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Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18–70 years, with an Eastern Cooperative Oncology Group performance status of 0–1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR- HER2 mut subtype, everolimus (10 mg orally daily) for the LAR- PI3K/AKT mut and MES- PI3K/AKT mut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES- PI3K/AKT WT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2–29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6–15·2]) than in the control group (5·8 months [4·0–6·7]; hazard ratio 0·44 [95% CI 0·30–0·65]; p<0·0001). The most common grade 3–4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

The Lanping basin is a significant Pb–Zn–Cu–Ag mineralization belt in the Sanjiang Tethyan metallogenic province. A series of sediment-hosted Himalayan Cu–Ag–Pb–Zn polymetallic deposits have been discovered in the western part of the basin, controlled by a thrust–nappe system. In the thrust–nappe system, the Cu orebodies mainly occur in the western and relatively deep part of the mineralization system (the root zone), whereas the Pb–Zn–Ag (± Cu) orebodies occur in the eastern and relatively shallow part of the system (the front zone), both as vein-type mineralization. In this paper we present new data, combined with existing data on fluid inclusions, isotopes and geologic characteristics of representative deposits, to provide the first study that contrasts mineralizing fluids in the Cu–Ag (Mo) and Pb–Zn–Ag (Cu) polymetallic deposits. Fluid inclusion and isotope studies show that the Cu–Ag (Mo) mineralization in the root zone formed predominantly from deep crustal fluids, with the participation of basinal brines. The deep crustal fluids are marked by high CO 2 content, relatively high temperatures (280 to 340 °C) and low salinities (1 to 4 wt.% NaCl equivalent), whereas the basinal brine shows relatively low temperatures (160 °C to 220 °C) and high salinities (12 to 22 wt.% NaCl equivalent), containing almost no CO 2 . In comparison, hydrothermal activity associated with the Pb–Zn–Ag (± Cu) deposits in the front zone is characterized by basinal brine, with relatively low temperatures (130 °C to 180 °C), high salinities (9 to 24 wt.% NaCl equivalent), and low CO 2 concentrations. Although evolved meteoric waters have predominantly been proposed as the source for deep crustal fluids, magmatic and metamorphic components cannot be completely excluded. The basinal brine was predominantly derived from meteoric water. The δ 34 S values of sulfides from the Cu–Ag (Mo) deposits and Pb–Zn–Ag (± Cu) deposits range from − 17.9 to 16.3‰ and from 2.5 to 11.2‰, respectively. These ranges may relate to variations in physicochemical conditions or compositional variation of the sources. Lead isotope compositions indicate that the ore-forming metals were predominantly derived from sedimentary rocks of the Lanping basin. [ABSTRACT FROM AUTHOR]