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.”
Back to topMutations 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.
Back to topMoving 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.
Back to topComments
Earl Waters
May 16, 2014 • 10:30 AM
I was detected with hi-grade bladder cancer many years ago and underwent nine consecutive weeks of BCG treatment. The cancer was gone. A year latter the cancer recurred. Another round of six consecutive weeks of BCG was again sucessful. For the past several years I have been on a schedule of one treatment of BCG every six months follow by cytoscopy the alternating six months. So far no recurrence of cancer.
Raejean Danielson
Jun 4, 2014 • 2:09 AM
My guy has had low level, small cancerous tumors removed from his bladder twice in the past year. After the second removal of tumors he underwent a course of 6 BCG treatments. After the 3rd treatment, he experienced flu-like symptoms with extreme fatigue which lasted 5 days. the 4th and 5th treatments were fine. Hours after the 6th treatment he again got sick with the same symptoms. We are now at one month and counting and he is not improving. He has been hospitalized twice during this month and has seen many doctors. He was healthy prior to the BCG. Any suggestions?
Memorial Sloan Kettering
Jun 4, 2014 • 8:51 AM
In reply to My guy has had low level, by Raejean Danielson
Raejean, unfortunately we are unable to answer specific medical questions such as this on our blog. We suggest that he speak with his physicians or If he would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.
Sashamore
Jun 15, 2014 • 10:01 PM
Memorial Sloan Kettering
Jun 16, 2014 • 10:39 AM
In reply to i finished my 6th infusion a by sashamore
Sashamore
Jun 16, 2014 • 11:05 AM
Bill
Aug 9, 2014 • 3:57 AM
I had my tumor removed in May, 2012. Started BCG treatment the following month. Continued to have BCG treatments through my second year. Started my third year of treatment today, with a lower dose of BCG & Interferon mixed in. Is it normal to start the combined drugs, at this point in the process?? Thanks.
Bill, unfortunately are unable to answer specific medical questions on our blog. As every person’s medical situation is unique, it it not possible to address what might be considered normal treatment for a given patient. To learn more about how Memorial Sloan-Kettering treats bladder cancer, you can go to http://www.mskcc.org/cancer-care. For additional questions about bladder cancer treatment, you might also call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237). To learn more about the CIS, including Live Chat help and how to send them an email message, go to http://www.cancer.gov/aboutnci/cis/page3.
Thanks for your comment.
Kay
Aug 25, 2014 • 8:10 PM
Kay, the course of treatment is something that varies between patients, and something you should discuss with your healthcare team. If you’d like to make an appointment to speak with someone at MSK, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information.
It is true that there are shortages of BCG in the United States right now. You can go here for more information: http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/A… If MSK does run into a problem with the shortage, other treatments are available. Thank you for your comment.
Judy Webb
Sep 6, 2014 • 3:03 PM
Judy it is true that there are shortages of BCG in the United States right now. You can go here for more information:http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/A… If MSK does run into a problem with the shortage, other treatments are available. Thank you for your comment.
Regarding options, we recommend your husband consult with his personal physician for the best course of action.
Jim Beckenhauer
Sep 28, 2014 • 2:32 AM
I recently had a "high-grade" "T-1" bladder tumor removed. It was described as a "papillary" type with superficial invasion of the lamina propria layer. Due to my age, 76, I am concerned about the BCG therapy which is to begin within the next two weeks, as I understand the side effects are usually more severe than the alternative "mytomycin". Is the age factor a signigicant consideration in treatment selection in deciding which is the better of the two alternative treatments?
Memorial Sloan Kettering
Sep 28, 2014 • 1:29 PM
In reply to I recently had a "high-grade" by Jim Beckenhauer
Dear Jim, thanks so much for your question. We can’t offer personal medical advice on our blog. If you’d like to get a second opinion, you can call 800-525-2225. Or you can learn more here: http://www.mskcc.org/cancer-care/appointment. Thanks again for reaching out to us.
HARRY WEISS
Oct 12, 2014 • 6:12 PM
Memorial Sloan Kettering
Oct 12, 2014 • 8:44 PM
In reply to I had a low grade tumor non by HARRY WEISS
Harry, we are not able to answer personal medical questions on our blog. We recommend you discuss this with your doctor. If you’d like to make an appointment to speak with a doctor at MSK, you can call 800-525-2225 during regular business hours or go to http://www.mskcc.org/cancer-care/appointment for more information. Thank you for your comment.
