Blood drawn for laboratory work before my last infusion included samples for two circulating tumor DNA (ctDNA) tests - Natera Signatera and Northstar Response (discussed in my previous blog entry).
This is the fourth Signatera test (one roughly every 3 months ) that did not detect ctDNA.  The Signatera test is based on genetic analysis of my tumor - looking for the DNA signature of my tumor and 16 likely mutations.
The Response test looks for methylated DNA - a byproduct of cancer at work.  It is estimated to have 10 times the "signal" of Signatera.  My oncologist indicated that, because of it's sensitivity, he has seen changes even between cycles (every 3 weeks for me).  I was encouraged to see that my second Response value was less than 25 and below its quantifiable range.  This was not considered a significant change from my baseline (57).  I will discuss with oncologist if I should draw blood for another Response test at my next infusion.
I've also had a PET/CT scan which indicated that my lymph nodes were no longer active and two subsequent  CT scans (all roughly 3 months apart) which showed no evidence of new metastatic disease.
This surveillance data suggests to me I have had a complete pathological response (pCR) - as did 29% of participants in the EV302 trial, which led to approval of my treatment (enfortumab vedotin+pembrolizumab) as a first line option.
I suspended enfortumab vedotin (Padcev) after 7 cycles due to adverse effects described previously.  I've continued pembrolizumab (Keytruda) - 11 additional cycles so far. 
With my second Response test being consistent with my Signatera test - it raises the question of when I can safely suspend my Keytruda.  pCR unfortunately does not mean that cancer is gone or will not recur.
A recent article suggests that adjuvant immunotherapy should not be given to patients who exhibit pCR after neoadjuvant chemoimmunotherapy and surgery.  The context is patients with resectable non-small cell lung cancer (NSCLC) - who receive a combination of immunotherapy and platinum-based chemo before surgery and demonstrate pCR after surgery.  Results of recent trials suggest that pCR has a prognostic value for high event free survival (EFS).  The authors note that the majority of patients (93% in the CheckMate-816 trial) who achieved pCR had no detectable ctDNA.  They point out that an additional year of immunotherapy comes with risks of adverse effects and a financial cost (to insurer or patient).  Given the encouraging results for patients who achieve pCR - they don't see the benefits outweighing risks in follow up immunotherapy.
In my case surgery was my initial transurethral resection of the bladder tumor (TURBT) and chemoimmunotherapy was Padcev+Keytruda.  My adjuvant immunotherapy is continuation of Keytruda.  I believe that I have achieved pCR and will seek forums to pose the question (including discussing with my oncologist) of how long I should continue my immunotherapy and monitor the literature for any related guidance about continuing immunotherapy (unless and until I see recurrence of my disease).

​It seems there is a name for approach I have been pursuing (and providentially led to) - risk adapted treatment for locally advanced muscle invasive bladder cancer: employing a systemic treatment - in my case enfortumab vedotin + pembrolizumab  (EV/pembro or Padcev/Keytruda) - and active surveillance to determine if  other treatment options are needed - which could include bladder removal (radical cystectomy) or chemoradiation (trimodality therapy).
The results of a phase 2 trial following this approach were just published.  The RETAIN-1 (NCT02710734) trial began 2016, before EV/Pembro was approved, and the neoadjuvant systemic therapy was  AMVAC (accelerated methotraxate, vinblastine, doxorubicin and cisplatin). 
Genetic analysis was done on the tumors after transurethral resection of the bladder tumor (TURBT) looking for ATM, RB1, FANCC or ERCC2 mutations.  After 3 cycles of AMVAC were completed and a second TURBT performed, patients with no residual disease and at least one of the listed mutations began active surveillance (AS). ​The end point of the trial was to be metastasis free survival IMFS) at 2 years for all enrolled.

