The 2021 San Antonio Breast Cancer Symposium (SABCS) was held on 7 – 10 December as a hybrid conference that brought together breast cancer researchers, oncologists, and patient advocates with the goal of learning and discussing the latest state-of the art treatment and new data from basic and clinical trials in breast cancer (BC). Below are snapshots from some of the trials that were presented.

• Early-Stage Hormone-Receptor Positive Breast Cancer in Premenopausal Patients  

Meta-analysis of four randomized trials
The meta-analysis included data of 7,030 pre-menopausal women with HR-positive, early-stage BC who had ovarian function suppression (OFS) or ablation and received endocrine therapy (ET) with either AI or tamoxifen in ABCSG XII, SOFT, TEXT and HOBOE randomized trials. ET was given for 3 years in ABCSG XII and 5 years in the other trials. The results showed that AIs reduced the risk of recurrence by 21% compared with tamoxifen treatment (rate ratio [RR] 0.98; P=0.0005). The median follow-up was eight years, and the main benefit was seen in the first four years after treatment initiation, with a 32% reduced risk of recurrence, which dropped to 2% between years five to nine. At 10 years, the rate of breast cancer recurrence was 14.7% with AI and 17.5% with tamoxifen. While distant recurrence was reduced with AI (RR 0.83; P=0.02), there was no difference in breast cancer mortality. Surprisingly, patients with ≥4 node-positive disease did not appear to benefit from AI treatment. Of note, patients receiving AI had a higher incidence of bone fracture than those receiving tamoxifen (5.0% vs 3.8%)

Updated analysis of the combined SOFT plus TEXT trials
After a median follow-up of 12 – 13 years, the reduction in the risk of recurrence with 5-year of adjuvant exemestane plus OFS (E+OFS) remained sustained compared with tamoxifen plus OFS (T+OFS). The 12-year disease-free survival rate was 80.5% vs 75.9%, respectively (hazard ratio, HR 0.79); 12-year invasive breast cancer-free interval was improved by 4.1%, and 12-year distant recurrence-free interval improved by 1.8%. At 12 years, overall survival (OS) was high in both groups at 90.1% for patients treated with E+OFS and 89.1% in patients receiving T+OFS. Interestingly, for patients with low clinical/pathologic features who did not require chemotherapy, the longer follow up from SOFT trial continues to support the use of tamoxifen alone.

• Metastatic Hormone Receptor-Positive Breast Cancer

Updated results of the phase 3 EMERALD trial of elacestrant, first oral estrogen receptor degrader (SERD)
In the EMERALD trial, 477 post-menopausal patients with estrogen receptor-positive, HER2- metastatic breast cancer (mBC) who had received 1 – 2 prior lines of endocrine therapy and ≤1 line of chemotherapy for mBC , and had prior progression on an endocrine therapy (ET) plus CDK 4/6 inhibitor, were randomized to receive either elacestrant or investigator’s choice of standard of care (SOC) ET (fulvestrant or aromatase inhibitor). Patients were stratified according to ESR1 mutation status, prior fulvestrant exposure and presence of visceral disease. Elacestrant improved PFS regardless of the presence of ESR1 mutations in these heavily pretreated patients. In all patients treated with elacestrant, the risk of progression or death was reduced by 30% (HR, 0.697; P=0.0018) and by 45% in patients harboring the ESR1 mutation (HR, 0.546; P=0.0005). The 12-month PFS rate was 22.3% with elacestrant vs 9.4% with SOC ET in all patients and 26.8% vs 8.2% in patients harboring the ESR1 mutation, respectively.

Pooled analysis of the phase 3 MONALEESA-2, -3, and -7 trials according to intrinsic subtypes
In the MONALEESA-2, -3, and -7 trials, ribociclib plus ET demonstrated a significant benefit in OS compared with placebo for patients with HR+/HER2- advanced breast cancer. In the pooled analysis of the MONALEESA-2, -3, and -7 trials, tumors underwent PAM50 molecular subtyping, and the results showed that the intrinsic breast cancer subtype was prognostic for OS in both the ribociclib and placebo arms (P < 0.0001); patients with luminal A subtype had the best OS outcomes in both the ribociclib and placebo arms, whereas patients with basal-like subtype had the worst OS outcomes. Intrinsic subtype was also predictive of OS with a consistent OS benefit with ribociclib treatment in all subtypes (luminal A, luminal B and HER-2-enriched) except for basal-like.