Karen Herman
Nov 4, 2014 • 11:35 PM
Hi: My husband was diagnosed with BC 6 weeks ago. They remove the tumor (flat) but the pathology results indicated the possibility of kidney cancer. The doctor wanted to postpone BCG treatment pending the results of the uteroscopy. Grateful that there was no sign of kidney cancer he attempted to schedule the BCG treatment only to discover that there is a worldwide shortage. We called the FDA and Merck. For three years Merck in the only manufacturer and was to begin releasing BCG on a first come first serve basis (end of October 2014). It seems he is on a long line waiting because there is no info as to when "his" medication will be available. Per the FDA they cannot force any company to make or increase production. Merck cannot give us any idea when all back orders will be filled. While Mitomycin C is reportedly an option, his oncologist suggested he wait for the BCG. He can't tell us how long we can safely wait. We located a urologist in another state who has BCG and could start treatment right away but it would require driving 300 miles round trip for six weeks. Do we wait a few more weeks in the hopes he wins the local BCG lottery or choose not to risk the loss of the opportunity to start treatment right away. While you can't comment on what he should do, in general, how important is it to start BCG treatment soon after diagnosis? Not wanting to miss the boat we are inclined to drive rather than be anxious about the delay and possibly BCG will be unavailable for months. We'd go to MSK immediately if we knew they have BCG. Crazy that there has been intermittent BCG shortage for years.
Memorial Sloan Kettering
Nov 5, 2014 • 1:36 PM
In reply to Hi: My husband was diagnosed by Karen Herman
Richard Miller
Nov 21, 2014 • 4:52 PM
Memorial Sloan Kettering
Nov 21, 2014 • 4:54 PM
In reply to Is it ok to have BCG therapy by Richard Miller
Sarika
Nov 25, 2014 • 9:46 PM
How long does it takes for the cure of the side effects of BCG injections(as given in the treatment of Bladder Cancer) as my father had taken the treatment about 2 months back and he is still suffering from burning or pain with urination, needing to urinate more often and urinating small amounts often. The doctor said this is because of the infection of BCG injections and has suggested corticosteriods for one month. Will this medicine help as he is not even able to sleep in night as he has to urinate more often. Kindly share if anyone else has gone through the same side effects.
Sarika, thank you for your comment. Unfortunately we are unable to answer specific medical questions on this blog. The side effect you describe is mentioned in information about BCG treatment, although how long it occurs can vary:
http://www.mskcc.org/cancer-care/patient-education/resources/bcg
We suggest your father continue consulting with his personal physician about alleviating this effect.
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment.
For additional questions about bladder cancer treatment, you also can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237). To learn more about the CIS, including Live Chat help and how to send them an email message, go to http://www.cancer.gov/aboutnci/cis/page3.
Elizabeth Sumpter
Jan 9, 2015 • 4:08 PM
I was diagnosed with grade 4 BC in June, 2013. I had 6 treatments then a cystocopy and still had the cancer. I then took 6 more rounds of treatmetns 3 times and then I was BC free. It is time for me to start maintenance treatments but now there is a nationwide shortage of BCG. How much is this going to impact me and others that desperately need the treatments?
Memorial Sloan Kettering
Jan 11, 2015 • 9:07 PM
In reply to I was diagnosed with grade 4 by Elizabeth Sumpter
Elizabeth, unfortunately we are not able to answer individual medical questions on our blog. If you’d like to make an appointment to speak with an MSK doctor about this, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information. However, please keep in mind that MSK is also affected by the BCG shortage.
Sheila
Jan 18, 2015 • 1:05 PM
My husband had bcg treatments for bladder cancer, carcinoma in situ, 8 years ago. After starting the treatment, he began to suffer joint pain. At the time there was no explanation of the cause. He has seen many health professionals, to try and identify and treat this chronic pain issue. So far, without success. We researched and found some reports of arthritic reactions as a result of bcg. I would appreciate any help or advice. He is crippled with this joint pain, which is not relieved with any treatment that he has tried. Thank you.
Sheila, thank you for your comment. Unfortunately, we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.
Ann
Jan 22, 2015 • 11:37 PM
Reading many of the posts Im so glad to hear that BCG can help. My Husband was diagnosed with carcinoma en situ in early Dec and was told he will need BCG. the problem is the doctor now says its not available and we are saddened. he needs this drug. does anyone know how we can obtain it? we live in California. Can anyone help me.
Ann, thank you for reaching out. Unfortunately, the BCG shortage is nationwide. There are some other treatment options for patients who are not able to get BCG. If you’d like like to learn more, we recommend you reach out to the National Cancer Institute’s Cancer Information Service at 800-4CANCER. You can also learn more about the BCG shortage here: http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/A…
Judy
May 15, 2015 • 12:52 PM
I find this article disturbing, because I was advised, on the basis of a a biopsy done in response to two recurrences in 6 months, to accept a 6-week round of not BCG, but mitomycin infusions.