The end point was not met, however of  the 25 patients enrolled in AS, 12 (48%) remained metastasis free with intact bladders at 2 years.
I began treatment with EV/pembro a bit more than a year ago.  EV/pembro is an "all comers" treatment.  EV delivers a chemothearpy payload to a Nectin-4 protein expressed on the majority of  urothelial cancer cells and pembrolizumab blocks the PD-1 protein on immune cells to energize the immune system.  Participants in the EV302 trial that led to EV/pembro approval were tested for PD-1 and Nectin-4.  There was success (and some failures) for those with both high and low expression of both biomarkers.  Therefore there is, at present, no biomarker to reliably select patients likely to have a positive response (which included a complete response for 29% of the participants in EV302).
After 4 cycles of treatment, I had my first indication that I no longer had evidence of disease by PET/CT imaging and tumor-informed circulating tumor DNA (ctDNA).  I've had two other surveillance data points, each roughly 3 months apart - CT scans showing no new metastases and no detected ctDNA by Signatera test.  We suspended Padcev after 7 cycles and have continued with Keytruda.
My oncologist told me of another ctDNA test - Northstar Response - which is tumor naive (not informed by analysis of my tumor).  It looks for methylated tumor DNA - a byproduct of cancer at work - shed in the blood.  The signal is potentially much higher and my oncologist has seen changes even between cycles (at the moment every 3 weeks for pembrolizumab alone).
I drew blood for my first Northstart Response test on December 6 - the results are shown above.
Not what I was hoping for,  my baseline result indicates that there is still cancer there - low, but above the level where the value is too low to be certain.  I drew blood for my second Response test on December 21 - where we can see if the trend is up, down or stable and plan action accordingly - again risk-adapted treatment.
The baseline test also called out a CHEK2 mutation - which was also identified in my germline test (discussed in a previous post).  The test also listed related clinical trials. NCT03375307 is  clinical trial is a Phase II study evaluating the efficacy of olaparib (a PARP inhibitor) in treating patients with metastatic or advanced urothelial cancer that has DNA-repair defects (including CHEK2 mutation).  I am reaching out to the investigators leading this trial to see if and when this might be a second line option if needed (restarting Padcev would be another option).  
Information is power and I know there is power in prayer and I plan to engage both.  The weather, holidays and perhaps a bit of complacence have conspired to slow the pace of my exercise and periodic fasting - along with an increase in my weight and blood glucose.  I will attend to these and  while I wait on the next ctDNA results - prayers are always welcome. 
​

I began treatment for locally advanced muscle invasive bladder cancer on December 15 last year.
Watching my sheep today reminds me of THE gift that secured my eternal destiny in a new creation free of disease. 
Until then my Christmas list...

Complete response to new systemic treatments (e.g. antibody drug conjugates and immunotherapy) for locally advanced muscle invasive bladder cancer and others will be shown to be durable.

AI will accelerate development and validation of better treatments.

Biomarkers will be developed for accurate patient selection for these treatments.

Molecular residual disease tests MRD (e.g circulating tumor DNA) will simplify surveillance and support prompt changes in management - including safe treatment de-escalation.

Improved overall survival prognoses with preservation of quality of life (including bladder preservation) will be the norm.

My fellow survivors will feel their Savior walking with them.

WIshing all a joyful and blessed Christmas!

A recent publication caught my eye where a study was done with mouse models of and human patients with prostate cancer.
In the mouse models, the addition of white button mushroom (WBM) extract to the diet resulted in reduction in the number of myeloid-derived suppressor cells (MDSC) which promoted antitumor immune responses mediated by T cells and natural killer (NK) cells.  They also observed increased anticancer activity of PD-1 antibodies
In patients a decline was observed in the circulating MDSCs and increase in cytotoxic CD8+ T and NK cells.  The City of Hope is recruiting for a phase 2 trial to further examine the effect of WBM on prostate cancer.
MDSCs are also  emerging target for bladder cancer.   They contribute to the ability of tumors to evade immune detection.  More research, such as that being pursied for prostate cancer, is needed to demonstrate the effect of reducing MDSCs in bladder cancer patients - however, the mechanism is the same for both.
White button mushrooms offer a number of health benefits  (including gut biome health and glucose control which I have mentioned elsewhere are of interest to me) and WBM extract is available as a supplement.
My single treatment for muscle invasive bladder cancer at the moment is pembrolizumab - an immune checkpoint inhibitor.  I've discussed with my oncologist and I am going to taking a daily dose of WBM extract to potentially enhance its effect.  I will start with dose recommended on the product I ordered (500 mg - roughly 1/4 teaspoon daily). I may adjust as I learn more of the dose used in clinical trials.  As always, with any change in diet or medication, you should consult with your care team.

