cells, usually during the mitotic cell division stage of the cell cycle. Patients with a higher proportion of Ki-67-expressing tumor cells tend to have lower 5-year disease-free survivals than those with fewer Ki-67-expressing tumor cells. The SOFT and TEXT trials of premenopausal women with HR+/HER2− breast cancer who received adjuvant LHRH agonist therapy plus antihormonal therapies following chemotherapy, showed an improvement in freedom from recurrence (Pagani et al, 2020). Secondary analyses of prognostic factors in these trials identified that higher Ki-67 expression was associated with worse prognosis. There was an 8-year freedom from distant recurrence rate of 96% for a Ki-67 expression level of < 14, 87% for a Ki-67 expression level of 20-25, and 82% for a Ki-67 expression level > 26. There is, however, a lack of standardization and consistency among different institutions and even within the same institution in Ki-67 staining and interpretation (OncoLetter, 2023; Polley et al, 2013).

Other tools, including genomic tests, help to determine recurrence risk in estrogen receptor (ER)-positive (ER+) early-stage breast cancer. PREDICT Plus is an online prognostic tool developed from clinical data from breast cancer patients and is endorsed by the American Joint Committee on Cancer (AJCC). This tool  helps patients and clinicians see how different treatments for early invasive breast cancer might improve survival rates following surgery. Once patient and disease details such as age, menopausal status, Ki-67 expression, ER status, PR status, HER2 status, tumor size, tumor grade, and types of therapies the patient is scheduled to receive have been entered, the tool provides 5-year and 10-year overall survival projections and quantifies the benefits of chemotherapy and hormonal therapy (https://breast.predict.cam/tool), similar to the previously employed prognostic tool Adjuvant! Online.

Multigene assays can help identify patients with EBC who have a higher risk of recurrence, and may also predict whether patients can benefit from adjuvant systemic therapy. Multiparametric genomic tests include the 21-gene assay, the 70-gene assay, and the 12-gene assay. The 21-gene assay, or Oncotype DX, is both prognostic and predictive of chemotherapy benefit and is the tool preferred by NCCN® Guidelines (Gradishar et al, 2024). It has been clinically validated for predicting the benefit of adjuvant chemotherapy in reducing the risk of recurrence for patients with HR+/HER2− EBC with 0-3 positive lymph nodes. Oncotype DX includes 16 cancer genes that are most prognostic of recurrence and 5 reference genes (McVeigh et al, 2017). The test generates a recurrence score between 0 and 100, which correlates with probability of distant disease recurrence. Patients with low-risk recurrence scores (0–17) are unlikely to derive a significant survival benefit from the addition of adjuvant chemotherapy to hormonal agents. Conversely, adjuvant chemotherapy has been shown to significantly improve survival in patients with high recurrence risk scores (≥31). In the TAILORx trial of over 10,000 women with HR+/HER2− axillary node–negative breast cancer, adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women who had  midrange (11-25) 21-gene recurrence scores, indicating that chemotherapy is not needed in the vast majority of patients with recurrence score under 25 (Sparano et al, 2018). However, patients with recurrence scores >26 had a 13.6% distant recurrence rate, despite use of chemoendocrine therapy, signifying  a need for other treatment options in addition to chemo and endocrine therapy. In the RxPONDER trial, women with node-positive disease and recurrence scores of 0-25 were randomized to chemotherapy followed by endocrine therapy vs endocrine therapy alone (Kalinsky et al, 2021). In postmenopausal patients at 5 years, there was no statistically significant difference in invasive disease-free survival (92% in both arms), However, in premenopausal patients, there was an absolute benefit with chemotherapy of 4.9% as well as a 5-year IDFS of 94% in the chemoendocrine arm versus 89% in the endocrine-only arm. In otherwords, post-menopausal women did not benefit from the addition of chemotherapy while pre-menopausal women did.

Another genetic tool is the 70-gene assay, or MammaPrint. In the MINDACT study, approximately 6,600 women with early-stage breast cancer had their genomic risk determined using the 70-gene signature and their clinical risk determined using a modified version of Adjuvant! Online (Cardoso et al, 2016). Women at low clinical and genomic risk (about 41%) did not receive chemotherapy; women at high clinical and genomic risk (about 27%) received chemotherapy. In women at high clinical risk but low genomic risk for recurrence (about 23%), there was no statistical difference between the chemotherapy and no-chemotherapy arms, with a 5-year distant metastasis-free survival rate of 94.7% among those not receiving chemotherapy, which was 1.5 percentage points lower those who received chemotherapy. Long-term follow-up results with an exploratory analysis by age for clinically–high, genomically–low-risk patients with HR+/HER2− disease, recorded an 8-year distant metastasis-free survival of 93.6% with chemotherapy versus 88.6% without chemotherapy in women < 50 years (absolute difference 5.0 percentage points), and 90.2% versus 90.0% in women > 50 years (absolute difference 0.2 percentage points; Piccart et al, 2021).

A third genomic assay, EndoPredict, is a 12-gene molecular tool that predicts for early and late recurrence. The molecular score is combined with tumor size and nodal status to determine the EPclin risk score (scale of 1-6), a prognostic test validated to inform decisions on adjuvant chemotherapy vs endocrine therapy alone for patients with ER+/HER2− breast cancer (Dubsky et al, 2013; Filipits et al, 2011; Sestak et al, 2019). In a combined analysis of two large trials, the TransATAC trial (that treated women with endocrine therapy alone) and the GEICAM/2003-02/9906 trial (that treated women with endocrine therapy and chemotherapy), the rate of increase in distant recurrence with increasing EPclin score was significantly reduced in women who received ET + chemotherapy versus ET alone (Sestak et al, 2019). Specifically, an EPclin score >3 is associated with a modest 1.9% absolute benefit from the addition of chemotherapy while a 33% absolute benefit is associated with an EPclin score of 6.

