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Purificación Martínez del Prado,1 Isabel Alvarez-López,2,3 Severina Domínguez-Fernández,4 Arrate Plazaola,5 Oliver Ibarrondo,6 Elena Galve-Calvo,1 Nerea Ancizar-Lizarraga,2,3 María Gutierrez-Toribio,4 Ainhara Lahuerta-Martínez,5 Javier Mar6,7 1Medical Oncology Service, Basurto University Hospital, Bilbao, Spain; 2Medical Oncology Service, Donostia University Hospital, Donostia-San Sebastián, Spain; 3Biodonostia Health Research Institute, Donostia-San Sebastián, Spain; 4Medical Oncology Service, Araba University Hospital, Vitoria-Gasteiz, Spain; 5Medical Oncology Service, Onkologikoa, Donostia-San Sebastián, Spain; 6AP-OSI Research Unit, Alto Deba Integrated Health Care Organization, Mondragon, Spain; 7Health Services Research on Chronic Patients Network, Kronikgune Group, Bilbao, Spain Purpose: The 21-gene recurrence score (RS) is a genomic test developed as a prognostic and predictive tool to improve the treatment decision making in cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer. This study examined the clinical and economic impact of its use in 4 Basque Country university hospitals. Methods: Taking into consideration the RS result, we recorded the recommended initial systemic adjuvant therapy (endocrine therapy with or without chemotherapy) according to standard clinicopathologic factors and the final decision about chemotherapy. Then, if the RS was high, chemotherapy was recommended; it was not recommended if the RS was low; for those with an intermediate RS, clinicopathologic factors were considered, and the initial recommendation based on those factors was maintained. In addition, the probability of switching treatment was calculated. Then, we developed an economic evaluation by measuring the treatment’s incremental short-term budget impact from both the societal perspective and that of the Basque Health System. Patients’ characteristics and chemotherapy use were analyzed using logistic regressions and receiver operating characteristic curves. Results: Without an RS, chemotherapy would have been prescribed to 56% of 401 patients, but, with RS use, that percentage decreased to 25. The overall rate of decision change was 35.4%. Test inclusion led to a reduction in chemotherapy costs of €922 per patient in the total population. Although this reduction did not entirely offset the cost of the test, the productivity loss per patient was reduced by €1,977. Conclusion: The 21-gene RS test significantly changed the indication for chemotherapy. As chemotherapy treatments with no benefit were avoided, patients’ quality of life was improved. The short-term economic impact was negative for the Basque Health Service, but savings resulted when sick-leave costs were included. Keywords: early-stage breast cancer, adjuvant chemotherapy, 21-gene assay, economic evaluation, health care costs

Background: Sapanisertib (S) is an investigational, oral, and highly selective adenosine triphosphate (ATP)-competitive inhibitor of target of rapamycin complex 1/2 (TORC1/2). Simultaneous inhibition of ER and phosphoinositide 3kinase (PI3K)/serine/threonine-specific protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway with S may restore sensitivity to endocrine therapies in patients (pts) with breast cancer, who have progressed during or after aromatase inhibitor (AI) therapy. Here we report data from a phase 2 study of continuous once-daily or once-weekly S + fulvestrant (F) compared with single-agent F in pts with breast cancer. Methods: Postmenopausal women with ER+ and HER2- advanced or metastatic breast cancer following progression during/after AI therapy were randomized 1:1:1 to receive F (500 mg intramuscularly on day 1 of a 28-day cycle) alone (Arm A) or in combination with oral S either daily (4 mg; Arm B) or weekly (30 mg; Arm C) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts were stratified according to presence/absence of visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors. Pts on Arm A could receive S at PD. Key exclusion criteria were: prior therapy with mTOR inhibitors, PI3K inhibitors, or F; >1 prior line of chemotherapy for MBC; recurrent disease or PD on >2 endocrine therapies for MBC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR; any duration and at 24 weeks), overall survival (OS), and safety. Results: Between Aug 2016 and May 2018, 141 pts were randomized (Arm A: 46; Arm B: 47; Arm C: 48). One patient in Arm C was not treated. Median age was 58 years (range 33-84). Stratification was well balanced across arms; overall, 65% had visceral metastases, 84% had prior sensitivity to hormonal therapy, and 34% had received prior CDK 4/6 inhibitors. Pts received a median of 4 cycles (range 1-40) of F on Arm A, 5 cycles (range 1-33) of daily S + F on Arm B, and 4 cycles (range 1-39) of weekly S + F on Arm C. The last follow-up visit was in Nov 2019. The main reasons for treatment discontinuation included PD (76%, 60%, 53%; Arm A, B, and C, respectively) and adverse events (AEs; 4%, 32%, 36%; Arm A, B, and C, respectively). Of the pts in Arm A with confirmed PD, 18 crossed over to Arm B and C (9 each); crossover was analyzed separately. Efficacy data are shown in the table; median PFS was 3.5, 7.2, and 5.6 months in Arm A, B, and C, respectively. OS data were immature at the primary data cut-off. Three pts died during the study (2 and 1 in Arm A and B, respectively); all deaths were attributed to underlying disease. Most common any-grade AEs were: asthenia (24%), hyperglycemia, fatigue, and headache (22% each) in Arm A; hyperglycemia (57%) and nausea (49%) in Arm B; nausea (87%) and vomiting (70%) in Arm C. Conclusion: Daily or weekly treatment with S + F demonstrated modest clinical benefit in ER+/HER2- advanced or MBC pts who progressed during/after AI compared with single-agent F. The S + F combinations had increased toxicity leading to more treatment discontinuations compared with single-agent F. Table: PFS and response dataArm A Single-agent F (n = 46)Arm B S (QD) + F (n = 47)Arm C S (QW) + F (n = 48)Median PFS (95% CI), months3.5 (1.9-5.6)7.2 (3.9-10.6)5.6 (4.1-9.0)HR (95% CI)0.77 (0.47-1.26)0.88 (0.53-1.45)ORR*, n/N (%)5/46 (10.9)10/47 (21.3)†6/47 (12.8)CBR*, n/N (%)28/46 (60.9)35/47 (74.5)31/47 (66.0)CBR≥6 months*, n/N (%)15/46 (32.6)23/47 (48.9)12/47 (25.5)*Safety population †Including 2 complete responses Citation Format: José Á García-Saenz, Noelia Martínez Jáñez, Miguel Martin, Ainhara Lahuerta Martínez, Santiago González-Santiago, Nieves Ferrer, Manuel Ramos Vázquez, José Luis Alonso Romero, Antonio Antón, Eva Carrasco, Jingjing Chen, Rachel Neuwirth, E Jane Leonard, Dennis Slamon. Open-label, randomized, phase 2 study of sapanisertib (TAK-228/MLN0128) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor-2-negative (HER2-) advanced or metastatic breast cancer (MBC) that previously progressed during or after aromatase inhibitor therapy (NCT02756364) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-01.