In its first return to a hybrid model since the COVID-19 pandemic began, the 2021 San Antonio Breast Cancer Symposium (SABCS) brought together researchers, clinicians, industry experts, patients, and advocates from across the globe to present and grapple with new data and important topics in breast cancer treatment. Breast cancer research has continued to progress, and the community is working hard to bring new developments to patients as quickly as possible despite challenging circumstances. With that in mind, we will discuss a few of the important, practice-informing studies presented in San Antonio.
Antibody-Drug Conjugates in Metastatic Breast Cancer
Antibody-drug conjugates are a rapidly expanding and promising new therapeutic class, with dozens of trials ongoing in various breast cancer clinical contexts, some showing dramatic benefits for patients. At the 2021 conference, important subgroup analyses from the phase III DESTINY-Breast03 trial were presented,1 which randomly assigned patients with treatment-refractory metastatic HER2-positive breast cancer to one of two HER2-targeted antibody-drug conjugates: fam-trastuzumab deruxtecan-nxki (T-DXd) vs ado-trastuzumab emtansine (T-DM1). A special focus was placed on the previously unreported subset of patients with stable brain metastases at baseline, in whom the intracranial response rate was 63.9% with T-DXd and 33.4% with T-DM1. Clinically meaningful improvements in progression-free survival with T-DXd over T-DM1 were consistently reported across many important prognostic signifiers, including hormone receptor status, prior pertuzumab treatment, visceral disease, and number of prior therapies. These results have important implications for the sequencing of HER2-targeted therapies in advanced HER2-positive breast cancer and underscore the observation that two antibody-drug conjugates with the same target can have markedly different clinical properties.
Guest Editors
Joshua Drago, MD
Shanu Modi, MD
Dr. Drago is a medical oncologist and Assistant Attending Physician in the Breast Medicine Service at Memorial Sloan Kettering Cancer Center. He specializes in caring for patients with breast cancer. Dr. Modi is Associate Professor of Medicine in the Department of Medicine at Weill Cornell Medical College and Associate Member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center. Her research is focused on the clinical development of new therapies for treatment of breast cancer, particularly targeted biologic anticancer agents.
Early results were also presented regarding the activity of the trophoblast cell surface antigen-2 (TROP-2)–targeted antibody-drug conugate datopotamab deruxtecan in metastatic triple-negative breast cancer, another area of unmet clinical need.2 For patients with triple-negative breast cancer in the multiarm phase I TROPION-PanTumor01 study (n = 44), an overall response rate of 34% was observed in heavily pretreated patients. When restricted to those who had never received a prior antibody-drug conjugate with topoisomerase 1 inhibitor payload, the overall response rate was 52%. Nausea, stomatitis, and vomiting were the three most commonly observed toxicities, and no cases of interstitial lung disease were adjudicated, despite the use of a similar linker/payload construct to T-DXd. We are just beginning to understand how antibody-drug conjugate construction manifests clinically and expect to learn much more about this topic in the coming years.
Refining Our Use of Immunotherapy
The discovery that some triple-negative breast cancers are responsive to immunotherapy was a major advancement, first shown in metastatic disease and now proven in the curative setting. At the 2021 meeting, sensitivity and subset analyses of the randomized phase III KEYNOTE-522 study confirmed the long-term event-free survival benefit of pembrolizumab when added to neoadjuvant polychemotherapy for stage stage II or III triple-negative breast cancer, now considered the new standard of care.3 In the metastatic setting, the final results of the randomized phase III KEYNOTE-355 study were presented, which confirmed that progression-free survival and overall survival benefits of pembrolizumab when added to chemotherapy were largely limited to the subgroup of patients with a PD-L1 combined positive score of ≥ 10, supporting the use of this biomarker cutoff as a selection factor for pembrolizumab in this setting.4
In search of other populations that might benefit from immunotherapy, the phase II NIMBUS trial investigated dual checkpoint blockade with ipilimumab and nivolumab in patients with metastatic hypermutated HER2-negative breast cancer (defined as a tumor mutational burden [TMB] of ≥ 9 mutations per megabase).5 Among the 30 included patients, the overall response rate was 16.7%, which included some patients with hormone receptor–positive disease. Although other studies have also shown that a subset of patients with breast cancer and a high TMB may benefit from immunotherapy, comparative studies are lacking, and the optimal cutoff for benefit is not yet known.
Developments in the Adjuvant Treatment of Hormone Receptor–Positive Breast Cancer
Curative-intent treatment of hormone receptor–positive breast cancer is becoming ever more complex as data emerge to help us try and balance therapy toxicity with long-term benefits. At the 2021 meeting, we heard an updated analysis of the RxPONDER trial, which investigated the use of the Oncotype DX recurrence score (RS) in patients with early-stage hormone receptor–positive, HER2-negative breast cancer with one to three lymph nodes involved.6 This updated report confirmed that although postmenopausal woman in this population with RS scores ≤ 25 did not benefit from chemotherapy, premenopausal women (including those with micrometastatic nodal disease alone) did benefit. Although efforts were made to disentangle the contribution of ovarian suppression to this finding (either secondary to chemotherapy or given pharmacologically), firm conclusions could not be made, and future trials are needed to answer this question definitively.
