The past year has been an exciting time for breast oncologists and patients with all stages of breast cancer, with new agents approved and long-term results from pivotal trials showing improved survival for patients with metastatic disease. Let’s take a look at some of the highlights in early-stage and metastatic disease.
GUEST EDITOR
Ruth M. O'Regan, MD
Ovarian Function Suppression in Early-Stage Breast Cancer
Hormone receptor–positive breast cancer is the most common subtype of breast cancer. The use of genomic assays has markedly decreased the use of adjuvant chemotherapy, especially in patients older than age 50.1,2 However, questions remain regarding the optimal management of hormone receptor–positive disease in younger patients and whether ovarian function suppression can be substituted for chemotherapy in some patients.
Aromatase inhibitors remain the optimal endocrine therapy in postmenopausal women with hormone receptor–positive, early-stage breast cancer. The SOFT and TEXT trials demonstrated a benefit for the addition of ovarian suppression and for an aromatase inhibitor rather than tamoxifen in premenopausal women with hormone receptor–positive, early-stage breast cancer.3,4 Ovarian suppression combined with an aromatase inhibitor decreased recurrence in patients with breast cancers that were high risk enough to justify chemotherapy, and patients who did not receive chemotherapy received minimal benefit from ovarian suppression and instead had a highly favorable outcome when treated with tamoxifen alone.3
A meta-analysis presented at the 2023 ASCO Annual Meeting, which included almost 15,000 premenopausal women from 23 trials, however, demonstrated a benefit of ovarian suppression regardless of receipt of chemotherapy.5 The study showed that women who did not receive chemotherapy or who remained premenopausal after chemotherapy had an almost 10% decrease in the risk of recurrence at 15 years when they received ovarian suppression, whereas patients who received chemotherapy and had an unknown menopausal status after treatment achieved a minimal benefit from the addition of ovarian suppression. Patients in the former group had a significant improvement in breast cancer–related and overall survival with the addition of ovarian suppression.
Given the short- and potential long-term toxicities of ovarian suppression plus aromatase inhibitors, as well as its impact on compliance, determining which premenopausal patients will benefit from this treatment is of critical importance. The Breast Cancer Index (BCI) comprises the molecular grade index and the HOXB13/IL17BR (H/I) index and is prognostic for recurrences after 5 years; the H/I index is predictive for the use of extended adjuvant endocrine therapy in patients with early-stage, hormone receptor–positive breast cancer. The BCI was shown to be prognostic in premenopausal women with hormone receptor–positive breast cancers enrolled in the SOFT trial, and a low H/I ratio was predictive for the benefit of ovarian suppression with exemestane.6
Fertility Preservation in Premenopausal Patients
A key issue for premenopausal patients diagnosed with breast cancer is fertility preservation. Multiple retrospective studies have shown that patients who become pregnant following a diagnosis of breast cancer do not have an increased risk of disease recurrence. In the PROMISE trial, patients interrupted endocrine therapy for up to 2 years to attempt pregnancy.7 At a follow-up of 41 months, the recurrence rate was approximately 9%, similar to what was reported in the SOFT and TEXT trials. Almost two-thirds of women had at least one pregnancy, and 86% of these patients had at least one live birth. Fetal outcomes were similar to those of the general public.
CDK4/6 Inhibitors in Hormone Receptor–Positive Breast Cancer
Abemaciclib is approved as adjuvant therapy in addition to endocrine therapy in patients with high-risk, node-positive, hormone receptor–positive breast cancer, based on the results of the monarchE trial, which were updated in December 2022.8 The NATALEE trial evaluated the addition of ribociclib for 3 years to endocrine therapy in patients with hormone receptor–positive, early-stage breast cancer, including a subset with node-negative disease. With a median follow-up of 27 months, patients who received ribociclib had a 3.3% and a 2.2% improvement in invasive disease–free and distant relapse–free survival, respectively, compared with patients in the control arm.9 Ribociclib at a dose of 400 mg was reported to be well tolerated with good compliance. Further follow-up of the NATALEE trial is awaited.
