Things to understand about targeted cancer treatmentjuniper88 made a big revelation the other day, my thoughts to him and his wife. Here is another one. I have metastatic neuroendocrine cancer since around 2005, maybe before that, I will never know for sure. The primary tumor was seen on CT-scan in 2008, while having a scan for another reason, it was the size of golf ball outside the end of the small bowel. The doctor told me then it was benign, to not worry about that. I had chronic fatigue during many years at the beginning of the 2010 decade, always complaining to my family doctor about that. I passed tests for sleep apnea, and it was not the problem, blood tests were fine. My mother had colon cancer so in 2016 so my family doctor sent me for a colonoscopy and an abdominal echography. I shortly got a call back from my family doctor. They saw something on the echography, but it is not a precise technique. He sent me quickly to pass a CT-scan and they saw I had lesions in the liver. Then I went to pass an octreoscan. It's a type of scan specifically desinged to detect neuroendocrine tumors overexpressing somatostatin receptors. It was my case. I got the final diagnostic, neuroendocrine tumor (NET) metastasized to the liver. A big shock and a lot of frustration toward the doctor who told me in 2008 it was benign and to forget that. I still regret not reaching for a second opinion. A surgery in 2008 would have likely cured me since the CT-scan and octreoscan showed nothing abnormal in the liver back then. So just removing the primary tumor before metastasis would have cured it.
Fast forward to 2016. The surgeon who sent me for the octreoscan wanted to operate me right away to go look at it directly. I declined and went to see an oncologist with expertise in NETs. She placed me right away on Sandostatin LAR intra-muscular injection every 28 days. This reduces hormones secretion by the NETs. These cells are endocrine cells, so they secrete different hormones, the most common one is serotonine, but there could be other hormones too depending on the specific cancer type. Sandostatin (octreotide) is a peptide analog of the natural peptide somatostatin. It binds to somatostatin receptors that are often overexpressed on NETs membranes. As I said, it slows down hormone secretion, but it can also slow down tumor progression. It's the first line of treatment.
So I was placed on Sandostatin and despite that, my tumor load progressed by 30% in the next six months. A progressing disease allowed me to be treated by Lu177-Dotatate. This is a PDC I spoke very often about here, and for good reason, I was a beneficiary of this drug at the time I was writing about it here. It was not approved in Canada at the time I got my first four treatments, but it was accessible through some bureaucratic mechanism to help patients that needed it. Even though it was not formally approved, it was widely known to be effective at stopping NET progression in patients that have NETs overexpressing somatostatin receptors. The higher the overexpression, the better it is. Before having my first treatment, I passed a Ga68-Dotatate PET scan. This is a much improved version of the octreoscan. It allows to see very small tumors and to precisely assess tumors somatostatin receptors overexpression. It allows to give the best possible dose of Lu177-Dotatate to the patient. The dose with the best efficacy/safety ratio.
So in 2017 I got four Lu177-Dotatate treatments every two months. I had some tumor regression, but not 30% or more, so it did not qualify as a partial response. After that I had Ga68 PET scans every six months to see if there was progression. In 2019 I got a surgery to remove the primary tumor, it was still the size of a golf ball. They needed to remove the end of the small bowel and the beginning of the colon to achieve that. The cancer in the liver did not progress and it represents about 99% of my tumor load, the remaining 1% is in the bones, still very small tumors, but after almost three years some of these very small tumors were bigger, still relatively small, but growing, with a few new very small one appearing. So in 2020, I got two more treatments at a three months interval to try to stop that. After almost five years, the cancer is still stable in the liver. The doctors told me some tumors in the liver grew, but after my treatments other tumors shrunk, so overall the tumor load in the liver is similar as it was five years ago.
In my last Ga68 PET scan this spring, they saw a few very little new tumors in some bones. They decided to give me two new Lu177-Dotatate treatments, but before doing that, I passed a CT scan and another type of PET scan, a FDG PET scan (FDG stands 18Fluorodesoxyglucose). It's a type of PET Scan that can detect aggressive cancers that are using glucose at a much higher rate than normal cells because the cells divide at a fast rate. The idea here was to be sure that I still only had relatively slow progressing NETs, not a mutated more agressive version of the cancer. In this case, they told me that giving me more Lu177-Dotatate treatments would have been pointless. Fortunately, I got a call from the doctor today, and the CT scan and FDG-PET scan were negative to show any other type of more aggressive cancer. I don't have at this time a mutated form of cancer that is aggressive. This is a great news for me. I still only have the relatively slow progressing neuroendocrine cancer that is still overexpressing somatostatin receptors. So in a few weeks I will have my 7th treatment of peptide receptor radionuclide therapy (PRRT) using Lu177-Dotatate and later in the fall the 8th treatment. Then I should be fine for two or three more years. I said I should, because you never know when the cancer will mutate to a more aggressive form.
