I got my head around the term ‘Somatostatin’ and ‘Somatostatin Analogues’ some time ago but the term ‘Somatostatin Receptor’ (SSTR) is still a bit of a mystery and it’s come to the top of my list of things to study. SSTRs do come up in conversation quite often and I’m fed up of nodding sagely hoping it will eventually become clear! On analysis it looks like a technical subject – and therefore a challenge 🙂 I’ve taken a logical approach working from ‘Somatostatin’ to ‘Somatostatin Analogue’ before commencing on the receptor bit. It is intentionally brief and simplistic!
It’s important to understand this hormone and why your ‘butt dart’ is called a Somatostatin Analogue’. Some Neuroendocrine Tumours secrete hormones and peptides that cause distinct clinical syndromes, including amongst others, carcinoid syndrome. Somatostatin is a naturally occurring hormone and a known inhibitor of some of these hormones and peptides that can be over secreted by NETs. For example, somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone (GH) and Thyroid Stimulating Hormone (TSH). In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon. However, the naturally produced Somatostatin does not have the lifespan to have any effect on Neuroendocrine Tumours which are over secreting these hormones and peptides.
Somatostatin Analogue (SSA)
These are manufactured versions of Somatostatin known as Somatostatin Analogues. These are designed to have a lasting effect to inhibit for much longer and therefore reduce the symptoms caused by the over secretion (i.e. the syndrome). Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline) and Pasireotide.
So how do Somatostatin Analogues actually work?
For the inhibition to work effectively, there needs to be a route into the over secreting tumours, normally via short or long acting injections or intravenously (IV). On the tumour cells, there are currently 5 known ‘Somatostatin Receptors’ which are ‘expressed’ by most NETs. These are known as SSTR1 – SSTR5. The SSA will attempt to bind with these receptors to inhibit certain hormones and peptides.
Without going into too much technical detail, let’s just say the SSA binds to these receptors (or at least tries to). The subtypes expressed by NETs are variable and the efficiency of different SSAs in binding to each SSTR subtype also varies. For example the table below lists the variability of Somatostatin Receptor efficiency in different types of NET. Interesting to note that non-functional NETs do have SSTRs and SSAs will bind to them albeit less efficiently.
Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)
|Tumour||SSTR1 (%)||SSTR2 (%)||SSTR3 (%)||SSTR4 (%)||SSTR5 (%)|
|Non-functioning pancreatic tumour||58||88||42||48||50|
|Carcinoid tumour of the gut||76||80||43||68||77|
This table above clearly shows the variability of SSTRs when binding with different types of NETs. It follows that manufacturers of SSAs will be using this data in the formulation of their drugs. If you now look at the table below, you can see how efficiently the 3 well-known SSAs inhibit NETs on each SSTR.
Table 2 – Somatostatin receptor subtype-binding affinity of somatostatin analogues (See Copyright)
|RECEPTOR SUBTYPE AFFINITY (IC50, nM)|
Octreotide and Lanreotide seem to have high affinity for SSTR2 and 5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, probably why it has been approved for Acromegaly and Cushing’s Disease. However, to date, there has not been enough evidence showing that Pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. You may find this video interesting as the doctor is suggesting it could be used by NET patients in certain scenarios.
What about SSA labelled diagnostics and therapies?
The same principles apply. For example, an Octreotide Scan (actually known as ‘Somatostatin Receptor’ Scintigraphy (SRS)) works by taking pictures using a gamma camera which is designed to see radiation from a ‘tracer’. The tracer in question is a radio labelled version of Octreotide (such as pentetreotide) which will bind to somatostatin receptors on the surface of the tumour cells In the simplest of terms, this shows up where NETs are. The same principles also apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.
With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on. In PRRT, Octreotide is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177). It binds with the SSRTs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect.
Do Somatostatin Receptors work for everyone?
Unfortunately not. Some people have more sensitive receptors than others and the figure of 80% appears to be the most common statistic indicating one-fifth of all NET patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/Ga 68 PET and/or PRRT. However, that needs to be taken into context and probably applies to midgut NETs measured against SSTR2 – the tables above tend to confirm this figure. During my research, I did read that higher than normal doses of SSAs may have some effect on those with less sensitive SSTRs. Also, SSAs seem to work better with well-differentiated tumours.
How do I know if my Somatostatin Receptors work?
