Your Tumor's Genetic Profile May Not Change Which Treatment Works Best for TNBC

New findings presented at ASCO 2026 show that a powerful drug combination works better than chemotherapy for triple-negative breast cancer patients regardless of their tumor's genetic makeup meaning more patients may benefit than previously understood.

For patients diagnosed with metastatic triple-negative breast cancer (TNBC) one of the most aggressive and difficult-to-treat forms of breast cancer every piece of information about their tumor feels crucial. Does it carry a BRCA mutation? How much of a protein called Trop-2 does it express? Is it HER2-low? These are questions patients and their doctors have long wrestled with when trying to figure out which treatment gives them the best chance.

But new research presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2026 is challenging the assumption that these biomarkers need to guide the treatment decision at least when it comes to one particular drug combination.

Dr. Sara Tolaney, is a breast medical oncologist and clinical researcher at Dana-Farber Cancer Institute, where she has dedicated her career to improving outcomes for patients with breast cancer, including some of the hardest-to-treat subtypes. She spoke with CURE about the ASCENT-04 biomarker findings and what they mean for patients navigating newly diagnosed metastatic TNBC. Her work sits at the intersection of clinical care and translational research, and she brings both depth of expertise and a clear commitment to making complex science accessible to the patients she serves.

What Was This Study Looking At?

The ASCENT-04 trial, which previously established that combining Trodelvy (sacituzumab govitecan) a targeted therapy known as an antibody-drug conjugate with Keytruda (pembrolizumab) significantly extended the time patients lived without their cancer progressing compared to chemotherapy plus Keytruda (pembrolizumab). That combination is now considered a standard of care option for patients with previously untreated PD-L1-positive metastatic TNBC.

The new analysis dug deeper, asking a more specific question: does a patient's tumor biology specifically their level of Trop-2 protein expression, their BRCA mutation status, and their HER2 expression affect how well they respond to Trodelvy plus Keytruda?

What Did the Findings Show?

The answer, across every biomarker examined, was consistent: Trodelvy plus Keytruda outperformed chemotherapy plus Keytruda regardless of tumor profile.

Patients with low Trop-2 expression benefited. Patients with high Trop-2 expression benefited. Patients with BRCA mutations benefited. Patients without BRCA mutations benefited. Patients whose tumors were HER2 IHC 0 benefited. Patients with HER2-low tumors benefited. In every subgroup analyzed, the Trodelvy based combination came out ahead.

"What we're seeing from the biomarker analyses across both ASCENT-03 and ASCENT-04 is that we don't have a biomarker that would help us distinguish which patient would need [Trodelvy] sacituzumab govitecan over chemotherapy plus [Keytruda] pembrolizumab simply because all patients benefited with [Trodelvy] over chemotherapy irrespective of biomarker status," said Tolaney.

What is an Antibody-Drug Conjugate?

Trodelvy (sacituzumab govitecan) is a type of therapy called an antibody-drug conjugate, or ADC. Think of it as a guided missile: the antibody portion seeks out a protein called Trop-2 that is found on the surface of many cancer cells, and once it locks on, it delivers a powerful cell-killing payload directly to the tumor. This targeted approach means the drug can attack cancer cells more precisely than traditional chemotherapy.

Why Does This Matter for Patients?

For a patient sitting across from their oncologist after a metastatic TNBC diagnosis, the question of which treatment to pursue is one of the most consequential they will face. Historically, biomarker testing has helped guide those decisions the idea being that certain tumor characteristics might predict whether a given drug is likely to work.

What this analysis suggests is that when it comes to Trodelvy plus Keytruda in the first-line setting, that calculus may be simpler than expected. You do not need to have high Trop-2 expression to benefit. You do not need to have a BRCA mutation or lack one to benefit. The drug combination appears to work broadly.

"It's not that you need to be testing your patient to know how high a level of Trop-2 they have, because irrespective of Trop-2 expression, [Trodelvy] based treatment is always doing better than chemotherapy," Tolaney said.

Why Getting the Best Treatment First Matters So Much

One of the most powerful points Tolaney made in discussing these findings is about timing specifically, why using the most effective therapy at the very start of treatment matters so deeply for patients with TNBC.

In the ASCENT trials, patients in the chemotherapy arm were offered Trodelvy if their cancer progressed, and more than 80% of them went on to receive it. Yet even with that crossover, patients who received Trodelvy first still fared better overall they had longer disease control from the time of their initial treatment through their next line of therapy.

"It's really important, particularly with triple-negative breast cancer, that we give our most effective therapy upfront. We know that it allows patients to have their disease controlled longer, and that also allows them to live better for a longer period of time," Tolaney said.

"Even if you give it second, you're still having a longer time with disease control than the people who got it second so giving this drug upfront is actually really important," she added.

What About Side Effects?

Managing side effects is a real and important part of life on this treatment, and Tolaney was candid about what patients and their care teams should know going in.

The most common significant side effect is neutropenia a drop in white blood cells that can increase the risk of infection. This is closely monitored with blood counts at each visit, which occurs on days one and eight of every 21-day cycle. For patients at higher risk such as those who are older, have had neutropenia before, or start with lower blood counts doctors may consider proactively giving growth factor support to help the body produce more white blood cells and reduce that risk.

Diarrhea is another side effect patients should be prepared for. Tolaney recommends that patients have loperamide (Imodium) on hand before they even start treatment, so they are ready to manage it quickly if it occurs.

Importantly, Tolaney noted that despite the treatment's side effect profile, patients actually discontinue Trodelvy due to adverse events less frequently than patients discontinue chemotherapy in part because the side effects of Trodelvy tend to be more manageable and less likely to become treatment-limiting over time.

"If they do get any infectious symptoms or low-grade fevers, they do need to call us right away, so that we can make sure they're not neutropenic at that time and initiate appropriate therapy," Tolaney said.

The Bottom Line for Patients

The message Tolaney wants patients with newly diagnosed metastatic TNBC to take away from these findings is one of clarity and encouragement. For patients whose tumors are PD-L1-positive, the combination of Trodelvy plus Keytruda is a strong upfront option and your specific tumor biomarker profile should not be a reason to hesitate.

For patients whose tumors are PD-L1-negative, Trodelvy alone, supported by data from the ASCENT-03 trial, is an option worth discussing with your oncologist.

"[Trodelvy] should be used in the upfront setting," Tolaney said. "I think overall it really just supports the use of [Trodelvy] plus Keytruda, irrespective of biomarker status, in patients who have previously untreated metastatic triple-negative breast cancer that is PD-L1-positive."

What Comes Next?

While these findings are practice-affirming, Tolaney and her colleagues acknowledge that questions remain. The subgroup analyses involved smaller numbers of patients, which means they should be interpreted with some caution. As more antibody-drug conjugates enter this space some targeting proteins other than Trop-2 the field will need to develop new ways of thinking about which patients should receive which ADC. Future research will likely focus on refining that picture further.

But for now, the consistency of the benefit across all biomarker subgroups is itself a meaningful signal and one that makes the treatment decision a little less complicated for patients and their doctors.

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