We also heard an update on the practice-changing SOFT/TEXT trials, launched nearly 2 decades ago to shed light on the optimal adjuvant antiestrogen therapy for premenopausal women with hormone receptor–positive breast cancer.7 Findings after 12 to 13 years of median follow-up suggest a meaningful reduction in distant relapse or death for high-risk patients who received ovarian suppression with endocrine therapy vs tamoxifen alone. A meta-analysis of individual patient data (n = 7,030), which included SOFT/TEXT plus the ABCSG 12 and HOBOE trials, confirmed that using an aromatase inhibitor as opposed to tamoxifen along with ovarian suppression resulted in a significant decrease in the distant recurrence rate.8 However, no difference in breast cancer mortality or overall survival was observed, and more fractures occurred in patients receiving aromatase inhibitors. Shared decision-making and cost-benefit analysis remain crucial tools to apply these findings in practice.
Two well-justified large-scale adjuvant studies also highlighted treatments ultimately found not to benefit patients. First, final results were presented for the PALLAS trial, in which more than 5,000 patients with stage II to III hormone receptor–positive breast cancer were randomly assigned to adjuvant palbociclib with endocrine therapy vs endocrine therapy alone.9 Approximately 45% of patients discontinued palbociclib before the recommended 2-year course, and no difference in invasive disease–free survival was observed in the overall population or in any clinicopathologic subgroup. The phase III CCTG MA.32 trial demonstrated that taking metformin for 5 years did not add anything to standard therapy in the adjuvant treatment of early-stage breast cancer.10
Selective Estrogen Receptor Degraders in Clinical Practice
The much-anticipated results from the first randomized phase III trial investigating an oral selective estrogen receptor degrader (SERD) were presented. The EMERALD trial compared elacestrant against investigators’ choice of endocrine therapy in refractory metastatic hormone receptor–positive breast cancer, with a primary endpoint of progression-free survival in all-comers and in those with ESR1 mutations.11 In the intention-to-treat population, progression-free survival with elacestrant was 2.8 months vs 1.9 months with the standard of care (P = .0018); in patients with ESR1 mutations, progression-free survival was 3.8 months with elacestrant vs 1.9 months with the standard of care (P = .0005). No difference in overall survival was observed in the presented interim analysis.
To prospectively evaluate the performance of SERDs vs aromatase inhibitors in patients with ESR1 mutations, the novel design of the PADA-1 trial randomly assigned patients receiving an aromatase inhibitor plus palbociclib to continue current therapy vs switch to fulvestrant plus palbociclib at the time when a rising ESR1 mutation could be detected in circulating tumor DNA.12 Median progression-free survival after randomization was 5.7 months in the standard-therapy arm vs 11.9 months in the fulvestrant arm (hazard ratio = 0.61, P = .005). These findings underlined the superiority of SERDs over aromatase inhibitors in patients with ESR1 mutations and raised compelling questions about longitudinally monitoring circulating tumor DNA in metastatic breast cancer. Longer follow-up and overall survival results will be important in fully evaluating the potential benefits of this proactive approach.
In conclusion, the 2021 SABCS brought exciting clinical developments across therapeutic modalities, breast cancer disease subtypes, and treatment contexts. Continuing efforts are underway to pair high-potential treatments such as immunotherapies, antibody-drug conjugates, and novel antiestrogen drugs with the patients who are most likely to benefit from them.
DISCLOSURE: Dr. Drago has served as a consultant or advisor to Intellisphere LLC and Biotheranostics; has served on speakers bureaus for Virology Education; and has received research funding from AstraZeneca. Dr. Modi has served as a consultant or advisor to MacroGenics, Daiichi Sankyo, AstraZeneca, and Seattle Genetics; has served on speakers bureaus for Genentech, Daiichi Sankyo, AstraZeneca, and Seattle Genetics; and has received research funding from Genentech, Daiichi Sankyo, AstraZeneca, and Seattle Genetics.
REFERENCES
1. Hurvitz S, Kim SB, Chung WP, et al: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: Subgroup analysis from the randomized phase 3 study DESTINY-Breast03. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 9, 2021.
2. Krop I, Juric D, Shimizu T, et al: Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: Triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 7, 2021.
3. Schmid P, Cortes J, Dent R, et al: KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 7, 2021.
4. Cortés J, Cescon DW, Rugo HS, et al: Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 7, 2021.
5. Barroso-Sousa R, Li T, Reddy S, et al: Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated HER2-negative metastatic breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-10. Presented December 8, 2021.
6. Kalinsky KM, Barlow WE, Gralow JR, et al: Distant-disease free interval in participants with 1-3 positive lymph nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence score ≤ 25 randomized to endocrine therapy +/- chemotherapy: SWOG S1007 (RxPONDER). 2021 San Antonio Breast Cancer Symposium. Abstract GS2-07. Presented December 8, 2021.
7. 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. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-05. Presented December 8, 2021.
8. Bradley R, Braybrooke J, Gray R, et al: Aromatase inhibitors versus tamoxifen in premenopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised trials. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-04. Presented December 8, 2021.
9. Gnant M, Dueck CC, 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. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 7, 2021.
10. Goodwin PJ, Chen BE, Gelmon KA, et al: CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin vs placebo in early breast cancer: Results of the primary efficacy analysis. 2021 San Antonio Breast Cancer Symposium.Abstract GS1-08. Presented December 7, 2021.
11. Bardia A, Neven P, Streich G, et al: Elacestrant, an oral selective estrogen receptor degrader vs investigator’s choice of endocrine monotherapy for ER+/HER2– advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-02. Presented December 8, 2021.
12. Bidard FC, Hardy-Bessard AC, Bachelot T, et al: Fulvestrant-palbociclib vs continuing AI-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2– metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-05. Presented December 9, 2021.
