Jame Abraham, MD, FACP
Among the high-quality abstract presentations at the annual San Antonio Breast Cancer Symposium (SABCS), a few always stand out as particularly meritorious. Each year, The ASCOPost asks its Senior Deputy Editor, breast cancer specialist Jame Abraham, MD, FACP, to offer his top picks for most impactful studies. Dr. Abraham is the Enterprise Chair of the Department of Hematology and Medical Oncology and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine.
Here are Dr. Abraham’s “Top Picks” from 2025 SABCS and his thoughts on their findings.
HER2CLIMB-05: Tucatinib Enhances Progression-Free Survival as First-Line Maintenance
The addition of tucatinib to trastuzumab and pertuzumab as first-line maintenance therapy significantly prolonged investigator-assessed progression-free survival in patients with HER2-positive metastatic breast cancer in the phase III HER2CLIMB-05 trial, meeting the study’s primary endpoint1, reported Erika Hamilton, MD, FASCO, of Sarah Cannon Research Institute, Nashville.
HER2CLIMB-05 was a randomized, double-blind, phase III trial of 654 patients with HER2-positive metastatic breast cancer and no evidence of disease progression after completing four to eight cycles of first-line taxane-based induction chemotherapy plus trastuzumab and pertuzumab. Patients received either tucatinib or placebo, in combination with trastuzumab plus pertuzumab or a fixed-dose combination of trastuzumab, pertuzumab, and hyaluronidase every 21 days. Endocrine therapy was permitted in patients with hormone receptor–positive tumors.
At a median follow-up of 23 months, median progression-free survival was 24.9 months with tucatinib plus trastuzumab and pertuzumab, compared with 16.3 months with trastuzumab and pertuzumab alone (hazard ratio [HR] = 0.641; P < .0001). In patients with hormone receptor–negative disease, the median increased from 12.6 to 24.9 months, representing an absolute benefit of 12.3 months (HR = 0.554; P = .002). It improved from 18.1 to 25.0 months, a 6.9-month benefit, in hormone receptor–positive disease (HR = 0.725; P = .039).
Overall survival data were immature but showed a positive trend for the tucatinib arm (HR = 0.539; P = .032). Median central nervous system (CNS) progression–free survival was not reached in either arm in the intention-to-treat population, but an exploratory analysis of patients with brain metastases at entry showed an increase from 4.3 to 8.5 months. The safety profile of tucatinib plus trastuzumab and pertuzumab was manageable and consistent with expected toxicities for this regimen.
Dr. Abraham: The standard first-line treatment of HER2-positive metastatic breast cancer typically involves induction chemotherapy (often a taxane) plus dual HER2-targeted antibody therapy with trastuzumab and pertuzumab. This is subsequently followed by maintenance trastuzumab and pertuzumab. Despite sustained disease control with this approach, disease progression is common, and many patients will never go on to receive second-line agents. There is a particular need to find agents that will be effective in the subset of patients who develop brain metastases.
The original HER2CLIMB registrational trial demonstrated that adding tucatinib to capecitabine and trastuzumab significantly prolonged both progression-free and overall survival in heavily pretreated patients, including those with brain metastases.2 This established the rationale for investigating tucatinib earlier in the treatment paradigm to further enhance initial maintenance therapy. The HER2CLIMB-05 trial demonstrated a significant progression-free survival advantage of 8.6 months with tucatinib added to trastuzumab and pertuzumab maintenance, with benefit observed across all patient subtypes and a numeric improvement in CNS progression in patients with baseline brain metastases.
