Following De-Escalated Neoadjuvant T-DM1 in HR+/HER2+ Early Breast Cancer, Biomarkers May Predict Outcomes

When comparing de-escalated neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla), with or without endocrine therapy, vs trastuzumab (Herceptin) plus endocrine therapy baseline tumor immunogenicity may be associated with higher pathologic complete response (pCR) rates and favorable outcomes in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer, according to data from the WSG ADAPT TP trial (NCT01779206) presented at the 2021 ESMO Congress.¹

“After de-escalated therapy, PIK3CA mutations are in 16% of all of our tumors, and was correlated with poor outcome, even after T-DM1, which was, of course, followed by standard chemotherapy and trastuzumab in all non pCR,” Nadia Harbeck, MD, PhD, head, Breast Center, and chair, conservative oncology, Department of OB&GYN, University of Munich, Germany, said during a presentation at the Congress. “The majority of pCR patients with luminal A subtype have the best outcome despite comparatively low pCR rates after HER2-directed therapy.”

In her presentation at the Congress, Harbeck discussed the translational research from the trial, focusing on biomarkers analyzed in the baseline biopsy, immune biomarkers, PIK3CA mutation status, and molecular subtypes.

The researchers found that baseline IHC expression of CD8 (hazard ratio, 0.61; range, 0.36-1.01; P = .052), of PD-L1ic (hazard ratio, 0.32; range, 0.10-1.07; P = .065), and CD8 expression by mRNA (hazard ratio, 0.66; range, 0.47-0.92; P = .015) were associated with a decreased invasive disease-free survival risk. TILs were not associated with a decreased risk.

The PIK3CA mutation was significantly associated with increased iDFS risk in the T-DM1 arms (hazard ratio, 3.66; 95% CI, 1.33-10.06; P = .012). The 5-year iDFS rate for those with PIK3CA-mutated disease was 68.4% (95% CI, 42.8-84.4), and 90.2% (95% CI, 82.5-94.6) in those with wild type disease.

“This is an interesting finding. We already know from the neoadjuvant setting that PIK3CA mutation is associated with poor outcome, particularly in the hormone receptor-positive/HER2-positive tumors. But so far, at least in the metastatic breast cancer setting, T-DM1 efficacy did not seem to be affected by PIK3CAmutation status.”

In total, 55% of patients were luminal A, and had improved 5-year iDFS, compared with others (96% vs 83%, respectively; hazard ratio, 0.50; 95% CI, 0.23-1.08; P = .079). Moreover, in a multivariate analysis, clinical nodal burden was significantly associated with poor iDFS, while ESR1 and CD8 gene expression were favorable factors.

“So our conclusion would be for further treatment de-escalation strategy,” Harbeck said. “They need to be based on pCR rate and outcome in the luminal A subtype. [It is] promising as pCR-directed approaches in the HER2-enriched subtype. Survival data of ADAPT TP II, evaluating paclitaxel pus a dual blockade in the same setting are still pending and will help us to clarify whether the results from ADAPT are representative for the hormone receptor-positive subtype as a whole.”

The multicenter, prospective phase 2 WSG ADAPT TP trial, which is part of the ADAPT umbrella trial (NCT 01779206), evaluated 375 patients with HR+/HER2+ early-stage breast cancer who were randomized 1:1:1 to receive 12 weeks of either 3.6 mg/kg T-DM1, with (n = 127) or without (n = 119) endocrine therapy, or trastuzumab plus endocrine (n = 129).

Standard chemotherapy was recommended after surgery. Chemotherapy omission was allowed in all patients with pCR after study treatment.

The primary end point was pCR, while secondary end points included safety, 5-year iDFS, overall survival (OS), and translational research.

Median follow-up was 60 months.

In 2017, the researchers observed pCR in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and endocrine therapy, and 15.1% with trastuzumab and endocrine therapy (P < .001). Early responders (67% of patients with an assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio [OR], 2.2; 95% CI, 1.24-4.19).²

At the 2020 ESMO Congress, the time to event analysis showed that a pCR was significantly associated with better DFS, with 5-year rates of 92.1% (95% CI, 77.5-97.4) versus 82.7% (95% CI, 77.0-87.1) among those without a pCR (P = .014). Moreover, 5-year DFS rates were comparable between the study arms, at 88.9% for patients given T-DM1, 85.3% for those given T-DM1 plus endocrine therapy, and 84.6% for patients receiving trastuzumab plus endocrine therapy. Distant 5-year DFS were also similar at 91.6%, 92.3% and 88.9%, respectively, and there were corresponding 5-year OS rates of 97.2%, 96.4% and 96.3%.³

_Reference:

_{1. Harbeck N, Nitz U, Christgen M, et al. Predictive impact of biomarkers on pCR and survival after de-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs. trastuzumab+ET in HER2+/HR+ early breast cancer: WSG ADAPT TP trial. Annals of Oncology. 2021;32(suppl_5):S1283-S1346. doi:10.1016/annonc/annonc741.}

_{2. Harbeck N, Gluz O, Christgen M, et al. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET. J Clin Oncol. 2017;35(26):3046-3054. doi:10.1200/JCO.2016.71.9815.}

_{3. Harbeck N, Nitz U, Christgen M, et al. De-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs trastuzumab+ET in early HR+/HER2+ breast cancer (BC): ADAPT-TP survival results. Annals of Oncology. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325.}