This leads me to today's news. In my mind, now, we have proof of concept and it has a chance to be great for me since 50% of neuroendocrine cancers are overexpressing the sortilin receptor. So if I am on the right side of the coin flip, SORT1+ platform could provide another PDC that would help me in a few years, hopefully in ten years. That being said, my story shows how far Thera are from using their PDC in the best possible way at the moment. What we got today is a positive signal in a lot of noise. Still, I believe the positive signal is strong enough to conclude that there is a proof of concept. That's the biggest news of all and the one I was hoping for. Now that this key element is established, Thera needs to get serious in they way they will develop this therapeutic platform starting now.
As I said previously, it was possible for me to be treated with Lu177-Dotatate only because my cancer cells are overexpressing the somatostatin receptor, and because this overexpression can be easily and precisely established through Ga68-Dotatate PET scan. If I would have low somatostatin receptors expression, they would not treat me because they would know in advance the therapy would be ineffective. The doctor today on the phone specifically pointed to me that I was still a very good candidate because the Ga68 PET scan showed that my tumors were still overexpressing the somatostatin receptor, hence, still catching the PDC from the bloodstream at a very good rate. With the Ga68 PET scan, doctors can know what dose to give me because they know what is exactly the affinity of my tumors for the drug (PDC). I think now you can understand why I was so adamant about Thara starting to work on an imaging PDC with Ga68. They need to wake up and do something about that asap, now that they have the proof of concept.
The other thing relates to tumor heterogenicity. Five years ago, after my diagnostic, i had a liver biopsy of the metastatic tumors in the liver. They then established that ny cancer was at the beginning of grade 2. There is three grades for cancer aggressiveness, grade 1 is slow cell division, and grade 3 is fast. So beginning of grade 2 five years ago was relatively good. I don't know what is the grade of my cancer now, but the doctor explained to me that the PRRT treatments normally kills the most aggressive cells, while the less aggressive ones are more likely to survive. So he told me that the treatments kind of reset the cancer to somewhat a lower grade. Obviously, it is not that simple since the treatments likely does not kill all the more aggressive cells. That being said, the fact that the doctors this time wanted me to pass a FDG-PET scan to detect any very aggressive cancer shows that they are aware that the more a cancer is for a long period in the body, the higher the odds it has to mutate to a more aggressive form, and the more advanced a cancer is, the more genetically heterogenous it is, and the less likely it can be treated by attacking a single target.
This brings us to the results of Thera today, and also to the the case of juniper88's wife. The more advanced a cancer is, the higher the odds are that it is genetically heterogenous and the less likely it is that a single drug will be effective against all the cancer sub-types (genetic mutations) the patient has. So it is normal to see some shrinkage on some tumors, and progression on others. They no longer really are the same cancer.
I know it's a very long message, but a meaningful one I hope. I am very happy with today's results. I think it's just the beginning, but I could not insist enough on the need to develop an imagery tool related to sortilin receptor expression. As long as they will not select patients with confirmed sortilin overexpression, there will be a lot of noise in the results, and the positive signal will be stuck in that noise. You cannot develop a targeted therapy without precisely aiming at the target. I know they cannot develop it overnight, but biopsies are not the best way to do it. Up to now, I think I got about 10 Ga68 PET scans. It is so easy to do, and in Sherbrooke they improved the method over the years. They have researchers there working on imaging with PDCs. It would be easy just to make a proof of concept on animals, a matter of a few months. Again, a targeted therapy needs to precisely aim at the target, not to rely on odds that a patient has a cancer type overexpressing sortilin. Hey Thera, hey Christian, it's time to switch gear. You can continue the phase Ib and at the same time start working on Ga68-TH19P01 PET Scan. You have the weapon, now you need the imaging technology to detect and quantify your targets.