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Prof Carol-Ann Benn likens the latest oncology drugs to treat breast cancer to snipers and spies and explains why they have a good kill-ability.
This is the era of precision medicine and no cancer demonstrates better the transition from nuke everything to take out the baddie (quietly) than breast cancer. By taking a look at how we changed the approach to breast cancer treatment over the last 60 years, we can understand how we moved from mustard gas warfare to clever sniper shots in-the-kill-the-cancer-terrorist scenario.
As I have mentioned before, the history of oncology was based on the concept of the surgeon (this mighty and powerful warrior cleaving off breasts with little regard to aesthetics); and experimental oncology treatment, such as using yes mustard and radiation for Evita Peron’s cervical cancer; and cleverly taking five different oncology drugs and mixing them together and actually getting a good five-year survival outcome (possibly the historic start of remission concepts) for inflammatory cancer in 1952.
Historical background of oncology warfare
So, let’s look at the historical background of how oncology warfare moved from just-blow-it-all-up to the spy masters of the subtle kill. Breast cancer was the first cancer that successfully used targeted therapies. Yup, those receptors for oestrogen and progesterone were the cornerstone of systemic therapy (whole body therapy for breast cancer). The treatment approach was the concept of endocrine therapy and from the swinging 60s’ discovery of tamoxifen (that ugly duckling that evolved into a swan of successful and gracious cancer treatment). From there, the discovery of the HER2 overexpression leading to the revolutionised multitude of HER2 targeted agents.
Understanding targeted approaches to cancer allows us to understand how we are heading into the future of precision medicine and the spy cancer game is evolving.
The oestrogen receptor
The first target was that of the oestrogen receptor. So, while the clever George Beatson started the process with removing ovaries in patients with advanced breast cancer, the actual finding of the oestrogen receptor on breast cancer cells was not to happen till the 60s. The first tamoxifen trials were performed on cancers that we didn’t know the receptor status on. A reminder: blocking oestrogen on a breast cancer cell is done with a selective oestrogen receptor modulator (SERM), such as tamoxifen.
We can eliminate or deprive the body of circulating oestrogen with aromatase inhibitors (AI), which were primarily used in post-menopausal women by inhibiting the enzyme (aromatase) which prevents the conversion of androgen to oestrogen or ovarian suppressive therapies (this was like removing the ovaries). These ovarian suppressive therapies can be surgical (originally done; radiation (then suggested) or biochemical drugs (luteinizing hormone-releasing hormone analogue, an example is goserelin)).
The use of these means that a young woman can be placed into menopause, or anyone who isn’t and combine it with an AI. It’s also advisable in a premenopausal woman menstruating on tamoxifen.
Original art of cancer war also involved a slightly conflicted original approach between the US and Europe; with the US chasing the nirvana to find treatment answers with the use of cytotoxic therapies and the European school with hormonal targeted therapies, a bit like the atomic bomb versus the subtle kill. Note, both are effective as cancer was and is that terrorist that tries to take out the whole world and leave no prisoners (that mad baddie that doesn’t listen to the gentleman’s rules of engagement). Resolving the transatlantic differences have been improved over the last 10 years with the release of more tumour genetic profiling studies.
Another important drug class is the selective oestrogen receptor downregulator (SERD), an example is fulvestrant. Block and degrade oestrogen down; this results in oestrogen-dependent cells not growing and cell death downregulates cellular levels of oestrogen- and progesterone receptors and therefore leads to decreased cell growth in oestrogen-dependent cells. Today this is used in the metastatic setting with some new novel combinations, and currently an oral option is on trial.
War strategy of the future
Obviously in luminal (ER and PR positive) breast cancers, endocrine treatment is recommended. How affective the treatment is often dependent on the receptor expression (how positive), which is why it’s so critical that the test is done by a lab with proper ability to assess the receptor expression assay.
Type of endocrine and length of endocrine treatment as well as combining them with biologic agents will map the war strategy of the future. Our ability to test for other biomarkers on cancer cells, particularly if treatment is given before surgery will improve our cancer kill-rate.
HER2 as a proto-oncogene
Fast forward to the 80s era. The next target was the identification of the HER2 as a proto-oncogene in 15 to 20% of breast cancers. This iconic publication, in 1989, was followed by many on the therapeutic benefits of targeting this cancer gene and the prognostic outcomes of such treatments; with no fewer than five drugs now available for use in the neoadjuvant and metastatic setting. These cells, because of a specific gene copy number amplification, grow rapidly as well as become the cancers prime driver (onco-addiction), meaning that treating the HER2 is critical even if the cancer reoccurs.