The complexity comes with positioning HER2CLIMB-05’s findings alongside other first-line options, which now include the highly potent fam-trastuzumab deruxtecan-nxki (T-DXd), based on outstanding benefit shown in DESTINY-Breast09.3 T-DXd plus pertuzumab upfront is clearly a highly effective regimen, offering large progression-free survival benefit, potentially more complete responses, and possibly preventing or treating brain metastases—though it carries the risk of interstitial lung disease and chemotherapy-like side effects. In this patient subset, adding palbociclib to a regimen of endocrine therapy and trastuzumab plus pertuzumab also showed significant superiority in survival in the PATINA trial.4
Now, there is an alternative—especially in estrogen/progesterone receptor–negative patients with HER2-positive disease—the HER2CLIMB-05 tucatinib-containing regimen, so patients with HER2-positive metastatic disease have many first-line options. As the role of T-DXd continues to evolve into early stages, we also need to see how these options fit into management. Clearly, our treatment decisions are becoming more nuanced, requiring careful consideration of clinical-pathologic factors, patient comorbidities, prior treatments, and preferences.
LidERA Breast Cancer Trial: Giredestrant Improves Invasive Disease–Free Survival
Giredestrant, a next-generation oral selective estrogen receptor degrader (SERD) and full antagonist, appeared to significantly improve invasive disease–free survival as adjuvant treatment for patients with estrogen receptor–positive, HER2-negative early breast cancer compared with standard-of-care endocrine therapy in the global, randomized phase III lidERA Breast Cancer trial.5 The findings are the first from a phase III study to show a benefit with an oral SERD in the adjuvant setting and position giredestrant as a potential new standard of care, said Aditya Bardia, MD, MPH, FASCO, of the University of California at Los Angeles (UCLA) Jonsson Comprehensive Cancer Center.
The lidERA Breast Cancer study randomly assigned 4,170 patients with stage I to III estrogen receptor–positive, HER2-negative early breast cancer to receive either giredestrant (with a luteinizing hormone-releasing hormone [LHRH] agonist for pre- and perimenopausal women and men) or standard endocrine therapy (tamoxifen or an aromatase inhibitor) for 5 years. Premenopausal patients also underwent ovarian function suppression. In the standard endocrine therapy arm, 84% received an aromatase inhibitor and 16% received tamoxifen.
At a median follow-up of 32.3 months, giredestrant reduced the risk of invasive recurrence or death by 30% (HR = 0.70; P = .0014). The 3-year invasive disease–free survival rates were 92.4% with giredestrant vs 89.6% with standard endocrine therapy. The superiority of giredestrant appeared consistent across all predefined subgroups. In addition, giredestrant demonstrated superiority in distant recurrence–free interval (HR = 0.69) and showed a positive overall survival trend (HR = 0.79) with immature follow-up.
The overall incidences of adverse events and grade 3 to 4 adverse events were found to be comparable between treatment arms. Of note, the discontinuation rate due to adverse events was lower with giredestrant (5.3%) compared with standard endocrine therapy (8.2%).
Dr. Abraham: Despite the efficacy of adjuvant endocrine therapy for estrogen receptor–positive breast cancer, up to one-third of patients will experience a recurrence. Aromatase inhibitors and, more recently, CDK4/6 inhibitors have improved outcomes but have also introduced toxicities that can lead to treatment discontinuation for many patients (up to 20%–30%), increasing their risk of recurrence. The need for more effective, better tolerated adjuvant endocrine therapies continues.
Giredestrant is a potent, next-generation oral SERD designed to induce full estrogen receptor antagonism and degradation. Because of its mechanistic advantages over aromatase inhibitors, it has been shown to be more potent and to have superior antiproliferative activity compared with standard endocrine therapies and other SERDs.
Giredestrant was the subject of what is probably the most impactful news at the meeting. The lidERA Breast Cancer trial provided the first positive data for an oral SERD in the adjuvant setting. In fact, these pivotal findings represent the first real advancement in endocrine therapy for early estrogen receptor–positive breast cancer in 20 or so years. The findings came from a well-designed study that included high-risk stage I patients and many node-positive patients, mandated ovarian function suppression in premenopausal patients, and allowed prior, short-term CDK4/6 inhibition before study entry but not during the study.
