Translating SABCS 2025: Integrating Breakthroughs in Breast Cancer Management Into Practice

SABCS 2025 reinforced the rapid migration of trastuzumab deruxtecan (T-DXd) into early-stage HER2-positive breast cancer. DESTINY-Breast11 evaluated neoadjuvant T-DXd–based strategies versus standard dose-dense anthracycline-based chemotherapy followed by paclitaxel, trastuzumab, and pertuzumab (ddAC→THP) in patients with high-risk (≥cT3N0-3 or cT0–4N1–3) disease. T-DXd alone arm closed early due to low pathologic complete response (pCR) rate (43%). T-DXd followed by THP (4 cycles T-DXd→4 cycles THP) significantly improved pCR compared with 4 cycles ddAC→ 4 cycles THP (67.3% vs 56.3%; absolute difference 11.2% [95% CI, 4.0–18.3]; P = .003), with consistent benefit across hormone receptor subgroups. T-DXd→THP demonstrated lower rates of neutropenia and left-ventricular dysfunction but higher gastrointestinal toxicity and peripheral neuropathy; interstitial lung disease (ILD) rates were low and similar across arms (~4%–5%).¹ However, interpretation remains cautious because the comparator (ddAC-THP) does not reflect contemporary U.S. practice, where TCHP (Docetaxel, Carboplatin, Trasutuzmab, Pertuzumab) predominates. Event Free Survival data remains immature. Given excellent pCR rates observed with THP, one of the strategies could also be to give THP x 4 cycles to begin with, re-image and if concern for residual invasive disease, then give T-DXd in neoadjuvant setting for another 4 cycles. This strategy in neoadjuvant setting could potentially result in lower exposure to T-DXd as opposed to the subsequent post neoadjuvant trial where patients may need to be treated with 14 cycles of T-DXd in the presence of residual disease. In contrast, DESTINY-Breast05 provided practice-changing adjuvant evidence in patients with high-risk residual invasive HER2-positive breast cancer with node-positive disease at surgery after neoadjuvant therapy or inoperable disease at diagnosis. In this study, patients were randomized 1:1 to receive T-DXd or ado-trastuzumab emtansine (T-DM1) for 14 cycles. 52% patients had inoperable disease at diagnosis and 81% were node positive after neoadjuvant therapy. Adjuvant T-DXd significantly improved 3-year invasive disease-free survival (iDFS) versus T-DM1 (92.3% vs 83.5%), with consistent benefit across all prespecified subgroups, thereby challenging the decade-long KATHERINE paradigm. The incidence of adjudicated drug-related interstitial lung disease (ILD) was higher with T-DXd than with T-DM1 (9.6% vs. 1.6%). Two patients with ILD in the T-DXd group died.² These findings support T-DXd as the preferred adjuvant therapy in this population, with careful ILD monitoring and proactive toxicity counseling essential in routine practice. Although the FDA has not approved the use of T-DXd in the adjuvant setting, the NCCN guidelines have been updated to include a category 1 recommendation for T-DXd in patients with a high risk of recurrence, defined as inoperable cancer at presentation prior to neoadjuvant therapy, or those with operable cancer and axillary node-positive disease following preoperative therapy.

SABCS 2025 confirmed a major frontline shift in metastatic HER2-positive breast cancer.

DESTINY-Breast09 demonstrated a significant improvement in progression-free survival (PFS) with first-line T-DXd plus pertuzumab (T-DXd + P) compared with standard docetaxel–trastuzumab–pertuzumab (THP) (40.7 vs. 26.9 months; HR 0.56; 95% CI, 0.44–0.71; P < .00001). T-DXd + P improved PFS vs THP, though interpretation warrants caution given many de novo cases and limited prior trastuzumab exposure; based on these data, FDA approved T-DXd in combination with pertuzumab in Dec 2025 as first-line treatment for HER2+ unresectable or metastatic breast cancer.³

