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Dr. Morales said in his webinar that BCG works for 70% of CIS and 60% Papillary type, i.e. T1HG. We did not get a chance to find out why BCG did not work for 30% of CIS and 40% of T1HG. As the cost has come down sharply in recent years to analyze cancer tissue at molecular level, there have been several attempts to find out biomarkers which make BCG treatment ineffective. One of approaches to find such biomarkers is by breaking down cancer tissue to subtypes. Using subtypes as biomarkers to predict effectiveness of a certain treatment was explored for breast cancer early on. 80% of breast cancers arise from ducts, which milk is pushed through to nipple area when a baby sucks. The structure of duct is such that there is typically a singe layer of luminal cuboidal shaped epithelial cells on the inner layer and the other cell type is the basal epithelial, which is the outer layer that rests on the basement membrane. It turned out that ductile cancers with characteristics of luminal epithelial cells are the most common and represent 50-60% of all breast cancers. These tumors tend to be low grade with good prognosis. These tumors with characteristics of luminal epithelial cells were then classified as luminal subtype. On the other hand, tumor which is comprised of cells with molecular characteristic similar to basal epithelial cells are associated with high grade and worse clinical prognosis. These tumors are classified as basal subtype. Interestingly clinical studies showed that platinum based chemotherapy, e.g. Cisplatin was effective to breast cancer with basal subtype but breast cancer with luminal subtype made no difference in prognosis with or without chemotherapy. Today, platinum based chemotherapy was administered for basal subtype as neoajuvant treatment before the surgery but no not for luminal subtype in breast cancer. Interestingly, in recent years, luminal subtype and basal subtype have been studied for muscle invasive bladder cancer to determine if neoajuvant chemotherapy (NAC) should be administered. It may have been mentioned in CUA guidelines for muscle invasive bladder cancers (MIBC), AUA updates on 2018 guidelines for (MIBC) citing that luminal tumors had the best over all survival with and without NAC. whereas basal tumors showed the most improvement in over all survival with NAC compared with surgery (cystectomy) alone. Subtypes MIBC may eventually integrated into routine clinical practice after more extensive validation.
Now going back to the topic of cancer subtypes for BCG unresponsive non muscle invasive bladder cancers (NMIBC) , there have been clinical studies to predict BCG unresponsive by o risk stratifying by subtypes. There are two such clinical studies of which the result were published recently. One study was led by a team in Netherland (Study 1) and others and the other study was led by a team from US, Canada, and some other countries (Study 2_. The summary of those studies are described below.
Study 1 divided into three subtypes, i.e. BRS1, BRS2, BRS3. BRS stands for BCG Resistant Subtype. Cohort A consisted of n=132 BCG naïve tumours (n=69 non-responders vs n-63 responders) and n=44 matching post -BCG recurrences. RNA-sequencing was performed on tumour tissue. The primary end point was progression free survival (PFS). Findings were validated in an independent Cohort (B), which consisted of n=151 BCG-naïve tumours.
Results: Patients with BRS3 tumours had reduced PSF as compared to patients with BRS1/2 tumours. BRS3 tumours expressed high Epithelial-Mesenchymal-Transition(EMT)-basal markers and had an immuno-suppressive profile. Tumours with recurred post-BCG were highly enriched for the BRS3 subtype. A commercially approved qPCR based assay (Philips OncoSignal) identified BRS3 tumours with high accuracy (AUROC 0.86).
Conclusion: Molecular subtyping identified tumors from high-risk NMIBC patients with an aggressive phenotype and a poor response to BCG. Our findings provide a clinical tool for improved identification of high-risk NMIBC patients at high risk of progression, which can be used to select patients for early radical cystectomy or to develop novel subtype-directed therapies.
Study 2 divided T1HG tumours into five subtypes
T1-luminal gnomically unstable (T1-LumGU), T1-inflamed (T1-Inflam), T1-Myc, T1-Early , T1-True Luminals (T1-TLum).
T1-TLum subtype was the most luminal and urothelial differentiated subtype. T1-T-Lum had the fewest 24 months recurrences.
T1-Early had 38% recurrences within 6 moths of Induction BCG with no further recurrences by 24 months.
T1-Myc had the most recurrences by 24 moths (71%)
T1-Inflam tumors represent and immune-active and inflamed T1 subtype.
T1-LumGU tumors had the highest frequency of pathological CIS(38% vs 18% of all samples)
One potential application of T1 subtypes is to direct precision therapy targeting the unique features of a patient’s subtype. T1-LumGU tumors had the highest expression of E2F and its target EZH2. In a test of EZH2 as a potential target in bladder cancer, we found that in vitro treatment of the luminal bladder cancer cell line HT-1376 with an EZH2 inhibitor (EPZ-011989, a generous gift from Epizyme) strongly enhanced expression of DEGs that were repressed or underexpressed in T1-LumGU. While preliminary, these data suggest that consideration of the unique expression signature of each subtype and/or its regulon network may identify novel therapeutic targets for T1 tumors.
In summary, using a cohort of patients with T1 NMIBC treated with BCG, we identified five distinct molecular subtypes that appeared to be associated with two major classes of regulon activity, and we describe the characteristics of each subtype. In the future, evaluation of T1 subtypes may help to risk-stratify T1 tumors and identify precision therapeutic targets.
To view the details of two studies, please do Google search with the description of each study as shown below. When I enter the link to the site, my posting kept disappearing, so this is workaround .
Study 1 :
Molecular Subtypes and Response to BCG Treatment in Patients with NMIBC – Expert Commentary
Study 2 :
Identification of Differential Tumor Subtypes of T1 Bladder Cancer
Hi Joe:
As usual you blow me away with all the useful information. Many thanks for this.
