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Spotlight

This roundtable series considers the use of CDK4/6 inhibitors in patients with hormone receptor–positive, HER2-negative, early-stage breast cancer as discussed by participants at virtual live events.

CDK Inhibition in HR-Positive, HER2-Negative Early-Stage Breast Cancer

A 52-year-old, postmenopausal woman presented with a newly discovered lump in her left breast.

Imaging identified a 2-cm solid mass in upper outer quadrant with no suspicious lymphadenopathy identified.

Core biopsy: positive for invasive ductal carcinoma; estrogen receptor, 100%; progesterone receptor, 98%; HER2 1+ and fluorescence in situ hybridization negative; Ki-67 42%; modified Bloom-Richardson grade 3

Lumpectomy and sentinel lymph node (LN) biopsy were performed.

Tumor size is 2.1 cm, and 2 LNs are positive for metastatic disease.

Twenty-one­–gene assay recurrence score (RS): 31.

If this was your patient, how would you handle their management after diagnosis? What factors influence your selection of adjuvant therapy for this patient? How would you explain your choices to the patient?

The patient was initially diagnosed with a clinical stage IA (T1N0) left breast hormone receptor-positive (HR+), HER2-negative (HER2-) invasive ductal carcinoma. Given the small size of the tumor and without evidence of lymph node (LN) involvement on imaging, we would recommend upfront surgery with a plan for adjuvant systemic therapy tailored to the final surgical pathology. If considering preoperative systemic therapy, then we would strongly consider use of a gene expression assay to guide the choice of systemic therapy (ie, neoadjuvant endocrine therapy versus chemotherapy); however, in this clinical scenario, upfront surgery to better guide adjuvant treatment strategy is indicated.

After lumpectomy and sentinel LN biopsy were completed, the pathologic stage is IIB (T2N1). If whole breast irradiation is planned, axillary LN dissection may be omitted per ACOSOG Z0011 criteria.

 The 21-gene assay recurrence score is used to determine adjuvant systemic therapy. Given the patient’s RS of 31, we recommend adjuvant chemotherapy, followed by adjuvant endocrine therapy. Unfortunately, results from the TAILORx (NCT00310180) and RxPONDER (NCT01272037) trials evaluating the omission of adjuvant chemotherapy in select patients cannot be applied to this case.

 TAILORx only included patients with node negative disease, while RxPONDER trial randomized patients with 1 to 3 lymph nodes involved with an RS of 25 or less to adjuvant endocrine therapy versus adjuvant chemotherapy plus endocrine therapy. While RxPONDER showed that postmenopausal women with up to 3 axillary lymph nodes involved and an RS of 25 or less did not benefit from adjuvant chemotherapy, our patient does not meet this criteria with an RS of 31.

Furthermore, previous analysis of the SWOG-8814 trial (NCT00929591) showed that post-menopausal women with LN involvement and an RS of 31 or more who were given chemotherapy plus tamoxifen had a survival benefit over those receiving tamoxifen alone.

 Therefore, we recommend adjuvant chemotherapy in addition to adjuvant endocrine therapy in this case. Per analysis of the ABC trials, it would be reasonable to offer docetaxel plus cyclophosphamide rather than doxorubicin, cyclophosphamide, and taxane given the tumor size and limited number of LNs involved.

 After chemotherapy, whole breast irradiation would be recommended as the patient underwent lumpectomy rather than a mastectomy. The decision to give regional nodal radiation should be individualized in the setting of 1 to 3 positive LNs.

After completion of radiation, we would recommend adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) given lower rates of 

 recurrence and 10-year breast cancer mortality with AIs compared to tamoxifen in post-menopausal women.

 The AI should be given for a minimum of 5 years. After considering drug tolerability and patient preferences, we would offer an additional 5 years of adjuvant AI, in keeping with current ASCO (American Society of Clinical Oncology) clinical practice guidelines for patients with LN involvement.

In addition to adjuvant endocrine therapy, adjuvant olaparib (Lynparza) and abemaciclib (Verzenio) have recently been approved for use in the adjuvant setting for select patients with high-risk, early-stage HR+ breast cancer. OlympiA is phase 3 trial (NCT02032823) for patients with HER2-, high-risk, early-stage breast cancer and germline 

 After receiving chemotherapy, patients were randomized to adjuvant olaparib versus placebo for 12 months. Patients who received olaparib had improved 3-year disease-free survival (DFS) compared to placebo (86% vs 77%, 

< .001) with a recently reported overall survival benefit at 3.5 years of median follow-up.10 Importantly, the OlympiA trial defined high-risk HR+ disease as those with least 4 positive LNs being treated with adjuvant chemotherapy or those without a pathologic complete response to neoadjuvant chemotherapy with a CPS+EG score of 3 or higher. Based on these criteria from OlympiA and the FDA indication for adjuvant olaparib in HR+, HER2- breast cancer, the patient would not be eligible for adjuvant olaparib even if found to have a germline 

Conversely, we would recommend adjuvant abemaciclib for 2 years concurrently with adjuvant AI for this patient based on the results of the monarchE trial.