“Updated data presented at ASCO 2024 examined DFS in RxPONDER in woman with low Oncotype scores less than 25 based on levels of anti-Müllerian hormone (Kalinsky et al, 2024). Anti-Müllerian hormone is a measurement of ovarian reserve. In the women under 50, who were presumably premenopausal, the only women who had a chemotherapy  benefit were those with premenopausal level of anti-Müllerian hormone greater than 10 picograms per mil (pg/mL), suggesting that maybe the chemo benefit here is actually ovarian suppression. The OFSET study (NCT05879926) takes women with Oncotype scores of 16 or greater with node-negative disease, or, any Oncotype score with node-positive disease, and randomizes these patients to ovarian function suppression plus endocrine therapy with or without adjuvant chemotherapy. We encourage people to enroll in the OFSET trial to answer this question once and for all in randomized data.” – Adam Brufsky, MD, PhD, Professor of Medicine, UPMC Hillman Cancer Center 

So, there are numerous ways to predict who has high-risk disease and would benefit from adjuvant therapy to reduce the risk of disease recurrence. The patients that experience recurrence or distant metastases in EBC are more likely to have high-risk clinical and/or pathologic features (Stuart-Harris et al, 2019). In addition to high tumor grade and high Ki-67 levels, high recurrence rates in patients with HR+/HER2− EBC include negative PR status, lymphovascular invasion, large tumor size, and luminal B subtype. Higher mortality rates have been observed in patients with HR+/HER2− EBC who have ≥4 positive lymph nodes, grade 3 tumors, and greater tumor size (Brown et al, 2019). In patients at high enough risk, adding an adjuvant CDK4/6 inhibitor has been shown to improve distant disease-free survival. In the monarchE trial, which led to the FDA approval of abemaciclib in EBC, node-positive, high-risk EBC was defined as 4+ positive nodes, or 1-3 positive nodes and at least one of the following: tumor size ≥ 5cm or grade 3 (Johnston et al, 2023).

Section 2: How Can We Drive Recurrence Risk Down With Intensified Adjuvant Therapy?

Adjuvant ET for 5 years results in a substantial reduction in the risk of local recurrence, contralateral BC, distant recurrence, and risk of death (Pan et al, 2017; Sheffield et al, 2022; Johnston et al, 2023; Gradishar et al, 2024). The addition of chemotherapy to adjuvant ET is recommended in certain patients with HR+/HER2− breast cancer based on recurrence risk (Oncotype Dx 21-gene assay). We know that the risk of recurrence in patients with early-stage disease is greatest within the first 2 to 4 years after diagnosis. Clinical trials of adjuvant CDK4/6 inhibitors in high-risk HR+ EBC aim to prevent recurrences during the expected peak timeframe for earlier recurrences, as show in Figure 2. Three CDK4/6 inhibitors and one PARP inhibitor have been studied as adjuvant treatment for EBC, and are reviewed below.

Figure 2. CDK4/6 Inhibitors for High-Risk Early HR+ EBC

monarchE: Abemaciclib + ET

The phase III monarchE study included patients with HR+, HER2−, node-positive, high-risk EBC, who had undergone surgery, radiotherapy and/or adjuvant/neoadjuvant chemotherapy (Johnston et al, 2020). Patients with 4 or more positive nodes, or 1 to 3 nodes and either tumor size ≥5 cm, histologic grade 3, or central Ki-67 expression ≥20% were deemed eligible and randomly assigned 1:1 to standard-of-care adjuvant ET with or without abemaciclib (150 mg twice daily) for 2 years (Figure 3). The primary endpoint was invasive disease-free survival (IDFS).

Figure 3. monarchE: Study Design

The 4-year IDFS absolute improvement with abemaciclib + ET was 6.4%, with a 34% reduction in the risk of developing an IDFS event (Table 1; Johnston et al, 2022, 2023; Hamilton et al, 2023). The 4-year distant relapse-free survival (DRFS) absolute difference with abemaciclib + ET was 5.9%, associated with a 34% reduction in the risk of developing a DRFS event. The IDFS and DRFS benefits persist and deepen beyond completion of the 2-year abemaciclib treatment period. Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes, were presented at the 2023 European Society for Medical Oncology (ESMO) Annual Meeting (Table 1; Harbeck et al, 2023; Rastogi et al, 2024). After the on-study treatment period of 2 years, ET was continued for an additional 3-8 years as clinically indicated. In this analysis, all patients were off abemaciclib and more than 80% of patients have been followed for at least 2 years since completing abemaciclib. Results show a sustained IDFS benefit in the ITT population, with a 32% reduction in the risk of developing an IDFS event. The Kaplan-Meier curves continue to separate and the absolute difference in IDFS rates between arms was 7.6% at 5 years. The IDFS benefit of abemaciclib + ET was consistent and observed in all subgroups, including patients with grade 1 and 2 disease, patients with 10 or more lymph nodes, and in both premenopausal and postmenopausal patients. The 5-year DRFS benefit was also sustained, with a 32.5% reduction in the risk of developing a DRFS event, and an absolute difference in DRFS rates between arms of 6.7% at 5 years.

