INAVO120: 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)

Speaker: Nicholas Turner

Introduction

Patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer were enrolled. A synergistic effect of co-targeting the estrogen receptor, CDK4/6, and PI3K pathways was hypothesized, but prior attempts were hindered by toxicity.

Inavolisib, a selective PI3Kα inhibitor that degrades mutant p110α, was evaluated in combination with Palbociclib and Fulvestrant.

Study Design

A randomized, double-blind, placebo-controlled phase 3 trial (INAVO120) was conducted.
Participants (N=325) were assigned to receive either:

• Inavolisib + Palbociclib + Fulvestrant, or
• Placebo + Palbociclib + Fulvestrant.

Eligibility required a measurable disease and progression on or within 12 mo of adjuvant endocrine therapy. Progression-free survival (PFS) was designated as the primary endpoint, and overall survival (OS) as a key secondary endpoint.

Efficacy Outcomes

• mPFS: 17.2 mo Inavolisib arm vs. 7.3 mo in the placebo arm (HR: 0.42). Early and sustained curve separation was noted.
• Overall Survival: Median OS was reported as 34 mo with Inavolisib vs. 27 mo with placebo (HR: 0.67; p = 0.019).
• Objective Response Rate (ORR): ORR was observed at 62.7% with Inavolisib vs. ~25% with placebo.
• Duration of Response: Responses lasted 19.2 mo with Inavolisib and 11.1 mo with placebo.
• Time to Chemotherapy: Median time was extended to 35.6 mo in the Inavolisib arm vs. 12.6 mo in the placebo arm.

Subgroup and Post-Progression Analyses

OS benefit was reported across subgroups, though small numbers limited power (e.g., 59 patients ≥65 years).

Fewer patients in the Inavolisib arm received second-line chemotherapy (55% vs. 72%) and third-line ADCs (16.7% vs. 35%).

Safety Profile

• Adverse Events: Serious adverse events were increased with Inavolisib, though discontinuation due to AEs was low.
• Key AEs (Any grade / Grade ≥3):
• Stomatitis: 55% / 5.6%
• Hyperglycemia: 63% / 6.8%
• Diarrhea: 52%
• Thrombocytopenia and anemia: Modest increase
• Neutropenia: Comparable between arms
• Ocular toxicity: Mostly grade 1 (e.g., dry eye, blurred vision)

Limitations

• Only Palbociclib was used among CDK4/6 inhibitors.
• Few patients had prior CDK4/6 inhibitor exposure.
• Low representation of Black/African American patients was noted.
• Subgroup analyses for secondary endpoints were underpowered.

Conclusion

A significant improvement in PFS, OS, objective response rate, and delay in chemotherapy initiation was achieved with the addition of Inavolisib. Adverse events were consistent with known PI3K inhibition profiles but were considered manageable, with low discontinuation rates reported.

Prospective Randomized Phase II Trial to Assess the Efficacy and Safety of Neo-adjuvant Olaparib/Carboplatin (OC) in Comparison to Docetaxel/ Epirubicin/Cyclophosphamide (TAC) in Patients with Early Triple-negative Breast Cancer (TNBC) with Homologous Recombination Deficiency (HRD): Primary Results from the ABCSG 45 Trial

Speaker: CS Singer

Introduction

BRCA1/2 pathogenic variants (PVs) are present in ~50% of HRD+ TNBC. HRD+ TNBC are highly sensitive to platinum agents and may benefit from PARP inhibitors like Olaparib.

Preclinical models support the synergistic efficacy of Olaparib + carboplatin.

Aim

To evaluate whether Olaparib + carboplatin offers effective neoadjuvant treatment compared to TAC in HRD+ early TNBC.

Study Design & Methods

• Design: Prospective, randomized, two-step phase II trial.
• Participants: 90 patients with HRD+ TNBC, based on:
  • Tumor BRCA1/2 PV or
  • Genomic instability score ≥42.

Arms

• Arm A: Olaparib (100 mg BID, days 4–19) + Carboplatin for 6 cycles.
• Arm B: 6 cycles of TAC.
• All patients underwent surgery post-treatment.

Stratification: Based on tumor BRCA1/2 status and menopausal status.

Endpoints

• Primary: Residual Cancer Burden (RCB) 0/1.
• Secondary: Pathologic complete response (pCR), safety, tolerability, quality of life.

Key Eligibility Criteria

• Inclusion:
  • Early invasive TNBC (tumor ≥1 cm).
  • HRD+ by BRCA PV or GIS ≥42.
• Exclusion: Inoperable tumors or drug contraindications.

Baseline Characteristics

• Mean age: 51 years.
• Postmenopausal: 49%.
• Tumor BRCA1/2 PV: 47%.
• Genomic instability: 92%.
• Tumor size ≥T2: 60%.
• Node-positive: 40%.

Results

Primary results (Overall)

Note: Difference was not statistically significant.

Subgroup Analysis

• Patients with BRCA1/2 PV:
  • Olaparib + Carboplatin: 77% RCB 0/1 (all had complete pathological remission).
  • TAC: 65%.
• Patients with BRCA Wild-Type:
  • Olaparib + Carboplatin: 29%.
  • TAC: 75%.

Safety Profile

• Olaparib + Carboplatin:
  • Grade ≥3 thrombocytopenia: 30%.
  • Grade ≥3 neutropenia: 43%.
• TAC:
  • Grade ≥3 neutropenia: 19%.
  • Leukopenia: 25%.
  • More non-hematological toxicities observed.

Conclusion

• HRD+ TNBC responds well to neoadjuvant TAC.
• BRCA1/2 PV-positive tumors showed strong response to Olaparib + carboplatin.
• Main adverse events in the Olaparib-carboplatin arm were hematological.
• HRD and tumor BRCA1/2 status may guide personalized treatment decisions in early TNBC.

Predicting Pathologic Complete Response (pCR) from Clinicopathologic Variables and HER2DX Genomic Test in Stage II/III HER2+ Breast Cancer Treated with Taxane, Trastuzumab, and Pertuzumab (THP): Secondary Results from the EA1181/CompassHER2 pCR Trial

Speaker: Nadine Tung

Study Objective

The primary aim of EA1181 was to evaluate whether 3-year recurrence-free survival (RFS) in patients with pathologic complete response (pCR) after less intensive neoadjuvant therapy (THP only) is equivalent to the RFS achieved with standard multi-agent chemotherapy plus trastuzumab and pertuzumab (HP).

Study Population

Eligibility Criteria

• Women with stage II or III HER2-positive breast cancer
• Tumor size >2 cm and/or axillary node involvement
• Excluded: T4 and N3 disease

Patient Demographics

• 2,175 patients enrolled
  • ~33% ER-negative
  • ~66% ER-positive
• Median age: 55 years (range up to 88)

Treatment Regimen (Neoadjuvant Phase)

Patients received 4 cycles (12 weeks) of:

• Either weekly paclitaxel, 80 mg/m2, qwk x12 or docetaxel, 75 mg/m2, q3 wk x 4
• Plus, trastuzumab + pertuzumab (HP), q3 wk x 4

Choice of taxane (paclitaxel vs. docetaxel) was at the discretion of the treating physician.

