Every fairy tale needs a good old-fashioned villain. But what the world fails to realise is that every villain is just a victim whose story has not been told. With this said, Professor Carol-Ann Benn equates HER2 positive breast cancer to the queen of villians, Maleficent.
Not every villain is a hundred percent bad, or as bad as they initially seem or are portrayed. Take the film, Maleficent, as an example: until this movie was released, we all thought that she was the queen of villainous fairies. So is the situation with the psychopath we’re discussing: HER 2 positive breast cancer.
Before we start this fairy tale, the setting, context and background needs to be established. Doctors and researchers have always noted that not all cancers are alike. Way back, when the world was thought to be flat, the word cancer was introduced and called “crab”, because crabs moved sideways, and not in a straight-forward manor like people and other animals.
Ancient physicians thought these diseases behaved in a similar non-orderly fashion. Some patients’ tumours grew quite slowly and never seemed to spread beyond the site where they first formed. But for other patients, tumours grew rapidly and seemed to spread like wildfire.
HER2 gene discovered
In the early 1980s, scientists were looking for genes that cause cancer. In 1987, an incredibly smart cancer researcher, Dennis Slamon, discovered the growth factor receptor gene HER2.
This gene produces HER2 proteins once mutated (think Deadpool here), and could stimulate excessive cell growth and division, making scientists wonder if certain genes might make cancers grow and spread rapidly.
Researchers around the world began searching for genes that spur cancer growth and another boffin, Stuart Aaronson, showed that HER2 protein could cause cells to grow uncontrollably.
The Slamon team then found that 30% of breast cancers had this HER2 protein present at high levels; and that if these cancers had high levels of this protein then there was a greater chance of metastasis and these patients were more likely to die.
Birth of trastuzumab
Suppose now if the HER2 protein could be blocked; thus, slowing the growth of HER2 positive breast cancer cells.
Dr Slamon’s team recognised that one way to block the action of this protein is to make a monoclonal antibody in the lab that attaches to a specific protein and disrupts it function. Thus, they showed that an antibody specific for HER2 could slow the growth of metastatic breast cancer cells in a lab dish.
The next step was ‘Pacman with cancer cells’: a collaboration between Genentech and UCLA showed HER2-specific antibodies could suppress the growth of HER2 positive tumours in mice. And, thus was born the HER2-specific antibody, called trastuzumab (Herceptin), for human use.
Using the calling card
The psychopath has a calling card – HER2. Now we need to catch it. To do that, the calling card must be obvious. Therefore, when the ‘personality of the cancer’ is documented on the path report, the following information is required:
A report of the HER2 overexpression is given a score of between (0-3+). Any score over 2 (which is determined by a count reading done by the pathologist looking down the microscope) then has further tests done.
These tests are like a forensic pathologist checking to see what material is left for DNA analysis, to confirm that the psychopathic cell is truly HER2. The genetic expression is also checked. So, now we have a way of identifying this villain. I could end here. But Sherlock, we still haven’t caught Moriarty.
Effectiveness of calling card
So, now we need a way to determine effectiveness of our trapping devise. Trial and error in catching criminals may work occasionally. In medicine, however, medical trials with strict ethics means that there is emphasis on less error. And, most trials on new drugs are performed on patients with advanced breast cancer.
Three clinical trials, using trastuzumab for patients with HER2 positive metastatic breast cancer, were launched in the mid-1990s. By 1998, the results of the phase three clinical trials showed that breast cancer in patients treated with trastuzumab and chemotherapy grew at a slower rate than in patients treated with chemotherapy alone.
Further trials also showed benefit in women with early-stage HER2 positive breast cancer.
Unfortunately, not all trials are well-structured trials. Some trials with fewer patients showing similar results on shorter treatment durations (not better, not worse). And, poorly structured trials, such as trials showing that large percentage of patients not receiving the medication relapsed (i.e. cancer elsewhere) within two years, drove two concerning outcomes:
- Medical funders saying less drug for less time is better.
- Patients taking out large bonds to fund a very expensive medication.
Only in November 2006, did the US Food and Drug Administration (FDA) grant approval for trastuzumab to be used with chemotherapy for women with HER2 positive breast cancer in the adjuvant setting (after cancer has been cut out).
Harder to catch
But psychopaths like these are harder to catch than your average B and E specialist. This is where the value of neo-adjuvant/primary oncology treatment comes in.
