CDK Inhibition in HR-Positive, HER2-Negative Early-Stage Breast Cancer
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.
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.1
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.2 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.3,4 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.5 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.6 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 breast cancer recurrence and 10-year breast cancer mortality with AIs compared to tamoxifen in post-menopausal women.7 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.8
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 BRCA1/2 mutations.9 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%, P < .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 BRCA1/2 mutation.
Conversely, we would recommend adjuvant abemaciclib for 2 years concurrently with adjuvant AI for this patient based on the results of the monarchE trial.11 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.12 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.13 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.14,15
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%).12 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. Breast Cancer Res Treat. 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. JAMA. 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. N Engl J Med. 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. N Engl J Med. 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. Lancet Oncol. 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). J Clin Oncol. 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. Lancet. 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. J Clin Oncol. 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. N Engl J Med. 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). J Clin Oncol. 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. Ann Oncol. 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'. Ann Oncol. 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. J Clin Oncol. 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. JCO Oncol Pract. 2022;OP2200140. doi:10.1200/OP.22.00140