Post-Neoadjuvant Management

• For patients achieving pCR:
  • No additional chemotherapy
  • Completion of 1 year of HP
  • Radiation and endocrine therapy if ER-positive
• For patients with residual disease:
  • Management left to the treating oncologist
  • Options included additional chemotherapy or enrollment in the COMPASS-HER2 RD trial

Endpoints

• Primary Endpoint (not yet mature): 3-year RFS in patients with pCR after THP-only
• Secondary Endpoints:
  • pCR rate with THP
  • Identification of clinical and molecular predictors of pCR: Focus on HER2DX genomic score
  • Evaluate feasibility of THP-only as a less toxic neoadjuvant regimen

Key Findings

• Overall pCR rate with THP: 44%
  • ER-negative: 64%
  • ER-positive: 33%
• Less than 1% progression during THP therapy.
• pCR was not associated with baseline clinical stage, emphasizing the importance of tumor biology over burden.

Clinical Predictors of pCR

• Significantly associated with higher pCR:
  • ER expression ≤70%
  • HER2 IHC 3+
  • Use of weekly paclitaxel (vs. 3-week docetaxel)
• Negative predictors:
  • Age >70
  • ECOG performance status = 1

HER2DX Genomic Score

• HER2DX provides a pCR likelihood score based on gene expression (immune activity, HER2/luminal features) and clinical parameters.
• A high HER2DX score was associated with a ~40% higher pCR rate in both ER-positive and ER-negative subgroups.
• In ER-positive tumors, only 10% had a high HER2DX score but 37% had high/medium scores—suggesting a subgroup who may benefit from THP alone.

Multivariable Analysis

Independent predictors of pCR

• HER2DX high/medium score
• ER ≤70%
• HER2 IHC 3+
• Weekly paclitaxel use

Exploratory Molecular Biomarkers

Three additional molecular predictors of pCR also showed significance:

• ERBB2 mRNA levels
• HER2-enriched intrinsic subtype
• IgG immune gene signature

These reinforce the need for integrated molecular tools in treatment planning.

Implications for Clinical Practice

A tailored approach using HER2DX and clinical factors may allow selected patients to receive less intensive neoadjuvant therapy (THP only), sparing toxicity. However, standard chemotherapy remains the recommended approach until long-term data confirms equivalent survival outcomes.

Conclusion

The study supports the potential of combining clinical and genomic markers (especially HER2DX) to personalize therapy for HER2+ breast cancer. Ongoing follow-up is needed to confirm if pCR with THP-only regimens translates to survival outcomes similar to standard multi-agent chemotherapy.

What is the Right-Size Treatment for HER2?

Speaker: Sara Hurvitz

Evolution of HER2+ Early-Stage Breast Cancer Treatment

The "toolbox" for HER2-positive early-stage breast cancer treatment has significantly evolved over the last 20 years. The goal now is to select the most appropriate treatment for each patient. Neoadjuvant (pre-surgical) studies play a crucial role in this, especially since long-term data from the Katherine study shows that addressing residual disease after neoadjuvant therapy can save lives and reduce the extent of surgery.

Key Questions and Insights from Neoadjuvant Studies

The webinar addresses five important questions regarding neoadjuvant treatment for HER2-positive breast cancer:

Can Carboplatin be Omitted from Standard Neoadjuvant Therapy?

• Historical Context: Early preclinical and phase II trials in the 1990s by Pegram and colleagues showed synergy with carboplatin, trastuzumab, and taxane (TCH regimen).
• Challenge to Carboplatin Use: The BCIRG 0067 study in the metastatic setting compared TCH to TH (without carboplatin) and found no benefit with carboplatin, though the taxane dose was higher in the TH arm.
• Recent Evidence (NeoCARP Study): The NeoCARP study, a large, prospective, non-inferiority trial, investigated omitting carboplatin.
  • Patient Population: Approximately 80% of enrolled patients had smaller tumors (T1/T2), and 75% had stage II disease. 44% received nab-paclitaxel.
  • Results: Pathologic complete response (pCR) rates were strikingly similar between arms with and without carboplatin.
  • Safety: Omitting carboplatin led to improved safety, with fewer grade 3/4 adverse events (nausea, vomiting, increased creatinine).
• Conclusion: Carboplatin can likely be omitted for stage I/II patients, but long-term follow-up data for stage III patients is still needed. Weekly dosing of paclitaxel/nab-paclitaxel regimens may be superior to every three-week dosing.

Is Four Cycles of THP Treatment Sufficient?

• WSG Studies: Two WSG studies used four cycles of THP.
  • Patient Population: 75% were stage I, and 72% had hormone receptor-positive disease.
  • Results: Showed very high pCR and five-year invasive disease-free survival (IDFS) rates exceeding 95%.
• EA 1181 Study: Also evaluated a shorter course of four cycles of THP.
  • Key Features: Large size, powered for RFS outcome, better inclusion of underrepresented minorities. Patient Population: Only 8% of patients were stage III.
  • Results: pCR rates compared favorably to historical results. Lower estrogen receptor (ER) and higher HER2 expression were associated with pCR. Paclitaxel use was also associated with pCR.
• Conclusion: Four cycles of THP appear sufficient for stage I patients and potentially some stage II patients. It could also be considered in the adjuvant setting as the APT regimen. Long-term results are awaited.

Is it Possible to Omit Standard Chemotherapy for Some Patients?

• WSG Trials (Chemo-Free Arms): Three WSG trials included neoadjuvant regimens without chemotherapy.
  • pCR Rates: Roughly 25% to 33% of patients treated with a chemo-free regimen achieved pCR.
  • Combined Analysis: When chemo-free arms (including two TDM-1 arms) were analyzed together, long-term outcomes were similar to THP arms.
  • Limitations: 75% of patients were early stage, and only a small number had hormone receptor-negative disease. TDM-1 technically contains chemotherapy, so the "chemo-free" classification might be debatable for those arms.
• Conclusion: Currently, there's insufficient evidence to recommend omitting chemotherapy entirely for chemotherapy-candidate patients without better patient selection methods.

Do Patients with pCR After Chemo-Free/ADC Therapy Need Adjuvant Chemo?

• Observation: Among patients who achieved pCR after chemo-free regimens, two-thirds received adjuvant chemotherapy, and one-third did not.
• Limitations: This was not a randomized comparison. Patients who received adjuvant chemo tended to have larger tumors, more node positivity, and hormone receptor-negative tumors.
• Propensity Score Analysis: Using a propensity score and Cox regression model, the study suggested similar IDFS outcomes regardless of whether adjuvant chemo was received after pCR, which is an intriguing finding.

Can Biomarkers be Used to Right-Size Therapy?

