Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR plus breast cancer

Abstract Background: Extended endocrine therapy (EET) has shown modest gains in absolute benefit to reduce the long-term risk of recurrence in hormone receptor-positive (HR+) breast cancer but is accompanied by serious adverse events (AEs), such as bone and cardiovascular toxicities, endometrial cancer and other side effects that impair quality of life (QOL). Novel approaches that quantify the benefit-risk balance integrating both survival benefit and harm to determine a net health outcome would advance EET decision making. BCI is a gene expression-based assay that predicts benefit from endocrine therapy. Here, the ability of BCI by HOXB13/IL17BR (H/I) to predict the net benefit from 2.5 vs 5y of extended letrozole in patients treated in the IDEAL trial was examined by integrating both efficacy and toxicity outcomes into a single analysis. Methods: All IDEAL patients with available tumor specimens were eligible for this analysis. The Net Treatment Benefit (NTB) and the Win Ratio (WR) were examined using generalized pairwise comparisons to analyze both efficacy and safety wherein all possible patient pairs, one from each treatment arm, were compared based on several prioritized outcome measures scored as favorable, unfavorable, neutral or uninformative. The first prioritized outcome was recurrence-free survival (RFI) with a clinical threshold of ≥3 months; the second prioritized outcome was toxicity based on the highest grade of treatment related AEs. NTB was estimated as the difference in the proportions of favorable vs unfavorable pairs, representing the net probability of an improved health outcome with EET. WR was calculated as the ratio of favorable vs unfavorable pairs, representing the relative risk of an improvement in health outcomes with EET. AEs were evaluated in annual follow-up visits during the active treatment period. Bone-related AEs of ≥ grade 3 included arthralgia, osteoporosis, decreased joint range of motion, back pain and fracture. The most prevalent QOL-related AEs of ≥ grade 3 included hot flashes, fatigue, depression, insomnia and vaginal dryness. Results: 908 HR+ patients (73% pN+, median age 59y, 45% pT1, 48% pT2) were included, with 88% and 68% receiving prior treatment with an aromatase inhibitor (AI) or chemotherapy, respectively. When toxicity was assessed with treatment related AEs ≥ grade 2, no significant improvement in the benefit-risk was observed for EET in either BCI (H/I)-High or BCI (H/I)-Low group. However, when severe toxicity was assessed with AEs ≥ grade 3, significant benefit-risk improvements were observed for EET in BCI (H/I)-High patients (NTB=7.2%, WR=1.76, p=0.044), but not in BCI (H/I)-Low patients (NTB=-0.7%, WR=0.96, p=0.869). BCI (H/I)-High patients demonstrated significant NTB=7.7%/7.4%, WR=2.24/1.92 when analyzing bone-related and QOL-related toxicities, respectively (p=0.024, 0.024), while no significant results were observed in the BCI (H/I)-Low patients (p=0.902, 0.780, respectively). Prioritizing toxicity over efficacy produced similar results. Conclusion: Novel findings demonstrate that BCI not only significantly predicts preferential survival benefit from longer durations of endocrine therapy, but also significantly predicts the overall benefit/risk and likelihood of an improved health outcome from EET in HR+ patients treated with primary adjuvant AI, when severe AEs are considered. It should be noted that the results of our analysis could be biased due to a shorter AE recording period in the 2.5y arm, hence the true benefit/risk of EET could be larger than reported here. Quantification of a net treatment benefit when considering the impact of both efficacy and toxicity may represent a new paradigm for evaluation of the overall EET benefit and aid in patient selection for EET. Citation Format: Marc Buyse, Jenna Wong, Samuel Salvaggio, Jean-Christophe Chiem, Yi Zhang, Kai Treuner, Elma Meershoek-Klein Kranenbarg, Mickaël De Backer, Gerrit-Jan Liefers, Catherine A Schnabel. Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-04.