When I was completing my NET checks after diagnosis, my Oncologist declared I was “Octreotide avid” shortly after my Octreoscan was compared with my CT. I’m guessing that is a simple and crude test and how most people find out they have working receptors. I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then you there is a good chance your SSTRs are working normally. I also suspect those who show clear signs of tumour on CT but not on Octreoscan or Ga 68 PET, could have a receptor issue. I suspect there is a more scientific method but I’m still looking for it!
I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs. Having just researched that, I can see that the researchers and the pharma industry will be working to produce more effective ‘binding agents’ to enhance diagnostics and treatment. I’ll maintain this blog as a ‘live’ feature making updates and improvements where necessary.
Thanks for reading
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In 2013, just when I thought everything seemed to be under control, I was told I had a ‘lesion’ on the left upper lobe of my thyroid. At the time, it was a bit of a shock as I had already been subjected to some radical surgery and wondered if this was just part of the relentless march of metastatic NET disease. The thyroid gland does in fact get mentioned frequently in NET patient discussions but many of the conversations I monitored didn’t seem to fit my scenario – cue relentless study! I’ve been meaning to write this blog for some time but here is a synopsis of my research translated into ‘patient speak’. This is intentionally brief, it’s a big subject. I’ll finish off with an update on where I am with my thyroid issue.
Where is the thyroid and what does it do? It lies in the front of your neck in a position just below your ‘Adam’s apple’. It is made up of two lobes – the right lobe and the left lobe, each about the size of a plum cut in half – and these two lobes are joined by a small bridge of thyroid tissue called the isthmus. It is sometimes described as butterfly shape. The two lobes lie on either side of your wind-pipe. The fact that it comes up a lot in NET patient discussions is hardly surprising as it’s an endocrine organ responsible for making two hormones that are secreted into the blood: Thyroxine (T4) and Triiodothyronine (T3). These hormones are necessary for all the cells in your body to work normally.
The main issues appear to be an underactive Thyroid or an overactive Thyroid – known respectively as Hypothyroidism (not enough thyroxine is produced for the body’s needs) and Hyperthyroidism (too much thyroxine is produced for the body’s needs).
Hypothyroidism – If too little of the thyroid hormones are produced, the cells and organs of your body slow down. If you become hypothyroid, your heart rate, for example, may be slower than normal and your intestines work sluggishly, so you become constipated. Key symptoms for Hypothyroidism (overactive): tiredness, feeling cold, weight gain, poor concentration, depression. Some of these symptoms look familiar? The word ‘hashimoto’s’ also comes up on patient forums frequently – this is related to hypothyroidism (underactive).
Hyperthyroidism – If too much of the thyroid hormones are secreted, the body cells work faster than normal, and you have Hyperthyroidism. If you become hyperthyroid because of too much secretion of the hormones from the thyroid gland, the increased activity of your body cells or body organs may lead, for example, to a quickening of your heart rate or increased activity of your intestine so that you have frequent bowel motions or even diarrhoea. Key symptoms – weight loss, heat intolerance, anxiety, and, sometimes, sore and gritty eyes. Hmm, again, some of these look familiar?
Routine ‘Thyroid blood tests’ from your doctor will confirm whether or not you have a thyroid disorder. I now test for TSH (thyroid-stimulating hormone), T3 and T4 every 6 months. All normal.
Remember: Hypo is ‘underactive’, Hyper is ‘overactive’. Sometimes there are very few symptoms
Also worth mentioning something called the ‘Parathyroid’ as these glands can frequently be related to NET Cancer (see my blog on Multiple Endocrine Neoplasia (MEN)). It’s another subject in its own right but I just wanted to emphasise that this is a totally different organ with a totally different function (it regulates Calcium). They are located adjacent to the Thyroid, thus the term ‘para’.
Thyroid Cancer. There can be other issues with Thyroids including cancer and clearly this was my concern when the word ‘lesion’ was mentioned. At this point, it’s worth mentioning something from my cancer history which I initially assumed was related but it would appear to be a coincidence (for the time being …..). I have a hotspot in my left supraclavicularfossa (SCF) lymph nodes (near the clavicle), geographically close to the thyroid (and my lesion is left-sided). 5 nodes were removed from this area in Feb 2012 for an exploratory biopsy which subsequently tested negative BUT …. there is still a hotspot showing on a subsequent Octreoscan. CT and Ultrasound both show nothing vascular or pathologically enlarged. For the record, I also had positive tested nodes removed from my left axillary (armpit) during the same procedure (my distant disease has always been left-sided).