Table 1. monarchE: IDFS and DRFS

Callout: FDA Approval and Guideline Recommendations

In 2021, the U.S. Food and Drug Administration (FDA) approved abemaciclib with ET (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR+/HER2−, node-positive EBC at high risk of recurrence, defined as those having either ≥4 pALN (pathologic axillary lymph nodes) or 1-3 pALN and either tumor grade 3 or a tumor size ≥50 mm (FDA.gov, 2021). In 2023, the original requirement of having a Ki-67 score ≥20% was removed as more deaths were observed with abemaciclib plus standard endocrine therapy compared to standard endocrine therapy alone in the cohort that included tumor Ki-67 score ≥20% (FDA.gov, 2023). The National Comprehensive Cancer Network (NCCN) Guidelines^Ò now recommends the consideration of 2 years of adjuvant abemaciclib in combination with ET in patients with HR+/HER2− high-risk breast cancer (category 1, preferred; Gradishar et al, 2024). 

In September 2024, the FDA approved ribociclib with an aromatase inhibitor for the adjuvant treatment of adults with HR+/HER2- stage II and III EBC at high risk of recurrence (FDA.gov, 2024). Additionally, FDA also approved the ribociclib and letrozole co-pack for the same indication.

At the third interim analysis, fewer deaths were observed in the abemaciclib + ET arm (208) versus the ET arm (234, HR 0.903), but a statistical overall survival (OS) significance was not reached (P = 0.284; Harbeck et al, 2023). However, there were also fewer patients with metastatic disease in the abemaciclib + ET arm (138 versus 269).

A smaller group of patients were enrolled in Cohort 2 with 1-3+ ALN, grade 1-2, tumor size <5 cm, and central Ki-67 ≥20%.

“Cohort 2 did not seem to have as much benefit. There were many fewer events. In these patients with lower risk disease, really stage 2 with grade 1 disease with a Ki-67 of 20% or greater, there were too few events to make any conclusions. We do not use the Ki-67 cutoff in our practice. In my practice, I will give a CDK4/6 inhibitor to women with a stage II grade 3 cancer and potentially a stage II grade 2 cancer with high-risk features. But generally I reserve CDK46i  for anatomic grade 3. However if someone younger (under 50) presents with a 4 cm tumor with 1 lymph node involved and grade 3, I think a lot of us may consider adjuvant CDK4/6i in that patient. But again, for me, it’s usually T3N1 or N2 and above that tend to be the ones that I offer abemaciclib to in my practice. And again, Ki-67 really was not a predictor of benefit. Patients had benefit regardless of Ki-67 expression.” – Adam Brufsky, MD, PhD, Professor of Medicine, UPMC Hillman Cancer Center

In looking at a biomarker subset to predict who would benefit from the addition of abemaciclib to ET in the monarchE trial, a consistent abemaciclib treatment benefit was noted across all intrinsic molecular subtypes as measured by RNA sequencing, including patients with luminal A, luminal B, HER2-enriched, and basal-like cancers (Turner et al, 2023). Luminal A cancers had the lowest risk of recurrence, while HER2-enriched and basal-like subtypes had the highest. A treatment benefit with abemaciclib + ET was also observed across inferred 21-gene expression signature scores, both with an inferred Oncotype-RNA score of less than 25 (HR 0.59) and over 25 (HR 0.73), so this score was not predictive of benefit from the use of the adjuvant CDK4/6 inhibitor.  Finally, a consistent treatment benefit of abemaciclib was also observed across the most prevalent genomic alterations, with a lower benefit from abemaciclib seen in the subset of focal high-level MYC-amplified tumors compared to MYC non-amplified tumors. So at least for now, there are very few, if any, biomarkers that predict benefit from abemaciclib in the adjuvant setting. 

NATALEE: Ribociclib + ET

The phase III NATALEE trial evaluated adjuvant ribociclib + ET in a broad population of HR+/HER2− EBC patients at risk for recurrence, including those with stage II or III disease and those with no nodal involvement (N0; Slamon et al, 2023). Men and pre- or postmenopausal women were randomized 1:1 to ribociclib (400 mg/day; 3 weeks on/1 week off for 3 years) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥5 years) or ET alone. Men and premenopausal women also received goserelin (Figure 4a). Patients with anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III disease were eligible. Since patients with stage II and III HR+/HER2− EBC, including those with no nodal involvement, are at risk of disease recurrence for decades after initial diagnosis, an extended treatment duration of 3 years was chosen to prolong cell cycle arrest and drive more tumor cells into irreversible senescence or death. A dose of 400 mg/day, lower than the 600 mg/day starting dose approved for treatment in metastatic breast cancer, was chosen to improve tolerability while maintaining efficacy (Figure 4b). The primary endpoint was IDFS.

