Real-world Study Of Platinum-based Chemotherapy For Advanced Triple-Negative Breast Cancer And An Exploratory Study Of Predictors Of Efficacy

Background and Objective:Platinum-based chemotherapy(PBC)has proven benefits in phase Ⅲ studies for advanced triple-negative breast cancer(TNBC)patients;however,real-world data of large samples from multiple centers are lacking.This study was to compare the effectiveness of PBC and non-PBC in advanced TNBC patients in multicenter real-world settings.Methods:After screening for 12568 advanced breast cancer patients,495 patients with advanced TNBC receiving PBC(n=350)or non-PBC(n=145)at four cancer centers in China between 2003 and 2019 were included.Treatment responses,outcomes and safety profiles were compared between the two groups from first-line to third-line treatment.Results:Of patients with PBC,249(71.1%)received PBC from first-line chemotherapy,86(24.6%)from second-line,and 15(4.3%)from third-line treatment.In first-line treatment,PBC was superior to non-PBC in objective response rate(ORR,53.0%vs.32.1%,P<0.001)and median progression-free survival(PFS,8.4 vs.6.0 months,P=0.022),whereas overall survival(OS)was similar(19.2 vs.16.8 months,P=0.439).When comparing patients receiving non-PBC doublets(n=221)with those receiving PBC doublets(n=249),the same trend was observed in ORR(53.0%vs.32.6%,P<0.001),median first-line PFS(8.4 vs.6.5months,P=0.041)and median first-line OS(19.2 vs.17.8 months,P=0.568).Paclitaxel/docetaxel+platinum was more likely to be used,followed by gemcitabin+platinum.In second/third-line treatment,PBC yielded a similar response and survival compared to non-PBC.Adding PBC in the first-line therapy was better than that in the latter-line of treatment in terms of ORR,PFS,and OS(P<0.001).Toxic effects of PBC were tolerable and the most common adverse event was neutropenia(38.6%).A total of 82 TNBC patients with liver metastasis were identified.Among these,59 patients without extrahepatic metastasis who receiving PBC or capecitabine-based chemotherapy(CBC)were included.33 patients were treated with PBC and 26 were treated with CBC.The ORR was higher in the CBC group than in the PBC group(57.7%versus 30.3%,P=0.035).Median OS was also greatly improved(19.2 versus 14.4 months,P=0.041).Docetaxel/cisplatin was more likely to be used for PBC,and paclitaxel/capecitabine was the main regimen for CBC.Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age,tumor size,nodal status,prior anthracyclines/taxanes use,and tumor grade(odds ratio=0.51;95%confidence interval,0.27-0.98;P=0.042).Adverse events were not different except gastrointestinal tract toxicities,hand-foot syndrome and hematologic toxicityConclusions:PBC doublets exhibited superior efficacy and manageable toxicity compared with non-PBC doublets in the first-line treatment for Chinese mTNBC patients.For TNBC patients with liver metastasis,capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment,as measured by objective response rate and overall survival.Further large-scale studies are warranted.Background:Previous studies have identified that at least 50%of triple negative breast cancer(TNBC)harbor mutation characteristics of homologous recombination deficiency(HRD).Thus,more sophisticated research into comprehensive genomic profiling of HRD is urgently needed.Whereas BRCA1/2-deficient advanced TNBC patients are sensitive to treatment with platinum,it is not yet clear whether HRD status could predict platinum response.Methods:The tumor tissues and adjacent tissues of 42 TNBC patients were retrospectively collected.The next-generation sequence technology was used to detect gene mutations.Then,HRD scores were calculated,and the correlation between HRD scores and prognosis was analyzed.HRD algorithm was developed based on loss of heterozygosity score(LOH)telomeric allelic imbalance score(TA1)and large-scale state transition score(LST)as previously described.HRD status was defined as HRD positive(deleterious mutation in BRCA1/2 or HRD score≥30)or HRD negative(no deleterious mutation in BRCA1/2 and HRD score<30).Results:Deleterious BRCA1/2 mutations were detected in 9.5%(4/42)of TNBC patients,and 17(40.5%)patients were defined as HRD positive.The most frequent mutations in HRD-positive patients were TP53(94%),PIK3R1(29%),ZHFX3(24%),LRP1B(24%),and PTEN(24%),while TP53(84%),MYC(32%),ZHFX3(28%),PIK3CA(24%),and NF1(14.8%)enriched in HRD-negative patients.In advanced TNBC cohort,22 patients received platinum-based and 20 received platinum-free chemotherapy in the first-line treatment.The PFS of the platinum-based group was longer than that of the platinum-free group(9.6 vs 3.0 months,HR 0.51,95%CI 0.26-0.99,P=0.025).In patients receiving PBC,the PFS was numerically but not statistically longer in HRD-positive group than that in the HRD-negative group(13.6 vs 7.3 months,HR 0.60,95%CI 0.26-1.41,P=0.235).The PFS of the HRD-positive group and HRD-negative group was similar(2.6 vs.6.8 months,P=0.572).In HRD-positive patients,median PFS was significantly longer in platinum-based group than platinum-free group(13.6 vs 2.0 months,HR 0.26,95%C10.08-0.80,P=0.0011).No significant difference was observed in PFS between platinum-based and platinum-free group(P=0.765)in patients with HRD-negative tumors.Conclusions:Our findings illustrate the potential of HRD status as a marker to guide chemotherapy in advanced TNBC.In HRD positive patients,platinum-based chemotherapy might be a preferable regimen.Prospective study with a larger sample-size is needed for further validation of our findings.