1 year and 6 days ago I had my first PET/CT scan .  [I've mentioned that I led software development for the first generation of PET/CT systems - but this was my first image as a patient.]  That scan showed locoregional spread of my muscle invasive bladder cancer (MIBC) to nearby lymph nodes and changed the standard of care options - and the options would change again 35 days later with the FDA approval of enfortumab vedotin + pembrolizumab (EV/pembo - Padcev/Keytruda) as a first line option for locally advanced and metastatic MIBC.
The performance in the phase 3 clinical trial (EV 302) that lead to approval was impressive - overall response rate of 67.7% and complete response rate of 29.1%.  Testing was done looking at Nectin 4 expression (which enfortumab vedotin targets) and PD-L1 (which pembrolizmab targets) and both high and low groups showed had benefits in progression free and overall survival - therefore, no testing is required to begin EV/pembro treatment for locally advanced and metastatic MIBC.
As I was seeing a good response - I was still curous if there were any explanation (beyond the power of prayer and God's grace) as to why.  I requested a genetic analyis and received the report from a sample of my tumor resected 217 days earier.
​

The report showed that I had a combined positive score (CPS) of 10 - which according to one study shows that I was likely to receive benefit from pembrolizumab. My tumor did not have FGFR mutations for which an FGFR inhibitor such as erdafitinib would be effective.
A Nectin-4 histology score (H-score) could evalute its expression in my tumor cells.  However, another study showed that a more common blood marker - C-reactive protein to albumin ratio (CAR) - can predict objective response to EV.

The results showed that lower CAR is associated with a better response.  I am familiar with C-reactive protein (CRP) from a previous health journey (see earlier in the blog) where I lost 100 lbs and reversed type 2 diabetes.  CRP is an indicator of inflammation - which is associated with type 2 diabetes.  It may be that maintaing my weight, exercising and maintaining a low carb real food diet (including healthy fats and proteins) has resulted in a CAR <1 and contributed to a good response to EV.  My lab work before each infusion includes an albumin measurement - I will ask to see if CRP can be measured as well to see if my CAR is below 1.

In conversation with my oncologist I was made aware that there are clinical studies which show that a probiotic could enhance the performance of immune checkpoint inhibitors - which was of particular interest as I was now taking pembrolizumab (Keytruda) alone.
The probiotic used in the studies is Clostridium butyricum MIYAIRA 588 - a specific strain of anaerobic, butyric acid forming, Gram-positive bacterium isolated from a soil sample in Japan.
Its primary use as a supplement is to regulate gut health (see the label above from the product I ordered from a supplier that imports from Japan).
As documented earlier in my blog - 7 years ago, I began a low carb/high fat diet which, along with green exercise and intermittent and periodic prolonged fasting, was key to losing 100 lbs and reversing type 2 diabetes.  I have maintained my weight and blood glucose by continuing to follow this regimen.  CBM 588 is believed to modulate some potential gastroinstestinal side effects of a ketogenic diet, increase insulin sensitivity and optimize lipid metabolism.  While more work needs to be done, in addition to bowel regulation, CBM 588 appears to be a good addition to my diet.
What is most impressive for my current health journey are the results being reported when CBM 588 is used with immune checkpoint inibitors - specifically for renal and non-small cell lung cancer.  The gut biome is known to play a key role in regulating the immune system.  Imbalances, known as dysbiosis can lead to immune disfunction. 
In a phase 1b trial for renal cancer - the objective response rate (ORR) was 58% for those receiving immunotherapy and CBM 588, compared to 20% for those receiving immunotherapy alone.  The immunotherapy was a combination of nivolumab (Opdivo) and ipilimumab (Yervoy).  Nivolumab is a PD-1 checkpoint inhibitor like pembrolizumab (Keytruda).   Ipilimumab targets the CTLA-4 receptor on T-cells.  The improvements are consistent with the hypothesis that supplementation with CBM 588 works to reduce dysbiosis, support the immune system and improve efficacy of immune checkpoint inhibitors.  A phase 1b trial examines safety - e.g. dosage and pharmokinetics.  A phase 2 trial is planned to look at efficacy (as well as further examination of safety and optimal dosing).
In the lung cancer study cited - 75% of the patients had a combination of chemotherapy and pembrolizumab.  The addition of CBM 588 was associated with a longer overall survival and progression free survival.
Less relevant for me, but interesting nonetheless - CBM 588 also been shown to be as effective against (non-muscle invasive) bladder cancer cells and potentially safer than the first immunotherapy  BCG in in-vitro and in-vivo laboratory studies.
I found a supplier of Strong Miyarisan, a supplement supplying CBM 588 on eBay (see label above).  Each tablet contains 30 mg CBM 588.  The recommended adult dose is 3 tablets 3 times per day or 270 mg.  The dose administered in the renal cancer trial was 80 mg twice per day or 160 mg.
I would welcome (and will lobby as I can for) a clinical trial of patients beginning a first line treatment of Padcev + Keytruda for locally advanced or metastatic muscle invasive bladder cancer  - one arm supplemented with CBM 588 - the other without.  This is the pathway that would allow doctors to prescribe CBM 588 as part of treatment.
In the meantime, I am proceeding with the assumption that CBM 588 may boost efficacy of pembrolizumab. I am going to start with 2 tablets 3 times per day or 180 mg.​  As this supplement is considered safe, I believe that at a minimum I will have good intestinal health, likely benefits for my ketogenic diet (including insulin sensitivity and improved bowel health) and potentially improved efficacy of Keytruda fighting any cancer that remains.  I will report any adverse effects.  I currently have no evidence of disease by imaging or circulating tumor DNA and I am just one patient so it will be difficult to know if the addition of CBM 588 has been effective (or harmful) - I will continue to monitor any relevant trials. 
As with any decision affecting treatment - patients should discuss with their care team.