Figure 4. NATALEE: Study Design

Overall, there was an absolute IDFS benefit of 3.3% at 3 years with ribociclib + ET (Table 2; Slamon et al, 2023). With a statistically significant hazard ratio of roughly .75, the risk of invasive disease was reduced by 25.2% with ribociclib + ET vs ET alone. The IDFS benefit with ribociclib + ET was consistent across prespecified key subgroups, including a benefit in stage II and stage III patients, as well as N0 patients. A consistent improvement in distant disease-free survival (DDFS) with ribociclib was also observed. DDFS is defined as the time from date of randomization to date of first event of distant recurrences, death (any cause), or second primary non-breast invasive cancer. The absolute DDFS benefit with ribociclib + ET at 3 years was 2.2%. The risk of distant disease was reduced by 26.1% with ribociclib + ET vs ET alone. Results from the final IDFS analysis were presented at the 2023 San Antonio Breast Cancer Symposium (SABCS; Table 2; Hortobagyi et al, 2023). The absolute IDFS benefit with ribociclib + ET was 3.1% at 3 years. The risk of invasive disease was reduced by 25.1% with ribociclib + ET vs ET alone. The absolute DDFS benefit with ribociclib + ET was 2.7% at 3 years. The risk of distant disease was reduced by 25.1% with ribociclib + ET vs ET alone at the final analysis. Overall survival was still very immature, but there was a trend for improved OS with ribociclib + ET.

Table 2. NATALEE: IDFS and DDFS

Conference Callout: ASCO 2024

A subgroup analysis presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting of patients with high-risk, node-negative (N0) HR+/HER2− EBC from the NATALEE trial showed an improvement in rates of IDFS, DRFS, and DDFS with ribociclib + ET compared to ET alone (Table 2; Yardley et al, 2024). The 3-year IDFS rate was 90.6% with ET alone versus 93.2% with ribociclib + ET, with a 28% risk reduction in IDFS in the subgroup of patients with node-negative (N0) disease at high risk of recurrence. The 3-year DDFS rate was 91.5% versus 94.3%, with a hazard ratio of 0.70, and the 3-year DRFS rate was 92.5% versus 96.3%, with a hazard ratio of 0.58, in patients with high-risk N0 disease. These results outline the benefits of adjuvant ribociclib in node-negative disease.

PALLAS and Penelope-B: Palbociclib + ET

The last set of CDK4/6 inhibitor trials, PALLAS and Penelope-B, examined palbociclib, the first CDK4/6 inhibitor that was approved in metastatic breast cancer. The PALLAS trial included patients with stage II and III HR+/HER2− breast cancer within 12 months of diagnosis, and within 6 months of starting adjuvant ET (Gnant et al, 2021, 2022). Patients were randomized to ET or 2 years of palbociclib plus standard ET. The trial showed no benefit from combination palbociclib + ET in the adjuvant breast cancer setting, and no significant difference in IDFS at 4 years was observed ( 84.2% with palbociclib + ET versus 84.5% with ET alone, [HR 0.96]). The Penelope-B trial included patients with HR+/HER2− EBC who had no pathological complete response (pCR) after neoadjuvant chemotherapy, and were thus at high risk of relapse with a clinical pathological staging-estrogen receptor grading (CPS-EG) score of greater than 3, or 2 with node-positive disease (ypN+; Loibl et al, 2021). Patients were randomized to palbociclib + ET or placebo + ET. Palbociclib added to ET did not improve IDFS versus ET + placebo (HR 0.93).

A biomarker analysis in the PALLAS trial was presented at SABCS 2023 (Stover et al, 2023). As part of PALLAS trial eligibility, all patient provided a tumor tissue block prior to randomization for translational analyses (TRANS-PALLAS). Genomic subtype (PAM50 intrinsic subtype) measured from whole-transcriptome RNA sequencing data was defined in the protocol of the PALLAS trial as the primary biomarker for analysis of prediction and prognosis. There were 2,370 unique patients with intrinsic subtype defined from their untreated primary tumor: 65.6% luminal A, 12.1% luminal B, 7.0% HER2-enriched, 13.1% basal-like, and 2.2% normal-like. The proportion of luminal A cancers was unexpectedly high, indicating a lower-risk distribution of cancers in this population. When looking at the intrinsic subtype, there is essentially no differentiation in terms of benefit from the addition of the CDK4/6 inhibitor. The potential interaction between PAM50 metrics and palbociclib treatment benefit was not significant. Ultimately, PALLAS did not identify any biomarkers predicting benefit to palbociclib in the adjuvant setting.

Callout: Why Do PALLAS/Peneople-B and monarchE Findings Differ?

PALLAS and Penelope-B did not show a benefit with palbociclib in the adjuvant setting, in contrast to monarchE, which was positive for abemaciclib. Why are these results different? Michael Gnant, MD of the Medical University of Vienna proposed: “There is one clear difference between how we use CDK inhibitors in these large trials, however, both palbociclib and ribociclib are given in a 3-week-on, 1-week off schedule, whereas abemaciclib is given continuously. Particularly in the early breast cancer setting, when we are not targeting proliferating disease but [inhibiting the] awakening of dormant cells, this could be an explanation for the observed differences in outcomes. At this point, however, this remains scientific speculation” (ASCO Post, 2022). Other reasons have been postulated, but discounted by Dr. Gnant: (1) rates of early discontinuation of palbociclib were substantial, however, now inadequate exposure to palbociclib has been ruled out based on the competing risk analysis, (2) differences in patient selection are also “definitely not” the cause of the differences in outcomes Penelope-B evaluated a high-risk population with residual tumor after surgery and also showed no benefit for palbociclib; this trial also had a “markedly lower” treatment discontinuation rate than PALLAS but was still negative, and (3) differences in the molecules is also not likely the cause since these two CDK4/6 inhibitors produced almost identical progression-free survival benefits in the first-line and second-line settings of advanced breast cancer. More recent data from “real world studies” that reflect current practices with respect to how patients react to treatment in terms of tolerance and efficacy have suggested that there may actually be a benefit from the addition of adjuvant palbociclib to ET (Palmieri et al, 2023).

