De-Escalated Neoadjuvant Treatment Does Not Compromise Survival Outcomes in HR+/HER2+ Early Breast Cancer

Oleg Gluz, MD

Comparable survival outcomes between a course of either neoadjuvant endocrine therapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta) or de-escalated chemotherapy plus the anti-HER2 blockade doublet reinforce the feasibility and safety of using shorter, de-escalated approaches in the neoadjuvant setting for patients with HER2-positive, hormone receptor–positive early breast cancer, allowing select patients to avoid prolonged chemotherapy, according to Oleg Gluz, MD.

Findings from the prospective phase 2 WSG-TP-II trial (NCT03272477), which were presented at the 2024 ESMO Congress, demonstrated high efficacy and tolerability with the 12-week neoadjuvant endocrine therapy regimen. Although the incidence of early pCRs were higher in the de-escalated chemotherapy arm (n = 100; 57 pCR cases) vs the endocrine therapy arm (n = 107; 23 pCR cases), long-term survival outcomes were similar with both regimens. The 5-year event-free survival (EFS) rates were 92.1% with the endocrine-based regimen vs 94.8% with the chemotherapy-based regimen (HR, 1.29; 95% CI, 0.26%-2.32%; P = .65); 5-year overall survival (OS) rates were 100% vs 97.9%, respectively. Notably, multivariable analysis revealed that only initial tumor burden, rather than treatment regimen, was predictive for EFS outcomes.

“In other words, it’s absolutely safe to start with de-escalated treatment with endocrine therapy plus double [anti-HER2] blockade and give chemotherapy only to patients with no response to the de-escalated treatment,” Gluz emphasized during an interview with OncLive®.

In the interview, Gluz, who is a member of the West German Study Group and the chief physician at Breast Center Niederrhein at the Johanniter Bethesda Clinic in Mönchengladbach, Germany, discussed the importance of comparing de-escalated neoadjuvant endocrine therapy vs chemotherapy in hormone receptor–positive, HER2-positive breast cancer; presented key findings showing similar 5-year survival outcomes with both regimens; and highlighted several trials further investigating the viability of these de-escalation strategies.

OncLive: What was the rationale for conducting the WSG-TP-II trial?

Gluz: Currently, all patients with early HER2-positive disease are treated with standard neoadjuvant or adjuvant chemotherapy [typically for] 18 to 24 weeks, in combination with trastuzumab and pertuzumab. This study was planned in 2016. We looked at whether it’s possible to spare one part of this treatment; we compared 2 de-escalated treatments in patients with early hormone receptor–positive, HER2-positive disease. The rationale for us was to [determine] which de-escalated treatment may be the best and the safest way for patients with early breast cancer.

What should be known about the study design and methodology?

[The study enrolled] 277 patients in Germany, and patients were treated with 12 weeks of neoadjuvant endocrine therapy plus trastuzumab and pertuzumab vs 12 weeks of paclitaxel alone in combination with trastuzumab and pertuzumab. After surgery, chemotherapy omission was strongly recommended by the protocol for all patients with a pCR after 12 weeks of neoadjuvant treatment and was recommended to be given to all other patients. Double [anti-HER2] blockade with trastuzumab and pertuzumab was done for 1 year in combination with standard endocrine treatment.

What key efficacy findings from the trial were presented at the 2024 ESMO Meeting?

The findings are interesting because the primary end point of the trial was pCR rate after 12 weeks of treatment. Early pCR rates were clearly higher with the chemotherapy regimen compared with the endocrine treatment. Interestingly, we achieved a pCR in approximately two-thirds of all patients after 12 weeks of treatment. [Conversely], the efficacy was lower in patients treated with endocrine therapy.

However, we looked at the 5-year results from the trial regarding survival, and we have observed very similar survival results from both groups. These findings are very important for the future trials, from this de-escalation point of view. [However,] this high efficacy of 12 weeks of chemotherapy in combination with double [anti-HER2] blockade confirms previous results from our study group [in the phase 2 WSG ADAPT HER2+/HR- trial (NCT01817452)]. This showed that in many patients with hormone receptor–negative, HER2-positive disease, 12 weeks of a fixed chemotherapy backbone may be sufficient enough to omit the longer treatment of 18 or 24 weeks in combination with double [anti-HER2]blockade.

How did outcomes with both regimens compare across key subgroups? Based on these data, are there any patient populations for whom you would not recommend a de-escalated treatment approach?

There were several markers which are clearly predictive for pCR after 12 weeks. For example, HER2 expression was found to be a clear predictive marker. If you look on the survival results, no groups were identified to have a different prognosis. [However], if you look at baseline characteristics, most of our patients had stage IIA disease. [This comprised] tumors more than 2 cm [that were] node negative, or a small tumor with 1 positive lymph node. For these groups of patients—and there are a lot of such patients in our clinical practices—the results are highly applicable in the future. There are few patients [who present with] locally advanced tumors more than 5 cm or with more than 4 positive lymph nodes. I would be careful with this group of patients with large tumors and positive lymph nodes, as they are not the best target for de-escalation.

Are any further investigations planned for this research?

There are several ongoing trials worldwide looking at the same question. There is one [set of] trials in the United States, the phase 3 Compass-HER2 pCR and RD trials [NCT04266249; NCT04457596], looking at 12 weeks of chemotherapy treatment in a larger proportion of patients. There is also the phase 2 PHERGAIN-II trial [NCT04733118] in Europe looking more at the combination of pertuzumab plus trastuzumab plus endocrine treatment in smaller tumors without chemotherapy.

We need the results from both trials to have better understanding and our group is performing the [phase 2] WSG-ADAPT-HER2-IV trial [NCT05704829] looking to compare 12 weeks of chemotherapy treatment with paclitaxel plus double anti-HER2 blockade compared with antibody-drug conjugates like fam-trastuzumab deruxtecan-nxki [Enhertu] given only for 12 weeks. These are the next steps from different groups, and we have to wait for results [from these studies] to figure out the best treatment for our patients.

Reference

Gluz O, Nitz UA, Christgen M, et al. Survival outcome of neoadjuvant endocrine therapy + trastuzumab and pertuzumab (ET+T+P) vs. de-escalated chemotherapy (CT)+T+P in hormone receptor positive (HR+)/HER2+ early breast cancer (EBC): WSG-TP-II trial. Ann Oncol. 2024;35(suppl 2):1-72. doi:10.1016/annonc/annonc1623