As T-DXd + P moves into the frontline setting, optimizing maintenance strategies has become increasingly relevant. The HER2CLIMB-05 trial evaluated tucatinib added to trastuzumab–pertuzumab maintenance following induction THP, showing a statistically significant PFS benefit (24.9 vs. 16.3 months; HR 0.64; 95% CI, 0.50–0.80; P< .0001), with consistent advantages across subgroups and greater benefit observed in hormone receptor (HR)–negative disease (HR ≈ 0.54) compared with HR–positive disease (HR ≈ 0.72).⁴ PATINA established the addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to anti-HER2 plus endocrine maintenance in HR-positive/HER2-positive metastatic disease. Updated 5-year data showed sustained PFS improvement (44.3 vs 29.1 months; HR 0.74; P = .01) and a lower cumulative incidence of central nervous system (CNS) progression, suggesting a potential protective effect.⁵ Together, these trials signal a paradigm shift from a single default frontline to induction-maintenance sequencing tailored by HR status, tumor burden, CNS risk, and tolerability. However, maintenance strategies with palbociclib or tucatinib post T-DXd + P in first line metastatic setting have not been investigated, with several investigators favoring treatment with T-DXd + P until maximal response and then adopt a maintenance strategy, guided by HR status.

Earlier ADC use increases the importance of proactive toxicity management. With T-DXd, clinically significant nausea and ILD require patient education and rapid pulmonary evaluation pathways as well as low dose CT scans in a curative intent setting. Tucatinib-based regimens necessitate counseling for diarrhea and liver enzyme elevations.

For stage I TNBC, SABCS 2025 reinforced a pragmatic approach: upfront surgery for very small tumors with high-confidence imaging, but neoadjuvant pembrolizumab-based therapy (KEYNOTE-522) once tumors approach 1.5–2 cm to enable response-adapted escalation.⁶ Carboplatin remains relevant given OS improvement observed in some recent clinical trials with addition of carboplatin, while interest continues to grow in anthracycline-sparing strategies such as the SCARLET regimen (carboplatin/taxane plus pembrolizumab).⁷

Metastatic TNBC is transitioning from single-agent chemotherapy +/- pembrolizumab to earlier ADC use. ASCENT-04 (PD-L1–positive) and ASCENT-03 (PD-L1–negative) support moving sacituzumab govitecan into first-line settings, improving PFS versus chemotherapy, although OS interpretation is confounded by crossover.^8,9

TROPION-Breast02 introduced datopotamab deruxtecan (Dato-DXd) as a frontline ADC option for PD-L1–negative metastatic TNBC and did not allow crossover to Dato-DXd upon progression in the chemotherapy arm. Compared with investigator's-choice chemotherapy, Dato-DXd significantly improved both PFS (HR 0.57; 95% CI, 0.47–0.69; P < .0001) and overall survival (OS) (HR 0.79; 95% CI, 0.64–0.98; P = .0291), reinforcing that ADCs represent an effective therapeutic class with distinct, non-interchangeable toxicity profiles.¹⁰

SABCS 2025 confirmed CDK4/6 inhibitors as foundational therapy in high-risk HR-positive early breast cancer. The 5-year NATALEE analysis showed ribociclib improved distant disease-free survival across subgroups, including node-negative disease (HR 0.54; 95% CI, 0.32–0.91). Ribociclib's broader eligibility complements abemaciclib's established OS benefit in node-positive disease; in patients eligible for both, selection is largely driven by toxicity profile and comorbidity considerations.¹¹

Oral selective estrogen receptor degraders (SERDs) emerged as the first major endocrine advance in decades. In the phase III lidERA trial, adjuvant giredestrant reduced invasive recurrence risk by approximately 30% versus standard endocrine therapy (aromatase inhibitor, AI/tamoxifen) after a median 32-month follow-up, with a favorable OS trend.¹² A clinically relevant question is patient selection for giredestrant if this becomes available, as current practice supports the combination of AI/tamoxifen and CDK4/6i in the adjuvant setting based on monarchE and NATALEE trials – a strategy not evaluated in monotherapy SERD trials. Consequently, giredestrant may be reserved for high-risk patients who are ineligible for oral CDK4/6i. In the absence of OS data for giredestrant, and given the established benefit from CDK4/6i, current practice may favor an initial regimen of AI/tamoxifen plus CDK4/6i for 2-3 years, follow by a switch to giredestrant in the adjuvant setting. Other ongoing trials in the adjuvant setting with SERDs (such as CAMBRIA-1, ELEGANT, EMBER-4) will provide further insights regarding sequencing and combination strategies.

