Study Clarifies How Bladder Cancer Treatment Works

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Pictured: BCG

Bladder cancer cells infected with BCG (shown in green), an effective treatment for early-stage bladder cancer. The same genetic mutations that cause bladder cancer also activate a mechanism in the cells that allows BCG to enter and destroy them.

Memorial Sloan Kettering researchers have shed light on how an important treatment for early-stage bladder cancer eradicates cancer cells. They also found evidence that the effectiveness of this bacterial treatment, called BCG therapy, may be determined partly by the presence of specific genetic mutations within cancer cells.

“This study shows that some of the same mutations causing bladder cancer also activate a process that allows the treatment to enter the cancer cells and destroy them,” says Gil Redelman-Sidi, an infectious diseases specialist who conducted the research together with physician-scientist Michael S. Glickman. “It raises the possibility that specific properties of a patient’s tumor cells might predict how well BCG therapy will work.”

The researchers, including Memorial Sloan Kettering physician-scientists and co-authors David B. Solit and Gopa Iyer, report this finding in the February 1 issue of Cancer Research.

Effective, But Mysterious

BCG (Bacillus Calmette-Guerin) is a weakened form of a bacterial pathogen that has been used widely as a vaccine for tuberculosis for nearly a century. Beginning in the 1950s, the late Memorial Sloan Kettering cancer immunologist Lloyd J. Old and other researchers began investigating BCG as a treatment for cancer, and clinical studies conducted at Memorial Sloan Kettering demonstrated the effectiveness of this therapy for early-stage bladder cancer.

Although BCG continues to be the preferred treatment for such cancers, it has not been clear how the pathogen invades the cancer cells and — once inside — leads to their destruction. Many researchers think BCG stimulates some form of antitumor immunity, but the exact mechanism has not been well understood. To add to the puzzle, approximately 30 percent of bladder cancer patients don’t respond to BCG treatment, and no test exists to predict which patients will be resistant.

“BCG is a mycobacterium — a type of bacteria usually taken in only by certain immune cells that are looking for invaders to destroy,” Dr. Glickman explains. “Mycobacteria are not equipped with a means to force their way into other kinds of cells, so it has been a bit of a mystery how BCG enters bladder cancer cells and why certain cells resist the treatment.”

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Mutations Open the Door

An important insight into what makes the entry of BCG into cells possible arose from a collaboration between the Glickman lab and Memorial Sloan Kettering cell biologist Xuejun Jiang. In June 2012, this team reported in the Journal of Biological Chemistry that cancer cells with mutations in the gene PTEN are highly susceptible to mycobacterial infection. The PTEN protein normally acts as a tumor suppressor; impaired PTEN function appears to increase a cell’s vulnerability to becoming cancerous and also to mycobacterial infection.

To investigate whether this correlation holds true in bladder cancer cells, Drs. Redelman-Sidi, Glickman, and colleagues treated six distinct cell lines — groups of genetically identical cells developed from a single cell — with BCG and measured the degree to which the BCG bacterium was taken up by the cells.

They discovered that the cell lines that most readily took up BCG contained one of several cancer-causing mutations, including mutations in PTEN, known to be involved in the onset of bladder cancer. The cell lines resistant to BCG did not have these particular mutations, but they could be converted to BCG-receptive cells if the mutations were induced. Moreover, these converted cells readily took up BCG via a pathway different from the one BCG usually employs to enter immune cells.

“These mutations activate a mechanism in the bladder cancer cells that allows BCG to enter and destroy them,” Dr. Glickman says.

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Moving from the Lab to the Clinic

Dr. Glickman’s laboratory is now collaborating with urologic surgeon Bernard H. Bochner to explore the clinical implications of this discovery — particularly, whether analyzing a patient’s bladder cancer cells can reliably predict his or her responsiveness to BCG therapy.

With the support of a grant from The Society of MSKCC, Dr. Redelman-Sidi is trying to develop a lab test that would analyze urine samples, which usually contain cancer cells shed from the bladder. These cells could be tested both for their tendency to take up BCG and also for the presence of BCG-activating, cancer-causing mutations.

“This would allow us to screen early-stage patients routinely before starting BCG therapy to make sure it’s the best course of treatment,” Dr. Glickman says.

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Dr. Redelman-Sidi’s work is supported by awards from the Lucille Castori Center for Microbes, Inflammation, and Cancer and from the Bladder Cancer Advocacy Network. The study reported in Cancer Research was supported by the Geoffrey Beene Cancer Research Center and the Starr Foundation.

Comments

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I have high grade bladder cancer. I've had a urine analysis in Jan. And again in urologist office which was negative or so I was told....Nocance cells. Yet after a cysto, Dr. found irregular cells, high grade. What good is it to get urine tests if it doesn't give correct results?? He is scheduling me for BCG.

Dear Lucy, we are sorry to hear about your diagnosis. Urine tests are a useful diagnostic tool, but a cystoscopy is the most accurate way to confirm a diagnosis of bladder cancer. We wish you our best as you prepare for treatment.