• Immunotherapy in Triple Negative Breast Cancer (TNBC)
  

Early stage TNBC – Updated results from KEYNOTE-522
The primary analysis of the phase 3 KEYNOTE-522 trial of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy alone in patients with early stage TNBC showed a statistically significant and clinically meaningful improvement in event-free survival (EFS) with pembrolizumab treatment. An updated analysis demonstrated that the treatment benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was robust and consistent across five prespecified EFS sensitivity analyses, and prespecified patient subgroups. The US Food and Drug Administration recently approved the combination for patients with high-risk, early stage TNBC and these updated results further support the regimen in this patient population.

Metastatic TNBC – Final results from KEYNOTE-355
The phase 3 KEYNOTE-355 trial evaluated pembrolizumab combined with chemotherapy vs placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC. The primary results showed statistically significant improvements in OS and PFS with pembrolizumab treatment in patients whose tumors expressed PD-L1 with a combined positive score (CPS) of ≥10. The final analysis of outcomes in subgroups of patients according to CPS cut-offs demonstrated that in the group with CPS 1 – 9, the efficacy of pembrolizumab was comparable with that of placebo (plus chemotherapy), whereas for CPS 10 – 19 and CPS ≥20, there was a similar treatment benefit with the addition of pembrolizumab. Results for PFS were generally consistent with OS. The results reinforce CPS ≥10 as a reasonable cut-off to select patients with metastatic TNBC who may be expected to derive benefit from pembrolizumab treatment.

• HER2-Positive Metastatic Breast Cancer

Subgroup analyses from DESTINY-Breast03 trial
In the phase 3 DESTINY-Breast03 trial, the efficacy and safety of trastuzumab deruxtecan (T-DXd) compared with trastuzumab emtansine (T-DM1) was evaluated in patients with HER2+ mBC previously treated with trastuzumab and taxane. The primary analysis showed that T-DXd treatment resulted in a clinically meaningful and statistically significant improvement in PFS versus TDM1. Results from exploratory analyses of efficacy and safety in patient subgroups, including hormone receptor status, prior pertuzumab treatment, prior lines of therapy, visceral disease or brain metastases at baseline, reported consistent PFS and ORR benefit with T-DXd versus T-DM1.

Updated results from the PHOEBE trial
The phase 3 PHOEBE trial evaluated the efficacy of pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2 and HER4) plus capecitabine compared with lapatinib plus capecitabine, in 267 Chinese patients with HER-2 positive mBC, previously treated with trastuzumab and taxanes. The interim analysis showed that pyrotinib/capecitabine improved PFS significantly compared with lapatinib/capecitabine. The median follow-up for the updated results was 33.2 months for the pyrotinib arm and 31.8 month for the lapatinib arm. Median OS was not reached for pyrotinib and was 26.9 months for lapatinib (HR, 0.69; P=0.019); estimated OS at 24 months was 66.6% and 58.8%, respectively. PFS was also significantly improved at 12.5 months vs 5.6 months, respectively (HR, 0.48; P<0.0001). These benefits were observed across most of the clinically relevant subgroups. The updated results endorse pyrotinib/capecitabine combination as an established treatment option for this patient population.

Updated results from the HER2CLIMB trial for HER2-positive mBC with brain metastases
In the randomized, double-blind phase II HER2CLIMB trial, tucatinib in combination with trastuzumab and capecitabine significantly prolonged PFS and OS in patients with HER2+ mBC, including patients with untreated, treated and stable, and treated and progressing brain metastases compared with the placebo/trastuzumab/capecitabine combination. Results from an exploratory efficacy analysis of tucatinib regimen in patients with brain metastases, with an additional 15.6 months of follow-up (median follow-up of 29.6 months), demonstrated a median OS of 21.6 months vs 12.5 months in all patients with brain metastases (HR, 0.6); 21.4 months vs 11.8 months in patients with untreated/treated progressing brain metastases (HR, 0.52) and 21.6 months vs 16.4 months in patients with treated stable brain metastases (HR, 0.39). The combination of tucatinib/trastuzumab/capecitabine resulted in a robust and durable prolongation of OS for all patients with HER2+ mBC and brain metastases. Additionally, the benefit of tucatinib combination treatment for CNS-PFS was shown to be consistent with the primary analysis.