PHARMACOTHERAPY

CDK 4/6 inhibitors in the treatment of advanced breast cancer

BJMO - volume 11, issue 5, september 2017

F.P. Duhoux MD, PhD, L. Lallemand

SUMMARY

Dysregulation of the cell cycle, especially in the cyclin D-cyclin dependent kinase (CDK) pathway, is a key component of carcinogenesis, also in breast cancer. Cyclin dependent kinase inhibition has emerged as an attractive targeted cancer therapy. Recently, three oral agents selectively targeting CDK 4/6 have been developed for the treatment of breast cancer: palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Clinical trials have shown an improvement in progression-free survival when palbociclib and ribociclib are used in combination with endocrine therapy. The next wave of studies will examine the efficacy of CDK 4/6 inhibitors in combination with other targeted therapies, in the (neo)-adjuvant situation, and in other breast cancer subtypes, such as HER2 positive breast cancer. Palbociclib and ribociclib recently received accelerated Food and Drug Administration approval for the treatment of hormone receptor positive advanced breast cancer in combination with endocrine therapy. This combination has become the new standard of care for the treatment of patients with hormone receptor positive breast cancer.

(BELG J MED ONCOL 2017;11(5):234–241)

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Chalcones as anti-invasive agents: challenges and opportunities

BJMO - volume 11, issue 1, february 2017

B.I. Roman PhD, MSc

SUMMARY

Invasion and metastasis are responsible for 90% of cancer-related mortality. An overview is presented of the issues and opportunities regarding the development of effective inhibitors of these phenomena. Our efforts in the discovery and (in vitro and in vivo) validation of synthetic chalcones as potent anti-invasive agents are summarised, taking into account various concerns regarding the suitability of the chalcone scaffold as a template for the development of bona fide pharmacological tools.

(BELG J MED ONCOL 2017;11(1):12–17)

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Parp inhibitors

BJMO - volume 10, issue 7, november 2016

C. Fontaine MD, E. Denayer MD, PhD, E. Teugels PhD, I. Pauwels , J. De Grève MD, PhD, L. Decoster MD, PhD, L. Vanacker MD, R.B. Shahi MSc, S. De Brakeleer PhD

Summary

Inhibition of Poly (ADP-ribose) polymerase 1 has relatively recently entered the clinic. The ground-breaking drug both scientifically and clinically was olaparib, but several other PARP inhibitors are in development. This treatment is the first to therapeutically exploit mutant recessive cancer genes. In this review we discuss the discovery of this treatment, the preclinical and clinical studies, as well as some future perspectives.

(BELG J MED ONCOL 2016;10(7):263–275)

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Treatment of metastatic melanoma: an update on the Belgian situation

BJMO - volume 10, issue 6, september 2016

I. Chevolet MD, PhD, K. De Wolf MD, L. Brochez MD, PhD, P. Ost MD, PhD, V. Kruse MD, PhD

Summary

The therapeutic landscape for the treatment of metastatic melanoma has been changing dramatically over the last years. Given the availability of several promising drugs, choosing the best sequence for the individual patient has become a challenge. Immunotherapy by means of checkpoint-inhibitors, such as the anti-CTLA4-antibody ipilimumab and the anti-PD1-antibodies nivolumab and pembrolizumab, has demonstrated unprecedented long-term survival rates. When prescribing an immunotherapeutic agent, the clinician should be aware that the patient is at risk of developing an immune-related adverse event, especially when anti-CTLA4 and anti-PD1 are administered together. A promising future strategy to increase response rates of the checkpoint-inhibitors is combining them with radiotherapy. Hereby an abscopal effect is induced, reducing both irradiated and non-irradiated tumour lesions. Another therapeutic strategy is based on the presence of a BRAF mutation among approximately 40–50% of melanoma patients. For those patients, combined therapy with a BRAF inhibitor and a MEK inhibitor is valued to be a convincing regimen, especially in case of a high disease burden, elevated LDH and a performance status of 1–2. In contrast, T-VEC is a valuable therapeutic option for patients with limited disease.

(BELG J MED ONCOL 2016;10(6):215–222)

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Cyclin-dependent protein kinase inhibitors in breast cancer treatment

BJMO - volume 10, issue 4, july 2016

G. Jerusalem MD, PhD, L. Lousberg MD, P. Frères MD

Summary

Dysregulation of the cell cycle is a classic hallmark of cancer. Cell cycle control by the inhibition of cyclin-dependent protein kinases represents new options for anticancer therapy. Abemaciclib (LY2835219), ribociclib (LEE011) and palbociclib (PD0332991) are selective oral inhibitors of CDK4/6 and are largely under evaluation in clinical trials in the field of breast cancer. In an open-label, randomised phase II study (PALOMA-1/TRIO-18 trial), the combination of palbociclib and letrozole, compared to letrozole alone, significantly prolongs progression-free survival of patients suffering from ER positive HER2 negative advanced breast cancer and who had not received any systemic treatment for their advanced disease. More recently, it has also been shown that palbociclib combined with fulvestrant resulted in longer progressionfree survival than fulvestrant alone in patients presenting ER positive HER2 negative advanced breast cancer and who had progression of disease during endocrine therapy. The toxicity profile of palbociclib is manageable. The most common grade 3 or 4 adverse events include neutropenia, anaemia, thrombocytopenia and fatigue. Toxicity related permanent discontinuation is unusual. Additional phase III data evaluating CDK4/6 inhibitors in patients with endocrine sensitive disease or after failure of previous endocrine therapy are expected in the very near future. Impact of CDK4/6 inhibitors on overall survival and the role of CDK4/6 inhibitors in the adjuvant or neoadjuvant setting are under evaluation. More treatment options are now evaluable for patients with ER positive HER2 negative advanced breast cancer. Optimal sequence of the available therapies remains unknown. Unfortunately, no trials have been designed to answer this important question.

(BELG J MED ONCOL 2016;10(4):132–138)

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Bone-targeted therapies in prostate cancer

BJMO - volume 10, issue 3, may 2016

G. Buelens MD, P. Dirix MD, PhD, P. Huget MD, P. Meijnders MD, PhD, P. Westerlinck MD

Summary

Skeletal involvement is very common in metastatic prostate cancer and is associated with (symptomatic) skeletal-related events. This article examines the clinical trial data that support the use of available bone-targeted therapies in prostate cancer.

(BELG J MED ONCOL 2016;10(3):97–100)

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Adjuvant treatment for uterine cancers, a review of the current evidence

BJMO - volume 10, issue 2, april 2016

A. Barbeaux MD, C. Kirkove MD, J-C. Verougstraete MD, J-L. Squifflet MD, PhD, J.F. Baurain MD, PhD, L. Duck MD, M. Luyckx MD, R. Poncin MD, V. Malvaux MD

Summary

To date, the main treatment of loco-regional uterine cancer is surgery. The benefit of adjuvant treatment depends on the subtype of cancer, stage, and risk factors. We describe here the current evidence-based data supporting the administration of adjuvant treatment after surgery, with a focus on chemotherapy.

(BELG J MED ONCOL 2016;10(2):63–68)

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