The invasive disease–free survival and distant recurrence–free interval data were promising, as there were early and sustained separations of the Kaplan-Meier curves. The absolute invasive disease–free survival difference of 2.8% at around 3 years seems small but is likely to grow with additional follow-up. Also reassuring was giredestrant’s tolerability, especially the low rate of discontinuation due to musculoskeletal symptoms.
However, the study does raise some questions for us in clinical practice, particularly regarding the use of CDK4/6 inhibitors that we now routinely include. The magnitude of benefit with CDK4/6 inhibitors, in fact, may be a bit bigger than we saw with giredestrant, and their supporting data are based on longer follow-up. Since giredestrant was not studied in conjunction with CDK4/6 inhibitors, one might favor using giredestrant in patients who are not receiving a CDK4/6 inhibitor. For patients in whom a CDK4/6 inhibitor is appropriate, one might also consider starting with an aromatase inhibitor plus a CDK4/6 inhibitor and then switching after 2 or so years to giredestrant, although this sequence has not been tested.
The lidERA Breast Cancer trial is a prelude to what should be a very interesting next few years in the adjuvant treatment of estrogen receptor–positive breast cancer. Many trials of oral SERDs are in progress, some incorporating CDK4/6 inhibitors and some evaluating sequencing of therapies.
EMBER-3: Imlunestrant Improves Overall Survival in Estrogen Receptor–Positive, HER2-Negative Advanced Disease
Updated analysis of the phase III EMBER-3 study validated the SERD imlunestrant as monotherapy or in combination with the CDK4/6 inhibitor abemaciclib, as an all-oral chemotherapy-free option after disease progression on endocrine therapy for patients with estrogen receptor–positive, HER2-negative advanced breast cancer, especially those with ESR1mutations.6 The U.S. Food and Drug Administration has approved single-agent imlunestrant for the treatment of patients with estrogen receptor–positive, HER2-negative ESR1-mutated advanced breast cancer with disease progression following at least one line of endocrine therapy.
The study randomly assigned 874 patients to imlunestrant monotherapy, imlunestrant plus abemaciclib, or the investigator’s choice of endocrine therapy (exemestane or fulvestrant). With an additional 14 months of follow-up since the primary analysis, at a median follow-up of 28.5 months (and 50% maturity for overall survival), a clinically meaningful overall survival improvement was observed in patients with ESR1 mutations who received imlunestrant. In that population, median overall survival in the imlunestrant monotherapy cohort was 34.5 months vs 23.1 months in the control group (HR = 0.60; P = .0043) although the boundary for significance was not achieved.
Median progression-free survival was 5.5 months in the imlunestrant cohort vs 3.8 months with the standard of care (HR = 0.62; P = .0007), which reached significance in the primary analysis. At 1 year, 26% vs 7% of the arms, respectively, were progression-free. Single-agent imlunestrant also delayed the time to chemotherapy in patients with ESR1 mutations, which was 15.6 months vs 10.2 months with standard therapy (HR = 0.66), reported Komal Jhaveri, MD, FACP, FASCO, of Memorial Sloan Kettering Cancer Center, New York.
For the combination of imlunestrant plus abemaciclib vs imlunestrant alone, among all patients, the median progression-free survival was 10.9 vs 5.5 months (HR = 0.59; P < .0001), with benefit maintained regardless of ESR1 mutation status. In the ESR1-mutated subset, the medians were 11.1 vs 5.5 months (HR = 0.49; P = .0002), and in those with both ESR1 and PI3K pathway mutations, medians were 12.0 vs 5.5 months, respectively (HR = 0.48; P = .0022). Patients previously treated with a CDK4/6 inhibitor also benefited from the combination, with median progression-free survival of 9.1 vs 3.7 months, respectively (HR = 0.53; P < .0001).
The global EMBER-4 trial has accrued approximately 8,000 patients with early breast cancer who received 2 to 5 years of adjuvant endocrine therapy with or without a CDK4/6 inhibitor and who are at increased risk of recurrence. Patients are randomly assigned to single-agent imlunestrant or to an aromatase inhibitor or tamoxifen.
