The Fight to Save the Bladder Turns to Genomics

Alexander Kutikov, MD

The search for effective alternatives to radical cystectomy (RC) in patients with bladder cancer has lasted more than 3 decades. Progress has been slow, but investigators have proved that a combination of radiation, chemotherapy, and maximal transurethral resection of the bladder tumor (TURBT) works as well as RC in carefully selected patients. At least 2 trials are investigating the further possibility that patients whose tumors have certain genetic profiles might fare just as well with chemotherapy alone as they do with chemotherapy and RC. Other groups, moreover, are planning checkpoint inhibitor trials that might shed light on other ways to reduce the number of bladder removals.

“Cystectomy is a high-risk surgery, particularly for the frail and elderly, who are the most likely to get bladder cancer,” noted Alexander Kutikov, MD, chief of the Division of Urology and Urologic Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “Even when the surgery goes well, it’s a life-changing event. You can have a high quality of life with a urinary diversion, but it’s challenging. Any advance that reduces the need for cystectomy is a significant advance, so it’s exciting that there are several promising alternatives in various trial stages.”

Bladder cancer is the sixth-most-common malignancy in the United States, with about 80,000 new diagnoses per year.¹ The disease is typically diagnosed when blood in the urine sends patients to the doctor. About 70% of all bladder cancers are found before the tumor becomes muscle invasive or metastasizes.² About 5% of all bladder cancers are already metastatic at the time of diagnosis.³

Cancers detected before they become muscle invasive are typically treated with TURBT and intravesical bacille Calmette-Guérin (BCG), a tuberculosis vaccine that spurs an immune attack on bladder cancer. This treatment is often curative. The 5-year survival rate for patients with stage 0 bladder cancer is 95.8%.⁴

RC has traditionally been the preferred treatment for 3 types of cancer: refractory disease, cancer that has progressed to muscle invasive bladder cancer (MIBC), and MIBC that is confined to the bladder or extends beyond it.

RC involves removal of not only the bladder but also the surrounding lymph nodes. In women, this procedure usually involves removal of the uterus, the ovaries, the fallopian tubes, and the upper vagina, and in men, the prostate and the seminal vesicles. After RC, surgeons restore urinary function by creating an ileal conduit that connects to a stoma, by inserting a pouch that also connects a stoma or by fashioning a piece of small intestine into a neobladder and connecting this to the urethra.⁵ The first 2 options require that patients drain urine through a hole in the abdomen, which, despite no ongoing physical pain, involves not only inconvenience but also significant long-term embarrassment and psychological distress. Patients who opt for neobladders, on the other hand, can sometimes learn to control them nearly as well as their normal bladders, but the work needed to master the neobladder is significant.⁶

Given the risks of surgery and quality-of-life (QOL) drawbacks associated with all 3 urinary reconstruction techniques, investigators have long sought treatments that would spare at least some patients from RC without shortening survival (Table^17-9). Indeed, efforts to compare RC with the combination of radiation, chemotherapy, and TURBT, known as trimodality therapy (TMT), began more than 30 years ago.

Investigators at Massachusetts General Hospital (MGH) enrolled 475 patients with MIBC between 1986 and 2013, performed TURBT, and followed up with concurrent radiation and chemotherapy. Those who experienced anything less than a complete response (CR) and those who experienced an invasive recurrence underwent RC as salvage treatment.

Overall, the rate of disease-specific survival (DSS) was 66% at 5 years and 59% at 10 years, and the rate of overall survival was 57% at 5 years and 39% at 10 years.⁷

Results, moreover, improved significantly over the course of the study. For patients treated from 1986 to 1995 versus those treated from 2005 to 2013, the CR rates were 66% and 88%, respectively. For the same periods, 5-year DSS rose from 60% to 84%, and the risk that returning cancer would necessitate RC as salvage therapy fell from 42% to 16%.⁷

These improvements were attributed to multiple factors, among them better standards for patient selection. Notably, patients with hydronephrosis were excluded because of data suggesting inferior response to chemoradiation. The authors also noted improvements in TURBT technique, radiation therapy, and optimized concurrent chemotherapeutic regimens, and improved supportive care may have contributed to improved CR rates and survival.