There are a number of different types of Thyroid Cancer:
Papillary thyroid cancer is the most common type of thyroid cancer, accounting for about 80% of thyroid cancers. While papillary thyroid cancer typically occurs in only one lobe of the thyroid gland, it may arise in both lobes in up to 10% to 20% of cases. Papillary thyroid cancer is most common in women of childbearing age. It sometimes is caused by exposure to radiation. Even though papillary thyroid cancer is usually not an aggressive type of cancer, it often metastasizes (spreads) to the lymph nodes in the neck. Papillary thyroid cancer treatment usually is successful.
Follicular thyroid cancer accounts for about 10% of thyroid cancers. Like papillary thyroid cancer, follicular thyroid cancer usually grows slowly. Its outlook is similar to papillary cancer, and its treatment is the same. Follicular thyroid cancer usually stays in the thyroid gland but sometimes spreads to other parts of the body, such as the lungs or bone. However, it usually does not spread to lymph nodes. It is more common in countries where diets do not contain enough iodine.
There is a type of thyroid tumour which has recently been removed as a type of cancer. “Encapsulated follicular variant of papillary thyroid carcinoma” is now known as “noninvasive follicular thyroid neoplasm with papillary thyroid-like nuclear features” or NIFTP. The word ‘carcinoma’ has gone. Read about this here.
Hurthle cell carcinoma, also called oxyphil cell carcinoma, is a type of follicular thyroid cancer. Most patients diagnosed with Hurthle cell cancer do well, but the outlook may change based on the extent of disease at the time of diagnosis.
Medullary thyroid cancer (MTC) is the only type of thyroid cancer that develops in the parafollicular cells of the thyroid gland. It accounts for 3% to 10% of thyroid cancers. Medullary cancer cells usually make and release into the blood proteins called calcitonin and/or carcinoembryonic antigen, which can be measured and used to follow the response to treatment for the disease. Sometimes medullary cancer spreads to the lymph nodes, lungs or liver before a nodule is found or the patient has symptoms. MTC can be treated more successfully if it is diagnosed before it has spread. There are two types of MTC:
- Sporadic MTC is more common, accounting for 85% of medullary thyroid cancers. It is found mostly in older adults and is not inherited.
- Familial MTC is inherited, and it often develops in childhood or early adulthood. If familial MTC occurs with tumours of certain other endocrine organs (parathyroid and adrenal glands), it is called multiple endocrine neoplasia type 2 (see my blog on MEN 2).
Anaplastic thyroid cancer is the most dangerous form of thyroid cancer. It is makes up only 1% of thyroid cancers. It is believed that anaplastic thyroid cancer grows from a papillary or follicular tumour that mutates further to this aggressive form. Anaplastic thyroid cancer spreads rapidly into areas such as the trachea, often causing breathing difficulties. Anaplastic thyroid cancer sometimes is called undifferentiated thyroid cancer because the cells are so different from normal thyroid tissue.
Do I have Thyroid Cancer? I’ve had a number of biopsies on my thyroid lesion, several fine needle aspiration (FNA) and one ‘core’. The FNAs were generally inconclusive and the core confirmed fibrous tissue only. However, the general diagnosis is inconclusive and I have been labelled “THY3F”. Curiously this decodes to “an abnormality is present but it could either be a benign (non cancerous) growth or a malignant cancerous growth of the follicular cells. My thyroid specialist is quite clear – this is a benign growth and is not related to NETs.
Thyroid cancer is not very common but diagnoses are ‘skyrocketing’ most likely due to advanced detection techniques. Most are slow-growing with 5 year survival of 97% according to MD Anderson. There is a very interesting article about the overdiagnosis of Thyroid cancer which I found useful given my situation. You can read it here. Thyroid ‘nodules’ would appear to be very common with 50-70% of all 50-70 year olds having at least one nodule present and statistically, 95% of these are benign (see EndocrineWeb)
The surgeon who operated on my left axillary and SCF nodes also specialises in Thyroids and so it was an easy decision to ask to be referred to him. He explained that whilst he could just take the left lobe or the whole thyroid, it would mean lifelong treatment to add to my current burden and perhaps for something which will never trouble me. As nothing is palpable and I have no symptoms, I agreed to a ‘watch and wait’ approach. I now have regular tests (blood results are normal) and I see him in the Endocrine MDT every 12 months for a blood test review and ultrasound check (initially this was 6 months, but now at the beginning of 2017, it’s changed to 12 months, a good sign). My 6 monthly NET scan also monitors my thyroid lesion – so it’s ‘double bubble’ surveillance.
Hope this was interesting and thanks for reading and sharing.
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