“Like any newer therapies, there is a learning curve with CDK4/6 inhibitors. Physicians need to conduct risk assessments on their patients following surgery, chemotherapy and radiation using the many tools currently available in order to determine who would benefit from the addition of these drugs. And then it is important to match potential adverse risks from these drugs to pre-existing patient comorbidities in order to minimize the risk of side effects.” - Robert Mocharnuk, MD, Emeritus Professor of Clinical Medicine

OlympiA: Olaparib, A PARP Inhibitor

What other therapies besides CDK4/6 inhibitors are available for women with HER2− breast cancer? The phase III OlympiA trial examined the PARP inhibitor olaparib as adjuvant therapy in HER2− (HR+ or TNBC) patients with high-risk stage II-III EBC who have germline BRCA1/2 mutations after (neo)adjuvant chemotherapy [N]ACT (Tutt et al, 2021). Patients were randomized 1:1 to one year of continuous oral olaparib at 300 mg BID or placebo (Figure 5).

Figure 5. OlympiA: Study Design

Olaparib significantly improved the primary endpoint of IDFS and secondary endpoint of DDFS compared with placebo at the first event-driven interim analysis, with a median follow up of 2.5 years. OS did not cross the pre-specified boundary. In the second pre-specified analysis of OS and updated IDFS and DDFS with a median follow-up of 3.5 years, adjuvant olaparib significantly improved OS versus placebo, as well as IDFS and DDFS (Tutt et al, 2022). The 4-year OS rate was 89.8% for olaparib versus 86.4% for placebo, a difference of 3.4% (HR 0.68). The IDFS difference was substantial, at 7.3%, with a 4-year IDFS rate of 82.7% with olaparib versus 75.4% with placebo (HR 0.63). The 4-year DDFS rate was 86.5% vs 79.1%, a difference of 7.4% (HR 0.61). The olaparib benefit was consistent across all subgroups, including HR+. In 2022, the FDA approved olaparib for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2− high-risk EBC who have been treated with neoadjuvant or adjuvant chemotherapy based on the OlympiA trial (FDA.gov, 2022).

Section 3: From Evidence to Practice: CDK4/6 Inhibitor Adverse Events

Adverse events with the CDK4/6 inhibitors abemaciclib and ribociclib in the adjuvant setting include neutropenia, liver function test (LFT) abnormalities, QT interval prolongation, diarrhea, and venous thromboembolism (VTE). The most frequent adverse events of any grade and any attribution in the monarchE trial were diarrhea, neutropenia, and fatigue in the abemaciclib + ET group, and arthralgia, hot flushes, and fatigue in the ET group (Johnston et al, 2022, 2023). Venous thromboembolic events were more frequent with abemaciclib + ET (2.5%) versus ET alone (0.7%). The most common grade 3-4 adverse events in the monarchE trial in the abemaciclib + ET group versus in the ET alone group were neutropenia (19.6% vs 0.9%), leukopenia (11.4% vs 0.4%), and diarrhea (7.8% vs 0.2%; Johnston et al, 2023). The most frequently reported serious adverse events in both groups were infections (5.3% vs 2.9%) and gastrointestinal disorders (2.1% vs 0.6%). Overall, abemaciclib was relatively safe with a manageable toxicity profile. In the abemaciclib + ET arm, 43.6% of patients required dose reductions due to adverse events, 61.7% had a treatment interruption, and 6.4% discontinued treatment. The most frequent causes of abemaciclib + ET discontinuation were diarrhea (2.4%) and fatigue (1.0%; Johnston et al, 2023). Abemaciclib treatment interruption due to adverse events were generally related to diarrhea, neutropenia, or fatigue. In the 5-year outcome update, no new safety concerns were identified, and there were higher rates of serious adverse events regardless of causality observed at long-term follow-up in the ET alone arm (7.3%) compared with abemaciclib + ET (6.5%), predominantly because of more infections and GI disorders (Rastogi et al, 2024). Dose adjustments and treatment discontinuations due to adverse events were more common in older patients, especially those > 75 years of age (Hamilton et al, 2023). More frequent surveillance with early intervention may be needed to manage these patients. However, multiple analyses have demonstrated that the effectiveness of adjuvant abemaciclib was not compromised by dose reductions (Hamilton et al, 2023; O’Shaugnessy et al, 2023; Figure 6).

Figure 6. Abemaciclib Benefit Is Maintained with Dose Modifications

In the NATALEE trial, ribociclib had a well-tolerated safety profile (Slamon et al, 2023). Adverse events of special interest included neutropenia, liver-related adverse events, QT interval prolongation, and interstitial lung disease or pneumonitis. Ribociclib at a starting dose of 400 mg showed lower rates of dose-dependent toxicities such as neutropenia and QTc prolongation and less need for dose modifications when administered up to 3 years, compared with the standard starting dose of 600 mg in metastatic breast cancer. Treatment discontinuation occurred in 19.5% of patients. The most frequent all-grade adverse events leading to ribociclib + ET discontinuation were liver-related adverse events (8.9%) and arthralgia (1.3%). Most discontinuations of ribociclib occurred early in treatment, with a median time to discontinuation of 4 months. While LFT abnormalities are an issue with ribociclib in the adjuvant setting, these are reversible in the vast majority of patients. In the final analysis, no new safety signals were observed, contributing to the manageable toxicity profile of ribociclib at the 400 mg starting dose (Hortobagyi et al, 2023).

