CDK4/6 inhibitors: a breakthrough in the management of luminal advanced breast cancer

Dr Devan Moodley educates us on a new targeted therapy, CDK4/6 inhibitors, for metastatic hormone receptor sensitive breast cancer.


How do CDK4/6 inhibitors work?

This newer class of drug therapy, CDK4/6 inhibitors, is used to treat metastatic hormone receptor sensitive breast cancer. Metastatic breast cancer is cancer that started initially in the breast but has now spread to other parts of the body like the bones, the liver or the lungs. 

In metastatic breast cancer, these CDK4/6 proteins become overactive which caused the cancer cells to grow and divide uncontrollably. CDK4/6 inhibitors interfere by preventing and slowing down this process.

It achieves this by targeting specific proteins in the cell cycle pathway, called cyclin-dependant kinases, specifically 4 and 6, hence the name CDK4/6 inhibitors. 

Availability in SA

There are currently three FDA approved molecules for this form of targeted therapy: palbociclib, ribociclib and abemaciclib. Of these new drugs, to date only ribociclib is registered for commercial use in South Africa.

CDK4/6 inhibitors: trials and research

Presently these agents are approved for use only in hormone receptor positive HER2 normal metastatic patients. However, studies underway have shown very good clinical utility even in HER2 positive patients with hormone receptor positivity and in patients with early stage breast cancer.  

These agents are oral therapies. Palbociclib and ribociclib are taken for three out of every four weeks, usually in combination with other hormonal therapies. Abemaciclib is taken daily, either alone or in combination with other endocrine treatments. 

These newer therapies are considered equally efficacious and the choice of therapy is a decision that you’ll make with your treating doctor, considering your set of circumstances regarding your disease factors and personal preferences.

All three of these agents have been tested in specific patient groups in the registering clinical trials and therefore may have slightly different approvals when they all become available in South Africa. 

In essence, they work in pre-or post-menopausal patients. In the former patient group, these women will need to be rendered post-menopausal by cessation of ovarian function. 

The CDK4/6 inhibitors can be used in women or men with hormone receptor positive breast cancer and in combination with either an aromatase inhibitor (anastrozole, letrozole or exemestane) or a selective oestrogen receptor down-regulator (fulvestrant). In addition to these combinations, abemaciclib is also supported by evidence for efficacy as a stand-alone agent.

Side effects

The side effects of these agents include nausea, diarrhoea, fatigue, low white cell counts, anaemia, and low platelet counts. It’s for this reason that patients on these drugs get their blood tested monthly to monitor for these possible side effects. 

Dose adjustments may need to be made for possible dose-limiting toxicities where appropriate. 

Doctors generally accept that switching between these agents when one doesn’t work is of no benefit but may occasional change between agents to manage side effects. Dose reductions may also be used to manage certain side effects.

Abemaciclib, for example, has a significant risk of gastrointestinal side effects but this can be easily manageable with anti-diarrhoeal agents. 

Palbociclib can cause a rare heart rhythm abnormality, therefore an ECG is always taken prior to the initiation of this agent and usually after a month of therapy.

Low white cell counts are common on palbociclib and ribociclib but this doesn’t usually result in patients getting a fever. These patients, however, are sometimes delayed because of this side effect. 

Fatigue is the commonest side effect of this class of drug but this can be manged by dose modification when appropriate. 

Bear in mind that you may experience different side effects not mentioned here and these effects will be a discussed with your oncologist at that stage.

Speak up about side effects

As with many oral medications, the ingestion of grapefruit while on CDK4/6 inhibitors isn’t permitted as this can interfere with drug efficiencies. 

It’s vital that you report any untoward effects to your oncology team so that they may advise you as to the best way forward. 

It’s essential with these highly-effective therapies that you persevere and find the correct dose for you so that you get the best effect with the least possible side effects.

Dr Devan Moodley is a medical oncologist at the Donald Gordon Medical Centre. His present medical interest includes breast cancer in solid tumour oncology, and leukaemia treatment in haematological malignancies that allows him to continue his interest in stem cell transplantation.

MEET THE EXPERT – Dr Devan Moodley

Dr Devan Moodley is a medical oncologist at the Donald Gordon Medical Centre. His present medical interest includes breast cancer in solid tumour oncology, and leukaemia treatment in haematological malignancies that allows him to continue his interest in stem cell transplantation.


References

  • National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. 2019

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