• WSG Prognostic Score: This score, combining genetic and clinical factors, was shown to identify patients with a low chance of pCR in chemo-free groups.
• Implication: For patients with a low prognostic score in chemo-free regimens who had a low pCR, giving them chemotherapy might improve outcomes.
• HER2Dx Score: This score has shown strong correlation with pCR in multiple validation studies.
• November Study Analysis: In 569 matched patients from the November study, observed pCR rates in both ER-negative and ER-positive patients were very similar to what was predicted by high and low HER2Dx scores. Medium scores tracked with high scores.
• Conclusion: The field of HER2-positive early-stage breast cancer treatment is rapidly advancing. We are getting very close to precisely tailoring treatments to individual patients, ensuring the "just right" therapy.

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

Speaker: Erika Hamilton

Introduction

Dr. Hamilton presented the phase 3 results of the VERITAC-2 trial, highlighting the clinical efficacy and safety of Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor degrader, in comparison to Fulvestrant in patients with ER+, HER2-negative advanced breast cancer.

Methods

• It was a randomized, global, open-label phase 3 study, enrolling 624 patients with ER+/HER2- advanced breast cancer who previously progressed on endocrine therapy and a CDK4/6 inhibitor.
• Patients were randomized in a 1:1 ratio to receive either Vepdegastrant 200 mg orally OD or Fulvestrant 500 mg intramuscularly, administered on days 1 and 15 of cycle 1 and day 1 of subsequent cycles.
• The primary endpoint was PFS in patients with ESR1 mutations, and secondary endpoints included OS, PFS in the intention-to-treat population, and ORR.

Results

• Of the participants, 43% were found to have ESR1 mutations, two-thirds had visceral disease, and nearly 40% had liver metastases. Less than 20% had bone-only disease. CDK4/6 inhibitors previously administered to all patients included Palbociclib, Ribociclib and Abemaciclib.
• Patients on Vepdegastrant had a extended mPFS of 5.0 months compared to 2.1 months with Fulvestrant (HR 0.57; p < 0.01).
• At 6 months, 45.2% of patients on Vepdegastrant remained progression-free versus 22.7% on Fulvestrant.
• In the intention-to-treat population, no significant PFS was observed (3.7 vs. 3.6 months).
• The clinical benefit rate was 42.1% with Vepdegastrant compared to 20.2% with Fulvestrant, while the objective response rate was 18.6% vs. to 4.0%, respectively.
• Treatment discontinuation occurred in only 3% of patients on Vepdegastrant (vs. 0.7% on Fulvestrant), with dose reductions required in 2%.
• The most common adverse events were fatigue (27% vs 15.6% with Fulvestrant), increased liver enzymes (13.5-14%), and nausea (13.5% vs 8.8%). No clinically significant QT prolongation risk was noted.

Conclusion

The phase 3 trial demonstrated clinically significant improvements in PFS with Vepdegastrant compared to Fulvestrant in patients with ESR1-mutated ER+/HER2− metastatic breast cancer. Vapdegastrant was well-tolerated and showed a favorable safety profile, with minimal dose modifications and treatment discontinuation rates.

Phase III of Oral Paclitaxel (DHP107) vs Intravenous Paclitaxel in HER2-negative Recurrent or Metastatic Breast Cancer (mBC): Primary Analysis of a Multinational Optimal Trial (NCT03315364)

Speaker: Kim Sung Bae

Introduction

The phase 3 trial evaluated the safety and efficacy of oral paclitaxel (DHP-107), a lipid-based formulation, compared to standard IV paclitaxel in patients with HER2-negative recurrent or metastatic breast cancer.

Methods

• A total of 550 patients with HER2-negative recurrent or metastatic breast cancer who had received no prior chemotherapy for advanced disease were randomized 1:1 to receive either DHP107(200 mg/m² orally, twice daily for three consecutive days each week) or IV paclitaxel (80 mg/m² intravenously once weekly).
• Patients were stratified by three key factors: disease-free interval, visceral disease presence, and hormone receptor status.
• The primary endpoint was investigator-assessed PFS, and secondary endpoints included OS, ORR, DCR, time to treatment failure (TTF), QoL, and safety.
• The median follow-up durations were 38 months (DSP-107) and 39 months (IV paclitaxel).

Results

Baseline Characteristics

• Among 549 patients, 88% of patients had hormone receptor-positive disease, while 12% had triple-negative disease.
• Visceral metastasis was present in 80% of patients.
• Previous exposure to taxanes was seen in 60% of patients in the DHP107 arms vs. 51% in the IV paclitaxel arm.

Efficacy

• Primary endpoint: mPFS was 10.02 months with DHP107 compared to 8.54 with IV paclitaxel (HR 0.86; upper limit of 95% CI within the non-inferiority margin).
• mOS was 32 months (DSP-107) vs. 31 months (IV paclitaxel) (HR 0.96).
• ORR was 43% with DHP107 vs. 38% with IV paclitaxel; DCR was 89% vs. 84%, respectively.
• The TTF was 7.62 vs 7.43 months (HR 0.875).

Safety and Tolerability

• Hematologic toxicities like neutropenia, febrile neutropenia, and anemia were more common in patients on DHP107.
• Gastrointestinal side effects, including diarrhea, nausea, and vomiting were also frequently reported but were mostly grade 1.
• Peripheral neuropathy was reported in 38% of patients on DHP107 compared to 48% on IV paclitaxel.
• The cumulative incidence of peripheral neuropathy and maximum grade of peripheral neuropathy were lower with DHP-107.
• Hypersensitivity and infusion-related reactions were also lower in the DHP107 arm (2% vs. 9% and 1 vs. 7).

Quality of Life

• QoL assessments using EQ-5D-3L and EQ-VAS across six time points showed comparable results between both groups.

Conclusion

DHP107 was found to be non-inferior to IV paclitaxel in improving PFS and OS in patients with HER2-negative recurrent or metastatic breast cancer. ORR, DCR, TTF, and QoL outcomes were also comparable. A favorable safety profile was noted with DHP-107, including lower incidence and severity of peripheral neuropathy, fewer hypersensitivity and infusion reactions.

Sacituzumab govitecan (SG) + Pembrolizumab (Pembro) vs Chemotherapy (Chemo) + Pembro in Previously Untreated PD-L1–positive Advanced Triple-negative Breast Cancer (TNBC): Primary Results from the Randomized Phase 3 ASCENT-04/KEYNOTE-D19 Study

Speaker: Sara M. Tolaney

Introduction

Dr. Sara presented the phase 3 ASCENT-04/KEYNOTE-D19 trial, evaluating SG with Pembro compared to chemotherapy plus pembrolizumab in patients previously untreated, PD-L1–positive, advanced TNBC.