In this open-label phase 3 study, more than 5000 patients with early-stage HR+, HER2- breast cancer were randomized to standard-of-care adjuvant endocrine therapy (ET) plus abemaciclib at 150 mg twice daily for 2 years versus ET alone. For trial eligibility, patients were required to have high-risk disease defined as 4 LNs involved or 1 to 3 LNs plus one of the following: tumor 5 cm or larger, histologic grade 3, or Ki-67 20% or more.

At follow-up analysis, the absolute improvement in 3-year invasive DFS of abemaciclib over ET alone in the intent-to-treat (ITT) population was 5.4 percentage points.

 The benefit was even greater in patients with a high Ki-67 index with a statistically significant improvement in 3-year invasive DFS of 86.1% versus 79.0% with the addition of abemaciclib to ET. While the survival data showed no benefit of abemaciclib in the ITT population (HR, 1.091; 95% CI, 0.818-1.455), overall survival data are immature and longer follow-up is required.

 The FDA approved adjuvant abemaciclib in combination with ET for those with high-risk disease per monarchE and a Ki-67 of 20% or more. The patient in this case fits this criteria and therefore should be offered abemaciclib for 2 years along with adjuvant endocrine therapy. Of note, we may also consider adjuvant abemaciclib in patients with high-risk disease as defined in monarchE of 4 or more positive axillary LNs or 1 to 3 positive axillary LNs and 1 or more of the following features: histologic grade 3 disease, tumor size 5 cm or larger, or Ki-67 index 20% or more per the 2021 ASCO Rapid Recommendation Update.

When considering adjuvant abemaciclib in patients with early-stage HR+, HER2- breast cancer, clinicians must consider clinicopathologic features and the risk of breast cancer recurrence, expected increase in toxicities with the addition of abemaciclib to adjuvant endocrine therapy, and patient preferences. The pros and cons of adjuvant abemaciclib in combination with ET must be discussed with the patient. While the patient’s overall prognosis is favorable, the addition of abemaciclib for 2 years in addition to adjuvant AI for at least 5 years may further reduce the risk of breast cancer recurrence. Common adverse events (AEs) of abemaciclib however, include diarrhea, neutropenia, and fatigue, as well as the rare but notable AEs of interstitial lung disease (3.2%) and venous thromboembolism (2.5%).

 Adjuvant abemaciclib should be discontinued if the AEs remain intolerable despite supportive care interventions or dose adjustments with continuation of adjuvant endocrine therapy.

1. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study. 

 2019;173(1):123-133. doi:10.1007/s10549-018-4964-y

2. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. 

. 2011;305(6):569-575. doi:10.1001/jama.2011.90

3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. 

. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710

4. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene assay to inform chemotherapy benefit in node-positive breast cancer. 

. 2021;385(25):2336-2347. doi:10.1056/NEJMoa2108873

5. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. 

. 2010;11(1):55-65. doi:10.1016/S1470-2045(09)70314-6

6. Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). 

 2017;35(23):2647-2655. doi:10.1200/JCO.2016.71.4147

7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. 

. 2015;386(10001):1341-1352. doi:10.1016/S0140-6736(15)61074-1

8. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. 

 2019;37(5):423-438. doi:10.1200/JCO.18.01160

9. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. 

 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

10. Helwick C. Adjuvant Olaparib significantly improves overall survival in germline BRCA-Mutated breast cancer. ASCO Post. Updated April 5, 2022. Accessed April 6, 2022. https://bit.ly/3NEQy1s

11. 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). 

2020;38(34):3987-3998. doi:10.1200/JCO.20.02514

12. 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. 

2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015

13. Harbeck N, Rastogi P, Shahir A, Johnston S, O'Shaughnessy J. Letter to the Editor for 'Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study'. 

2022;33(2):227-228. doi:10.1016/j.annonc.2021.10.015

14. Giordano SH, Freedman RA, Somerfield MR; Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Expert Panel. Abemaciclib with endocrine therapy in the treatment of high-risk early breast cancer: ASCO optimal adjuvant chemotherapy and targeted therapy guideline rapid recommendation update. 

 2022;40(3):307-309. doi:10.1200/JCO.21.02677

15. Freedman RA, Graff SL, Somerfield MR, Telli ML, Wolff AC, Giordano SH. Adjuvant abemaciclib plus endocrine therapy in the treatment of high-risk early breast cancer: ASCO guideline rapid recommendation update Q and A. 

. 2022;OP2200140. doi:10.1200/OP.22.00140

Physicians cover the options for a patient with hormone receptor–positive, HER2-negative, early-stage breast cancer, which course of action they would take, and the data supporting that choice.

Management of HR+, HER2- Early-Stage Breast Cancer After Diagnosis

Manali A. Bhave, MD, assistant professor in the department of hematology and medical oncology at Emory University School of Medicine, discusses the updated results of the MonarchE study (NCT03155997) of abemaciclib in patients with hormone receptor-positive, HER2-negative, breast cancer.