The addition of CDK4/6 inhibitors to endocrine therapy is now the standard first-line approach for patients with hormone receptor–positive metastatic breast cancer, based on randomized trials demonstrating a significant improvement in progression-free survival as well as overall survival with ribociclib. The MONALEESA-2 trial demonstrated a median overall survival of more than 5 years for patients who received ribociclib in addition to letrozole.10 Likewise, the MONARCH-3 trial showed improved overall survival of similar magnitude with the addition of abemaciclib to a nonsteroidal aromatase inhibitor in the first-line setting, though the results did not quite meet statistical significance.11
However, results of the SONIA trial question whether all patients should receive a CDK inhibitor in the first-line setting.12 In this trial, patients with hormone receptor–positive metastatic breast cancer were randomly assigned to receive a nonsteroidal aromatase inhibitor alone or with a CDK inhibitor in the first-line setting. At disease progression, patients switched to fulvestrant, and those who had not received a CDK inhibitor in the first line received one in the second line. Although first progression-free survival was improved in patients who received a CDK 4/6 inhibitor in the first-line setting, there was no significant improvement in the median time to second progression-free survival. Given the dramatic survival benefit noted with ribociclib and abemaciclib, the standard of care in the United States remains a CDK inhibitor in the first-line setting, though a predictive biomarker is clearly needed.
Targeted Therapies for Metastatic Breast Cancer
The management of patients with hormone receptor–positive metastatic breast cancer who experience disease progression depends on genomic drivers. The SOLAR and BYLieve trials previously demonstrated the efficacy of the PI3K inhibitor alpelisib in combination with fulvestrant in patients whose breast cancer harbors a PIK3CA mutation.13-15 The CAPItello-291 trial evaluated the addition of the AKT inhibitor capivasertib to fulvestrant in patients with pretreated hormone receptor–positive metastatic breast cancer.16 Progression-free survival was doubled in patients who received the AKT inhibitor in the overall population, as well as in those whose cancers had mutations in the AKT pathway (such as AKT, PIK3CA, and PTEN).
Based on the results of the EMERALD trial, patients should have tumor tissue or circulating tumor DNA assessed for the acquisition of an ESR1 mutation; if present, the oral selective estrogen receptor degrader elacestrant has been shown to be more effective than other endocrine therapy in patients who had received a prior CDK inhibitor with endocrine therapy.17 A subset analysis of the EMERALD trial demonstrated a greater benefit for elacestrant over endocrine therapy in patients who received a CDK inhibitor for more than 12 months, compared with those who received shorter durations of therapy.18 For patients whose cancers do not have an actionable mutation, treatment choices include everolimus with endocrine therapy, standard chemotherapy, or more recently antibody-drug conjugates.
Three trials have evaluated the use of CDK4/6 inhibitors through disease progression.19-21 The MAINTAIN trial demonstrated a significant improvement in progression-free survival with the addition of ribociclib to either fulvestrant or exemestane in patients whose disease progressed following first-line treatment of CDK4/6 inhibition (predominantly palbociclib).19 In contrast, neither the PACE21 nor the PALMIRA20 trial demonstrated a benefit for the addition of palbociclib to endocrine therapy in patients who were treated with a CDK4/6 inhibitor (predominantly palbociclib) in the first-line setting. Taken together, continuing the same CDK4/6 inhibitor through disease progression does not appear to be effective—but switching to a different CDK4/6 inhibitor may be an option in select patients.
Sacituzumab govitecan-hziy, an antibody-drug conjugate that targets TROP-2, was found to prolong progression-free and overall survival in patients with pretreated hormone receptor–positive metastatic breast cancer in the TROPiCS-02 study.22 Likewise, fam-trastuzumab deruxtecan-nxki (T-DXd), an antibody-drug conjugate targeting HER2, improved outcomes for patients with HER2-low, hormone receptor–positive metastatic breast cancer. The DESTINY-Breast03 trial demonstrated the superiority of T-DXd over ado-trastuzumab emtansine in the second-line setting for patients with HER2-positive metastatic breast cancer.23 Antibody-drug conjugates will likely replace standard chemotherapy within the next 5-years as a “targeted” approach to delivering chemotherapeutics.