Study Design and Methods

• It was a randomized, open-label, phase 3 trial involving 443 patients with untreated locally advanced unresectable or metastatic TNBC, with PD-L1 positivity (CPS ≥ 10; 22C3 assay).
• Patients were randomized in a 1:1 ratio to:
• SG (10 mg/kg IV, day 1 & 8) + Pembro (200 mg, day 1, max 35 cycles) in 21-day cycles
• Chemotherapy of physician’s choice (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel) + pembrolizumab 
• The primary endpoint was PFS by independent central review (BICR). Secondary endpoints consisted of OS, ORR, DoR, time to deterioration in physical functioning, QoL, and safety.

Baseline Characteristics

• De novo metastatic disease was observed in 34% of patients.
• The recurrence was seen in 18% of patients within 6-12 months and in 48% more than 12 months after early-stage therapy.
• Visceral metastases were common, involving the lung (50%), liver (25%), and brain (4%).
• In the chemotherapy arm, nearly 50% received taxanes or gemcitabine/carboplatin.
• Only 5% of patients had prior exposure to checkpoint inhibitors in early-stage disease.

 Results

Efficacy

• Progression-Free Survival (Primary Endpoint)
• mPFS: 11.2 months with SG + Pembro vs. 7.8 months with chemotherapy + Pembro (HR 0.65, p<0.001)
• 12-month PFS: 48% in SG + Pembro vs. 33% in chemotherapy + Pembro
• Investigator-assessed PFS: 11.3 vs. 8.3 months, HR 0.67
• OS: A positive trend was observed (HR 0.89). However, only 26% of OS events had occurred. 81% of patients in the chemotherapy arm received SG post-progression.
• ORR: 60% in SG + pembrolizumab vs. 53% in chemotherapy + Pembro
• CR rate: 13% vs. 8%
• DoR: 16.5 months in SG + Pembro vs. 9.2 months with chemotherapy + pembrolizumab

Safety and Toxicity Profile

• The grade 3 and 4 events were similar across both arms.
• Serious adverse events were more common in SG + pembrolizumab, but there were fewer treatment discontinuations (12% vs. 31%) and fewer dose reductions.
• Common toxicities with SG + pembrolizumab included neutropenia, nausea, and diarrhea, while chemotherapy + pembrolizumab was associated with neutropenia, fatigue, and anemia.
• Immune-related adverse events were not increased with the SG + pembrolizumab combination.

Conclusion

SG plus Pembro led to clinically significant improvements in PFS compared to chemotherapy plus Pembro in previously untreated, PD-L1–positive, advanced TNBC. Response rate and duration of response was superior with the SG plus Pembro. Safety profile was consistent, with no new additive toxicity. 

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.

Speaker: Marina De Brot

Introduction

The speaker discussed the increasing relevance of HER2-targeted antibody-drug conjugates in breast cancer treatment has necessitated improved accuracy in detecting HER2-low and HER2-ultralow tumors which were previously categorised as HER2-negative or HER2-0 classifications. HER2 IHC scoring remains challenges in in cases with low level of HER2 expression. In manual interpretation, the observer variability is often high, with misclassification rates of 30%. An AI powered digital pathology training platform was developed to support pathologist in HER2 IHC evaluation and to enhance scoring consistency. 

Methods

• 105 pathologists from 10 countries participated in 13 virtual master classes assessing 20 digital HER2 IHC-stained breast cancer with or without AI assistance. Each master class consisted of three sequential exams:
• Exam A: Five HER2 whole-slide image scored manually, followed by an education lecture on HER2 scoring
• Exam B: Seven additional manual scoring cases, followed by a group review of both exam A and B
• Exam C: Eight HER2 IHC cases scored using AI assistance
• The HER2 IHC scoring followed the ASCO/CAP 2023 guidelines, which include HER2-ultralow (IHC 0 with membrane staining) and HER2 null (IHC 0 with no membrane staining).
• The AI platform displayed tumor cells using color-coded indicators based on membrane staining intensity and completeness. The markers included no staining, incomplete staining, weak-to-moderate complete staining and strong complete membrane staining.
• The side panel of the software displayed the tumor count, percentage of each staining class and the resulting HER2 IHC along with the clinical categorization.

Results

• Across 1,940 HER2 readings, pathologist accuracy and interobserver agreement significantly improved with AI assistance (89.1% vs. 96.1%).
• HER2 clinical categorization accuracy and concordance also observed (accuracy 90.1% vs 95.0%; concordance: 0.49 vs. 0.73).
• Sensitivity improvements across HER2 classification
• HER2 null: 54.08% vs, 88.24% with AI
• HER2 ultralow: 50.08% vs. 93.22% with AI
• HER2 low: 78.64% vs. 90.35% with AI
• For HER2 clinical categories the accuracy jumped to 88.5% with AI (66.7% without AI).
• Misclassification of HER2 low dropped from 45% to 11% (AI-assisted) and HER2 ultra-low misclassification lowered from 30% to 5.4%.

Conclusion

The integration of AI into HER2 IHC training significantly improved diagnostic performance leading to enhanced scoring accuracy, higher inter-reader concordance and lowered misclassification of HER2 low and HER2 ultra-low tumors. 

HER2-ADC Trastuzumab Rezetecan (SHR-A1811) in HER2-positive breast cancer with brain metastases: Update results from REIN trial

Speaker: Li Ting

Introduction

This session presents updated results from the REIN trial, a Phase 2 study evaluating a novel HER2 ADC, Trastuzumab Rezetecan (SHR-A1811), for HER2-positive breast cancer patients with brain metastases.

Addressing a Major Challenge: Brain Metastases:

Brain metastases remain a significant challenge in HER2-positive breast cancer, with limited systemic treatment options. While some HER2-targeted therapies like T-DXd (Trastuzumab Deruxtecan) and small molecule TKIs have shown intracranial activity, there's still a need for effective treatments. SHR-A1811 is a novel HER2-targeted ADC, composed of trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. It has previously shown efficacy in advanced HER2-expressing breast cancer in a Phase 1 trial.

REIN Trial Design

• The REIN trial is a two-cohort, multi-arm Phase 2 study designed to explore SHR-A1811 in HER2-expressing breast cancer with brain metastases.
• Patient Population: HER2-positive or HER2-low breast cancer patients with at least one measurable intracranial lesion who did not require immediate local radiotherapy.
• HER2-Positive Cohort Regimens:
  1. Arm 1: SHR-A1811 monotherapy
  2. Arm 2: SHR-A1811 in combination with Pyrotinib (data not presented in this update)
  3. Arm 3: SHR-A1811 in combination with Bevacizumab
• HER2-Low Cohort Regimens: SHR-A1811 monotherapy and SHR-A1811 combined with Bevacizumab (data not presented in this update)
• Primary Endpoint: Intracranial Overall Response Rate (ORR).
• Current Update: This presentation provides updated results for Arm 1 (SHR-A1811 monotherapy) and an interim analysis for Arm 3 (SHR-A1811 + Bevacizumab) in the HER2-positive cohort. enrollment for Arm 1 and Arm 3 was completed.