When monitoring for adverse events with CDK4/6 inhibitors, CBC, LFTs, ECGs, and electrolyte testing should be enlisted (KISQALI [ribociclib] prescribing information, 2024; VERZENIO [abemaciclib] prescribing information, 2024; Table 3). For diarrhea typically associated with abemaciclib, at the first sign of loose stools, antidiarrheal therapy should be initiated along with an increase of oral fluids. The CDK4/6 inhibitor can be withheld and potentially dose-reduced for the next cycle. Patients should be monitored for signs and symptoms of thrombosis and pulmonary embolism, such as shortness of breath or limb swelling, usually a lower extremity.

Table 3. CDK4/6 Inhibitors: Patient Monitoring

“It is important to consider setting up a system for periodic symptom assessment, laboratory monitoring, and management for these patients knowing that cytopenias and GI symptoms can be a concern for tolerability and adherence to treatment. Additionally, many of these medications have potential for CYP3A4 drug interactions that may require dose adjustments. Utilizing clinical oncology pharmacists (whether that be through collaboration with specialty pharmacies and/or involvement directly in ambulatory care clinics) can be beneficial in reducing the burden on providers by assisting in timely monitoring and management, as well as increasing identification on drug interactions and dose adjustments.” - Adrienne N. Nedved, PharmD, MPA, BCOP, Hematology/Oncology Pharmacist, Mayo Clinic

Although rare, there is an increased risk of ILD with CDK4/6 inhibitors (FDA.gov, 2019). Patients need to be monitored regularly for pulmonary symptoms indicative of ILD and/or pneumonitis, including hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Patients should notify their healthcare professional immediately if they have sudden shortness of breath that is worse than usual, especially when climbing stairs, or develop a sudden cough or fever.

“In my experience, ILD from the CDK4/6 inhibitors is uncommon, but when it does occur, it tends in my experience to be reversible on discontinuation of the drug.” – Adam Brufsky, MD, PhD, Professor of Medicine, UPMC Hillman Cancer Center

Section 4: Promoting Patient Engagement to Maximize Adherence, Persistence, and Outcomes

Adherence to oral adjuvant therapy is challenging, and manageable toxicity profiles are crucial for new treatments. Dose reductions are frequently used to manage treatment-related toxicity and improve treatment adherence. By adjusting the dosage to better align with individual patient tolerability, clinicians can mitigate side effects and enhance the overall adherence to the prescribed treatment regimen.

Maintaining treatment compliance involves medication adherence (degree of medication-taking behavior aligning with physician recommendations, including timing, dosage, and frequency) and persistence (duration of therapy from commencement to discontinuation) (Sella, 2020). Optimal adherence and persistence require an effective and convenient drug regimen with minimal side effects and a positive and supportive approach to treatment, especially through the patient-physician relationship (Cavazza, 2020). Both early discontinuation and nonadherence to adjuvant therapy were associated with increased risk of breast cancer recurrence and mortality (Sella, 2020). Nonadherence is associated with poor outcomes, and can lead to increased physician visits, more frequent or longer hospitalizations, disease progression, development of resistance, and even death.

“For oral therapy there is an improved quality of life. There are fewer clinic visits, less travel, you avoid the intravenous infusions, and the patients empower themselves to treat themselves. There is, however, increased patient responsibility.” – Adam Brufsky, MD, PhD, Professor of Medicine, UPMC Hillman Cancer Center

Addressing various patient factors, including patient mental health, disease severity, patient perceptions, effective intervention components such as good communication/shared decision-making (SDM) and patient education, and improved coordination for continued follow-up may improve patient adherence/persistence to therapy (Heiney, 2019; Cavazza, 2020). Shared decision-making can help with adherence to CDK4/6 inhibitors in the adjuvant setting. Treatment decisions should involve shared decision-making (SDM) between patients and healthcare providers, and take into consideration individual preferences, goals, and values (Agency for Healthcare Research and Quality, 2014). Patients desire information and active involvement in the decision-making process for their treatment, leading to higher satisfaction and better outcomes (Josfeld, 2021). Additionally, the Oncology Nursing Society (ONS) has developed evidence-based guidelines for interventions to support patient adherence to oral anticancer medications, including adherence risk assessment, education, ongoing assessments, proactive follow-up, coaching, motivational interviewing, and implementation of a structured program (Belcher, 2022).

“Shared decision-making – this is where a healthcare provider and patient work together to make sure that the healthcare decision is in the best interest of the patient. I think that it takes into account available options, the provider’s knowledge, and the patient’s values – they are important. In the SHARE approach to shared decision-making, you seek your patient’s participation, help your patient explore and compare treatment options, assess your patient's values, reach a decision with the patient, and then evaluate your patient’s decision. It is an interactive approach.” – Adam Brufsky, MD, PhD, Professor of Medicine, UPMC Hillman Cancer Center

Focused education and follow-up over time are needed to ensure patients are taking their medications properly.  One strategy to enhance patient adherence is to make it “simple” by following the mnemonic in Table 4 (Atreja et al, 2005).

