Dr Viansone on the Implications of the DESTINY-Breast11 Trial in HER2+ Breast Cancer

“For the first time, we have some data supporting us about the de-escalation of anthracyclines, [which] are the biggest therapy with a lot of toxicity for breast cancer.”

Alessandro A. Viansone, MD, a medical oncologist at Gustave Roussy, discussed how findings from the phase 3 DESTINY-Breast11 trial (NCT05113251), which is evaluating neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) in patients with high-risk HER2-positive early breast cancer, could support a move away from anthracycline-based chemotherapy, and where genomic signatures may further personalize treatment de-escalation in this population.

Anthracyclines have anchored breast cancer chemotherapy for several years and are used across young and elderly patients alike, but they carry substantial acute toxicity and long-term comorbidities, including cardiac effects that persist through extended follow-up, Viansone explained. Data, such as those from DESTINY-Breast11, raise the prospect of curing patients with HER2-positive disease without exposing them to anthracyclines, Viansone said.

He cautioned that the data are not yet mature, and that longer follow-up is needed to determine whether the pathological complete response advantages seen with T-DXd followed by THP vs dose-dense doxorubicin plus cyclophosphamide followed by THP translates into an overall survival (OS) benefit rather than local disease control alone, Viansone noted. Once a pCR and OS benefit are confirmed, the field could move directly to using T-DXd and bypass anthracycline use in these patients, Viansone added.

Additionally, in the adjuvant setting, data from the phase 3 DESTINY-Breast05 trial (NCT04622319) confirmed the benefit of adjuvant T-DXd over ado-trastuzumab emtansine (Kadcyla) in patients with high-risk, HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. If T-DXd migrates into the neoadjuvant phase, Viansone asked, what treatment should follow in the adjuvant phase? THP is an option for most patients, but anthracyclines may retain a role for high-risk disease or tumors that do not respond to neoadjuvant therapy with T-DXd and a taxane, he explained.

A further open question is how genomic signatures will refine these treatment decisions, Viansone said. Data continue to emerge for the HER2DX genomic assay, and the ongoing DEFINITIVE trial (NCT06446882) is randomly assigning patients with clinical stage II to III HER2-positive breast cancer to HER2DX-guided treatment or standard of care to test the value of genomic testing, as is done in hormone receptor–dependent disease, to spare anthracyclines and pertuzumab, or select carboplatin as chemotherapy, Viansone concluded.