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  • br Table Effect of Everolimus Treatment on PFS br Subgroups

    2022-04-26


    Table 1. Effect of Everolimus Treatment on PFS
    Subgroups
    Variable
    P value was calculated using Fisher’s exact test (nb5) for subgroup comparison between the indicated subgroups.
    (PIK3R2 and PIK3CA) mutation frequencies decreased (Figure 5), whereas patients who did not receive everolimus had increased PIK3CA, PIK3R2, and AKT1 mutation frequencies (Figure 4). These results support that ER-positive MBC patients might benefit from everolimus in conjunction with chemotherapy.
    Apart from the PI3K-AKT pathway genes, ESR1 and GATA3 are endocrine therapy resistance Echinomycin in breast cancer [6,14,19]. In ER-positive patients, the presence of ESR1 mutations following endocrine therapy indicates treatment resistance [39–43]. In this study, 31/44 (70.45%) patients had a history of endocrine treatment (Table S1); however, ESR1 mutation was not common, with only two ER-positive/ HER2-negative (ID=7, 15) patients presenting with baseline ESR1 mutations. Interestingly, both of these patients also had baseline PIK3CA mutations. One of these patients (ID=7, Table S3) received chemotherapy alone and progressed within 6 months with increased mutation frequencies for both ESR1 and PIK3CA (Figure 4). In contrast, the other non-PD patient (ID=15, Table S4) received everolimus plus chemotherapy and was controlled without progres-sion and with decreased mutation frequencies for both ESR1 and PIK3CA (Figure 5). Moreover, in one patient (ID=9) who had no ESR1 mutation prior to treatment (Figure 2B), ESR1 mutation emerged as PIK3CA and GATA3 mutation frequencies increased and the disease progressed (Figure 4B). These findings suggest that the mutation of PIK3CA and ESR1 varies with progression in MBC patients.
    Furthermore, the frequencies of GATA3 gene mutation also increased in two PD patients (ID=33, 9). In one of these patient (ID= 33), the GATA3 mutation frequency increased as AKT1 mutation frequency increased. In the other patient (ID=9), the GATA3 mutation frequency increased as both PIK3CA and ESR1 mutation frequencies increased (Figure 4, A and B). Therefore, both GATA3 and ESR1 mutations seem to be coupled with mutation of the PI3K-AKT pathway genes.
    Interestingly, in this study we observed chemotherapy-induced selection of preexisting mutations as well as new mutations that arose after chemotherapy. More specifically, some patients had preexisting mutations, and these ctDNA mutation frequencies increased after treatment, indicating the resistance of mutation bearing clones to chemotherapy in patients with PD. In addition, some patients did not have preexisting mutations prior to chemotherapy, and tumor gene mutations emerged after treatment. For example, patient ID33 (Figure 4A) did not have a GATA3 mutation before chemotherapy, but after treatment, the GATA3 mutation frequency was 1.6%. Occasionally, these two phenomena coexisted. For example, patient ID5 did not have a PIK3CA amplification mutation before chemotherapy, but after capecitabine treatment, the PIK3CA amplification mutation frequency was 3.2%. Moreover, this patient also had a PIK3CA H1047R mutation frequency of 42.4% before treatment that increased to 59.6% after chemotherapy. 
    ctDNA mutation is complicated, with both time and space heterogeneity. It is difficult to divide ctDNA mutation into just two or three types. Each mutation may be significant for an individual patient. In this study, we summarized the overall trend of ctDNA mutations following chemotherapy in ER-positive patients. We aimed to provide important and valuable clues for clinicians.
    At baseline, PIK3CA gene mutations were common in both HER2-negative and HER2-positive patients. After treatment, the mutation frequency of PIK3CA increased in the majority of ER-positive PD patients. Chemotherapy is a common choice for treatment of MBC; however, baseline TP53 mutation predicts a poor response to chemotherapy in breast cancer patients [44]. Indeed, we found that PIK3CA wild-type patients with baseline TP53 mutation had a significantly poorer PFS than patients without baseline TP53 mutation (P=.04, Figure S1F). PIK3CA mutation has been found to be positive prognostic indicator for overall survival and breast cancer–specific survival in 590 patients (at a single center) and 2587 patients (from 12 independent studies) [45,46]. However, due to the small sample size of this study, this benefit was not significant, and patients with baseline PIK3CA mutation failed to show improved PFS (Figure S1B).
    Tumors acquire resistance to systemic treatment as a result of clonal selection [47]. PIK3CA p.E545K mutation is associated with chemoresistance in breast epithelial cells [48], and its mutation frequency increases significantly after paclitaxel treatment [47]. Our study further confirmed this finding, supporting an alternative treatment regimen involving everlolimus in ER-positive patients by inhibiting the mTOR pathway.