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Even when diagnosed early, triple-negative breast cancer (TNBC) has a higher mortality rate compared with other breast cancer subtypes due to its aggressive nature.

However, results from the randomized KEYNOTE-522 study showed an improvement in overall survival (OS) in patients with stage II-III TNBC who received pembrolizumab (Keytruda) before and after surgery plus neoadjuvant chemotherapy compared with those who received only neoadjuvant chemotherapy, with 5-year OS rates of 86.6% versus 81.7% (HR 0.66, 95% CI 0.50-0.87, P=0.00150).

Based on the results of this study, current recommendations suggest that TNBC patients with tumors larger than 2 cm or with axillary lymph node involvement should be treated with a combination of four chemotherapy drugs and an immune checkpoint inhibitor for 1 year.

"All stage II-III TNBC patients should get neoadjuvant therapy that includes pembrolizumab, as long as the patient has no contraindications to immunotherapy, because I worry that the same level of benefit with immunotherapy may not exist after the tumor has been removed," Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, told 名媛直播.

In KEYNOTE-522, all patients received pembrolizumab postoperatively, irrespective of the response at the time of surgery, "but that's not how we practice," she said. "If a patient has residual disease, we tend not to give pembrolizumab alone but capecitabine plus pembrolizumab."

Not all patients with early TNBC need such intensive treatment, and researchers are exploring possibilities to de-escalate therapy in certain patient subgroups.

"The five-drug regimen is a lot of therapy for a patient with stage II-III TNBC," Tolaney said. "We have no biomarkers at this point to help us determine who needs immunotherapy or who needs all the drugs in the regimen."

The study is aiming to determine whether neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab (Imfinzi) followed by adjuvant durvalumab improves efficacy and safety compared with the pembrolizumab-based regimen in patients with previously untreated early TNBC or hormone receptor-low/HER2-negative breast cancer. Dato-DXd is a TROP2-directed antibody-drug conjugate (ADC) that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor.

"In essence, the ADC is replacing all of the chemotherapy given in KEYNOTE-522," said Tolaney.

Stage I TNBC

The optimal management strategy for patients with stage I TNBC is less clear. These patients represent a large proportion of those with TNBC yet have been underrepresented in clinical trials of systemic therapy, creating a knowledge gap, said Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City.

"In most academic medical centers, we tend not to treat with chemoimmunotherapy for stage I TNBC," she told 名媛直播.

Tolaney noted that "we tend to take patients to upfront surgery if they have very small triple-negative cancers [<1.5 cm] and are node negative. Otherwise, I will give them preoperative chemotherapy, but not with immunotherapy."

Fewer than 10% of patients with stage I TNBC will recur when treated with chemotherapy.

"Whether patients with T1c tumors should receive neoadjuvant systemic therapy versus surgery first and adjuvant therapy differs by physician choice and the institution," said Sharma. "We know from retrospective large datasets that patients with T1b and T1c TNBC have suboptimal outcomes if we do not give chemotherapy, so it is recommended that patients with T1b and T1c disease receive some form of systemic chemotherapy, and whether that should come before or after surgery, and for T1c, whether that should include immunotherapy, is an open question."

Neoadjuvant chemotherapy in patients with T1c TNBC would provide an opportunity to tailor adjuvant treatment (such as capecitabine) based on response, she added.

High-risk biology and younger age are other factors that may point to the need for neoadjuvant therapy in patients with stage I TNBC, since toxicity from systemic therapy is more likely with older age, Sharma said.

In addition, a research genomic tool called TNBC-DX integrates clinical variables and tumor and immune biologic factors across 15 genes to provide a comprehensive risk assessment of early-stage TNBC, with the potential to guide treatment decisions. The to predict pathologic complete response with neoadjuvant chemotherapy in stage I-III TNBC.

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