Dr. Abraham: The discovery of the ESR1 mutation spurred the development of multiple oral SERDs that fully inhibit and degrade both the mutant as well as the wild-type estrogen receptor. In EMERALD, the first phase III study of an oral SERD, elacestrant was superior to standard endocrine therapy in patients with ESR1 mutations but not in those without this mutation.7 In the primary analysis of EMBER-3, we saw the same pattern: imlunestrant was clearly superior to standard endocrine therapy in the presence of ESR1 mutations, but not in all patients, which made the coprimary endpoint negative. Now we have the updated progression-free survival analysis, which was very consistent. And we’ve seen updated interim overall survival where there is clear separation of the curves (HR = 0.6) and a numerical improvement, but lacking sufficient power for an overall survival analysis, the study is unlikely to show a statistically significant benefit.
For the second randomization, imlunestrant plus abemaciclib vs single-agent imlunestrant, we saw an improvement in progression-free survival in patients overall (HR = 0.59) as well as in ESR1-mutated patients (HR = 0.49). With no significant overall survival benefit shown for the combination of imlunestrant and abemaciclib, EMBER-3 provided no evidence that continuing CDK4/6 inhibition beyond disease progression improves overall survival, though these data are not mature.
The study adds information to our clinical questions:
- Does targeting ESR1 mutations with an oral SERD improve overall survival? It seems so. EMBER-3 joins two other registration trials showing clear separation of the survival curves with these endocrine agents.
- Which patients should we treat with oral SERD monotherapy? Multiple studies have now shown that single-agent endocrine therapy is not particularly active after CDK4/6 inhibitors, and, unfortunately, we are also seeing that with oral SERDs. By combining the SERD with a targeted agent for patients with ESR1 mutations, however, we can greatly reduce the risk of this early disease progression; therefore, for most patients with ESR1 mutations, a combination of a SERD and targeted agent is likely to become the new standard of care. As for which agent and which combination, we need clinical trials to sift this out.
- When should we initiate treatment for patients with ESR1 mutations? At documented tumor progression? That is the established standard. Or should we perhaps implement oral SERDs as first-line therapy, instead of aromatase inhibitors, which theoretically might prevent ESR1 mutations from developing? This is an important question, but we need more data before acting on it.
WISDOM 1.0: Thumbs Up for a Personalized Screening Approach
A personalized breast cancer screening approach based on individual risk, rather than age alone, can reduce the incidence of advanced cancers while ensuring appropriate screening frequency, according to results of the WISDOM 1.0 study.8 It is testing the noninferiority of risk-based vs annual screening for the primary outcome of stage IIB or higher breast cancer and asking whether a risk-based approach is safe, less morbid, and as acceptable as mammography to women, said Laura Esserman, MD, MBA, FASCO, of the University of California, San Francisco.
The conclusion, based on findings in 23,373 U.S. participants, was that risk-based screening that includes population-based genetic testing safely stratifies risk and screening intensity without compromising the detection of stage IIB or higher cancers.
Women aged 40 to 74 years with no prior diagnoses of ductal carcinoma in situ and no prophylactic bilateral mastectomy were stratified into four groups based on their age, breast cancer genetics, lifestyle, health history, and breast density, using well validated risk models, and were randomly assigned to one of the two screening approaches. Women in the lowest risk category (26% of the cohort) initiated screening at age 50 or when an algorithm predicted their risk would meet the level of a 50-year-old. Those with average risk (62%) were told to screen every 2 years. Women with more elevated risk (8%) underwent annual mammography, while those at the very highest risk (2%) underwent biennial screening, alternating between mammography and MRI; these groups also received personalized recommendations on breast cancer risk reduction.
The number of cancers in each of the arms was about the same—260 in the risk-based arm and 263 in the annual arm—and in each approach they were stratified by risk. These included, respectively, 132 and 121 stage I cancers; 36 and 43 stage IIA cancers; 15 and 17 stage IIB cancers; 5 and 13 stage III cancers; 1 and 1 stage IV cancers; and 12 and 9 with stage unknown. The rates of stage IIB or higher cancers per 100,000 person-years were 20 with risk-based screening and 48 with annual screening, representing a noninferior rate difference. Mammograms were performed less often in the risk-based arm, but there was no decrease in biopsy rates.
