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Rachana Yendala, Kyaw Thein, Sriman Swarup, Anita Sultan, Somedeb Ball, Miguel Quirch, Myo H. Zaw, Yin M. Myat and Catherine Jones

Background: Pain, fatigue, hot flushes, and rash significantly contribute to quality of life in breast cancer patients undergoing chemotherapy. Hormone receptor-positive breast cancer is a common entity among women worldwide. In cancer cells, CDK4/6 activity is over expressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D, ultimately leading to endocrine therapy resistance. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. RTCs that mention HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95%CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: fatigue, 1.226 (95% CI: 1.079–1.393; P=.002); back pain, 0.971 (95% CI: 0.844–1.117; P=.681); arthralgia, 0.978 (95% CI: 0.830–1.152; P=.790); headache, 1.046 (95% CI: 0.928–1.179; P=.459); alopecia, 2.635 (95% CI: 1.966–3.533; P<.001); hot flushes, 0.901 (95% CI: 0.766–1.060; P=.210); and rash, 2.068 (95% CI: 1.604–2.666; P<.001). The RR of high-grade side effects were as follows: fatigue, 3.487 (95% CI: 1.765–6.889; P<.001); back pain, 1.364 (95% CI: 0.695–2.679; P=.367); arthralgia, 1.148 (95% CI: 0.509–2.593; P=.740); headache, 0.807 (95% CI: 0.303–2.147; P=.667); and rash, 3.018(95% CI: 0.954–9.554; P=.060). Conclusions: Our study showed that the risk of developing all grades of fatigue and any-grade alopecia and rash was significantly with CDK 4/6 inhibitors. Prompt intervention with good supportive care is required.

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Anita Sultan, Sriman Swarup, Somedeb Ball, Miguel Quirch, Meily Arevalo, Yin M. Myat, Ye Aung, Myo H. Zaw and Kyaw Z. Thein

Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.

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Kyaw Z. Thein, Somedeb Ball, Sriman Swarup, Anita Sultan, Myo H. Zaw, Lukman Tijani, Sanjay Awasthi, Fred Hardwicke and Catherine Jones

Introduction: Ribociclib, a cyclin-dependent kinase 4/6 inhibitor, has improved survival in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER 2)-negative advanced breast cancer. Despite remarkable efficacy, potential cardiac toxicities remain a concern. We undertook a combined analysis of randomized controlled trials (RCT) to estimate the incidence of prolongation of corrected QT interval (QTcF) associated with ribociclib. Methods: We performed systematic search of Embase, MEDLINE, and meeting abstracts till September 30, 2018, to find all phase 3 RCTs comparing ribociclib with other agents or placebo in patients with advanced breast cancer and reporting QTc prolongation as adverse event. Mantel-Haenszel method was used to calculate the pooled risk ratio (RR) and absolute risk difference (RD) with 95% CI. Fixed effects model was applied. Heterogeneity was assessed using I2 statistic. Results: Three phase III studies with 2,062 participants were included. Randomization ratio was 1 to 1 in MONALEESA-2 and 7 studies and 2 to 1 in MONALEESA-3 study. I2 statistic was 0, suggesting homogeneity across studies. Prolongation of QTcF >60 msec from baseline was observed in 72 patients (61 had post-baseline QTcF >480 msec) in ribociclib arm, compared to 7 in control arm. Pooled RR for prolongation of QTcF was 7.956 (95%CI: 3.683–17.187; P<.001) and RD was 0.055 (95%CI: 0.040–0.070; P<.001). The risk of having a post-baseline QTcF >480 msec was significantly higher with ribociclib vs control (pooled RR, 4.002; 95%CI: 2.161–7.412; P<.001; and RD, 0.039; 95%CI: 0.024–0.055; P<.001). A total of 16 (1.38%) patients in the ribociclib arm had dose reduction, interruption, or discontinuation due to QTcF prolongation, as opposed to 3 (0.33%) in control arm. Pooled RR and RD were statistically significant at 4.204 (95%CI: 1.333–3.260; P=.014) and 0.012 (95%CI: 0.004–0.021; P=.006), respectively. Conclusion: Advanced breast cancer patients may have cardiac dysfunction due to prior cardiotoxic chemotherapies. In our meta-analysis, ribociclib was associated with significantly higher risk of QTc prolongation and the resultant dosing inconsistencies and discontinuation. Early detection of this potential adverse event and timely intervention are critical.

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Sriman Swarup, Anita Sultan, Somedeb Ball, Francis Mogollon-Duffo, Nimesh Adhikari, Yin M. Myat, Myo H. Zaw, Catherine Jones and Kyaw Z. Thein

Background: Breast cancer is the most common cancer in women, and the majority of breast cancers express the estrogen receptor or progesterone receptor. Inhibition of CDK4/6 signaling pathway has shown survival benefit in advanced breast cancer by overcoming endocrine therapy resistance. Yet, there are considerable hematologic toxicities associated with CDK 4/6 inhibitors and hence, we performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018 were queried. RCTs that mention anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II studies) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: anemia, 3.494 (95% CI: 2.535–4.814; P<.0001); thrombocytopenia, 6.066 (95% CI: 3.055–12.046; P<.0001); leukopenia, 10.376(95% CI: 7.236–14.879; P<.0001); and neutropenia, 14.387 (95% CI: 10.877–19.031; P<.0001). The RR of high-grade adverse effects were as follows: anemia, 2.251 (95% CI: 1.393–3.637; P=.001); thrombocytopenia, 3.696 (95% CI: 1.417–9.642; P=.008); leukopenia, 22.083(95% CI: 12.126–40.217; P<.0001); neutropenia, 33.527(95% CI: 17.271–65.082; P<.001). Neutropenic fever was noted in 71 (3.73%) in CDK 4/6 inhibitors group vs 28 (2.18%) in control arm. The pooled RR was statistically significant at 12.056 (95% CI: 1. 352–3.127; P=.001) and RD was 0.014 (95% CI: −0.002–0.029; P=.078) Conclusion: CDK 4/6 inhibitors–based regimen significantly contributed to all hematologic toxicities as well as febrile neutropenia. The improved efficacy outcomes and manageable toxicities with CDK 4/6 inhibitors are observed with proper supportive care and close monitoring.