By giving the drug first with the cancer still inside the body; clinicians can recognise which cancers are killed with what drugs. Overtime clinicians started to recognise that not all HER2 villains were the same. Some HER2 cancers are HER2 positive and not hormone-sensitive (ER and PR negative and HER2 positive). These are driven primarily by the HER2. Some are ER positive; have little PR sensitivity and are less endocrine-sensitive. A few are strongly ER and PR positive with a low Ki-67 (the takkies) and may even have a stronger hormonal driver.
Correct strategic attack
Right, so what is the approach to catching this potential killer that can be recognised and nabbed?
Different units have different approaches. Though the golden rules still apply: the diagnosis should not be made in theatre; needle biopsies (core biopsies first prior to treatment).
Do not undergo any treatment until your cancer is discussed in a multi-disciplinary meeting and feedback is given to you by the treating team and an independent nurse navigator.
Before we plan an attack strategy; remember that each cancer is an individual; each person is unique so personalised treatment regimens are important, if not essential.
The rule is that almost every patient who has an HER2 overexpressed (3+ SISH; FISH or BDISH positive) breast cancer should have traztuzamab at least (this includes tiny HER2 positive cancers under 10mm that haven’t spread to the lymph nodes).
Our unit prefers to give HER2 treatment prior to surgery (aim 100% kill-rate; success in the unit is good) with specific attention being paid to whether the cancer is hormone-sensitive and to what the Ki-67 is.
Standard of care
Standard of care to treat curable HER2 positive breast cancer has been to give chemotherapy with the HER2-targeted monoclonal antibody, trastuzumab.
In the US and in SA, a commonly used regimen is ACTH (doxorubicin and cyclophosphamide) for four cycles, followed by a taxane, with trastuzumab given concurrently with the taxane; and trastuzumab continued for a full year (T&Cs apply depending on what medical funders agree to pay and co-pay…and don’t just roll over and accept these).
Another regimen, with some studies indicating that it’s more commonly used now, is docetaxel and carboplatin plus trastuzumab, or the TCH regimen. Here the chemotherapy is given every three weeks for six cycles concurrently with trastuzumab, and then trastuzumab is continued for a full year.
Benefits of TCH over ACTH is less heart toxicity and lower risk of blood-related disorders. A useful study, BCIRG-006, shows that the two regimes have similar efficacy and thus remain standards of therapy for HER2 positive breast cancer. Again, you and your cancer are unique. T&Cs apply; discuss with your oncologist; ask for second opinions and MDM feedback.
30% increase in survival rate
So, the survival rate improved by 30%. It doesn’t sound great to a non-math person like myself but this meant certain regimes in certain patients showed a 97% seven-year survival.
And for patients that developed resistance (there is always one Moriarty), there are many ‘cancer Sherlock developments’ on the HER2 front.
Treatments that specifically target HER2 are very effective. These treatments are so effective that the outcome for HER2 positive breast cancer has outstripped that of other cancers.
Treatment options for HER2 positive cancers include:
- Ado-trastuzumab emtansine (Kadcyla)
- Lapatinib (Tykerb)
- Neratinib (Nerlynx)
- Pertuzumab (Perjeta)
- Trastuzumab (Herceptin)
A drug recently approved is pertuzumab; approval was based on the APHINITY study.
Several new medications being developed that also target HER2 are being tested in clinical trials (always ask about clinical trials in your unit and check international trial sites). Check with your treating oncology team what is available; what the options are and how to access some of these medicines.
De-escalation of therapy
Another interesting concept with early stage HER2 positive breast cancer (i.e. node-negative, smaller tumours) is the strategy of de-escalation of therapy.
Patients are not subjected to so much treatment and all the toxicities that go along with that treatment (less is more as long as the more has a HER2 treatment specific drug), such as single agent taxane (paclitaxel) given weekly for 12 weeks in conjunction with trastuzumab – 93% seven-year survival.
An example of this is four cycles with docetaxel, cyclophosphamide, and trastuzumab in small HER2 positive cancers. The disease free-survival rate exceeding 97%. So, those are some options available.
Watch the press
Some studies, such as the ATEMPT study, are looking at T-DM1 (ado-trastuzumab emtansine) patients with lower-risk disease. Should be interesting.
So, Sherlock has had major success in converting Moriarty into Maleficent: wings clipped and mostly ‘Pacmaned’ this cancer out the park.
With so many mixed analogies, we can only say this cancer has had its wings clipped, and is a good reason to go for your mammograms to pick up cancers early.[/vc_column_text][/vc_column][/vc_row]
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 Breast Health Foundation.