Patient Characteristics (Arms 1 & 3)

• Enrollment: 33 patients in Arm 1, 25 patients in Arm 3.
• Intracranial Lesion Size: Over 40% of patients in both arms had intracranial target lesions with a diameter greater than 2 cm, indicating a significant disease burden.
• Prior Treatment: One-third of patients in both arms had received prior Pyrotinib-based regimens as the last systemic therapy.
• Other Prior Therapies: 6.1% in Arm 1 had received prior local radiotherapy (RT) alone and Bevacizumab as prior line therapy.

Results (Arms 1 & 3):

Efficacy: As of the data cut-off, 32 patients in Arm 1 and 22 patients in Arm 3 received at least one efficacy evaluation.

• Confirmed Intracranial ORR:
  • Arm 1 (monotherapy): 84.4%
  • Arm 3 (combination with Bevacizumab): 72.7%
• Median Progression-Free Survival (PFS):
  • Arm 1 (monotherapy): 13.2 months
  • Arm 3 (combination with Bevacizumab): Only 6 PFS events were reported, indicating that the PFS data was immature for this arm.

Safety Profile:

The most common Grade 3 and 4 treatment-related adverse events (TRAEs) were hematologic toxicities.

TRAEs and Dose Reductions:

• Arm 1 (monotherapy): 18.2% experienced TRAEs, and over 75% had dose reductions.
• Arm 3 (combination with Bevacizumab): Only one patient experienced TRAEs, and dose reductions were less common.
• Discontinuations: No SHR-A1811 discontinuations were reported due to adverse events.
• Interstitial Lung Disease (ILD): Only two patients reported ILD (one in each arm).

Limitations:

• The REIN trial is an investigator-initiated, small-sample, exploratory trial. Key limitations include:
• Lack of a randomized controlled design.
• Absence of pharmacokinetic and biomarker analysis due to limited funding.

Conclusion

SHR-A1811 monotherapy or in combination with Bevacizumab both demonstrated high intracranial response rates and moderate safety in radiotherapy-naive HER2-positive breast cancer patients with active brain metastases. These findings provide strong evidence for the use of SHR-A1811 in this challenging patient population and support further exploration in larger, more definitive studies.

Sacituzumab Tirumotecan (sac-TMT) as First-line Treatment for Unresectable Locally Advanced/Metastatic Triple-Negative Breast Cancer (a/mTNBC): Initial Results from the Phase II OptiTROP-Breast05 Study

Speaker: Yongmei Yin

Introduction

This session presents initial results from the Phase II OptiTROP-Breast05 study, evaluating sac-TMT as a first-line treatment for unresectable a/mTNBC.

The Unmet Need in TNBC Treatment

The current standard first-line treatment for PD-L1 negative TNBC is chemotherapy. However, this approach yields modest outcomes, with an ORR of only 35-45% and a mPFS of 5-7 months. These figures highlight a critical need for more effective treatments in this patient population.

Sac-TMT: A Promising Therapeutic

Trop-2, a protein overexpressed in 70-80% of TNBC cases and associated with poorer prognosis, is the target of sac-TMT. Sac-TMT is a Trop-2 ADC that has already been approved in China for second-line or later TNBC treatment. In prior studies, sac-TMT demonstrated superior efficacy compared to chemotherapy, with a median PFS of 6.7 months versus 2.5 months (HR: 0.32), and median Overall Survival (OS) not reached versus 9.4 months for chemotherapy (HR: 0.53).

OptiTROP-Breast05 Study Design and Patient Characteristics:

• The OptiTROP-Breast05 study is a Multicenter, open-label, Phase II trial investigating sac-TMT monotherapy (5 mg/kg) as first-line systemic therapy for a/mTNBC.
• The study included patients regardless of their PD-L1 status, requiring a Disease-Free Interval (DFI) of at least six months.
• Primary Endpoint: ORR by investigator assessment.
• Secondary Endpoints: PFS, DOR, DCR, and OS.

Baseline Characteristics

• Over 61% of patients had visceral metastases, and 29.3% had de novo metastases.
• Regarding DFI, 19.5% had a DFI of 6-12 months, and 51.2% had a DFI of over 12 months.
• Prior treatments included radiotherapy (36.6%) and chemotherapy (65.9%).
• 6% of patients had received prior immunotherapy.
• The majority of patients exhibited low PD-L1 expression.

Results

Efficacy: The study reported compelling efficacy data for sac-TMT:

• ORR:
  • All patients: 70.7%
  • PD-L1 CPS < 10 subgroup: 71.9%
  • This indicates anti-tumor response regardless of PD-L1 expression.
• DCR:
  • All patients: 92.7%
  • PD-L1 CPS < 10 subgroup: 93.8%
  • Median Duration of Response (DOR): 12.2 months, with a 12-month DOR rate of 40.6%.
• mPFS:
  • All patients: 13.4 months, with a 12-month PFS rate of 64.6%.
  • PD-L1 CPS < 10 subgroup: 13.1 months, with a 12-month PFS rate of 59.1%.
  • The PFS benefit was consistently observed regardless of PD-L1 expression.

Safety Profile

• Sac-TMT demonstrated a manageable safety profile:
• Most Common Grade 3 or Higher TRAEs: Neutrophil count decrease, white blood cell count decrease, and anemia.
• Neuropathy and Interstitial Lung Disease (ILD): No new reports of neuropathy or ILD were observed.
• Treatment-Related Deaths: No treated or treatment-related deaths were reported.

Conclusion

The OptiTROP-Breast05 study's initial results confirm that sac-TMTexhibits promising anti-tumor activity as a first-line treatment for patients with a/mTNBC, independent of their PD-L1 status. The high ORR (70.7% overall, 71.9% in PD-L1 CPS < 10 subgroup) and favorable mPFS (13.4 months overall, 13.1 months in PD-L1 CPS < 10 subgroup) are notable. Coupled with a manageable safety profile and no treatment-related deaths, these findings strongly support the ongoing Phase III studies, suggesting sac-TMT could become a new therapeutic cornerstone for this aggressive disease.

De-escalated Neoadjuvant Taxane plus Trastuzumab and Pertuzumab with or without Carboplatin in HER2-positive Early Breast Cancer (neoCARHP): A Multicentre, Open-Label, Randomised, Phase 3 Trial

Speaker: Kun Wang

Introduction

Dr. Kung Wang from Guangdong Provincial People's Hospital presented the neoCARHP trial during the ASCO 2025 breast cancer oral abstract session. The study evaluated de-escalated neoadjuvant therapy in HER2-positive early breast cancer, specifically comparing THP (taxane + trastuzumab + pertuzumab) with TCHP (THP + carboplatin).

Neoadjuvant TCHP is recommended by ASCO, NCCN, and ESMO for stage II–III HER2+ breast cancer. Prior studies (e.g., BCIRG-007) showed no benefit from adding carboplatin in HER2+ metastatic disease. Weekly paclitaxel + trastuzumab showed comparable efficacy to 3-week regimens. Limited data existed on de-escalated HER2 blockade regimens with or without carboplatin on a 3-week schedule.

