Evolving Approaches to Early-Stage and Metastatic TNBC
December 19, 2025
Key Points
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Patients with clinically staged T2 tumors or node-positive triple-negative breast cancer (TNBC) are eligible for KEYNOTE-522. Dose-dense Adriamycin/cyclophosphamide (ddAC) may be considered, although robust evidence supporting this dosing schedule is limited.
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The ASCENT-03 and ASCENT-04 trials demonstrated the efficacy of sacituzumab govitecan (SG), with or without pembrolizumab, in first-line treatment of metastatic TNBC.
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Despite both targeting TROP2, SG and datopotamab deruxtecan (Dato-DXd) differ in adverse effect profiles. SG is commonly associated with neutropenia requiring growth factor support, whereas Dato-DXd primarily causes stomatitis and requires CT chest monitoring due to the risk of interstitial lung disease (ILD).
At a satellite event during the 2025 San Antonio Breast Cancer Symposium, Rahul Gosain, MD, MBA, and Rohit Gosain, MD—the Oncology Brothers—reviewed potential practice-changing clinical trials in early-stage and metastatic TNBC with two breast oncology leaders: Erika Hamilton, MD, FASCO, of Sarah Cannon Research Institute, and Paolo Tarantino, MD, PhD, of Dana-Farber Cancer Institute.
Neoadjuvant Decision-Making in Early-Stage TNBC
The discussion first covered early-stage TNBC and the criteria for neoadjuvant therapy in node-negative disease. Dr. Tarantino explained that patients with tumors less than or equal to 1.5 cm may undergo upfront surgery. In contrast, those with tumors greater than 1.5 cm may be candidates for neoadjuvant therapy to help “figure out if it’s a bad tumor or good tumor,” based on residual disease or pathologic complete response (pCR) at surgery. He noted that for very small tumors, the threshold for omitting adjuvant chemotherapy is still debated—generally around 3 mm—but most oncologists agree that 5 mm is the definitive threshold. Anthracycline-free regimens may be considered for tumors smaller than 1 cm, whereas anthracyclines are typically reserved for tumors larger than 1.5 cm.
For tumors of at least 2 cm, both experts agreed that neoadjuvant therapy with the KEYNOTE-522 regimen is appropriate. Dr. Hamilton said she typically obtains midtreatment imaging and, in select older patients, has omitted AC while still achieving pCR. However, she cautioned that this approach must be carefully discussed with patients.
When deciding on the AC dosing schedule for the KEYNOTE-522 regimen, Dr. Tarantino tends to favor ddAC, based on pre-pembrolizumab data, rather than the every-3-week schedule. He acknowledged that limited evidence supports this approach. In contrast, Dr. Hamilton takes an individualized approach when deciding on ddAC, noting that the combined chemo-immunotherapy regimen is already challenging for some patients to tolerate.
For patients with residual disease, Dr. Hamilton considers capecitabine if patients have limited response (eg, 2- or 3-cm tumors with 4 or 5 mm of residual disease). She also recommends completing 1 year of adjuvant pembrolizumab, even in patients who achieved a good response.
Treatment Considerations in BRCA-Mutated TNBC
The discussion then shifted to the use of carboplatin in patients with tumors greater than 2 cm who have a germline BRCA mutation. Dr. Tarantino stressed that the decision depends on patient age and fitness, favoring neoadjuvant therapy with carboplatin in younger patients but not in older patients with comorbidities. Dr. Hamilton added that BRCA-mutated tumors often respond briskly to chemotherapy and frequently achieve pCR regardless of regimen.
TROP2-Targeted ADCs in Metastatic TNBC
Transitioning to metastatic TNBC, Dr. Tarantino reviewed ASCENT-03 and ASCENT-04, which evaluated SG in PD-L1-negative and PD-L1-positive tumors, respectively. Both trials demonstrated significant improvement in progression-free survival compared with standard chemotherapy, including in patients with recurrent TNBC and de novo metastatic disease. He said that although no overall survival benefit was observed, likely due to crossover, he favors a TROP2 antibody-drug conjugate (ADC) in the first line “to avoid the dropout of patients that may not receive a second-line treatment.”
Dr. Hamilton discussed the TROPION-Breast02 trial, which compared Dato-DXd to standard chemotherapy, emphasizing that “not all ADCs are created equal,” not even those with the same target. Unlike SG, Dato-DXd’s primary adverse effect is stomatitis, which can be managed with a steroid mouthwash. She noted that TROPION-Breast02 included only patients with PD-L1-negative disease, which poses a challenge because oncologists must await PD-L1 results before selecting treatment.
Toxicity Management and Sequencing of ADCs
The discussion then delved into ADC-related adverse effects. Dr. Hamilton described her use of prophylactic growth factor for SG—typically, a long-acting growth factor after day 8. Dr. Tarantino highlighted the risk of ILD with DXd ADCs, including Dato-DXd and trastuzumab deruxtecan, noting that the risk is lower in Dato-DXd. He explained that early detection of grade 1 ILD may allow for rechallenge, potentially at a reduced dose, if imaging shows improvement after steroid treatment. However, based on current guidelines, grade 2 ILD generally warrants permanent discontinuation. Dr. Hamilton noted that she has rechallenged patients with grade 2 ILD, specifically those with mild cases.
Finally, when asked about ADC sequencing, Dr. Tarantino highlighted that real-world data suggest reduced efficacy with a second ADC, with retrospective studies indicating potential cross-resistance. He said that a reasonable strategy might be a “so-called sandwich approach, meaning giving some chemotherapy after the first ADC and then considering another ADC later on in the treatment course.”