The primary end point of the randomized phase 3 MonarchE trial of adjuvant endocrine therapy with abemaciclib (Verzenio) was invasive disease-free survival (IDFS) in the intent-to-treat (ITT) population. The updated results of a median 27-month follow-up showed that 90% of patients received abemaciclib for 2 years, and the 3-year IDFS was 88.8% with abemaciclib versus 83.4% with endocrine therapy alone, Bhave says.

The updated results analyzed the IDFS of patients with a high Ki-67 status. Cohort 1 enrolled patients regardless of Ki-67 status, while cohort 2 enrolled patients with a high Ki-67 status starting 1 year after cohort 1.

A Ki-67 of 20% or greater was found to be prognostic of high risk of disease recurrence, but abemaciclib showed benefit regardless of Ki-67 status. In the Ki-67–high population, there was a 4.5% absolute improvement in 2-year IDFS with abemaciclib. Ki-67­ status could serve as a biomarker for patients who will benefit from abemaciclib, according to Bhave.

 [In] the updated 27-month follow-up on these patients, in which 90% of patients actually completed the 2 years of abemaciclib, we did see that across the board, in cohort 1, there was an improvement in the IDFS. So, in the ITT population, we actually saw 3-year IDFS to be about 88.8% in patients with abemaciclib versus approximately 83% in patients who just received the standard endocrine therapy.

That benefit was actually higher if they had a Ki-67 that was 20% or greater. And those patients in that high-risk group with a Ki-67 of at least 20% actually had closer to about a 7% improvement in 3-year IDFS. So it looks like based off of the data, that Ki-67 was definitely prognostic of risk because patients with high Ki-67, overall, did slightly worse than those that had a low Ki-67, but may also be a marker to help us predict which patients absolutely benefit from the addition of abemaciclib to endocrine therapy.

Manali Bhave, MD, discusses the updated results of the MonarchE study of abemaciclib in patients with hormone receptor-positive, HER2-negative, breast cancer. 

Abemaciclib Shows Long-Term IDFS Benefit in HR+, HER2- Breast Cancer

: What were the findings related to patients with Ki67-high status in the monarchE (NCT03155997) trial of abemaciclib (Verzenio)?

In this trial, most of the patients have high Ki67 but there was about a third of them that did not have a high Ki67.

For patients with high Ki67, [based on invasive disease-free survival data,] there was a 30% relative risk reduction in the patients that got abemaciclib vs the ones who didn’t, and then the absolute benefit comes out to a 5% or 6% range.

 This was very similar to the overall results.

This showed that aside from anything else, having a high Ki67 made a difference. This was true in patients in [the higher-risk] cohort 1 who had high levels or low levels of Ki67, but the interesting thing is that even if the level was low, [abemaciclib benefit was consistent].

What are the outcomes for patients with low Ki67 levels?

Patients with low Ki67 do better even if they don’t get abemaciclib.

 However, if they did, there was a very significant benefit. It looks like the magnitude of benefit is very similar, so Ki67 is prognostic of the worst outcome, but you got benefit from taking the adjuvant abemaciclib and you did better whether you had a high Ki67 or you didn’t. So, it was independent [Ki67 level].

I think that gives us some comfort in not using Ki67 as the only indicator of who should get abemaciclib and who should not get abemaciclib.

How should physicians practice based on these data, considering that the FDA only approved abemaciclib for patients with high Ki67 and high risk?

Officially, patients have to have a high risk and a high Ki-67.

 When I’ve talked to leaders in the field…I was in the advisory panel with some oncologists from Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and a couple of other large cancer centers a few weeks ago and they were struggling with the same thing. Most of them said [that abemaciclib could be given to patients without high Ki67], and I would agree.

My personal practice is that if you were otherwise eligible to go on to the monarchE trial, I would consider this and I would fight with a patient’s insurance company. If they were eligible to go on the trial and the intent-to-treat [ITT] data are positive in the trial, then I think they need to go to the trial. That’s generally what I’ve heard from thought leaders in the field, although I admit there could be other people that say something else. But that’s what I’ve heard from some.

If the trial had showed that if the patient’s Ki67 is low, [and] the drug can’t work, I would follow that, but that’s not what we’re seeing here.

What was the rationale for the FDA indication that resulted from this trial?

In terms of overall survival, it looks better in the overall ITT population, which was everybody, but again, this is hormone receptor-positive primary breast cancer. It will take a long time to really get a very significant survival benefit. So, the data are immature at this point. There has been uncertainty regarding the rationale for the indication granted by the FDA because a lot of us, including my practice in Fort Myers, have not routinely been testing patients’ Ki67 level. Now we are sending it out to have it done, but I think there will be a divergence between the 2 results and it’s going to be a difficult thing to settle out.

I think that sometime in the next few years, this will settle out. Or if we see a clear-cut survival benefit comes out in the ITT population a year or so from now, I believe the FDA will drop that eventually.

[Patients with Ki67-high status are] going to have earlier events and then the later events are going to happen in the Ki67 lower group. So, it’s going to take a while for that to show up in the whole ITT population.

What stood out about the safety profile of abemaciclib in this trial?

During a live virtual event, Lowell Hart, MD, discussed the findings of the monarchE trial of abemaciclib in high-risk patients with early breast cancer. 