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Margaret is a 64-year-old woman from British Columbia, Canada, who was originally treated for estrogen receptor (ER) positive breast cancer ten years ago, and had been on anti-estrogen therapy until her disease progressed. The MRI and CT imaging scans that Margaret’s public system oncologist had ordered showed that she had new metastases in her bones and lungs, and that her prognosis was dismal.
Since she had endured surgery, multiple rounds of chemotherapy, radiation therapy and many years of antiestrogen therapy, her oncologist told her that they had run out of treatment options and she was offered palliative care with a chemotherapeutic drug called capecitabine, which was unlikely to provide her with any benefits. She was told to get her affairs in order.
Importantly, Margaret was told she only had a few months to live. Margaret wasn’t ready to just accept this, so she reached out to CTOAM.
1. Introduced Advanced Diagnostics
First, we obtained a sample of Margaret’s tumour tissue and sent it for tumour DNA sequencing. We looked for cancer causing mutations in the DNA of over 340 genes involved in breast cancers.
Secondly, we asked Margaret to contact an independent community oncologist near her home town whom we had experience working with, and suggested that she get a PET/CT to establish the exact state of her disease.
PET/CT, unlike other forms of medical imaging, is able to identify active tumours at a very small size, based on the biological activity of the tumour.
While most forms of imaging look at the density of the tumour and compare it to the surrounding tissues, PET/CT uses a harmless radioactive isotope that is bound to a sugar molecule.
Since tumour cells are constantly growing and therefore highly metabolic, they drink up more of the sugar-isotope solution than the surrounding tissues, and any tumour will glow like a Christmas tree light.
Since only live tumours will drink the sugar-isotope solution, PET/CT can tell if a tumour is alive or if it has been affected (killed) by a specific treatment. No other form of imaging can reveal this essential information!
Furthermore, since the amount of the sugar-isotope solution a specific tumour drinks depends on how fast it is growing, a PET/CT can determine how aggressive a specific tumour is compared with other tumours in the body.
This can allow doctors to focus surgery and treatments on the tumours that are most likely to metastasize.
We uncovered extensive data indicating that a newly approved drug, called afinitor, was providing significant increases in disease free and overall survival rates for postmenopausal women with metastatic ER positive breast cancer who have failed all other options.
We also identified clinical trial data that a specific type of drug used to prevent bone loss, called zometa, also had cancer fighting properties and provided a survival benefit for post-menopausal women with ER positive breast cancers. The drug that she was currently taking for bone loss, called clodronate, had no such benefits.
Next, we researched the British Columbia Cancer Agency’s (BCCA) treatment guidelines for advanced breast cancers, and identified provisions in the guidelines to treat patients such as Margaret with afinitor.
We immediately wrote up a patient report for Margaret’s new health care treatment team, and her community oncologist was able to get the costs of both a PET/CT and the cost of the afinitor covered by BCCA [British Columbia Cancer Agency].
However, Margaret had to pay out of pocket for zometa which cost her about $800 per year.
During the course of her treatment, Margaret’s DNA sequencing results indicated that her cancer would potentially be sensitive to a variety of targeted therapies, including a recently approved drug called palbociclib, which was providing superior survival benefits to breast cancer patients.
Since recent data was showing that a new class of immunotherapy drugs, called PD-1 inhibitors, was also showing significant benefits to women with breast cancer whose tumours were PD-1 positive, we performed a liquid biopsy RNA sequencing (blood test) test to identify if any of Margaret’s tumours were PD-1 positive.
The PD-1 ligand is a protein that every cell in the body is required to have on its outside surface. It acts much like a security guard in that it tells the immune system that the cell is a normal body cell, so when the PD-1 ligand binds with the PD-1 receptors on the immune cells, it disables them.
In these cases, the tumours have a blanket of PD-1 ligand surrounding them, allowing them to turn off the immune response.
This is one of three known mechanisms that tumours use to avoid detection by the immune system. The other two are known as the CTLA4 and the IDO axis.
Treatment with PD-1 inhibitors results in removal of the protective PD-1L blanket surrounding the tumours, resulting in reactivation of the immune system against the tumours. These drugs act like a vaccination and are given via injection every three weeks. Importantly, they have minimal side effects compared with standard radiation or chemotherapy.