Study Design

• Name: neoCARHP (NCT04858529)
• Design: Multicenter, open-label, randomized phase 3 trial
• Population:
• Adults ≥18 years
• Untreated, stage II–III HER2-positive breast cancer
• Sample Size: 774 patients randomized 1:1
• Stratification: Hormone receptor status and nodal status

Arms and Interventions

• THP × 6 Q3W (n=387)
  • Drugs:
    • Investigator-selected taxane*
    • Trastuzumab IV 6 mg/kg (loading 8 mg/kg)
    • Pertuzumab IV 420 mg (loading 840 mg)
  • *Taxane options: Docetaxel, Paclitaxel, or Nab-paclitaxel
  • Frequency: Every 3 weeks × 6 cycles
• TCbHP × 6 Q3W (n=387)
  • Same as THP plus Carboplatin IV AUC 6 mg/mL/min
  • Frequency: Every 3 weeks × 6 cycles
• Post-Treatment: All patients proceeded to surgery

Endpoints

• Primary Endpoint: Pathologic complete response (pCR: ypT0/is ypN0)
• Secondary Endpoints:
  • Safety
  • Clinical response during neoadjuvant therapy
  • EFS, DFS, OS

Results

Efficacy

• pCR rate:
  • THP: 64.1%
  • TCHP: 65.9%
  • Absolute difference: -1.8% (95% CI lower bound -8.5%)
• Conclusion: THP was non-inferior to TCHP (non-inferiority margin = -10%).
• Subgroup analysis:
  • HR-negative/HER2+: pCR ~78% in both arms.
  • HR-positive/HER2+: THP = 56%; TCHP = 58.8%.
• Overall response rate (ORR): THP = 92%, TCHP = 94%.

Safety

• Grade ≥3 hematological AEs were significantly lower in THP:
  • Neutropenia: 7% (THP) vs 60% (TCHP)
  • Thrombocytopenia: 0.3% (THP) vs 4% (TCHP)
  • Anemia: 6% (THP) vs 10% (TCHP)
• Non-hematologic AEs (e.g., nausea, vomiting, creatinine increase) were also less frequent in THP.
  • Vomiting: 17% (THP) vs 29% (TCHP)
  • Creatinine increase: 2.6% (THP) vs 16% (TCHP)

Conclusion

THP regimen (without carboplatin) was non-inferior in pCR compared to TCHP, with better tolerability and fewer adverse events. This supports carboplatin omission as a de-escalated neoadjuvant strategy for HER2+ early breast cancer when dual HER2 blockade is used.

NRG-BR003: A Randomized Phase III Trial Comparing Doxorubicin Plus Cyclophosphamide followed by Weekly Paclitaxel with or without Carboplatin for Node-positive or High-risk Node-negative Triple Negative Breast Cancer (TNBC)

Speaker: Vicente Valero

Introduction

Dr. Valero presented the results of the NRG-BR003 trial, a randomized Phase III study. The trial compared a standard chemotherapy regimen (doxorubicin plus cyclophosphamide followed by weekly paclitaxel) with or without the addition of carboplatin in patients with node-positive or high-risk node-negative TNBC.

Study Design

• Patients: Resected node-positive or high-risk node-negative TNBC (tumor > 3 cm).
• Treatment Arms:
  • Control Arm: Dose-dense AC (doxorubicin + cyclophosphamide) for 4 cycles, followed by weekly paclitaxel for 12 weeks.
  • Experimental Arm: Dose-dense AC for 4 cycles, followed by weekly paclitaxel for 12 weeks plus carboplatin (AUC 5 every 3 weeks).
• Primary Endpoint: Invasive Disease-Free Survival (IDFS).
• Randomization: 769 patients were randomized (385 to control, 384 to experimental).

Patient Characteristics

• About one-third of patients were 60 years or older, with the majority being white.
• Most patients had ER less than one.
• Approximately one-third had node-negative breast cancer; the majority of node-positive patients had 1-3 positive nodes.
• About 10% of patients who underwent genetic testing had a germline mutation.
• Approximately 60% of tumors were T2 in size, and the great majority were Grade 3 breast cancer.

Results

• Drug Delivery: The addition of carboplatin did not significantly impact the administration of paclitaxel. Approximately 75% of patients in the experimental arm received carboplatin as planned.
• Invasive Disease-Free Survival (IDFS):
  • At five years, IDFS was 82.7% for the carboplatin arm versus 77.8% for the control arm.
  • The addition of carboplatin did not result in a statistically significant improvement in IDFS.
• Overall Survival (OS): At five years, OS was 87.7% for the carboplatin arm versus 84.4% for the control arm (Hazard Ratio: 0.81).
• Distant Recurrence-Free Survival (DRFS): At five years, DRFS was 84.4% for the carboplatin arm versus 84.4% for the control arm (Hazard Ratio: 0.76).

Adverse Events (AEs)

• The carboplatin arm had a higher number of Grade 3 and Grade 4 adverse events.
• There was a significant increase in hematopoietic toxicity, including a higher incidence of anemia and thrombocytopenia in the carboplatin arm.
• No significant difference in the rate of neutropenic fever.
• Two patients in the control arm and three in the carboplatin arm developed myelodysplasia leukemia.

Conclusion

The addition of carboplatin (AUC 5 every three weeks for four cycles) to weekly paclitaxel, following dose-dense AC for four cycles, as adjuvant therapy for node-positive or high-risk node-negative TNBC, did not lead to a statistically significant improvement in invasive disease-free survival. However, it did increase treatment-related Grade 3 and higher adverse events.

A Phase 2 Study of Response-guided Neoadjuvant Sacituzumab Govitecan and Pembrolizumab (SG/P) in Patients with Early-stage Triple-negative Breast Cancer: Results from the NeoSTAR Trial

Speaker: Rachel Abelman

Introduction

• SG is a Trop-2 directed antibody-drug conjugate approved for metastatic TNBC and HR-positive/HER2-negative metastatic breast cancer.
• Pembrolizumab (Pembro) is an anti-PD-1 monoclonal antibody approved for early TNBC and metastatic PD-L1 positive TNBC.
• The current standard of care for stage II/III TNBC involves preoperative chemotherapy with four agents, including an anthracycline and pembrolizumab.
• Previous NeoSTAR A1 study of SG monotherapy in early TNBC showed a 30% PCR rate. This presentation details NeoSTAR A2, which combined SG and Pembro.