A report on the trial published in 2017 noted that DSS rates for TMT patients in the study were similar to those for patients who underwent RC in other trials, and the paper recommended that physicians offer TMT to suitable candidates.⁷

The MGH studies represent the largest and longest institutional trials with TMT in patients with MIBC who would normally undergo RC, but the regimen has undergone at least a dozen other trials.8 Most TMT trials include patients with T2 to T4a disease, and for this population, the CR rate for TMT is approximately 70%.¹⁰

TMT trials have typically confined eligibility to patients who seemed relatively well suited to TMT through selection criteria that have evolved over time. Analyses of results show that only carefully selected patients with MIBC should undergo TMT rather than RC. The ideal TMT candidate has stage T2 disease, no hydroureteronephrosis, a unifocal tumor, no carcinoma in situ (CIS), and good bladder function and capacity. Stage T3 or T4a disease, incomplete TURBT, multifocal tumors, poor bladder control, diffuse CIS, and lymph node—positive disease are all lessthan-optimal characteristics that indicate a patient may be better off undergoing RC. TMT is contraindicated in patients with T4b disease, tumor-related hydronephrosis, prior pelvic radiation therapy, the inability to tolerate chemotherapy, and prostatic stromal invasion.¹⁰

Table 1. Select Trials Examining Alternatives to RC^7-9

“We believe that the trial data amassed over the years strongly support consideration of this approach in selected patients. This bladder-sparing approach provides comparable survival and often better [QOL] in appropriately selected patients,” said Philip J. Saylor, MD, an assistant professor at Harvard Medical School, an attending physician in the Department of Hematology/Oncology at MGH, and a coinvestigator in some of the MGH research. How many patients with MIBC are eligible for TMT? Investigators have yet to quantify it exactly, but sources interviewed for this story estimated that roughly 15% of patients are very well suited for the procedure and up to a third are at least marginal candidates. Although the downside to taking a chance on the bladder-saving treatment is low, the proportion of who actually undergoes TMT is significantly lower.

Investigators have studied patients who had RC after failure of TMT, “and the complication rates seem to be reasonably low, comparable to what you’d see in patients who started off with standard cystectomy surgery,” Saylor said. “The biggest difference is that patients generally cannot have a neobladder constructed at the time of cystectomy if they have previously received radiation.”

TMT is currently the only fully validated alternative to RC, but at least 2 groups of investigators are researching another bladder- sparing alternative that capitalizes on tumor markers that predict for good response to chemotherapy.

A 2003 trial by Grossman et al found that neoadjuvant chemotherapy increased median survival over RC alone from 46 months to 77 months,⁸ so 3 neoadjuvant cycles of methotrexate, vinblastine, doxorubicin, and cisplatin quickly emerged as the standard predecessor to RC, at least in patients who can tolerate platinum-based chemotherapy. That addition to the old standard of care led, in turn, to another exciting discovery: More than 20% of all patients with MIBC who undergo neoadjuvant chemotherapy respond so well that no trace of cancer is left in the tissue that pathologists examine after RC.¹¹

Such patients derived no obvious benefit from RC, but they still underwent the surgery because clinicians had no way to predict from tumor biopsies or demographic data who would and would not respond completely to chemotherapy. The only definitive proof of CR was organ dissection after RC.

Several teams of investigators sought to discover what is different about patients who respond completely to chemotherapy. They waited for the bladder dissections that take place after RC, separated patients with good and bad responses to chemotherapy into 2 groups, and analyzed tissue samples collected before treatment began.

A Fox Chase study performed DNA sequencing on about 1.5 megabase pairs of the total tumor genome, including 4557 exons of 287 cancer-related genes, 47 introns of 19 genes frequently rearranged in cancer, and 3549 polymorphisms located throughout the genome. The initial discovery set represented 34 patients whose tumors collectively exhibited 728 mutations in 212 genes.¹²

Decision tree analysis showed that 13 (87%) of 15 patients with a good response to chemotherapy— and none of the nonresponders&mdash;had an alteration in 1 or more of the genes ATM, RB1, and FANCC (P <.001). This decision rule for response was calculated to have 87% specificity (95%; CI, 60%-98%), 100% sensitivity (95% CI, 82%-100%), 100% positive prediction value (PPV; 95% CI, 75%-100%), 90% negative prediction value (95% CI, 70%-99%), and 94% accuracy (95% CI, 80%-99%).¹²

Table 2. Invasive Bladder Cancer Trials Examining Efficacy of Chemotherapy in Patients With Genetic Biomarkers^14,15

The investigators then validated their data with tumor samples and post-RC dissections in 24 more patients who were taking part in a similar trial of neoadjuvant platinum-based chemotherapy and RC. Analysis showed that 7 (64%) of 11 responders and 2 (15%) of 13 nonresponders had an alteration in 1 or more of the genes ATM, RB1, and FANCC (P = .033).¹² A team at Memorial Sloan Kettering (MSK) Cancer Center performed next generation sequencing of bladder tumors from 32 patients who had received chemotherapy followed by cystectomy for bladder cancer using the in-house assay MSK-IMPACT. They identified deleterious mutations within DNA damage response (DDR) genes predicted for sensitivity to cisplatin-based chemotherapy: 8 of 9 patients with DDR gene alterations were chemotherapy responders. The positive predictive value of a deleterious DDR gene mutation for chemotherapy response was 89%. The 2-year recurrence-free survival in patients with a deleterious DDR gene alteration wsa 100% vs 61% in patients without a deleterious DDR gene alteration.¹³

