ASCO 2025 - ASCO Data Identify Potential New Standards of Care in the Management of Breast Cancer

Chicago--A series of late-breaking abstract presentations at the 2025 ASCO Annual Meeting hold practice-changing potential in the treatment of various types of breast cancer. Following is a quick summary of the highlights of each, and other abstracts with treatment implications in breast cancer.

A new standard in HER2-positive metastatic breast cancer?

Trastuzumab deruxtecan (T-DXd) in combination with pertuzumab as first-line treatment of HER2-positive locally advanced or metastatic breast cancer improved progression-free survival (PFS) over that with standard of care THP (taxane plus trastuzumab plus pertuzumab) in the phase 3 DESTINY-Breast09 clinical trial.

After a median of follow-up of 29 months, patients randomized to T-DXd plus pertuzumab had a median PFS by blinded independent central review of 40.7 months compared with 26.9 months in patients randomized to THP (HR, 0.56; 95% CI, 0.44-0.71; P<.00001), for an absolute improvement of 13.8 months.

T-DXd is currently approved as a standard second-line treatment option in the metastatic HER2 positive setting as a result of an unprecedented 29-month PFS observed in DESTINY-Breast03, but Prof. Tolaney advocated for its earlier use given the results of DESTINY-Breast09 and data showing that “one third of patients who initiate treatment for metastatic HER2-positive disease are not able to go on to receive a second line of therapy, either due to deterioration in health or death.

” DESTINY-Breast09 is a randomized multicenter open-label 3-arm phase 3 study of 1,157 patients with HER2-positive advanced or metastatic who were disease free for >6 months from their last chemotherapy or HER2-targeted therapy in the neoadjuvant/adjuvant setting.

At 24 months, 70.1% of patients in the trastuzumab deruxtecan plus pertuzumab arm were free from disease progression compared to 52.1% in the THP group.

Source: Trastuzumab deruxtecan (T-DXd) ± _pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Primary results from DESTINY Breast09. Abstract LBA1008.

ADC with immune checkpoint inhibitor as first line in TNBC

Prof. Tolaney also presented the results from the phase 3 ASCENT-04/KEYNOTE-D19 study, which showed that the combination of sacituzumab govitecan (SG) and pembrolizumab as first line treatment led to an improvement in median PFS compared with chemotherapy and pembrolizumab in patients with PD-L1-positive locally advanced unresectable or metastatic triple-negative breast cancer (TNBC).

ASCENT-04/KEYNOTE-D19 enrolled 443 patients with previously untreated, locally advanced unresectable or metastatic TNBC who were PD-L1-positive (combined positive score ≥ 10 by the 22C3 assay). They were randomized to SG plus pembrolizumab or to chemotherapy of physician’s choice plus pembrolizumab.

Median PFS in the SG plus pembrolizumab arm was 11.2 months, versus 7.8 months in the chemotherapy plus pembrolizumab arm, representing a 35% improvement (HR, 0.65; 95% CI, 0.51-0.84; P < 0.001).

Overall survival (OS) data remain immature, with only 26% of survival events having occurred at the time of data analysis, at which point a trend in improvement in OS favored SG plus pembrolizumab (HR, 0.89; 95% CI, 0.62-1.29).

Source: Sacituzumab govitecan (SG) + pembrolizumab vs chemotherapy + pembrolizumab in patients with previously untreated PD-L1+ advanced or metastatic triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. Abstract LBA109.

Investigational oral SERDs prolong PFS in breast cancer with ESR1 mutations

Camizestrant. A next-generation investigational oral selective estrogen receptor (ER) degrader instituted at the first sign of emergent ESR1 mutations on circulating tumor (ct) DNA significantly improved PFS following first-line therapy HR-positive/HER2-negative advanced breast cancer.

Results from the randomized SERENA-6 trial showed that substituting just the aromatase inhibitor (AI) for camizestrant after detection of ESR1 mutation on ctDNA in patients responding to first-line treatment with a CDK4/6 inhibitor and an AI improved PFS by 56% (HR, 0.44; 95% CI 0.31-0.60, P<0.00001) compared with maintaining the AI, reported Nicholas Turner, MD, PhD, of the Royal Marsden Hospital, London.