SABCS 2025 highlighted increasingly precise treatment for endocrine-resistant HR-positive disease. The INAVO120 trial established inavolisib plus endocrine therapy as the first phosphatidylinositol-3-kinase–pathway (PI3K) inhibitor to demonstrate both PFS (~17 months) and OS benefit in endocrine-resistant PIK3CA-mutant disease. Median OS was 34.0 months with inavolisib versus 27.0 months with placebo (HR 0.67; 95% CI, 0.48–0.94; P = .019).¹³

SERD-based strategies also advanced with SERENA-6, which evaluated early endocrine switching upon detection of emergent ESR1 mutations during first-line AI plus CDK4/6 inhibitor therapy for HR-positive, HER2-negative advanced breast cancer. Switching to camizestrant while continuing the CDK4/6 inhibitor significantly improved PFS versus maintaining AI therapy (16.6 vs 9.2 months; HR 0.46; 95% CI, 0.34–0.62; P < .00001). Updated analyses demonstrated profound suppression of ESR1-mutant circulating tumor DNA (ctDNA), with a median variant allele frequency (VAF) change of −100% in the camizestrant arm versus +66.7% with control and marked ESR1 expansion (≥500% increase) observed in only 0.8% versus 24.4% of patients, respectively. These findings provide biologic confirmation of effective ESR1 targeting. Notably, the time to initiation of first subsequent chemotherapy was delayed in the camizestrant arm compared with control, reflecting both sustained disease control and clinical benefit consistent with molecular suppression of ESR1-mutant clones. However, concerns remain if SERD use at the time of disease progression would be associated with similar improvement in PFS2 as SERENA-6 did not allow cross-over to camizestrant in the control arm. There are also concerns about resources spent, that is financial toxicity incurred secondary to blood tests for ctDNA and imaging requirements (only 1/10^th of the screened patients enrolled in the randomized clinical trial). Additional SERD-based combinations further extended endocrine therapy beyond CDK4/6 inhibitor progression. In the phase III evERA trial, giredestrant plus everolimus improved PFS versus exemestane plus everolimus (approximately 8.8 vs 5.5 months; HR 0.56; 95% CI, 0.44–0.71; P < .0001). The magnitude of PFS benefit was greater in the ESR1‑mutant population (median PFS 10.0 vs 5.5 months; HR ≈ 0.38) than in ESR1 wild‑type disease, where a more modest effect was observed. Notably, improvement in overall response rate was seen across the overall study population, irrespective of ESR1 mutation status.¹⁴ In EMBER-3, among patients with ESR1-mutant disease, imlunestrant improved OS versus standard endocrine therapy (34.5 vs 23.1 months; HR 0.60; 95% CI, 0.43–0.86; P = .0043), while imlunestrant plus abemaciclib prolonged PFS versus imlunestrant alone (10.9 vs 5.5 months; HR 0.59; 95% CI, 0.47–0.74; nominal P < .0001).¹⁵ The VIKTORIA-1 trial showed that the pan–PI3K/mTOR inhibitor gedatolisib, combined with fulvestrant with or without a CDK4/6 inhibitor, significantly improved PFS compared with fulvestrant alone in patients with HR-positive/HER2-negative, PIK3CA wild-type advanced breast cancer following CDK4/6 inhibitor progression.¹⁶ We await regulatory decisions regarding the incorporation of these novel SERDs into clinical practice. The NCCN guideline list the combination of imlunestrant and abemaciclib as a category 2A recommendation for second- and/or subsequent-line therapy, with a footnote that this combination may be most effective in patients with ESR1 mutations and no prior CDK4/6 inhibitor. Nevertheless, the emerging data are encouraging and suggest that combination strategies incorporating SERDs may overcome resistance mechanisms. Notably, this approach may signal a shift toward mutation-agnostic treatment strategies rather than the strictly genomically guided paradigm that has historically defined this space.