The discovery of the connection between mutations within these particular genes and very good response to chemotherapy has led to a pair of phase II trials, 1 by Fox Chase and the other a National Cancer Institute cooperative group trial (Table^214,15). Both analyze patient tumors captured in standard, pretreatment TURBT and offer the possibility of omitting RC (but substitute close monitoring) in patients whose tumors look most likely to respond to chemotherapy alone based on the genetic profile of the tumor.

Fox Chase is working with Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, and The Johns Hopkins Medicine in Baltimore, Maryland, on a phase II trial (N = 38) of cisplatin-based chemotherapy followed by active surveillance rather than RC in patients with ATM, RB1, FANCC, and ERCC2 mutations. The surveillance regimen will include regular cytologic, cystoscopic, and radiographic evaluations. The primary endpoint is metastasis-free survival at 2 years, and the estimated study primary completion date is April 2020.¹⁴

The MSK team is working with facilities across the country through the Alliance for Clinical Trials in Oncology (A031701) to perform a larger trial (N = 271) along very similar lines. Tumor samples extracted during TURBT at all participating sites will go to MSK for analysis using the MSK-IMPACT CLIA-certified sequencing platform while patients begin platinum- based chemotherapy. When the MSK lab identifies a patient whose tumor genetics predict good response, that patient will be offered the chance to undergo active surveillance rather than RC. The primary endpoint of the study is event-free survival at 3 years.¹⁵

“Even after we find mutations that predict a good response to chemotherapy, we still have patients undergo imaging and cytoscopic evaluation after chemotherapy,” said Gopa Iyer, MD, a genitourinary specialist who is heading the Alliance trial. “If we see no signs of cancer in the bladder, then we put them on the monitoring protocol. The hope is that the chemotherapy will prove curative, and we can accurately select these patients using a combination of genomic sequencing and clinical response after chemotherapy,” he said.

“Both the Fox Chase trial and the Alliance trial are looking at the same class of DDR genes. Although the Fox Chase trial isn’t looking at exactly the same genetic mutations that we are, the genetic mutations in their trial are very similar. All the genes that tumors are being tested for in both trials are DNA damage response [DDR] genes,” Iyer said. “Normally, these genes work to protect us against cancer because they find damaged DNA that we’re constantly getting from things like sun exposure, and they repair it…. However, the primary way that chemotherapy works is by damaging DNA, and so it makes sense that it might be advantageous for patients with cancer whose tumors have these DDR gene mutations to receive certain chemotherapy drugs. That might be one reason they have such great responses to chemotherapy.”

Another possible strategy for bladder preservation in MIBC involves the use of checkpoint inhibitors. Two of these agents—pembrolizumab (Keytruda) and atezolizumab (Tecentriq) &mdash; have been approved as first-line therapy for platinum-ineligible patients with metastatic bladder cancer.¹⁶

Ongoing trials are examining the effect of such medications on patients with earlierstage bladder cancer. Many such trials are now accruing patients, but preliminary data from the KEYNOTE-057 trial indicate that checkpoint inhibitors could further reduce the need for RC. Investigators gave pembrolizumab to 103 patients with high-risk nonmuscle invasive bladder cancer (NMIBC) with CIS. Such patients would typically undergo RC because they had stopped responding to (or had never responded to) intravesical BCG, but the trial patients had either refused surgery or been classified as ineligible for surgery. The interim data, which were reported in Munich, Germany, at the European Society for Medical Oncology 2018 Congress, showed a CR rate (3 months after the start of treatment) of 38.8%. Responses lasted 6 months or longer in 80% of the patients.⁹ For physicians with patients who might be interested in participating, KEYNOTE-057 is still enrolling.¹⁷

Most recently, the FDA approved erdafitinib (Balversa) for advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy. The approval was based on the BLC2001 trial, in which the overall response rate was 32.2% (95% CI, 22.4-42.0), with CRs in 2.3% of patients and partial responses in 29.9%. Median response duration was 5.4 months (95% CI, 4.2-6.9). Responders included patients who had previously not responded to anti—PD-L1/ PD-1 treatment.¹⁸

In addition, investigators have reported positive results extending the viability of BCG treatment. Use of a cytokine agonist in combination with BCG was highly successful in stimulating an immune response in previously BCG-unresponsive patients with CIS highgrade NMIBC.¹⁹

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