Treatment in HR+ Early Breast Cancer May be Best Guided by Risk of Recurrence

After settling the debate of which patients with early-stage, hormone receptor–positive breast cancer require chemotherapy in addition to endocrine therapy, investigators have set their sights on determining whether ovarian function suppression can deliver the same effects of chemotherapy and when to recommend abemaciclib and olaparib.

William J. Gradishar, MD, FASCO, FACP

William J. Gradishar, MD, FASCO, FACP

After settling the debate of which patients with early-stage, hormone receptor–positive breast cancer require chemotherapy in addition to endocrine therapy, investigators have set their sights on determining whether ovarian function suppression can deliver the same effects of chemotherapy and when to recommend abemaciclib (Verzenio) and olaparib (Lynparza).

In the footnotes of the National Comprehensive Cancer Network (NCCN) guidelines for adjuvant endocrine therapy new guidance indicate that abemaciclib may be considered in combination with endocrine therapy in patients with hormone receptor–positive, HER2-negative, high-risk disease with at least 4 positive lymph nodes or 1 to 3 positive lymph nodes with grade 3 disease, a tumor size of at least 5 cm, or a Ki67 score of 20% or higher. Moreover, olaparib may be considered in the BRCA-mutant population; chemotherapy should be given in combination with endocrine therapy in premenopausal patients; and 5 years of an aromatase inhibitor or tamoxifen plus ovarian function suppression can be considered for premenopausal patients at higher risk of recurrence.1

The recommendations are based on data from the TAILORx (NCT00310180), RxPONDER (NCT01272037), SOFT (NCT00066690) and TEXT (NCT00066703), monarchE (NCT03155997), and OlympiA (NCT02032823) trials, which William J. Gradishar, MD, FASCO, FACP, reviewed in a presentation delivered at the 40th Annual Miami Breast Cancer Conference®.2 Gradishar is the Betsy Bramsen Professor of Breast Oncology and chief of Oncology/Hematology at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, Illinois.

Tackling Treatment Intensity in TAILORx and RxPONDER

For women with an OncotypeDx recurrence score of less than 26, the importance of adding chemotherapy to endocrine therapy was shown in the phase 3 TAILORx trial. In the study, women with high-risk, node-negative, estrogen receptor (ER)–positive, HER2-negative breast cancer underwent testing with the OncotypeDx assay to determine risk of recurrence. Patients with a low score between 0 and 10 received endocrine therapy alone and those with a high score between 26 and 100 received endocrine therapy plus chemotherapy. Patients with a mid-range score between 11 and 25 were randomly assigned to endocrine therapy with or without chemotherapy.

Findings from an updated analysis presented at the 2022 San Antonio Breast Cancer Symposium3 mirrored those presented in the primary analysis, showing that endocrine therapy alone (n = 3399) was noninferior to its use in combination with chemotherapy (n = 3312) in the intention-to-treat population. However, when further stratified by age, investigators showed improved invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) in patients aged 50 years or younger and a recurrence score between 21 and 25 with the addition of chemotherapy.

“This begs the question of whether optimal endocrine therapy with ovarian suppression could achieve the same thing,” Gradishar said.

The phase 3 RxPONDER trial similarly evaluated the benefit of added chemotherapy, but in women with node-positive disease and a recurrence score between 0 and 25. Although results showed no statistically significant difference for iDFS in the postmenopausal population, premenopausal patients experienced a 5-year absolute difference in iDFS of 5.2% with chemotherapy (HR, 0.54; 95% CI, 0.38-0.76; P = .0004).4

The ongoing BR009 trial will formally address whether chemotherapy has any advantages over ovarian function suppression with endocrine therapy in the premenopausal population, results of which will prove “very useful,” according to Gradishar.

“Based on the RxPONDER as well as the TAILORx trial, we now have tools that help define those patients who really need chemotherapy, and a significant chunk of them [for whom] we can avoid chemotherapy,” Gradishar said. “We’re still learning a great deal from certain subsets in these trials that will prove to be informative with further updates.”

Sorting Through Optimal Endocrine Therapy in SOFT and TEXT

“The SOFT and TEXT trials have been around for a long time, and we’ve heard data presented from them over the years. We now have very mature data from this dataset,” Gradishar said.

Both trials evaluated tamoxifen and exemestane in combination with ovarian function suppression in premenopausal patients. In both trials, adjuvant chemotherapy was permitted for patients at high risk per the treating physician. In data presented at the 2021 San Antonio Breast Cancer Symposium, the addition of ovarian function suppression to either tamoxifen or exemestane demonstrated clear benefit, with a 12-year overall survival (OS) rate of 89.0% and 89.4%, respectively, vs 86.8% with tamoxifen alone (P = .06).5 Moreover, in a joint analysis of both trials, exemestane plus ovarian function suppression showed a 3.3% improvement in OS benefit compared with tamoxifen and ovarian function suppression in the HER2-negative chemotherapy cohorts.

“Where that benefit was most evident is in patients who are deemed to have the highest risk. So, for those clinicians who decided chemotherapy should be part of the plan, often patients with higher-risk disease, clearly younger patients, [are the] group [for which] maximal ovarian suppression and endocrine therapy really showed the most benefit,” Gradishar said.

“The SOFT and TEXT trials have told us that in very high-risk patients, particularly those who are young with high-risk features, the addition of ovarian suppression plus endocrine therapy may further reduce the risk of recurrence. There are trials that are ongoing that will help define whether ovarian suppression plus endocrine therapy could serve as a substitute for chemotherapy with an equally good outcome,” Gradishar said.