Study Design

• Eligible patients: At least T2 or node-positive early TNBC.
• Treatment regimen: Four cycles of SG (10 mg/kg on days 1 and 8 of a 21-day cycle) and Pembro (200 mg on day 1 of a 21-day cycle).
• Response-guided approach:
  • After initial 4 cycles, patients underwent imaging.
  • If residual disease was suspected, a research biopsy was performed. If positive, additional neoadjuvant chemotherapy (investigator discretion, off-study) was given.
  • If no residual disease was suspected, patients proceeded directly to definitive breast surgery.
  • Patients achieving pCR remained on trial and received four cycles of taxane and carboplatin along with pembrolizumab to complete one year of treatment.
  • Those with residual disease at surgery received adjuvant chemotherapy off-study (investigator discretion).
• Primary outcome: PCR after neoadjuvant SG and Pembro only.
• Secondary outcomes: Need for additional chemotherapy, radiographic response, safety and tolerability, and event-free survival.

Patient Characteristics

• 50 patients were enrolled.
• Median age: 57 years.
• 96% were Stage II at diagnosis & remaining 4% at Stage III.
• 5 patients (10%) had a pathogenic germline BRCA mutation.
• 32 patients (64%) had a node negative lymph node status.
• ER status was negative in 42 patients (84%) at initial biopsy.

Results

• All 50 patients completed the trial regimen of neoadjuvant SG/Pembro for four cycles.
  • 24 patients had no residual disease suspected after the initial regimen.
  • 16 patients (32%) achieved PCR after SG/Pembro only.
  • Overall PCR rate: 32%.
• 26 patients had suspected residual disease and received additional neoadjuvant chemotherapy.
• Nine of these patients achieved PCR after SG/Pembro plus additional non-anthracycline chemotherapy.
• Patients with germline BRCA mutations (n=5): 60% PCR rate with SG/Pembro alone, with one additional patient achieving PCR after SG/Pembro and additional chemotherapy.
• 18-month event-free survival: 90.6%.
• Radiographic response rate: 66%.

Safety

• No unexpected or new toxicities were observed.
• 88% of patients completed the trial regimen.
• 26% of patients utilized growth factor for secondary prophylaxis.

Conclusion

This was the first trial to investigate the SG/Pembro combination in early TNBC. Four cycles of SG/Pembro achieved a 32% PCR rate with no new safety signals and minimal treatment discontinuations. A total of 50% of the cohort achieved PCR with either the initial regimen or with subsequent non-anthracycline chemotherapy. Further research is needed to determine if longer durations of SG/Pembro could increase PCR rates. Ongoing translational analysis aims to identify biomarkers for response to SG/Pembro.

Dalpiciclib (Dalp) plus Endocrine Therapy (ET) as Adjuvant Treatment for HR+/HER2– early Breast Cancer (BC): The Randomized, Phase 3, DAWNA-A Trial

Speaker: Zhi-Ming Shao

Introduction

HR-positive, HER2-negative breast cancer is the most common subtype, often diagnosed at an early stage. Adjuvant endocrine therapy is crucial for reducing recurrence and metastasis risk, but a substantial risk of recurrence remains. Dalpiciclib, a potent CDK4/6 inhibitor, has shown significant improvement in progression-free survival when combined with ET in advanced breast cancer.

The DAWNA-A trial aimed to evaluate dalpiciclib with ET as adjuvant therapy for HR-positive, HER2-negative early breast cancer.

Study Design

Eligibility Criteria

Pathologically confirmed Stage II or III HR-positive, HER2-negative breast cancer.

• Patients with either:
  • More than four positive lymph nodes.
  • One to three positive lymph nodes AND one or more high-risk factors (tumor size > 5 cm, histological Grade 3, or residual invasive breast cancer after neoadjuvant therapy, or Ki-67 > 30%).

Randomization: Patients were randomized into two groups:

• Experimental Group: Dalpiciclib plus standard-of-care endocrine treatment.
• Control Group: Placebo plus standard-of-care endocrine treatment.

Primary Endpoint: Invasive Disease-Free Survival (IDFS).

Secondary Endpoints: Disease-Free Survival (DFS), Distant Disease-Free Survival (DDFS), Overall Survival (OS), and Safety.

Patient Disposition and Characteristics:

• A total of 5,274 patients were randomized, with approximately 2,625 patients in each group.
• Patient characteristics (age, ECOG PS, menopausal status, hormone receptor status) were well-balanced between the two groups.

Results

• Primary Endpoint (IDFS):
  • The dalpiciclib group showed a 2-year IDFS rate of 94.7% compared to 90.2% for the placebo group, representing an absolute difference of 4.5%.
  • The hazard ratio (HR) for IDFS was 0.56 (p < 0.001), indicating a statistically significant benefit with dalpiciclib.
  • The benefit was consistent across all pre-specified subgroups.
• Secondary Endpoints (DFS, DDFS):
  • DFS: Events were 4.1% in the dalpiciclib group versus 7.4% in the placebo group (HR: 0.53, p = 0.001).
  • DDFS: Similar favorable trends were observed for DDFS.
  • Clinically meaningful improvements in DFS and DDFS were observed with dalpiciclib plus endocrine treatment.

Safety Profile

As expected, the dalpiciclib arm experienced more Grade 3/4 adverse events, particularly neutrophil count decrease and diarrhea. However, the side effects were well-tolerated by patients and were consistent with previous data from advanced settings.

Conclusion

The Phase III DAWNA-A trial met its primary endpoint at the first internal analysis, demonstrating a significant IDFS benefit with dalpiciclib plus endocrine treatment compared to placebo plus endocrine treatment. The benefits were consistent across subgroups, and clinically meaningful improvements were seen in DFS and DDFS. These data support dalpiciclib plus endocrine treatment as a new treatment option for HR-positive, HER2-negative early breast cancer, particularly in Chinese populations.

15-year Outcomes for Women with Premenopausal Hormone Receptor-positive Early Breast Cancer (BC) in the SOFT and TEXT Trials Assessing Benefits from Adjuvant Exemestane (E) + Ovarian Function Suppression (OFS) or Tamoxifen (T) + OFS

Speaker: Prudence A. Francis

Introduction

The SOFT and TEXT trials were designed to assess the value of adding OFS to adjuvant T in premenopausal women. There was also interest in whether aromatase inhibitors (like exemestane) would be more effective than T in this population when combined with OFS, similar to their known benefits in postmenopausal women.

• SOFT Trial: Randomized premenopausal women to 5 years of adjuvant endocrine therapy with T alone, T + OFS, or exemestane + OFS. Prior chemotherapy was optional, but a premenopausal estradiol level was required afterward.
• TEXT Trial: All patients received OFS and were randomized to T or exemestane. Chemotherapy, if given, was concurrent with OFS.

A joint analysis of TEXT and the two OFS arms from SOFT provided a median follow-up of 16 years.

The analysis primarily focused on HER2-negative patients, as adjuvant trastuzumab was not standard when the trials were planned.