Hi , How react patient with TCC bladder on BSG treatment if he has in past tuberculosis vaccination?
Thank you

Thank you for reaching out. A previous tuberculosis vaccination will not cause any problems regarding BCG treatment for bladder cancer.

WHAT IS THE PERCENT OF CIS RETURNING AFTER A COURSE OF BCG AND BEING CLEAN AFTER THAT FOR SIX MONTHS ?

Dear Harry, according to this 2014 clinical update on our website “Bladder Cancer Management after BCG Failure” https://www.mskcc.org/clinical-updates/bladder-management-after-bcg-fai…, “BCG therapy is highly effective for managing high-risk non-muscle-invasive urothelial carcinoma of the bladder, with complete response rates at times as high as 83 percent. However, recurrence may occur within a year in up to half of patients with high-risk disease, and within five years in as many as 90 percent of these patients.” It’s important to understand that these general statistics should not be applied to any one individual, as every patient is unique and responds to treatment differently. We see many people do better than expected. You should follow up with your doctor for a better understanding of your particular risk factors for recurrence. Thank you for reaching out to us.

What is the update on this study? I cannot find it on clinicaltrials.gov. Which medical facilities check for pTEN mutations and can induce if not present?
I asked a doc and he said results are not out, but I felt like he didn't know what I was talking about...

I was diagnosed with bladder cancer and had surgery at MSK to remove the tumor . I never heard about BCG treatment. Am I missing a better chance of survival? I had two 3 months check ups and they were clear. I was told, though, that the type of bladder cancer I had can reoccur. Is this something I should be concerned about?

Lorraine, thank you for reaching out. BCG is used for early-stage bladder cancers that do not require surgery. We suggest you consult with your treating physician about your concern regarding the cancer recurring and your best options, which may include chemotherapy.

What about the risk on contracting TB through this process? Are there any measures to reduce any risk?

Paul, thank you for reaching out. Although BCG is also used as a vaccine for TB, it is not given in the US.

BCG is not TB and you can’t get TB from being exposed to BCG.

I have had two resection of low grade non-invasive bc. They now plan BCG treatment. I had a BCG vaccination for TB prevention 40 years ago. Will this affect the BCG cancer therapy?

Kirk, thank you for your question. Your previous vaccination will not affect BCG therapy you may receive for bladder cancer.

What are the early symptoms of a BCG infection. I had 6 BCG treatments after a TURBT, last BCG 20 days ago. I've had some symptoms for over 2 weeks, including being shakey and ringing in the ears, but no fever or cough. Is there a treatment if this is a BCG infection? B

This article is nearly 4 years old. Has the test been developed yet? Would a person being treated at MSKCC be tested first, before BCG is prescribed?

Nancy, thank you for your question. The test is still under development. MSK has several active studies evaluating how best to identify patients that may respond to BCG treatment, but it is still a ways off from being commercially available.

You can learn more about treatment for bladder cancer at MSK here:

https://www.mskcc.org/cancer-care/types/bladder

Any news/links on BCG treatment for T1/HG NMIBC from SK?

What about suggested treatments for T1/HG NMIBC patients that have completed full BCG maintenance (24 installations) ? Anything on the horizon from SK? Thanx.

Dear Paul, we are not able to offer treatment recommendations without more information about the individual patient’s disease and medical history. If you or a loved one would like to make an appointment with one of our specialists to discuss possible next steps in your care, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

Can I work as a R.N. in a hosp. while receiving BCG for bladder cancer. Have not started tx. yet.

I have the non-evasive T1, had the surgery to
remove the tumor and finished the six BCG
Treatments. The treatments varied as one would expect in burning sensations, big time urge to go, etc. but not extreme. Next is 2
treatments a month apart with a cis 3 months later. My question is
the last treatment was so easy I wondered if
it was given and could have kept the med in
all day over the 2 hours. Since then I have a
reaction of complete normal functioning. In reading through this wonderful site I found no other similar reaction. Any answer would be appreciated.

Dear John, we are sorry to hear about your diagnosis. Everyone’s response and recovery from treatment is unique. We recommend that you discuss any questions or concerns you have about your treatment with your physician. Thank you for reaching out to us.

What are the early steps to prevent from Bladder Cancer and I also want to know can we cure it naturally?

The best way to prevent bladder cancer is to not smoke, and if you do smoke, to quit. Experts estimate that about half of all bladder cancers are caused by smoking. Thank you for your comment.

The posts on your web page regarding PTEN screening and mutation therapy in conjunction with BCG are almost 2 years old. Has progress been made in formalizing this research into an effective clinical protocol since?

Kirk, thank you for your question. thank you for your question. The test looking at PTEN mutations in bladder cancer cells as a predictor of BCG responsiveness is still under development. MSK has several active studies evaluating how best to identify patients that may respond to BCG treatment, but it is still a ways off from being commercially available.

You can learn more about treatment for bladder cancer at MSK here:

https://www.mskcc.org/cancer-care/types/bladder

I finished the 6 week treatment and was scoped by my doctor. He noted that the cancer was diminished but there were 4 small growths. We started an additional 6 week treatment with BCG and Interferon. The treatments are pain free with a little discomfort voiding. Not bad at all.

