8P Mutational analysis of circulating tumour DNA (ctDNA) in patients with ER+/HER2- advanced breast cancer (ABC) receiving palbociclib (P): Results from the TREnd trial
Luca MalorniDario RomagnoliMatteo BenelliFrancesca GalardiChiara BiagioniGiuseppe CuriglianoAlessandro Marco MinisiniErica MorettiEmanuela RisiFrancesca De LucaAmelia McCartneyAngelo Di LeoLaura BiganzoliIlenia Migliaccio
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Palbociclib
Progression-free survival
Abstract Background: Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (Her2-) is the most prevalent subtype of breast cancer, representing 70% of the cases with metastatic disease. Endocrine therapy plus FDA-approved cyclin-dependent kinases (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have improved the treatment of HR+/Her2- advanced breast cancer patients. However, patients develop clinical resistance (acquired) during the long-term treatment, and in some cases, they do not respond within the first 3 months of treatment (intrinsic resistance), leading to disease progression. Although these inhibitors have the same nominal targets, CDK4/6, abemaciclib can inhibit other kinases that are not inhibited by palbociclib/ribociclib, such as CDK9/7/2/1, GSK3α/β and CAMK2γ/δ. As such, abemaciclib has been shown to inhibit cell growth in Rb deficient cells, in which palbociclib/ribociclib are ineffective. Therefore, we hypothesized that 1) mechanisms driving palbociclib acquired resistance are distinct than those mediating abemaciclib resistance, 2) palbociclib resistant models may be responsive to abemaciclib, and 3) pathways underlying these mechanistic differences can be exploited as alternative therapies to overcome resistance. Methods: We generated several models to examine mechanisms of resistance to different CDK4/6 inhibitors: 1) MCF7 and T47D (ER+) palbociclib resistant breast cancer cells with increasing concentrations of palbociclib, starting at 1.2 µM (initial IC 50) up to 5 µM (plasma concentrations in patients) in a stepwise manner over a 6 month period, 2) MCF7 abemaciclib resistant cells (0.5, 1 and 1.5 µM), and 3) organoids derived from patient derived xenografts (PDXs) with a similar molecular profile to palbociclib acquired resistance models. Cell cycle changes were evaluated by western blot analysis and flow cytometry. Results: Western blot analysis revealed a dose dependent downregulation of ERα, Rb, p-Rb and p27, while levels of cyclin E and p-CDK2 increased in a stepwise fashion in palbociclib resistant cells, which were only partially cross resistant to abemaciclib and sensitive to CDK9 inhibitors LDC067 and SNS032. FACS analysis of abemaciclib resistant cells showed an increase in G2/M accompanied by a drastic reduction of p-Rb and a gradual decrease of Rb. ERα levels were slightly decreased in abemaciclib resistant cells compared to the complete loss in palbociclib resistant cells. As in the palbociclib resistant cells, a dose dependent increase in cyclin E and p-CDK2 were also observed. However, Rad51, a key mediator of DNA repair, was downregulated in a stepwise manner only in abemaciclib resistant cells, but not in palbociclib resistant cells. Therefore, we evaluated if a combination therapy targeting DNA repair pathways plus abemaciclib could render palbociclib resistant models more responsive to targets other than cell cycle inhibitors. To this end, we examined the combination of abemaciclib and niraparib in organoid cultures generated from PDX models that are transcriptomic surrogates of palbociclib resistance cells and found a significant reduction of viability, number and density of these organoids. In vivo, using the same PDX models, the combined treatment reduced the tumor growth rate and increased overall survival. Conclusion: Our results suggest that mechanisms underlaying palbociclib and abemaciclib acquired resistance exhibit differentially altered pathways, such as DNA damage/repair pathways, which can be exploited to overcome CDK4/6 inhibitors therapy resistance in breast cancer patients. Citation Format: Juliana Navarro-Yepes, Xian Chen, Tuyen Bui, Nicole M Kettner, Kelly K Hunt, Khandan Keyomarsi. Differential mechanisms of acquired resistance to abemaciclib versus palbociclib reveal novel therapeutic strategies for CDK4/6 therapy-resistant breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-05.
Palbociclib
Cyclin-dependent kinase 4
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Limited evidence suggests that inherited predisposing risk variants might affect the disease outcome. In this study, we analyzed the effect of genome-wide association studies—identified breast cancer-risk single nucleotide polymorphisms on survival of early-stage breast cancer patients in a Chinese population. This retrospective study investigated the relationship between 21 GWAS-identified breast cancer-risk single nucleotide polymorphisms and the outcome of 1177 early stage breast cancer patients with a long median follow-up time of 174 months. Cox proportional hazards regression models were used to estimate the hazard ratios and their 95% confidence intervals. Primary endpoints were breast cancer special survival and overall survival while secondary endpoints were invasive disease free survival and distant disease free survival. Multivariate survival analysis showed only the rs2046210 GA genotype significantly decreased the risk of recurrence and death for early stage breast cancer. After grouping breast cancer subtypes, significantly reduced survival was associated with the variant alleles of rs9485372 for luminal A and rs4415084 for triple negative breast cancer. Importantly, all three single-nucleotide polymorphisms, rs889312, rs4951011 and rs9485372 had remarkable effects on survival of luminal B EBC, either individually or synergistically. Furthermore, statistically significant multiplicative interactions were found between rs4415084 and age at diagnosis and between rs3803662 and tumor grade. Our results demonstrate that breast cancer risk susceptibility loci identified by GWAS may influence the outcome of early stage breast cancer patients’ depending on intrinsic tumor subtypes in Chinese women.