Treating With Targeted Therapy in monarchE and OlympiA

“Transitioning to one of the newer wrinkles that we have in adjuvant endocrine therapy, and for that matter, endocrine therapy in general, is the notion of partnering endocrine therapy with targeted therapies,” Gradishar said.

A total of four trials evaluating CDK4/6 inhibitors have been performed in the adjuvant setting, but only one has proved positive to date: monarchE, which showed a 30% reduction in invasive disease with abemaciclib plus endocrine therapy vs endocrine therapy alone (HR, 0.70; 95% CI, 0.59-0.82; P < .0001).6 Both the phase 3 PALLAS (NCT02513394) and PENELOPE-B (NCT01864746) trials, which evaluated postoperative palbociclib (Ibrance), failed to demonstrate statistical significance vs placebo for the primary end point of iDFS (HR, 0.96; 95% CI, 0.81-1.14; P =.65; HR, 0.93; 95% CI, 0.74-1.17; P = .53, respectively).7,8 Results from the phase 3 NATALEE trial (NCT03701334) are still pending.

monarchE enrolled patients with pre- or postmenopausal hormone receptor–positive, HER2-negative, node-negative, high-risk early breast cancer. “Keep in mind that these are high-risk patients who had certain features that allowed them to be participants in this trial, [such as] greater than 4 positive nodes, or 1 to 3 nodes with other features, including high-grade or larger tumors. There was a smaller cohort that was driven largely by proliferation or Ki67,” Gradishar said.

Endocrine therapy was continued for 3 to 8 years as clinically indicated after completion of 2 years of study treatment. At 4 years, abemaciclib continued to display improved iDFS (HR, 0.664; 95% CI, 0.578-0.762; P < .0001), increasing from an absolute benefit rate of 2.8% and 4.8% at 2 and 3 years, respectively, to 6.4%.9 Similar improvements were reported for DRFS. OS data have yet to mature (HR, 0.929; 95% CI, 0.748-1.153; P = .5027).

“We do have data with the monarchE trial that suggest in high-risk patients, the use of abemaciclib is helpful in further reducing the risk. As a result of these data, the NCCN, American Society of Clinical Oncology, and European Society of Medical Oncology have endorsed the use of abemaciclib in this setting for this population of patients who met the criteria for this trial,” Gradishar noted. “We await the NATALEE trial, which looks at 3 years of therapy.”

Gradishar also took the time to spotlight data from the phase 3 OlympiA trial (NCT02032823). “Oftentimes, when we think of BRCA mutations, we’re thinking about TNBC where the frequency is higher, but in terms of absolute numbers, because there are so many ER-positive patients, the absolute numbers of patients with BRCA mutations who have ER-positive disease is actually numerically greater,” Gradishar explained.

The study enrolled patients with germline BRCA mutations and high-risk disease following neoadjuvant or adjuvant therapy. Patients were randomly assigned to 300 mg of olaparib for 1 year or placebo.

Gradishar noted that approximately 18% of patients had positive hormone receptor status.

At 4 years, all end points—including OS (HR, 0.68; 98.5% CI, 0.47-0.97; P = .009), iDFS (HR, 0.63; 95% CI, 0.50-0.78), and distant disease-free survival (HR, 0.61; 95% CI, 0.48-0.77)—were positive, favoring the addition of olaparib.10

“This begs the question: What do you give patients who are ER-positive with high risk? Do you give them abemaciclib or do you give olaparib, or both? In the monarchE trial, you were allowed up to 16 months before you had to start the patients on abemaciclib, so there may be patients who have sufficiently high risk where you could start with olaparib and then if you’re still worried about them, put them on abemaciclib,” Gradishar said. “The use of PARP inhibitors in ER-positive patients can be considered either with monarchE somewhere integrated into the therapy or in lieu of monarchE with endocrine therapy alone.”

In addition to clinical judgement, Gradishar pointed to the Breast Cancer Index, now endorsed by the NCCN and ASCO to help guide treatment decisions regarding extended adjuvant therapy in patients with 1 to 3 positive lymph nodes.11

Disclosures: None provided


  1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast cancer. National Comprehensive Cancer Network. March 4, 2023. Accessed March 4, 2023.
  2. Gradishar W. Endocrine approaches for ER+ early-stage breast cancer. Presented at: 40th Annual Miami Breast Cancer Conference®; March 2-5, 2023; Miami Beach, FL.
  3. Sparano J, Gray RJ, Makower D, et al. Trial assigning individualized options for treatment (TAILORx): An update including 12-year event rates. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022. Abstract GS1-05.
  4. Kalinsky KM, Barlow WE, Gralow JR, et al. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER). Cancer Res. 2022;82(suppl 4):GS2-07. doi:10.1158/1538-7445.SABCS21.GS2-07
  5. Regan MM, Walley BA, Fleming GF, et al: Randomized comparisons of adjuvant aromatase inhibitor exemestane plus ovarian function suppression vs tamoxifen in premenopausal women with hormone receptor–positive early breast cancer: Update of the TEXT and SOFT trials. Cancer Res. 2022;82(suppl 4):GS2-05. doi:10.1158/1538-7445.SABCS21-GS2095
  6. 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
  7. 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. doi:10.1200/JCO.21.02554
  8. Loibl S, Marme 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. doi:10.1200/JCO.20.03639
  9. 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. Cancer Res. 2023;83(suppl 5):GS1-09. doi:10.1158/1538-7445.SABCS22-GS1-09
  10. Geyer CE, Garber JE, Gelber RD, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022;33(12):1250-1268. doi:10.1016/j.annonc.2022.09.159
  11. Andre F, Ismaila N, Allison KH, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. J Clin Oncol. 2022;40(16):1816-1837. doi:10.1200/JCO.22.00069

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