CDKs: the chart-topping hit on the breast cancer playlist

Prof Carol-Ann Benn explains why CDK inhibitors are topping the breast cancer playlist for luminal breast cancers.

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Times change: I feel that time gets faster, the older I get. Kind of like music, from vinyl to CD and now Apple playlists, YouTube and Spotify. 

Cancer treatment has also changed over the decades and breast cancer treatment has moved into the techno cool age of a personal playlist for each cancer. This is a good thing as most people have an issue with the word chemotherapy (which is antibiotics for cancer).

The good news is that the new playlists are digital and personalised (like multi-disciplinary meetings and consults can be) whereas with vinyl plastic, you play the whole record to find your song for fear of scratching the surface. 

The vinyl era of playing the whole record was similar to when we treated cancers on stage. Based on your stage, you got a treatment. One size fitted all. The bigger the cancer, the more advanced the cancer, the more aggressive the treatment. 

Bigger cancers that were in the glands got chemotherapy and smaller cancers that hadn’t spread to the glands didn’t. I’m asked regularly: what stage is my cancer? Stage of cancer is useful for documentation, for providing a framework for what treatments may be available to you from your medical aid, and for understanding the starting size, and need for treatments such as radiation. 

An important reminder about stage and surgery is that the more advanced the cancer, the more important it’s to start with some form of oncology treatment and the smaller the surgery should be. There is no role for a bilateral mastectomy, particularly if you have an advanced or metastatic cancer; and there is most definitely no place for an emergency mastectomy (ever).

The era of the CD

The era of the CD was about age. With CDs, looking at the shiny disc didn’t give you an idea of what the content was, you only knew if you looked at the package: Golden oldies, Best of the 80s; Hip-hop, etc. 

This was the time when younger people got more aggressive treatment than older people. Young people got chemo because it was thought if you got a cancer when you were under 40, it had to be more aggressive. Younger people got bilateral mastectomies as it was thought recurrences affected survival and that they were more likely to get a second cancer. 

We know now that you treat the cancer and even if you have a genetic risk of cancer, you do a risk-reducing surgery at a later stage if you wish. The golden oldies got hormonal treatment and men got mastectomies in these times.

The new breast cancer playlist

With modern playlists, you can pick your theme. The playlists I’m going to concentrate on are those specific for hormone-sensitive breast cancers, known today as luminal A and B breast cancers.

These cancers all have some degree of oestrogen and progesterone sensitivity, and a Ki-67 (proliferation index of between 1 and 15 to 20% are luminal A and Ki-67 values over 15% are luminal B). These type of cancers account for 67 to 80% of all cancers in women, and 90% of male cancers are oestrogen positive, whilst 80% of male breast cancers are progesterone positive.

Treating Luminal A and B with low KI-67

Endocrine therapy

A reminder that hormonal therapy (endocrine therapy) slows down or stops the growth of hormone-sensitive tumours. They work by interfering with effects of hormone receptors on breast cancer cells or by blocking the body’s ability to produce hormones. This therapy isn’t the same as hormone replacement therapy (HRT). Endocrine therapy for breast cancer blocks the growth of hormone-positive breast cancer, and HRT can feed the cancer cells. That is why women taking HRT are asked to stop it. 

Strategies to treat breast cancer cells vary from blocking ovarian function in young pre-menopausal women; this is done with ovarian ablation. In the vinyl era, this was done surgically (but isn’t done today), then with radiation (definitely no longer done). Today drugs such as GnRH agonists interfere with signals that stimulate the ovaries to produce oestrogen.

Aromatase inhibitors

The next group of drugs are those called aromatase inhibitors; they block the enzyme called aromatase which the body uses to make oestrogen in the ovaries and other tissue (fat). This is why it’s important to treat hormone-sensitive breast cancer with exercise and maintaining a BMI under 30, preferably under 25.

If these drugs are used in pre-menopausal women (whose ovaries produce too much aromatase for inhibitors to block effectively), they need to be used in conjunction with a GnRH agonist. The three aromatase inhibitors that are used in breast cancer treatment are anastrozole and letrozole which temporality inactivate aromatase, and exemestane which permanently inactivates aromatase.