Table 4. Strategies to Improve Medication Adherence: SIMPLE

“Healthcare teams must utilize a collaborative approach to improve medication adherence. The involvement of team members such as nurses, pharmacists, advanced practice providers, and physicians is pivotal to ensure patient understanding and compliance. Supportive oncology team members such as dieticians, physical therapists, and psychologists also play an important role in helping patients to mitigate side effects from treatment including but not limited to diarrhea, fatigue, and deconditioning. Team members should be called upon to provide education, monitoring, and continued follow-up starting at the time when medications are initially discussed and prescribed and not just when side effects arise.” - Melissa Duffy, MSPAS, PA-C, Physician Assistant, Northwestern Medicine

Section 5: Practical Application Case Review

Links to Helpful Resources

• Predict Breast Cancer: https://breast.predict.cam/tool
• What is Early Breast Cancer?: https://verzenio.lilly.com/early-breast-cancer#what-is-ebc
• Addressing Side Effects
  • Abemaciclib: https://verzenio.lilly.com/addressing-side-effects
  • Ribociclib: https://us.kisqali.com/metastatic-breast-cancer/side-effects/managing-side-effects
• Prescribing and Patient Information:
  • Abemaciclib: https://uspl.lilly.com/verzenio/verzenio.html#pi
  • Ribociclib: https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf
• Shared Decision Making: https://www.ahrq.gov/health-literacy/professional-training/shared-decision/index.html
• Adherence: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1681370/
• ONS Guidelines™ to support patient adherence to oral anticancer medications: https://www.ons.org/ons-guidelines-support-patient-adherence-oral-anticancer-medications
• NCCN Guidelines® for Breast Cancer: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
• Downloadable Slide Deck:here

References

Agency for Healthcare Research and Quality. The SHARE approach--essential steps of shared decision making: quick reference guide. July 2014. https://www.ahrq.gov/health-literacy/professional-training/shared-decision/index.html

Atreja A, Bellam N, Levy SR. Strategies to enhance patient adherence: making it simple. MedGenMed. 2005;7(1):4.

Belcher SM, Mackler E, Muluneh B, et al. ONS Guidelines™ to support patient adherence to oral anticancer medications. Oncol Nurs Forum. 2022;49(4):279-295.

Brown J, Method MW, Nelson DR. Mortality rates associated with clinical and pathological characteristics of hormone receptor positive human epidermal growth factor receptor 2 negative early breast cancer: An analysis of the 2010-2016 surveillance, epidemiology, and end results data. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, TX; December 10-14, 2019. Poster P5-08-18.

Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729.

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194-1220.

Cavazza M, Banks H, Ercolanoni M, et al. Factors influencing adherence to adjuvant endocrine therapy in breast cancer‑treated women: using real‑world data to inform a switch from acute to chronic disease management. Breast Cancer Res Treat. 2020;183(1):189-199.

Colleoni M, Sun Z, Price KN, et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the International Breast Cancer Study Group Trials I to V. J Clin Oncol. 2016;34(9):927-935.

Dang CM, Giuliano AE. Local recurrence risk factors in women treated with BCT for early-stage breast cancer. Oncology (Williston Park). 2011;25(10):895-899.

Dubsky P, Brase JC, Jakesz R, et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer. 2013;109(12):2959-2964.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717. 

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352.

Fasching PA, Gass P, Häberle L, et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat. 2019;175(3):617-625.

FDA.gov. FDA approves abemaciclib with endocrine therapy for early breast cancer. October 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer

FDA.gov. FDA approves Kisqali with an aromatase inhibitor and Kisqali Femara Co-Pack for early high-risk breast cancer. September 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-kisqali-aromatase-inhibitor-and-kisqali-femara-co-pack-early-high-risk-breast-cancer?utm_medium=email&utm_source=govdelivery

FDA.gov. FDA expands early breast cancer indication for abemaciclib with endocrine therapy. March 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-early-breast-cancer-indication-abemaciclib-endocrine-therapy

FDA.gov. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. September 13, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung-inflammation-ibrance-kisqali-and-verzenio-breast-cancer

FDA.gov. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. March 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer

Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011;17(18):6012-6020.

Gil Gil, M, Alba E, Gavila J, et al. The role of CDK4/6 inhibitors in early breast cancer. Breast. 2021;58:160-169.

Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib in HR+/HER2- early breast cancer: final results from 5,760 patients in the randomized phase III PALLAS trial. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, TX; December 7-10, 2021. Abstract GS1-07.

Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293.

Gradishar WJ, Moran MS, Abraham J, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer (Version 4.2024). © 2024 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.

Győrffy B, Hatzis C, Sanft T, Hofstatter E, Aktas B, Pusztai L. Multigene prognostic tests in breast cancer: past, present, future. Breast Cancer Res. 2015;17(1):11.

Hamilton EP, Kim JH, Eigeliene N, et al. Efficacy and safety results by age in monarchE: adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). Abstract presented at: American Society of Clinical Oncology Annual Meeting; Chicago, IL; June 2-6, 2023. Abstract 501.

Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581.

Harbeck N, Rastogi P, O’Shaughnessy J, et al. Adjuvant abemaciclib plus endocrine therapy for HR+, HER2-, high-risk early breast cancer: Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. Abstract presented at: European Society for Medical Oncology Annual Meeting; Madrid, Spain; October 20-24, 2023. Abstract LBA17.

Heiney SP, Parker PD, Felder TM, et al. A systematic review of interventions to improve adherence to endocrine therapy. Breast Cancer Res Treat. 2019;173(3):499–510.