Of note, the study showed that 30% of women found to harbor a genetic variant associated with breast cancer risk did not report a family history of breast cancer and, therefore, would not normally have been referred for genetic testing. Use of a polygenic risk score refined the prediction algorithm and shifted 12% to 14% of participants to a different level of risk.
WISDOM 2.0 is enrolling women aged 30 to 74 years and is designed to identify younger women at high risk and improve prediction of fast and slow growing cancers using genetics and mammographic artificial intelligence (AI).
Dr. Abraham: The results support shifting to a model that entails a comprehensive risk assessment and personalized screening schedule. As Dr. Esserman asked in her presentation, can we afford new screening approaches? Fortunately, it turns out that concentrating more resources on patients at highest risk is cost-effective. The U.S. spends about $13 billion on screening per year, she indicated. And she has estimated that among four sets of screening guidelines—those of the American College of Radiology (ACR), American Cancer Society, U.S. Preventive Services Task Force, and the risk-based approach of WISDOM 1.0—the WISDOM 1.0 model is the most cost-effective. Its national annual cost is about $7 billion. The costliest screening approach is the ACR’s, at around $30 billion, because it recommends supplemental imaging (ie, MRI) for women with dense breasts. In the WISDOM 1.0 study, MRI was recommended only for 2% of the population.
Dr. Esserman described the impact on the country in these terms: In 2025, almost 320,000 new cases of breast cancer were diagnosed. If one-third could be detected at stage IIB or lower (where there is the sharpest demarcation in log hazard for death), 5,000 breast cancer deaths might be avoided at a lower projected cost and lower screening burden for women at lower risk. This accounts for about 54 million of the 60 or so million women of screening age, probably about one-third of whom don’t need to be screened until age 50.
This is the basis upon which Dr. Esserman and her team recommend that risk-based screening should become the new standard of care, though she acknowledged the need for a national screening program to track the results. I certainly agree. And I believe that their “slogan,” so to speak, makes sense and is in line with our overall approach to cancer management: “More for those that need it, less for those who do not.”
Preoperative MRI Does Not Change Oncologic Outcomes in Early Breast Cancer
A study evaluating the utility of using preoperative breast MRI for surgical planning in early hormone receptor–negative breast cancer failed to show an improvement in local-regional control, distant recurrence, and overall survival.9 In a population enriched for higher-risk patients, the 5-year rate of local-regional recurrence in triple-negative and estrogen receptor/progesterone receptor–negative, HER2-positive patients was less than 7%. There was no indication of benefit to breast MRI, based on age and tumor subtype, according to Isabelle Bedrosian, MD, FACS, of the University of Texas MD Anderson Cancer Center, Houston.
The study enrolled 319 patients from 73 sites with newly diagnosed, stage I to II hormone receptor–negative, HER2-positive or -negative, BRCA wild-type tumors. All were eligible for breast-conserving surgery, and multifocal disease had to be encompassed in a single resection. The protocol was amended to allow neoadjuvant treatment, after which breast-conserving eligibility was assessed. Patients were randomly assigned to MRI (followed by breast-conserving surgery or mastectomy) or no MRI (followed by breast-conserving surgery). Management of MRI-detected disease was evaluated according to whether it impacted plans for breast-conserving surgery vs mastectomy and whether biopsy was performed.
Oncologic outcomes were found to be comparable, whether patients underwent MRI or not. For MRI vs no MRI, the primary endpoint of 5-year local-regional recurrence rate was 93.2% vs 95.7% (P = .8326); local-regional recurrence rate after breast-conserving surgery was 94.3% vs 95.4% (P = .9268); overall 5-year distant recurrence–free rate was 94.3% in both arms (P = .9894); and overall 5-year overall survival rate was 92.2% in both arms (P = .8297). There appeared to be no significant differences by estrogen receptor status, HER2 status, or age.