I received my third negative circulating tumor DNA (Signatera) test today.
I discovered my disease - which turned out to be locally advanced muscle invasive bladder cancer (MIBC) - 390 days ago.
I had a transurethral resection of the bladder tumor (TURBT) 15 days later and began treatment with enfortumab vedotin + pembrolizumab (EV/pembro or Padcev/Keytruda) 89 days after discovering the disease.  The tumor sample was used by Natera to design my Signatera test to find evidence of residual disease by detecting tumor DNA shed into the blood from anywhere in the body. 
3 months after my TURBT, 1 month after beginning treatment, I underwent an endoscopic procedure to remove and possibly replace a stent in my right ureter placed during the TURBT due to the tumor obstructing flow from my right kidney.  The kidney flow was now brisk and there was no evidence of my primary tumor in the bladder.
84 days after beginning treatment (4 cycles) PET/CT now showed no significant uptake in my previously active pelvic lymph nodes or evidence of new metastatic disease.  Two follow-up CT scans with contrast would also show no new significant findings.
Given the good results, due to low grade adverse effects, we suspended the Padcev component after 7 cycles and have continued with Keytruda alone (currently 7 more cycles).  Sensation in my fingertips and toes, sense of taste and hair have since returned.
29% of the participants in the EV 302 trial (that led to the accelerated approval of EV/pembro as a first line treatment for patients with locally advanced or metastatic muscle invasive bladder cancer) had a complete pathological response.  I have no plans to pursue removal of or chemoradiation to the bladder.  I am working to see that more high responders are followed to see how durable the response is.  In the meantiume I hope to encourage more patients try EV/pembro as their first line treatment before pursuing radical cystectomy or bladder sparing with trimodality therapy.  The vision was articulated by a leader in the field - Dr. Shilpa Gupta - at the recent EMSO 2024 meeting

​I began my 7th cycle of enfortumab vedotin and pembrolizumab (Padcev+Keytruda) on May 31.  I continued with pembrolizumab only on June 21.  On September 13 I began my 6th cycle of pembrolizumab only.  This is my second follow-up using CT with contrast since changing to immunotherapy alone.  I would like to schedule a PET/CT and/or circulating tumor DNA to confirm - but I am happy to see a report of no evidence of recurrence or new disease by CT.   

My cancer journey is documented on this blog.  After over 30 years of leading software development of medical devices for the detection and treatment of cancer, I've had the opportunity to view the state of the industries I've contributed to as a member of the population they exist to serve.  I've also begun work as a patient advocate and have had a chance to meet many fine folks who have walked or are walking through a bladder cancer (or other cancer) journeys.  I now have a series of recommendations and new causes to pursue:

Educate and advocate for PET/CT staging of advanced  muscle invasive bladder cancer
After transurethral resection of my bladder tumor (TURBT), pathology confirmed it as invasive high grade papillary urothelial cell carcinoma with musclaris propria present.  Anatomic imaging - CT and MRI, with and without contrast, were ordered for staging.  No incidental findings were observed.
I then requested a PET/CT.  A whole-body PET/CT scan found locoregional spread to left presacral and left pelvic lymph nodes.   This significantly changed the standard of care guidance for my case.
Review of the current data demonstrates the promise of PET/CT relative to CT and MR for detection of lymph node or metastatic involvement in muscle invasive bladder cancer (MIBC).  Standardization of the process may lead to wider adoption and reimbursement and reduced understaging of MIBC. 

