UNDER THE KNIFE – What revs your motor?

Prof Carol-Ann Benn exposes the engine of cancer cells – genetic profiling of tumours.

We have got faster, stronger and can now travel to Mars. So, why is it that an abnormal cell line that divides and grows and behaves like a terrorist still confounds us so? My standard response, when I am asked “Why do I need any oncology treatment, if you have cut the cancer out?” is that the problem with cancer is its ability to wake-up down the line and do a ‘911’. In other words, when we find it or remove it, we are never sure that it has not left some sleeper cells in the bone or elsewhere that may want to wake-up at a later stage.

Besides the well-let’s-just-give-you-treatment-anyway-approach, how can we fine-tune systemic cancer treatment further? Many academics feel that cancer, once invading and no matter how small, is probably a systemic disease already. This means that by virtue of having dividing and invading cells, these cells have the ability to move in blood vessels, lymph vessels, nerves or anywhere they want to.

Bearing this in mind, the concept of just-send-out-the-SWAT-team-and-kill-anything-that-looks-like-a-terrorist-cell sounds like a good idea. If not a little hectic and not very civilian cell friendly. The problem is always the innocent victims in warfare – other actively dividing cells, like the gut mucosa and hair etc.

Many years ago, we were size prejudiced. When it comes to breast cancer cells, I have said that it is not about size but personality. Now that we have relooked breast cancer, reclassifying it not on how big it is (size T1<2cm; T2 2-5cm; T3 >5cm; T4 (what are you doing…invading deep structures (a) skin; (b) both; (c) and inflammatory (hot red breast; with an orange peel appearance (d); or local spread to glands in the armpit; N1 (small; mobile and <2cm) or N2 (big, not mobile (fixed) or >2cm), we then became age prejudiced. Young people got chemo, menopausal women did not. Finally, we recognised it is about understanding the behaviour of tumours and what your (patient) personality is.

Luminal A: strongly oestrogen and progesterone sensitive with a well-behaved look from the microscope lens, with a Ki-67 <15% i.e. can’t walk or spread so easily.

Luminal B: still oestrogen and progesterone sensitive but not so cute looking from the microscope lens, with a Ki-67 >15% i.e. takkies – can move it.

HER2+: cancers which have the HER2 oncogene almost always require a group of target therapies, drugs like trastuzumab (Herceptin). These cancers can be called triple-positive, if they ER/PR+ and HER2+ and 3+ or just HER2+ (if not endocrine sensitive).

Triple-negative: the last group of baddies. They are called triple-negative because they aren’t oestrogen and progesterone sensitive (negative) and HER2-. Some have extremely high Ki-67 scores (sprint takkies) while others may have high heel shoes, so they are not all the same.

Besides it is not so simple. It is not always about ‘me’ (the tumour) but also about the person (the patient) – their general health, their body’s ability to fight disease and manage treatment.

There is a whole new field called immunotherapy. This is treatment that uses certain parts of a person’s immune system to fight diseases, such as cancer. Our own immune system (defence force) is stimulated to work harder or smarter to attack cancer cells. Drugs help train the immune system to attack cancer cells specifically, which means using the immune system and drugs that alter a person’s immune system to kill cancer cells. What is evident is that it works in some cancer patients (killing the cancer spectacularly) but unfortunately in some people it makes cancers spread. Oh vey! Therefore, we know each body reacts to cancer differently, that is why all treatment needs to be under careful oncology care.

The concept of having broad groups is fine but as can be seen: one size has never fitted all. This has resulted in confusion. The biggest confusion is that the cancer does not read the text book. Looking at only luminal A and B cancers (ones that are oestrogen and progesterone sensitive), we have observed that they don’t all follow the rules. Some luminal A cancers that seem all ‘sweetness and light’ spread or metastasise, while some luminal B cancers that look like real little horrors, don’t.

When I chat to patients (being a mother of a teenage girl), I often use the dating analogy. Your daughter likes two boys simultaneously. You meet specimen A: good-looking, good job, brings you chocolates and your daughter flowers. Perfect, you think. Then, you meet specimen B: ain’t got no money, tells you “Dude, I’m studying life, has lots of tats, scuffed leather jacket, and on a bike. You think – please no! But behind the scenes, specimen A is an emotional abusive jerk, who is going to make her life miserable, leave her heartbroken with kids and debt. And, specimen B is well…just growing up. He will love and care for her forever (Disney soundtrack here). So, what’s on the outside – what is portrayed as personality – may not represent the genetic makeup or behaviour of the person/cancer.

And so, launches genetic profiling. How this works (pardon the bad car analogy): this is like looking inside the engine to determine how the car can drive. Car looks like a Ford Escort but boy can it move (the ride has been pimped on the engine side).

Luminal A and B cancers that don’t fit the box in terms of physical (size characteristics) can have their genetic insides studied and translated to a recurrence score (chance of the cancer coming back with or without chemotherapy).

Basically, scientists studied certain genes inside cancer cells and looked at cancers from years ago, and based on the how they interpreted the cancers behaviour created a scoring system. This was then compared to the treatment given at that time, and further compared to whether that cancer came back (if no chemo was given) or did not come back without chemo. And voila, the genetic profiling specialists got it right…to an extent. Hence, the recurrence score graph of low chance of coming back without chemo, or high chance of coming back without chemo. Remember this is a graph – percentage chances are given, and there is no absolutely.

And so, we then stepped into the frontier of cancer that has already spread, and used profiling to determine in certain luminal A and some luminal B cancers, which have spread to the lymph nodes, that they may not need chemo either.

DISCLAIMER: all these luminal A and B cancers that are oestrogen and progesterone sensitive all require a minimum of five years (mostly and more usually 10) of endocrine treatment.

Then genetic profiling was developed: do we need to give radiation in certain non-invasive breast cancers that are excised locally (breast-saving surgery)? Genetic profiling of triple-negative breast cancers can determine what treatments may be more effective.

And so, cancer genetic profiling expanded even bigger. Studying the sensitivity of cancers to certain drugs and whether certain chemo combinations may be more effective than others, by understanding the genetic profiling of the cancer cell, has resulted in more personalised cancer care.

What is important in this growing field is that none of these tests are done without robust discussion in a multi-disciplinary meeting.

Decisions on which cancers should be tested and for which profiling are not simple and should not just be done because the test can be afforded. Remember many factors come into play when treating patients.

To all the sci-fi geeks out there, who hate to travel and are waiting for the ‘Beam me up, Scotty’ era: distant travel and immediate travel are not a reality yet but personalised oncology care is mostly here to stay.

Prof Carol-Ann Benn heads up breast cancer centres at Helen Joseph Hospital and Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.

MEET OUR EXPERT – Prof Carol-Ann Benn

Prof Carol-Ann Benn heads up breast cancer centres at Helen Joseph Hospital and Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.

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