Hortobagyi G, Stroyakovsky D, Yardley D, et al. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, Texas; December 5-9, 2023. Abstract GS03-03.

Howlander N, Altekruse S, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014 Apr 28;106(5):dju055.

Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25(15):2127-2132.

Huppert LA, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023;73(5):480-515.

Johnston SRD, Harbeck N, Hegg R, 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):3987-3998.

Johnston S, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, TX; December 6-10, 2022. Abstract GS1-09.

Johnston SRD, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90.

Josfeld L, Keinki C, Pammer C, Zomorodbakhsch B, Hübner J. Cancer patients’ perspective on shared decision-making and decision aids in oncology. J Cancer Res Clin Oncol. 2021;147(6):1725-1732.

Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347.

Kalinsky K, Barlow WE, Pathak HB, et al. Correlation of serum anti-Müllerian hormone (AMH) levels on identification of premenopausal patients (pts) with hormone receptor positive (HR+), HER2-negative, node-positive breast cancer most likely to benefit from adjuvant chemotherapy in SWOG S1007 (RxPONDER). J Clin Oncol. 2024;42(16_suppl.):505.

KISQALI (ribociclib). Prescribing information. Novartis; 2024.

Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-The Penelope-B Trial. J Clin Oncol. 2021;39(14):1518-1530.

Mamounas EP,Tang G, Paik S, et al. 21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology. Breast Cancer Res Treat. 2018;168(1):69-77.

Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212-222.

McVeigh TP, Kerin MJ. Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer. Breast Cancer (Dove Med Press). 2017;9:393-400.

National Cancer Institute at the National Institutes of Health. Early-stage breast cancer. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/early-stage-breast-cancer.

OncoLetter. Accessed August 18, 2023. http://web.oncoletter.ch/files/cto_layout/Kongressdateien/SABCS2013/S2-07.pdf

O’Shaughnessy J, Cicin I, Testa L, et al. Impact of dose reductions on efficacy of adjuvant abemaciclib for patients with high-risk early breast cancer (EBC): Analyses from the monarchE study. Abstract presented at: European Society for Medical Oncology Annual Meeting; Madrid, Spain; October 20-24, 2023. Abstract 274P.

Pagani O, Francis PA, Fleming GF, et al. Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: results from TEXT and SOFT. J Clin Oncol. 2020;38(12):1293-1303.

Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846.

Piccart M, van 't Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476-488.

Polley MY, Leung SC, McShane LM, et al. An international Ki67 reproducibility study. J Natl Cancer Inst. 2013;105(24):1897-1906.

Predict Breast Cancer. https://breast.predict.cam/tool. Copyright Ⓒ 2024 University of Cambridge.

Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207.

Rastogi P, O’Shaughnessy J, Martin M, et al. 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(9):987-993.

Reddy TP, Rosato RR, Li X, Moulder S, Piwnica-Worms H, Chang JC. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations. Breast Cancer Res. 2020;22(1):121.

Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2):113-126.

Richman J, Dowsett M. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol. 2019;16(5):296-311.

Sestak I, Martín M, Dubsky P, et al. Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone. Breast Cancer Res Treat. 2019;176(2):377-386.

Sella T, Chodick G. Adherence and persistence to adjuvant hormonal therapy in early-stage breast cancer patients: a population-based retrospective cohort study in Israel. Breast Care (Basel). 2020;15(1):45–53.

Sheffield KM, Peachey JR, Method MW, et al. Recurrence risk in early breast cancer as defined by clinicopathologic features. J Clin Oncol. 2021;39(15).

Sheffield KM, Peachey JR, Method M, et al. A real-world US study of recurrence risks using combined clinicopathological features in HR-positive, HER2-negative early breast cancer. Future Oncol. 2022;18(21):2667-2682.

Slamon DJ, Fasching PA, Patel R, et al. NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (EBC). J Clin Oncol. 2019;37(15_suppl):TPS597.

Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023;15:17588359231178125.

Slamon D, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the Phase III NATALEE trial. Abstract presented at: American Society of Clinical Oncology Annual Meeting; Chicago, IL; June 2-6, 2023. Abstract LBA500.

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121.

Stuart-Harris R, Dahlstrom JE, Gupta R, Zhang Y, Craft P, Shadbolt B. Recurrence in early breast cancer: Analysis of data from 3,765 Australian women treated between 1997 and 2015. Breast. 2019;44:153-159.

Stover D, Hlauschek D, Mayer EL, et al. Protocol-defined biomarker analysis in the PALLAS adjuvant trial (AFT-05; ABCSG-42): genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, Texas; December 5-9, 2023. Abstract GS03-07.

Turner N, Goetz MP, Desmedt C, et al. Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial. Abstract presented at: San Antonio Breast Cancer Symposium; San Antonio, Texas; December 5-9, 2023. Abstract GS03-06.

Tutt ANJ, Garber J, Gelber RD, et al. Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. Abstract presented at: ESMO Virtual Plenary; March 16-17, 2022. Abstract VP1-2022.

VERZENIO (abemaciclib). Prescribing information. Eli Lilly and Company; 2024.

Viale G, Giobbie-Hurder A, Regan MM, et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 2008;26(34):5569-5575.

Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer. 2019;19(1):1091.

Yardley DA, Untch M, Barrios CH, et al. Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC): NATALEE trial. Abstract presented at: American Society of Clinical Oncology Annual Meeting; Chicago, Illinois; May 31-June 4, 2024. Abstract 512.