Educate and advocate for bladder sparing treatment with trimodality therapy (particularly with protons)
A majority of patients with muscle invasive bladder cancer undergo radical cystectomy (surgical removal of bladder, lymph nodes and often other nearby organs) and a urinary diversion: ileal conduit (incontinent diversion), neobladder(continent diversion) or continent cutaneous diversion. There remains a significant rate of recurrence with radical cystectomy (RC).  There may also be neoadjuvant or adjuvant chemotherapy to minimize microscopic disease.
Trimodality therapy is a bladder sparing option which employs radiation therapy and concurrent chemotherapy following TURBT.  Having lead software development for a new proton therapy system, I had intended to pursue trimodality therapy with radiation delivered by a proton therapy system.  I had access at a facility 20 minutes away in Knoxville or with the system I had lead software development for in Franklin Tennessee (where my sister now lives).  I was initially disappointed to see that bladder cancer was not listed as an indication on the web site of either facility.  After inquiring, I was happy to learn that a limited number of  bladder cancers and lymph nodes had been treated at both facilities.  
A recent publication concluded that their "multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision-making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option.”
I believe that proton therapy provides improved sparing of health tissue and quality of life and had initiated a consultation. A recent review comparing proton and x-ray therapy in MIBC showed improved overall survival with proton therapy - calling for more study and follow up. Access and reimbursement remains a challenge for the proton therapy industry and trimodality therapy for bladder sparing seems to me to be a significant opportunity to collaborate in demonstrating its benefits.

Educate and advocate for potential bladder sparing with EV/pembro 
I knew that in Tennesse, my best route for approval of proton therapy was through Medicare.  On learning of my diagnosis I resigned my job, left my employer insurance and applied for Medicare Part B (I was 66).  My application was delayed (although I had sent in all the required forms) and while I was waiting, I read of the practice changing results presented for enfortumab vedotin and pembrolizumab (EV/Pembro) in the EV-302 phase III trial.  My Medicare was approved on Dec 1, 2023 (retroactive to Nov 1, 2023).  I began treatment with EV/pembro on Dec 11, 2023.  On Dec 15, the FDA granted accelerated approval of EV/pembro as a first line option for locally advanced or metastatic urothelial cell cancer.  29% of the participants in the EV-302 trial had a complete pathological response.  The details are presented in this blog - I currently have no evidence of disease by imaging or circulating tumor DNA and at present have no plans to pursue chemoradiation or surgery.  More data needs to assembled following high responders to EV/pembro to quantify durability of the response to see if trimodality or RC can be avoided.  As part of this activity, guidance for dose de-escalation for high responders to EV/pembro needs to be generated.

​Advance biomarker development to predict response to EV/pembro
EV/pembro is an all comers treatment not requiring biomarker tests for inclusion.  Tests exist today to evaluate expression of PD-L1 to predict response to pembrolizumab.  I did have genetic testing done (after beginning treatment) which showed I have a PD-L1 CPS score of 10 - indicating likelihood of benefit to pembrolizumab.
Enfortumab vedotin is an antibody drug conjugate which binds to an immunoglobulin like protein Nectin-4.  Nectin-4 is overexpressed in 97% of bladder cancers.  The diagnostic and prognostic potential of Nectin-4 is currently being explored.  A PET radiotracer (68)Ga-N188 has been developed for imaging of Nectin-4 and may offer a tool for diagnosing bladder cancer and selecting patients for treatment with/predicting response to enfortumab vedotin.  It may also be possible someday to engineer theranostic pairs employing alpha and beta emitting radionuclides similar to those available today for prostate cancer.

Recognize importance of insurance navigation resources
As noted above, I orignally pursued enrolling in Medicare to increase likelihood of reimbursement for proton therapy.  I was extremely fortunate to be recommended to an excellent Medicare guide shortly after I was diagnosed with cancer.  He recommended a Medigap G plan for my Medicare Part C. The Medigap coverage adds a monthly premium (in total less than my previous private insurance) - however, along with Part A, B and a Part D drug plan - my medical costs for my EV/pembro treatment have been very manageable.