When I asked why not BCG, I was told that "research shows that BCG isn't an effective deterrent for low grade, superficial disease." It is now May, 2015 and I note that the above article was published in 2013. So... what is the latest? Is BCG or mitomycin infusion best for preventing low-grade, superficial recurrences?
Judy, thank you for your comment. We consulted with one of our experts, who responded:
“BCG is not routinely administered for low-grade, non-muscle invasive (cTa) disease. The National Comprehensive Cancer Network recommends 3 options that are preferable, ie, observation, intravesical chemotherapy as a single dose, or induction intravesical chemotherapy (multiple doses over weeks).
High grade Ta disease and more invasive tumors are treated differently.”
For further questions about bladder cancer treatment, you also can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237). To learn more about the CIS, including Live Chat help and how to send them an email message, go to http://www.cancer.gov/aboutnci/cis/page3.
Norm Leon
Jun 2, 2015 • 9:28 PM
Kathryn
Jun 5, 2015 • 11:37 PM
Kathryn, we are not able to make personal healthcare recommendations on our blog. We recommend that you speak with your husband’s healthcare team about this. If you’d like to make an appointment for a consultation with a doctor at MSK, you can call 800-525-2225 during regular business hours or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment.
Birney Belfield
Jun 24, 2015 • 11:26 PM
Anonymous
Jul 12, 2015 • 12:16 PM
Memorial Sloan Kettering
Jul 13, 2015 • 9:03 AM
In reply to Hello, My friends parent has by Anonymous
Although BCG is also used as a vaccine for TB, BCG is not TB and you can’t get TB from being exposed to BCG. We don’t consider friends and family members at risk for being infected with BCG because it is a weakened bacterium that is given to most of the world’s children and is very safe. Thank you for your comment.
Marcia
Sep 3, 2015 • 11:55 PM
My father just received BCG treatment and he is VERY concerned that, due to bleeding in his urinary tract (an open small wound that was bleeding after the cathater was removed), that he could get TB. He believes that the BCG is strong enough to give him the disease, if exposed to his blood system. Is he at risk for TB with exposure to his blood?
Raji Siva
Oct 26, 2015 • 4:52 PM
My mom had non invasive, high grade cancerous tumor in Bladder. It is been removed 10 days back. Dr suggests either wait and watch or do BCG. The question i have are 1. Can blood thinner Xarelto and BCG will have any impact? 2. She had taken TB Vaccine when young, and gets tuberculin positive. Can she take BCG with that condition. She had no TB though.
Thanks in advance
Harry Weiss
Nov 4, 2015 • 12:35 PM
Memorial Sloan Kettering
Nov 4, 2015 • 4:40 PM
In reply to when is bcg maintenace given… by harry weiss
Harry, to find out more about how bladder cancer is treated, including when BCG is given, you can go to https://www.mskcc.org/cancer-care/types/bladder/treatment and http://www.cancer.gov/types/bladder/patient/bladder-treatment-pdq. Thank you for your comment.
Birney Belfield
Nov 16, 2015 • 7:09 PM
Maria
Dec 1, 2015 • 3:33 PM
Hello. My mother just started her first round of BCG following TURBT. She didn’t experience any side effects following BCG. She is originally from Russia where as a child she received a commonly administered TB vaccine. Can you please provide any insight on whether the TB vaccine she had as a child can make BCG not/less effective for her treatment?
Thank you.
Maria
Vural Kugu
Dec 12, 2015 • 2:58 AM
Vural, thank you for your question. We consulted with MSK physician Gopa Iyer, who responds: “We are currently attempting to identify the genetic differences within tumor cells between patients and to try and correlate these differences with sensitivity to BCG therapy. This is an ongoing effort through the Center for Molecular Oncology. However, there are probably more than just genetic differences which will affect sensitivity to BCG therapy. We are also trying to identify immune factors present within the tumor and the patient which may dictate how effective BCG therapy will be for an individual person.”
ROYAL J. NADEAU
Feb 24, 2016 • 2:11 PM
Memorial Sloan Kettering
Feb 27, 2016 • 10:57 AM
In reply to I have non-invasive Stage 0… by ROYAL J. NADEAU
Lee, thank you for your comment. We consulted with Dr. Glickman and he responds:
BCG does not use the Mycobacterium tuberculosis bacterium, and you can’t get TB from being exposed to BCG. Even in someone with latent TB, undergoing BCG therapy would not pose any risk of contracting or reactivating latent TB.