DISCLOSURE: Dr. O’Regan has received honoraria from AstraZeneca/MedImmune, bioTheranostics, Genentech, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, Puma Biotechnology, and Seagen; has served as a consultant or advisor for AstraZeneca/MedImmune, bioTheranostics, Genentech, Immunogenics, Lilly, MacroGenics, Novartis, Puma Biotechnology, and Seagen; and has received research funding from Novartis and Puma Biotechnology.
REFERENCES
1. Kalinsky K, Barlow WE, Gralow JR, et al: 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 385:2336-2347, 2021.
2. Sparano JA, Gray RJ, Makower DF, et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018.
3. Francis PA, Fleming GF, Lang I, et al: Adjuvant endocrine therapy in premenopausal breast cancer: 12-year results from SOFT. J Clin Oncol 41:1370-1375, 2023.
4. Pagani O, Walley BA, Fleming GF, et al: Long-term follow-up of the combined TEXT and SOFT trials. J Clin Oncol 41:1376-1382, 2023.
5. Gray RG, Bradley R, Braybrooke J, et al: Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 premenopausal women in 25 randomized trials. 2023 ASCO Annual Meeting. Abstract 503. Presented June 2, 2023.
6. O’Regan R, Zhang Y, Fleming GF, et al: Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS1-06. Presented December 6, 2022.
7. Partridge AH, Niman SM, Ruggeri M, et al: Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med 388:1645-1656, 2023.
8. 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 24:77-90, 2023.
9. Slamon DJ, Stroyakovskiy D, Yardley DA, et al: Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2– early breast cancer. 2023 ASCO Annual Meeting. Abstract LBA500. Presented June 2, 2023.
10. Hortobagyi GN, Stemmer SM, Burris HA, et al: Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 386:942-950, 2022.
11. Goetz MP, Toi M, Huober J, et al: MONARCH 3: Interim overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor in patients with HR+, HER2– advanced breast cancer. ESMO Congress 2022. Abstract LBA15. Presented September 9, 2022.
12. Sonke GS, Van Ommen-Nijhof A, Wortelboer N, et al: Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 inhibitors for patients with hormone receptor-positive, HER2-negative advanced breast cancer. 2023 ASCO Annual Meeting. Abstract LBA1000. Presented June 5, 2023.
13. Andre F, Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.
14. Andre F, Ciruelos EM, Juric D, et al: Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1. Ann Oncol 32:208-217, 2021.
15. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol 22:489-498, 2021.
16. Turner NC, Oliveira M, Howell SJ, et al: Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med 388:2058-2070, 2023.
17. Bidard FC, Kaklamani VG, Neven P, et al: Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 40:3246-3256, 2022.
18. Kaklamani V, Bidard FC, Neven P, et al: EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2– metastatic breast cancer: Updated results by duration of prior CDK4/6 inhibitor in metastatic setting. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 8, 2022.
19. Kalinsky K, Accordino MK, Chiuzan C, et al: Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol 41:4004-4012, 2023.
20. Llombart-Cussac A, Harper-Wynne C, Perello A, et al: Second-line endocrine therapy with or without palbociclib maintenance in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: PALMIRA trial. 2023 ASCO Annual Meeting. Abstract 1001. Presented June 2, 2023.
21. Mayer EL, Ren Y, Wagle N, et al: Palbociclib after CDK4/6 inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pretreated ER+/HER2– metastatic breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-06. Presented December 8, 2022.
22. Tolaney SM, Bardia A, Marmé F, et al: Final overall survival analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan in patients with hormone receptor–positive/HER2-negative metastatic breast cancer. 2023 ASCO Annual Meeting. Abstract 1003. Presented June 5, 2023.
23. Hurvitz SA, Hegg R, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401:105-117, 2023.