Key Findings

 Breast Cancer-Free Interval (BCFI)

• Exemestane + OFS demonstrated the highest BCFI, followed by T + OFS, and then T alone.
• Adding OFS to T resulted in a durable, significant reduction in invasive breast cancer recurrence, leading to a 3.7% absolute improvement in 15-year BCFI compared to T alone.
• Exemestane + OFS showed a further reduction in events, with a 30% relative reduction and a 6.5% absolute improvement in 15-year BCFI compared to T alone.
• Despite these benefits, invasive breast cancer events continued to occur over 15 years in all treatment arms.
• In the SOFT chemotherapy cohort, the addition of OFS to T led to a 5.4% absolute improvement in 15-year BCFI, while exemestane + OFS showed an 8.4% absolute improvement compared to T alone.
• OFS had a greater impact on local, regional, and contralateral invasive breast cancer events than on distant metastases, especially in the no-chemotherapy cohort.

Overall Survival (OS)

• In the no-chemotherapy cohort, high rates of 15-year OS were observed across all three arms.
• In premenopausal women who received prior chemotherapy, the addition of OFS to T did not result in a meaningful improvement in OS. However, exemestane + OFS showed a 4.3% absolute improvement in 15-year OS compared toT alone.
• The joint analysis of SOFT and TEXT (comparing exemestane + OFS vs. T+ OFS showed an 11% relative reduction in deaths favoring the exemestane group. This translated to absolute improvements in 15-year OS of 2.5% for TEXT (prior chemotherapy cohort) and 3.9% for SOFT (prior chemotherapy cohort), both favoring exemestane + OFS.

Outcomes in High-Risk Subgroups

• Very Young Women (under 35 years at diagnosis with HER2-negative tumors): This subgroup, at higher risk for recurrence, showed large absolute improvements in BCFI and OS with OFS. Despite this, approximately one-third of these patients still experienced an invasive breast cancer event by 15 years with exemestane + OFS.
• For women under 40, exemestane + OFS compared to T + OFS showed an approximate 7.5% absolute difference in 15-year freedom from distant recurrence and an approximately 3.7% absolute improvement in 15-year OS.

Patients with Grade 3 Tumors (HER2-negative)

• Exemestane + OFS showed a large absolute increase in 15-year BCFI compared to T+ OFS.
• In TEXT (grade 3 tumors), exemestane + OFS showed a 4.5% absolute improvement in 15-year OS compared to T + OFS.
• In SOFT (grade 3 tumors), exemestane + OFS showed an 8.4% absolute increase in 15-year OS compared to T alone. Adding OFS to T did not significantly improve OS in this subgroup.
• The largest absolute benefits in freedom from distant recurrence and OS with exemestane + OFS versus T + OFS were observed in patients with grade 3 tumors and women 40 years of age.

Conclusion

Long-term follow-up from the SOFT and TEXT trials confirms a durable reduction in invasive breast cancer events with OFS. Exemestane + OFS provides additional benefits over T alone (6.5% absolute improvement in 15-year BCFI) and T + OFS (25% relative risk reduction for distant recurrence). However, invasive breast cancer events continue to occur over 15 years across all treatment arms, particularly in younger patients.

While OFS reduced local, regional, and contralateral events, many patients, especially in the no-chemotherapy cohort, did not derive a meaningful clinical benefit in overall survival from OFS. Significant absolute benefits in BCFI and OS with OFS were observed in high-risk subgroups, specifically very young women (under 35) and those with grade 3 tumors. For patients with grade 3 tumors, the aromatase inhibitor + OFS option significantly improves outcomes compared to T+ OFS, suggesting that adding OFS to T alone may not be sufficient for these high-risk cases.

Updated Survival Outcomes and Predictors of Benefit from Ovarian Function Suppression in Premenopausal Women with Hormone-receptor–positive Breast Cancer: Results from the ASTRRA Trial

Speaker: Jai Min Ryu

Introduction & Study Design

• The ASTRRA trial aimed to evaluate the benefit of adding OFS to T in premenopausal HR+ breast cancer patients.
• Eligibility: Premenopausal women aged 45 and younger, with HR+ (ER positive) Stage I-III primary breast cancer, who had undergone definitive surgery and anthracycline or taxane-based chemotherapy.
• OFS Assessment: Ovarian function was evaluated every six months for two years based on FSH levels and vaginal bleeding.
• Randomization: Patients who remained or resumed premenopausal status were randomized to either five years of T alone or five years of T with two years of OFS.
• Endpoints: The primary endpoint was disease-free survival (DFS) from enrollment, with secondary endpoints including overall survival (OS). An unplanned analysis also included breast cancer-free interval (BCFI).
• Extended Follow-up: This presentation includes extended follow-up data (median 127 months) from 29 of 35 participating institutions.

Key Findings: Disease-Free Survival (DFS)

• Consistent and Significant Benefit: The updated data demonstrates a consistent and significant benefit from adding two years of OFS to T.
• Hazard Ratio: The hazard ratio for DFS was 0.68 for the T + OFS group compared to the T-only group.
• Absolute DFS Improvement: There was a notable 7.8% absolute improvement in 10-year DFS, with rates of 83.7% for T + OFS versus 75.9% for T alone.
• Similar DFS results were observed when measured from the randomization point.

Key Findings: Overall Survival (OS)

• No Significant Difference in OS: No significant difference in overall survival was observed between the two treatment groups.
• Predictors of Benefit: Composite Risk Model (HER2-Negative Cohort)
• A simplified composite risk model was developed for the HER2-negative cohort to identify patients who would derive the greatest benefit from OFS. This model incorporates:
  • Tumor size
  • Lymph node status
  • Tumor grade

Patients were categorized into low, intermediate, and high-risk groups based on this composite score.

• Low-Risk Group: The addition of OFS did not significantly improve BCFI in the low-risk group, as their 10-year BCFI rates already exceeded 90%.
• High-Risk Group: The high-risk group showed a significant benefit from the addition of OFS in terms of 10-year BCFI.

Age-Specific Benefits within High-Risk Group

• Younger than 40 years old (High-Risk): Patients younger than 40 within the high-risk group did not show a significant improvement with OFS, as their 10-year BCFI rates remained below 75%.
• Aged 40-45 years (High-Risk): This specific subgroup demonstrated the most notable improvement from OFS. They experienced an 18.3% absolute increase in 10-year BCFI, with rates of 82.9% for T + OFS compared to 64.7% for T alone.

Conclusion

• The ASTRRA trial's extended follow-up confirms a consistent and significant disease-free survival benefit (7.8% absolute improvement at 10 years) from adding two years of OFS to T in premenopausal women with HR+ breast cancer who maintain or restore premenopausal status after chemotherapy.
• No significant overall survival benefit was observed.
• A composite risk model (tumor size, lymph node status, tumor grade) was developed to enhance patient selection.
• The greatest benefit from OFS was observed in high-risk patients aged 40-45 years, who showed an 18.3% absolute increase in 10-year BCFI.
• These findings can guide shared decision-making by balancing the benefits of recurrence reduction with the potential toxicities and impact on quality of life associated with OFS.

ASCO 2025, May 30 – June 3, Chicago