We started using PD-1 inhibitors about five years ago, and they’ve had dramatic effects on some patients.
We decided on the liquid biopsy rather than a biopsy of her tumour because not all tumours will express the PD-1 at the same time, and the expression of it varies between different tumour sites. Single biopsy based PD-1 testing is not an accurate predictor of responses to PD-1 inhibitors because different tumours use the PD-1 signalling cascade to inhibit immune responses against them at different times during the progression of the disease.
Testing all of the body’s tumours at the same time using liquid biopsies is much more accurate in determining if there is a potential for responses to these drugs.
Margaret’s ctDNA test showed that her tumours were highly PD-1L positive and that she would be a good candidate for pembrolizumab immunotherapy.
Since Margaret’s PD-1 liquid biopsy test came back as positive, she will be able to enter a local clinical trial using PD-1 inhibitors if she chooses. Additionally, she can access these drugs via her community private oncologist.
6. Patient Outcome
Afinitor has been working very well for Margaret over the last six months, and is known to delay disease progression significantly, reduce hospital visits, and increase comfort as it is a non-chemotherapy targeted drug. Importantly, Margaret is able to continue working.
Since this drug was approved and covered by her local cancer agency, she got the treatment she needed with much less stress and financial strain.
Furthermore, when afinitor stops working, she has a variety of other targeted therapies that have the potential of providing her with more time, without the damaging side effects of standard chemotherapy.
Recently, Margaret’s tumour markers started to rise, and a recent PET/CT showed that she was becoming resistant to afinitor, and that her cancer was progressing.
We went back to her F1 tumour sequencing panel, and with some extra research, identified a drug called votrient that would target the mutations in her FGFR signalling pathway. The FGFR signalling pathway has recently been found to be associated with certain forms of breast cancer and there is some new evidence that shows inhibition of this pathway can slow the growth of breast cancers. We suggested that Margaret take this drug in conjunction with a newer estrogen inhibitor that we have been using for years, called fulvestrant.
Women with estrogen positive breast cancer typically take drugs to inhibit the production of estrogen, which drives the progression of this type of cancer. The most common drugs are steroidal inhibitors such as exemestane and nonsteroidal inhibitors such as anastrozole and letrozole. These drugs work by inhibiting a key component (aromatase enzyme) of the estrogen synthesis process.
Unfortunately, there are many side effects to inhibiting estrogen production. And eventually, the cancers become estrogen independent and develop resistance to these drugs. This is because:
Fulvestrant works by binding to and degrading the ERa, and therefore allows for a much more effective reduction in ERa signalling. Furthermore, it can be combined with an aromatase inhibitor for a much greater overall reduction.
Currently, Margaret is responding very well to a combination of fulvestrant, exemestane, votrient, and Zometa.
We have great news regarding Margaret! Her application for our prefered new combination was accepted, and she will now start a combination of palbociclib, fulvestrant, letrozole and zometa. Furthermore, she will receive this combination for free and no longer has to pay for her votrient.
Palbociclib is a CDK4/6 (cyclin-dependent kinase) inhibitor. CDK’s are proteins that allow a cell to go to the next stage of the cell cycle while they are reproducing. In many cancers, CDK’s are over-activated and this allows cells to move quickly through the reproduction cycle without any regulation.
In women with advanced estrogen positive breast cancer, the addition of palbociclib to the anti-estrogen drug letrozole resulted in an increase of the median progression-free survival (PFS) from 10.2 months to 20.2 months.
We are happy to announce that Margaret has responded very well to this new combination, and her doctor has reported that she is showing significant reductions in her disease, both via imaging and tumour cell markers. Importantly, she reports that she has not felt this good since she first started treatment in 2005 – and almost three years after she was first told she only had months to live!
As you can see, CTOAM’s advanced diagnostics, records review, and consultations can result in significant benefits to a patient’s outcome. Having access to a team of precision oncology specialists, doctors, and patient advocates can make all the difference in the outcome of your disease.
If you or a loved one has cancer, contact us today so we can do a brief review of your medical records. CTOAM’s cancer research and patient advocacy experts will ensure that you have access to the most advanced tests and treatments available for your unique form of cancer – as close to home as possible.
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