Median PFS improved from 9.2 months for those who remained on the AI to 16 months with the switch to camizestrant.

Patients screened for SERENA-6 were on first-line treatment with an AI plus a CDK4/6 inhibitor for ≥6 months. They were tested for ESR1 mutations in ctDNA every 2 to 3 months at the time of routine staging exams. A total of 315 patients with ESR1 mutations were then randomized to camizestrant plus continuation of their CDK4/6 inhibitor or continuing AI (anastrazole or letrozole) plus their CDK4/6 inhibitor.

said Prof. Turner. “This therefore presents a potential new treatment strategy in oncology to treat developing resistance before it causes progression.”

Camizestrant also delayed time to deterioration in quality of life compared with continued AI treatment (23 vs. 6.4 months, respectively; adjusted HR 0.53, 95% CI 0.33-0.82).

Source: Camizestrant + CDK4/6 inhibitor for the treatment of emergent ESR1 mutations during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer: Phase 3, double-blind ctDNA-guided SERENA-6 trial. Abstract LBA4

Vepdegestrant. Another investigational ER degrader, vepdegestrant, more than doubled median PFS compared with fulvestrant in patients with previously treated ER-positive metastatic breast cancer with ESR1 mutations, according to results from the global phase III open-label randomized VERITAC-2 trial.

Vepdegestrant is a a proteolysis-targeting chimera (PROTAC) ER degrader.

Data form VERITAC-2 showed that among 270 patients whose ESR1-mutated tumors progressed on first-line treatment with a CDK4/6 inhibitor and hormone therapy, median PFS was 5 months with vepdegestrant compared with 2.1 months with fulvestrant (HR 0.57, 95% CI 0.42 0.77, P<0.001).

The PFS benefit support vepdegestrant as a potential monotherapy option for patients in this setting, said lead investigator Erika P. Hamilton, MD, from the Sarah Cannon Research Institute, Nashville.

Source: Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. Abstract LBA1000.

An improvement in OS in PIK3CA-mutated breast cancer

The PI3K-pathway inhibitor inavolisib, when added to palbociclib and fulvestrant, significantly improved OS in patients with PIK3CA-mutated, endocrine-resistant breast cancer, according to updated results from the INAVO120 phase 3 trial.

In patients receiving the standard first-line doublet, median OS improved from 27 months in the placebo arm to 34 months with the addition of inavolisib (HR 0.67, 95% CI 0.48-0.94, P=0.0190), reported Prof. Turner. The OS data build on previous findings showing a PFS benefit to the addition of inavolisib, a benefit that was sustained at the latest follow-up.

The need for chemotherapy was also delayed by nearly 2 years with the inavolisib combination, from 12.6 months with placebo to 35.6 months with inavolisib.

Source: NAVO120 phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2-), endocrine-resistant advanced breast cancer (aBC). Abstract 1003.

Using artificial intelligence to identify HER2 expression

Artificial intelligence (AI) has been used successfully in a global study to train pathologists to enhance their accuracy in identifying HER2-low or -ultralow expression in breast cancer tissue, thereby reducing the rate of “missed calls” that could lead to denial of effective HER2-targeted therapy.

With institution of AI as part of a training program to assist pathologists in HER2 scoring of breast cancer samples, the percentage of HER2-ultralow cases that were misclassified as HER2 null (complete absence of HER2 expression) was reduced by more than 25%, reported Marina De Brot, MD, PhD, from A.C. Camargo Cancer Center, São Paolo, Brazil.

Only 4% of immunohistochemistry (IHC) readings from whole slide images were misclassified when pathologists used AI assistance compared with 29.5% of readings that were misclassified when AI assistance was not used.

With AI support, HER2 scoring sensitivity increased from about 76% to 90%, and pathologists’ agreement with central reference scores improved by about 13%.

Source: Use of artificial intelligence-assistance software for HER2-low and HER2-ultralow IHC interpretation training to improve diagnostic accuracy of pathologists and expand patients’ eligibility for HER2-targeted treatment. Abstract 1014