Dear John, thank you for sharing your thoughts and experience on our blog. We wish you all our best.

I have been treated for low grade, non-invasive bladder cancer for over 20 years by TURBT. I am 74 years old. I have had about 50 TURBTs during this period and tumors continue to reoccur.
What other treatments might are available? Thank you.

Appointment to discuss recommended treatment
intravesical mitomycin vs BCG

I was diagnosed with 0 stage bladder ca. appx. 1 year ago. after Cystoscopy one growth was removed. cystology rep. on urine stated "cannot rule out low grade non invasive urothelial papillary carcinoma"- no muscle involvment. I was clean for 1 and 1/2 yrs. had a recurrence and a second TURBT appx. 3 wks. ago. they called these lesions neoplasms. since there was more than one "sprouting" my uro. decided to start BCG therapy. as soon as everything heals. my question is- does the 70% success rate apply to all stages of this disease?

Dear Lawrence, BCG treatment is used only for early-stage disease, so the response rates apply only to those who are eligible for this treatment. It’s important to remember that every patient is different, and that average rates are statistical measurements that may not apply in every case. We recommend that you discuss your concerns with your healthcare team. Thank you for your comment, and best wishes to you.

Have you recently changed the BCG protocol for Ta high grade superficial to include maintenance treatments? I saw a clinical study comparing mitomyacin vs BCG with maintenance, but could not find the results of that clinical trial. Thank you in advance for your comments.

Janice, thank you for reaching out. MSK does not currently use BCG maintenance therapy for superficial bladder cancer.

Can one get a positive PPD skin test from 6 BCG treatments for bladder cancer?

I am following up on a post I submitted on July 29, 2013, three years after surgery for a T-1 high-grade bladder tumor and then followed by 3 years of successful BCG treatment. I have a cytology test every 3 months and a cysto once a year. Every urine test since my surgery has shown atypical cells, and in February 2017 the cytology test showed cells that were "suspicious for malignancy." Two weeks later a cytology, a CT scan, and a cysto revealed only my "usual" atypical cells. My question is this: Is it common for a BC survivor to have atypical cells for many years (7 years for me) after BC surgery and BCG treatments?

Dear David, unfortunately we are not able to answer medical questions on our blog. We recommend you discuss your test results with your doctor. If you are interested in coming to MSK for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

I finished 9 rounds of BCG treatment about 2 months ago. I also take a blood thinner for AFib. I have experienced bleeding from time to time while urinating. I’m scheduled to have a cystoscope later this month. When I do see bleeding, if I drink plenty of water, it the blood disappears . I have talked to my doctor and he tells me that my bladder has been through a lot. Should I be concerned?

Dear Mark, unfortunately we are not able to answer individual medical questions on our blog. We recommend that you discuss your concerns with your healthcare team. Thank you for your comment, and best wishes to you.

I have diabetes take metformin and dulaglutide .75 and amlodipine 5 mg and Valsartan
320 mg. Since starting on BCG my BP has increased by 20 systolic and about 10 diastolic. I also take Symbicort. Any explanation for BP increase related to BCG? Next treatment #5, have had no significant side effects.

Dear Tony, we’re sorry to hear about your health problems. We recommend that you discuss your concerns about drug side effects with your healthcare team. Thank you for your comment, and best wishes to you.

First I would like to say THANK YOU to Dr. Guido Dalbagni and the entire staff at MSK.
I am living proof BCG works!
Diagnosed 11/2014 underwent Two TURBT's and was told they would have to totally remove my bladder since the cancer was so large. 2nd opinion at Sidney Kimmel Center and one more TURBT and two 6week rounds of BCG I am now CANCER FREE! I have been moved to an annual checkup routine. (From 3months)And still have all the parts I was born with! My previous Urologist is watching and learning and very happy I chose MSK. Keep up the great work. If anyplace will find a cure it will be MSK!

Dear Al, we’re glad to hear you’re doing well. Thank you for your comment, and best wishes to you.

My mother in law is diagnosed with BC in mid-2017. Dr removed the tumor and started her BCG treatment for 6 weeks, once in a week. After treatment she cleared her cysto and no tumor was found. in Next 3 months checkup Dr found again some cells. In report they said it Low grade Urothelial Carcinoma TCC(same as first report). And they have again started 3 weeks treatment from 26March2018. but Dr said they can't give more BCG if they found cells again in cysto after 3 months of this BCG treatment. I want to understand as it’s a low grade can't we keep giving BCG if they found cells again. She had tumor around 15-20 years back as well and in 2017 it came back. She is in India.

Dear Mads, we’re sorry to hear about your mother-in-law’s diagnosis and recurrence. Unfortunately we are not able to answer individual medical questions on our blog. We recommend that she discuss this with her medical team. If she would like to arrange a records review with an expert at MSK, she can contact our International Center at international@mskcc.org go to https://www.mskcc.org/experience/become-patient/international-patients/… for more information. Thank you for your comment and best wishes to you and your family.