The authors concluded, “In the context of systemic therapy [which most patients received] and radiation therapy, surgical resection of MRI-detected disease may not be necessary. Advances in mammographic imaging and widespread use of ultrasound [97%] may have limited the utility of MRI for local staging.”
Dr. Abraham: Breast MRI is often used for preoperative evaluation of local disease extent and surgical planning, though there has been no consensus around its optimal use. Studies have consistently shown it to be more sensitive than mammography for detecting disease, and it often impacts surgical management, frequently converting patients from lumpectomy to mastectomy. But data have been limited as to whether this additional disease detection and its resulting surgery improve long-term local-regional control, and most of the data have been retrospective. The prospective study by Dr. Bedrosian and colleagues, therefore, provides useful information.
These data are consistent with the theme of 2025’s SABCS: that doing more is not always the right thing for our patients. So, we need to be mindful of making the blanket recommendation that our patients undergoing neoadjuvant therapy have an MRI of the breast, without factoring in clinical and existing radiologic data.
But to add a cautionary note, as pointed out by the study’s invited discussant Bruce Mann, MBBS, PhD, FRACS, of the University of Melbourne, Australia, the study accrued half its target size and was probably underpowered to show a difference in local-regional recurrence according to the expected recurrence rate of about 5% with modern treatment. Also, several factors point to some differences between the arms that could reflect selection bias against the MRI group. Dr. Mann also stated that preoperative MRI might identify patients with truly localized disease in whom local ablation is curative, those who might benefit from partial breast irradiation, those who might safely omit radiotherapy altogether, and those who might need additional treatment for occult malignancy. Finally, it would be helpful to have more information about MRI quality assurance and MRI findings. The authors have indicated more findings from the study are forthcoming, and we look forward to this.
DISCLOSURE: Dr. Abraham has served on an advisory board for ThinkBio.Ai. For full disclosures of the study authors, visit sabcs.org.
REFERENCES
1. Hamilton E, Curigliano G, Martin M, et al: Her2climb-05: A randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic breast cancer. SABCS 2025. Abstract GS1-01. Presented December 10, 2025.
2. Curigliano G, Mueller V, Borges V, et al: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): Final overall survival analysis. Ann Oncol 33:321-329, 2022.
3. Tolaney SM, Jiang Z, Zhang Q, et al: Trastuzumab deruxtecan + pertuzumab vs taxane + trastuzumab + pertuzumab for first-line treatment of patients with human epidermal growth factor receptor 2–positive advanced/metastatic breast cancer: Interim results from DESTINY-Breast09. J Clin Oncol 43:LBA1008, 2025.
4. Metzger O, Mandrekar S, Goel S, et al: Palbociclib for hormone-receptor–positive, HER2-positive advanced breast cancer. N Engl J Med 394:451-462, 2026.
5. Bardia A, Schmid P, Martín M, et al: Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: Results from the global phase III lidERA Breast Cancer trial. SABCS 2025. Abstract GS1-10. Presented December 10, 2025.
6. Jhaveri KL, Neven P, Casalnuovo M, et al: Imlunestrant with or without abemaciclib in advanced breast cancer: Updated efficacy results from the phase 3 EMBER-3 trial. SABCS 2025. Abstract GS3-08. Presented December 12, 2025.
7. Bidard F-C, 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.
8. Esserman LJ, Fiscalini AS, Naeim A, et al: Risk-based breast cancer screening is safe, preferred by women and identifies highest risk individuals: Results from WISDOM 1.0. 2025 SABCS. Abstract GS3-07. Presented December 12, 2025.
9. Bedrosian I, Ballman K, McCall LM, et al: Effect of preoperative breast MRI staging on local regional recurrence in early stage breast cancer: Alliance A011104/ACRIN 6694. 2025 SABCS. Abstract GS2-07. Presented December 11, 2025.