The first drug against anti-HER2 was created as an antibody, specifically formulated at the transmembrane HER2 receptor (situated sort of outside the cell (extracellular). This cleverly formulated engineered antibody was a really new and innovative way of attacking cancer cells. Reminder, all oncology studies are done on patients with advanced disease and these study results showed excellent results even though the accuracy of the HER2 testing took a while to refine.
So, by adding trastuzumab (anti-HER2 drug) to different chemo regimens resulted in FDA approval in 1998 (at this stage the safest chemo combination was a taxane; giving trastuzamab with doxorubicin showed a high cardio-toxicity (just under 30%)). Now biosimilars are also acceptable as well as using trastuzumab with a variety of chemo combos as well as hormonal medication, and can be reused in different combos in patients with advanced disease.
From advanced cancer treatment to kill the cells before they are locked up. I was at the 2005 American Society of Clinical Oncology (ASCO) presentation (in New Orleans), where, I think the first time in oncology history, a standing ovation was given when the data of HER2 treatment in early stage HER2 positive breast cancer was presented. The studies that revolutionised our treatment were based on three trials (NCCTG, N9831 and NSABP B-31) and a European study: HERA study. The first two mentioned showed the use of a combination of anthracycline/taxane-based regimen (AC-TH), and the HERA used chemo followed by HER2 treatment.
Other studies combined trastuzumab with docetaxel plus carboplatin (TCH) also showed phenomenal results in terms of overall survival. Most oncology trial results are considered spectacular if there is a few percentage gain in survival; 10% absolute survival would be like winning a war without major casualties. And as the Cancer War Generals got braver, they tried using a single agent taxane (x12) (non-hair losing, less side effects and heart safer with trastuzumab for 1 year (TH)).
So, now we were starting to use snipers with a 98% disease-free survival at four years. So, low risk (hormone-sensitive) HER2 Stage 1 disease (good reason to screen). Generally, trastuzumab is given for one year; shorter duration attempted trials have been a bit iffy. Thus, the development of more sniper-type HER2 meds became a thing.
Sniper-type HER2 drugs
I remember being involved with a few trials for a small-molecule HER1/HER2 dual inhibitor called lapatinib. Patients battled some side effects but if you adjust the dose, this is a very useful drug in combination with capecitabine, particularly in patients that have relapsed on HER2 treatment and with disease in the brain.
A sexy sniper is pertuzumab; different kill-mechanism to trastuzumab (hence slightly different side effects; look at the CLEOPATRA trial) and hence the combo resulted in a new first-line treatment. What is interesting about this drug is when it was used in the neo-adjuvant setting (before surgery), the pathological complete response rate was excellent and as a result the FDA approved a drug based purely on its primary killing-ability in the pre-surgery setting. The kill-ability was again confirmed in the after-surgery setting using AC-THP or TCHP. Because the kill results weren’t spectacularly better, most clinicians reserve its use for high-risk disease (hormone receptor negative, node positive disease).
The secret assassins
Do you remember the concept of a Trojan horse? A very clever drug is an antibody-drug conjugate called T-DM1. What the drug does is link something to trastuzumab (a tubulin inhibitor emtansine), allowing itself to be delivered into the HER2 overexpressing cells. At this stage, although a clever concept, the use hasn’t shown superior outcomes and is still used as a second-line treatment.
Another spy drug that has been tested by many companies is neratinib, an irreversible HER1/2 inhibitor, and well it’s used and is currently trialled with mixed results (basically a secret agent in training).
The real 007s of cancer treatment
Mammalian target of rapamycin (MTOR) inhibitors have 007 status as they help with endocrine-resistant breast cancer. In my opinion CDK4/6 inhibitors are too; this spy terminology is for a pathway that is upregulated in endocrine resistant cells. By blocking this pathway, the endocrine snipers could take back control of the cancer cells. And boy, first came the clever results of palbociclib, followed shortly thereafter by ribociclib and abemaciclib! And did these clever 007s help save lives, and seem to be now used for those big hormone-sensitive breast cancers, those big fat and lazy cancers (those that an oncologist says are like removing chewing gum from your hair).
So, for both hormone-sensitive and HER2-sensitive breast cancer, there are a variety of super clever kill-agents to ensure that cancer baddies are killed off in a smarter fashion than just blow-it-all-up.
MEET THE EXPERT – Prof Carol-Ann Benn
Prof Carol-Ann Benn heads up an internationally accredited, multi-disciplinary breast cancer centre at Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.
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