I haven’t taken the time to read the studies yet but will at some point in the near future. I think we talked about this before but I can’t remember for sure – Is there any research out there about the effectiveness of the different types of BCG against high grade bladder cancer? I seem to remember some earlier conversation about concerns regarding the effectiveness of the VERITY brand of BCG against CIS. I brought this topic up with my uro and the BCG clinic back in the spring and no one could give me a definitive answer. As you know, I went ahead with the VERITY because that was the only BCG here in Calgary at the time. I was informed by the nurse at my cysto in September that the clinic does now receive some MERCK from time to time but the supply is inconsistent at best so if I were to continue with BCG treatments there is no guarantee that I would be given MERCK. GEM/DOC is now on the back burner for me should it be decided that I need to resume treatments. I’m really nervous about having any chemo agents in my bladder after the Epirubicin fiasco post TURBT last October.
Despite my misadventures with the VERITY BCG I still think that immunotherapy is the way to go in treating cancer. I’m not medically trained so this is just my opinion but it makes the most sense to me to work with a person’s immune system to get it to activate against invading cancer versus bombarding our bodies with powerful and often toxic drugs. I know that it is not possible for everyone to be treated with immunotherapy but I’m hoping that there will be more breakthroughs in this area not only for bladder cancer but other cancers as well. Here’s to hoping. Many thanks once again for all this info. (((HUGS)))
Hi Marysue,
There have been only handful comparisons between different BCG strain at clinical level.
a) Connaught strain (ImmuCys by Sanofi) 6.6-19.2×10**8 CFU vs Tice strain (OncoTice by Merck) 2-8×10**8 CFU, 142 patients (HG,CIS, LG with >2 recurrences) between 1998 to 2010, 6 weekly induction only as benefits of maintenance was not established then. Swiss study
Recurrence Free Survival (RFS) at 60 months : ImmuCys 75% Onco-Tice 50%
Progression Free Survival (PFS) at 60months : ImmuCys 95% Onco-Tice 90%
Note that there was a subsequent retrospective study which showed that with maintenance Onco-Tice (Tice strain BCG) was better than ImmuCys (Connaught strain BCG)
b) Connaught strain (ImmuCys by Sanofi) 81 mg Tokyo-172 strain (Japan BCG Lab) 80mg, 178 patients (Ta 57, T1HG 43, CIS 29) between 2004 to 2012, 6 weekly induction only as benefits of maintenance was not established then. Japan study
Complete response (CR) at 24 months : Tokyo-172 90.3% ImmuCys 85%
Recurrence Free Survival (RFS) at 24 months : Tokyo-172 73.2% ImmuCys 68.8%, at 1500 days 63% for both BCG
C) Tice Strain (OncoTice by MERCK) 2-8×10**8 CFU vs RIVM strain (MEDAC-BCG by MEDAC in Germany) 25×10**9 CFU
Retrospective study at a two hospitals in Europe between 2004 and 2018 for high risk NMIBC (T1HG, CIS) 266 patients
Recurrence Free Survival (RFS) at 5 years : OncoTice 56% BCG-MEDAC 48%
Recurrence Free Survival (RFS) at 5 years for those whose had the second TURBT : OncoTice 75% BCG-MEDAC 50%
Progression Free Survival (PFS) at 5 years : OncoTice 80% BCG-MEDAC 80%
Progression Free Survival (PFS) at 5 years for those whose had the second TURBT : OncoTice 85% BCG-MEDAC 85%
D) Tice Strain (OncoTice by MERCK) 2-8×10**8 CFU vs Tokyo-172 Strain
SWOG S-1602 randomized clinical trial for 1000 patients which started in 2017 is expected to report the result in early 2024.
Verity-BCG vs OncoTice
As far as I know there are no published direct clinical comparison between Verity-BCG vs another BCG.
Verity Pharmaceutical was allowed to release Serum Institute of India (SII) ONCOBCG (Russian strain BCG) under the product name Verity-BCG under a certain condition that it is used only for non CIS and Verity conducts randomized non inferior clinical test vs Onco-Tice (Tice strain BCG), which Verity has not started as far I know. Health Canada released with those condition the use of Verity-BCG in Canada back in September, 2021. 2 years later, Verity has not started promised clinical trial. Ordinarily, I think Health Canada could withdrawn Verity-BCG from Canadian market because Verity has not met the commitment. But. programmatically speaking, I do not think there are other BCGs readily available easily replacing Verity-BCG as Canada’s approach is to use full dose BCG including full maintenance treatments, which is very different from the strategy of the US.
As I expressed my concerns before, the market condition for future BCG supply has changed significantly when MERCK announced in October, 2020, the construction of a new production line which can produce 3 million vials a year, three times of the current demand requirement. According to AUA, Merck already had a ground breaking, and expects the production will be ready by late 2025-late 2026. So, there isn’t business incentive for Verity to conduct a clinical multi years with 500 patients which will cost millions of dollars. Also, I expect Tokyo-132 strain BCG will have been approved by FDA sometimes in 2024 though how Tokyo-132 strain BCG should be used in conjunction with Merck Onco-Tice is to be decided at the time of the approval. Once FDA approves Tokyo-132 strain BCG, then I see no reason Health Canada approves Tokyo-132 strain. Then, it is possible for Health Canada to withdraw Verity-BCG from Canadian market as Verity has not met the condition to conduct the clinical trial with reasonable time frame. One thing I do not know if Japan BCG Lab wants to go though the approval process by Health as I see it Japan BCG Lab is not a growth oriented company like SII.
Who knows there may be a retrospective Canadian comparison between OncoTice (Tice strain BCG) vs SII OncoBCG (Russian strain BCG) in the future.
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