The annual 2024 San Antonio Breast Cancer Symposium (SABCS) brings together breast cancer providers from around the globe to advance the care of individuals with breast cancer. Potential practice-changing studies were presented as well as updates on previous studies.
HER2-Positive Breast Cancer
DESTINY-BREAST06
An updated analysis of the DESTINY-Breast06 was presented by Dr. Aditya Bardia. In this phase 3 randomized trial, patients with hormone-receptor positive (HR+), HER2-low or ultralow, chemotherapy naïve metastatic breast cancer (MBC) were randomized to trastuzumab deruxtecan (T-DXd) or physicians’ choice (TPC) of systemic therapy (capecitabine, nab-paclitaxel, paclitaxel) following progression on endocrine therapy (ET). This analysis reported on the efficacy of subsequent therapies post progression on T-DXd/TPC or progression-free survival two (PFS2—time from randomization to second progression or death). T-DXd demonstrated a clinically meaningful benefit (mPFS 12.9-14.0 months versus TPC 6.5-8.2 months) regardless of time to progression on first-line therapy with ET and CDK 4/6 inhibitors. PFS2 favored T-DXd over TPC in the overall population (mPFS 20.3 months with T-DXd) and in all time to progression subgroups (mPFS 17.1-20.0 months with T-DXd), demonstrating a sustained benefit with T-DXd beyond initial disease progression. T-DXd demonstrated efficacy regardless of disease burden. T-DXd is an effective treatment option in patients with HR+/HER2- low/ultralow MBC following progression on ET and should be considered as a first-line chemotherapy option given these updated results.
PATINA
The CLEOPATRA regimen (docetaxel/trastuzumab/pertuzumab; THP) remains the standard of care (SOC) for individuals with HER2+ MBC in the first-line setting. Approximately 25%-30% of patients overexpress HER2 and half of HER2+ tumors co-express estrogen receptors. CDK4/6 inhibition is an established effective therapeutic option in HR+HER2- disease, however, the benefit of this approach in women with HR+/HER2+ MBC has not been established. At SABCS 2024, Dr. Otto Metzger presented the potentially practice-changing results of PATINA, a phase 3 study of patients with HR+ HER2+ MBC (n=518) who had completed six to eight cycles of trastuzumab +/- pertuzumab (97%), and a taxane or vinorelbine, randomized to maintenance trastuzumab/pertuzumab and ET +/- palbociclib (125 mg PO daily d1-21 of a 28-day cycle). The mPFS in the palbociclib-containing arm was 44.3 months versus 29.1 months in the standard-of-care (SOC) arm (HR 0.74; range 0.58,0.94), a statistically significant and clinically meaningful improvement. Overall survival data are immature. Toxicities were consistent with the known safety profile of palbociclib with more neutropenia, fatigue and stomatitis, however, there was a 11.1% incidence of grade 3 diarrhea. Palbociclib added to dual HER-2 therapy and ET may now represent a new SOC for patients diagnosed with HR+, HER2+ MBC following first-line induction therapy and emphasizes the need for more individualized systemic therapy, abandoning the “one size fits all” approach in HER2+ MBC.
Triple Negative Breast Cancer (TNBC)
OLYMPIA
Dr. Judy Garber presented the 10-year prespecified analysis of invasive disease-free survival (IDFS), distant disease-free survival (DDFS), and overall survival (OS) of the OLYMPIA trial, a randomized study of placebo versus olaparib (300 mg PO BID x 1 year) in patients with germline BRCA-1/2 mutations, stage 2 or 3 breast cancer (TNBC, ER or PR+; HER2-) after completion of (neo)adjuvant systemic therapy. The six-year IDFS was 79.6% in the olaparib arm versus 70.3% in the placebo (absolute difference 9.4%, HR 0.65: 95% CI: 0.53,0.78). A similar benefit was seen in women with both HR + and HR – breast cancer. The six-year DDFS rate was 83.5% in the olaparib arm versus 75.7% in the placebo arm (absolute difference 7.8%)(HR 0.65: 95% CI: 0.53,0.81). The six-year OS benefit was 87.5% vs 83.2% (4.4% difference) HR -0.72 (95% CI; 0.56, 0.93). There were no new safety signals. Especially notable, there was no evidence of increased risk of MDS or AML. These data support continued use of adjuvant olaparib as an SOC for patients with germline BRCA-1/2 high-risk HER2- primary breast cancer and provides reassurance that adjuvant olaparib does not pose an increased risk for MDS/AML.
