Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

BACKGROUND: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. METHODS: This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ(2) test) in the same molecular subgroups. RESULTS: Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment. CONCLUSIONS: This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status. TRIAL REGISTRATION: NCT01459757.

Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study.

BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

Health-Related Quality of Life Among Patients With HR+/HER2- Early Breast Cancer.

PURPOSE: The goal of this study was to characterize health-related quality of life (HRQOL) among patients diagnosed with early-stage, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. METHODS: A multinational (United States, Japan, France, Germany, Italy, Spain, and United Kingdom) study of patients diagnosed with stage I to III HR+/HER2- breast cancer, either receiving adjuvant treatment or under postadjuvant surveillance, was conducted between June and October 2019. Patients were identified by their consulting physician and invited to complete the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the EQ-5D-5L pen and paper questionnaires. EQ-5D-5L index scores were derived by using available country-specific health state value sets, where available, and numerically compared with general population scores derived from published normative and population data. Descriptive summary statistics were reported for FACT-B, Functional Assessment of Cancer Therapy-General (FACT-G) (total and specific subscales), the EQ-5D index scores, and the EQ-VAS scores for each country. Results were stratified according to disease-free treatment status (active adjuvant treatment or postadjuvant surveillance), age (25-44, 45-54, 55-64, or ≥65 years), stage (I, II, or III), and menopausal status at the time of questionnaire completion (pre-/peri-menopausal or postmenopausal). FINDINGS: Overall, 1110 patients completed the HRQOL questionnaires (mean age, 59 years; 79% active adjuvant treatment, and 21% under surveillance postadjuvant treatment at time of questionnaire administration; 31% stage I, 48% stage II, and 20% stage III at diagnosis). Of these, 1102 completed the FACT-B and 1083 completed the EQ-5D-5L questionnaires. The mean (SD) FACT-B total score was 99.0 (21.9). The mean FACT-G total score was 72.5 (17.8), which was comparable to the published normative score. The mean EQ-5D index and EQ-VAS scores for each country were similar to corresponding population means; EQ-5D index scores ranged from 0.842 (0.098) in Japan to 0.916 (0.109) in France, and EQ-VAS scores from 68.0 (18.4) in Germany to 78.6 (16.4) in the United States. In addition, mean scores were comparable between the active adjuvant treatment and postadjuvant surveillance groups for the FACT-B total (99.4 [22.5] and 97.7 [19.7], respectively), FACT-G total (72.8 [18.3] and 71.3 [16.0]), EQ-5D index score (0.868 [0.135] and 0.869 [0.142]), and EQ-VAS (74.9 [17.2] and 74.4 [16.1]). IMPLICATIONS: Patient-reported HRQOL among patients with HR+/HER2- early breast cancer who were disease-free was high, with reported scores comparable to normative scores. These results improve our understanding of HRQOL among patients with early disease and may facilitate future studies examining the potential impact of adjuvant treatment and disease recurrence, including metastasis.

Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive metastatic breast cancer: Patient-reported outcomes in the PEARL study.

BACKGROUND: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. PATIENTS AND METHODS: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. RESULTS: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. CONCLUSION: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. TRIAL REGISTRATION NUMBER: NCT02028507 (ClinTrials.gov). EUDRACT STUDY NUMBER: 2013-003170-27.

The methyl-CpG binding protein MBD1 is required for PML-RARalpha function.

PML-RARalpha induces a block of hematopoietic differentiation and acute promyelocytic leukemia. This block is based on its capacity to inactivate target genes by recruiting histone deacetylase (HDAC) and DNA methyltransferase activities. Here we report that MBD1, a member of a conserved family of proteins able to bind methylated DNA, cooperates with PML-RARalpha in transcriptional repression and cellular transformation. PML-RARalpha recruits MBD1 to its target promoter through an HDAC3-mediated mechanism. Binding of HDAC3 and MBD1 is not confined to the promoter region but instead is spread over the locus. Knock-down of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviates PML-RAR-induced promoter silencing. We further demonstrate that retroviral expression of dominant-negative mutants of MBD1 in hematopoietic precursors compromises the ability of PML-RARalpha to block their differentiation and thus restored cell differentiation. Our results demonstrate that PML-RARalpha functions by recruiting an HDAC3-MBD1 complex that contributes to the establishment and maintenance of the silenced chromatin state.

Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.

DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.