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In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC.A therapy-sequencing disease model that approximates treatment outcomes in up to five lines of treatment was developed for patients with nsNSCLC. The primary source of data for progression-free survival (PFS) and time to death was published pivotal trial data. All patients were treatment-naïve and in the PFS state, received first-line treatment with either bevacizumab-based therapy or doublet chemotherapy (including the option of pemetrexed + cisplatin). Patients would then progress to a subsequent line of therapy, remain in PFS or die. In case of progression, it was assumed that each survivor would receive a subsequent line of therapy, based on EMA licensed therapies. Weibull distribution curves were fitted to the data.All bevacizumab-based first-line therapy sequences analyzed achieved total PFS of around 15 months. Bevacizumab + carboplatin + paclitaxel (first line) → pemetrexed (second line) → erlotinib (third line) → docetaxel (fourth line) resulted in total mean PFS time of 15.7 months, for instance. Sequences with pemetrexed in combination with cisplatin in first line achieved total PFS times between 12.6 and 12.8 months with a slightly higher total PFS time achieved when assuming pemetrexed continuation therapy in maintenance after pemetrexed + cisplatin in first-line induction. Overall survival results followed the same trend as PFS.The model suggests that treatment-sequencing strategies starting with a bevacizumab-based combination in first line yield better survival outcomes than those starting with pemetrexed-based combinations, a result that is attributable to the possibility of one further line of treatment with first-line bevacizumab-based treatment sequences.
Pemetrexed
Carboplatin
Progression-free survival
Erlotinib Hydrochloride
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Palbociclib
Progression-free survival
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This article discusses the problems associated with the search of the most effective treatment strategies for HER2-negative metastatic breast cancer in premenopausal women. Until recently, ovarian suppression and hormone therapy had been the main treatments used in this group of patients. The development of palbociclib, called a “breakthrough therapy”, as well as promising results of trials evaluating the efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors added to hormone therapy in postmenopausal women suggested a need for the assessment of this treatment regimen in combination with ovarian suppression in younger patients. According to the results of randomized trials and subgroup analysis, the addition of a CDK4/6 inhibitor to ovarian suppression and hormonal therapy significantly increases survival. The safety profile is similar to that of older patients. Randomized trials comparing the efficacy of palbociclib + ovarian suppression + aromatase inhibitor vs. chemotherapy in premenopausal women demonstrated significant benefits of a new treatment strategy: a CDK4/6 inhibitor as a part of combination therapy reduced the risk of progression by 36 % compared to capecitabine.
Palbociclib
Aromatase inhibitor
Cyclin-dependent kinase 4
Combination therapy
Hormonal Therapy
Regimen
Hormone Therapy
Letrozole
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Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS.Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models.PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS <6 month.Of palbociclib plus ET, luminal type showed better prognosis and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy and resistance.
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Palbociclib
Letrozole
Progression-free survival
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Introduction of EGFR-TKI has changed the treatment paradigm for NSCLC patient with activating mutations of EGFR exons 18–21, replacing chemotherapy as standard first line treatment. Given the delays in molecular study results we sometimes face the need to start treatment in very symptomatic patients with high tumor burden. The reason for this retrospective study is to analyze the survival impact of performing an induction cytotoxic therapy until obtaining the molecular profile (EGFR mutation), followed by targeted therapy. This is a retrospective analysis of 31 patients who did upfront chemotherapy (ChT) before switching to EGFR TKI upon the molecular profile result. The calculated survival endpoints were progression-free survival (PFS), duration of TKI response and overall survival (OS). All patients were treated with upfront chemotherapy with a median of one cycle (range 1–3) followed by a first generation EGFR-TKI. Median PFS was 13 months (95% CI, 6.6–19.4) and median OS 33 months (95% CI, 11.9–54.0). After first line progression 14 patients were treated with Osimertinib. In this subgroup median OS was 52 months (95% CI, 34.0–69.9). In the multivariable Cox model, only body mass index retained independent prognostic significance for progression-free survival (p = 0.045). Survival outcomes in this cohort are in line with published data regarding first generation EGFR-TKI, both in terms of PFS and OS. Despite the limitations of this study, starting with upfront chemotherapy doesn't seem detrimental in terms of survival outcomes, with the potential advantage of symptomatic control. To our knowledge, this is the first study to address this strategy, which requires further confirmation.
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The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment patterns and time to treatment failure (TTF) of subsequent therapy after palbociclib in a Japanese real-world setting.
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Abstract Breast cancer is a frequent female malignant tumor with high mortality and poor prognosis. Peroxidasin like (PXDNL) has many biological functions, including characteristic activity of hormone biosynthesis, host defense, and cell motility. In addition, PXDNL is closely connected with the progression of breast cancer. In this study, we found that PXDNL may be an independent prognostic biomarker of breast cancer. We tested the mRNA expression of PXDNL in breast cancer by detecting The Cancer Genome Atlas (TCGA) database. The chi-squared test was used to evaluate clinical correlation. The receiver operating characteristic (ROC) curves were drawn to evaluate diagnosis potential in breast cancer. Subsequently, survival analyses were performed to identify the relevance between the expression of PXDNL and the overall survival/relapse-free survival of patients with breast cancer. Univariate/multivariate Cox regression model was executed to detect risk factors affecting the prognosis of patients with breast cancer. PXDNL is highly expressed in breast cancer tissues and is related to survival status of patients. The ROC curve showed that PXDNL had beneficial diagnostic ability in breast cancer. Survival analysis indicated that patients with breast cancer with high PXDNL expression generally had decreased overall survival/relapse-free survival. Univariate/multivariate Cox model analyses further suggested an association between PXDNL expression and prognosis of patients with breast cancer. High PXDNL expression is a potential and independent prognostic biomarker in breast cancer.
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