Hormone-Positive/HER2-Negative Breast Cancer
EMBER-3
ET in combination with a CDK4/6 inhibitor is SOC for patients with HR+/HER2- MBC; however, patients eventually develop resistance to this approach. EMBER-3, presented by Dr. Komal Jhaveri, is a randomized phase 3 study in patients with MBC (n=874) progressing on first-line aromatase inhibitor (AI) +/- CDK 4/6 inhibitor, or recurrence on or within 12 months of completion of adjuvant AI therapy. Patients were randomized 1:1:1 to imlunestrant (an oral selective estrogen receptor degrader [SERD]) 400 mg daily, or SOC ET (exemestane or fulvestrant), or imlunestrant 400 mg daily in combination with abemacicilb 150 mg BID. The mPFS for all patients treated with imlunestrant versus SOC ET was 5.6. versus 5.5 months respectively. For patients with an ESR1 mutation, the mPFS was 5.5 months in the imlunestrant arm versus 3.8 months in the SOC arm (HR =0.62; P<0.001). In the combination arm (imlunestant/abemaciclib) versus imlunestrant alone, there was a significantly improved mPFS of 9.4 months vs 5.5 months (HR 0.57; p<0.001). Additionally, mPFS for patients with an ESR1 mutation treated with combination therapy was 11.1 versus 5.5 months in the imlunestrant arm (HR 0.53; 0.38-0.80). There was notably more toxicity in the combination arm with 86% of patients reporting all grade diarrhea (8% > grade 3). Patients discontinued therapy due to toxicity more frequently in the combination arm (6%) with less toxicity noted with single-agent imlunestrant. Imlunestrant combined with abemaciclib represents an additional oral targeted therapeutic option following progression on ET+/-CDK4/6i in patients with HR+ HER2- MBC. Single-agent imlunestrant could be considered a treatment option in patients with ESR1 mutations. Results of this study were published in NEJM on December 11, 2024 with forthcoming FDA review. Imlunestrant is not yet readily available or FDA approved at this time.
Ductal Carcinoma in Situ (DCIS)
COMET
The standard treatment for individuals diagnosed with DCIS has been surgery +/- radiation to prevent progression to invasive BC. There has been an increasing interest in re-evaluating the role of surgery and radiation in the treatment of low-risk DCIS given that DCIS does not always progress to invasive BC. Dr. Shelley Hwang presented the results of the COMET trial, a phase 3 noninferiority trial of 955 patients with newly diagnosed low-risk DCIS (> 40 years old, grade 1 or 2, HR +, no evidence of invasive BC) randomized to guideline concordant therapy (GCC) (surgery +/- radiation; ET permitted) versus active monitoring (AM) (ipsilateral breast imaging every six months; biopsy for imaging changes, ET allowed). Of note, one-third of patients did not adhere to their randomized arm; more elected for AM. Primary outcome was the two-year cumulative rate of invasive BC following randomization. The two-year cumulative rate of invasive BC was 5.9% in the GCC (95%: CI 3.71-8.04) versus 4.2% in the AM arm (95% CI: 2.31-6.00) (absolute difference 1.7 %), which met the noninferiority threshold. Dr. Ann Partridge presented patient-reported outcomes, including quality of life, anxiety, and depression, and noted no significant differences in these parameters between the two treatment approaches. These short-term results are encouraging; however, additional follow-up is needed to determine long-term outcomes, feasibility, and acceptance of this approach before being implemented as a new SOC. The results of this study were published on December 12, 2024, in JAMA.
Dr. Susan Dent is a Medical Oncologist at Duke University, with a focus on breast cancer. She is also the Associate Director of Breast Cancer Clinical Research and the Co-Director of the Duke Cardio-Oncology Program. Dr. Dent has no financial interests or conflicts of interest to report.
Dr. Moore is a Clinical Oncology Pharmacist at Duke Univeristy, with a focus on breast cancer. Her research interests include toxicity management to include alpelisib-induced hyperglycemia, ILD, and cardio-oncology. Dr. Moore has received consulting fees or honorarium from Pfizer, Novartis, AstraZeneca, Genentech, and Lilly.
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