SERMs

Certain drugs interfere with oestrogen’s ability to stimulate the growth of breast cancer cells. Selective oestrogen receptor modulators (SERMS) bind to oestrogen receptors. Tamoxifen and toremifene are approved for cancer use. Depending on where these drugs bind, they can also mimic the action of oestrogen. So, they block the effect of oestrogen to breast tissue but have an oestrogen positive effect on the uterus and bone. 

Another group of SERMs are pure anti-oestrogens that bind to the oestrogen receptor and target the receptor for destruction. Previously only available as a monthly injection (fulvestrant), there are now oral options coming onto the market.

The chart-topping playlist: target therapies

This new playlist, a novel group of target therapies, that work on luminal cancers has been around for a while and is tried and tested in metastatic luminal cancers with excellent long-term results.

Before we look at all the new treatment options for these cancers, it’s important to understand how treatments work at a cell level.

Understanding what the drivers are in breast cancer cells help explain the new target treatments for luminal cancers.

Cell cycle 101

A cell is much like the inside of a watch; different cogs working together that can be manipulated. Normal cells grow, divide and die; cancer cells continue to multiply.

There are four stages in a normal cell cycle: G1 (Gap 1), S (DNA synthesis), G2 (Gap 2), and M (Mitosis). With cancer cells, they transform due to genetic and regulatory alterations. The cell cycle is regulated by oncogenes and tumour suppressor genes. These include oncogenic genes: cyclin-dependent kinases (CDKs) and cyclins, and tumour suppressor genes: cyclin-dependent kinase inhibitors (CKIs).

Proteins, such as CDK4 and CDK6, are critical for the transition from the G0 and G1 phases into the S phase. 

They are critical to the cell cycle. Abnormalities in these proteins push increase in cell division.

CDK4/6 inhibitors

A class of drugs that interfere with these proteins are known as CDK4/6 inhibitors. They work by arresting the cell cycle, causing the cancer cells to stop dividing so they lose the ability to cycle and grow, causing the cancers to shrink. CDK4/6 inhibitors can be effective in treating oestrogen receptor-positive and HER2-negative breast cancer.

As with all cancer drugs, they were first used for metastatic breast cancer. There are three CDK4/6 inhibitors that are used in advanced breast cancer. The first is palbociclib initially used with letrozole or fulvestrant. This drug inhibits two cyclin-dependent kinases (CDK4 and CDK6) that appear to promote the growth of hormone-positive breast cancer cells. 

The second drug is abemaciclib which is approved to be used in combination with fulvestrant for post-menopausal women with hormone-positive, locally advanced or metastatic breast cancer.

The third drug is riboclicib, which is approved to be used in combination with an aromatase inhibitor. 

Historically these medicines were used with amazing results for metastatic luminal breast cancer, then for locally advanced non-metastatic breast cancer. Now just to shrink some big fat and lazy luminal cancers. We are using them in this scenario with excellent outcomes. 

Lazy HER2 cancers that are lobular or luminal A may also be considered for CDK, hormonal blockers and HER2 treatment. 

Side effects of CDKs

The future looks very promising for this targeted treatment. Being targeted treatments, their side effect profile is different to chemotherapy, and for some more manageable. The side effect profile may not include hair loss but can range from nausea and diarrhoea (which can be excessive), to fatigue and occasional increase in blood clots, anaemia and low white cells and platelets. Though, remember, like most side effects, it doesn’t happen to everyone and can be managed.

Up and coming hit on this playlist

Alpelisib is approved to treat breast cancer that is hormone-positive and HER2-negative and has a mutation in the PIK3CA gene. 

As the tech gets smarter, some cancers try and get smarter too and develop resistance to this fancy new gold standard plated playlist. Both resistance to endocrine and CDK inhibitors does occasionally occur. 

The plan then is to stop the music, repeat the biopsy and find other new funky playlists available. 

So, what’s that song playing on the radio? It’s the platinum number one on the charts: CDK inhibitors. Ask your treating team about them and if you are a candidate. Insist that your multi-disciplinary team is an orchestra and not a three-man band because then you’ll realise the vast number of up and coming music hits that are available for download from the funky oncology juke box.

Header image by Freepik