The future of prostate testing

Over the past few decades, fighting breast cancer has been one of medicine’s big success stories. Accurate mammograms and quicker surgery now mean that the five-year survival rate for women with stage I breast cancer is close to 100%, and for those with stage II and stage III it is roughly 93 and 72% respectively.

Overall, the breast cancer mortality rate has halved since 1970. These medical leaps have also been accompanied by cultural changes. High-profile campaigns such as ‘Breast Cancer Awareness Month’ and ‘Run for Breast Cancer’ have brought the disease into the cultural and social sphere.

But if we now have a better understanding of breast cancer, many are still in the dark regarding other types, despite them being just as common.

Prostate cancer is a striking example. About 524,000 new cases of the disease are diagnosed in the US and Europe every year, and over 25,000 American men will die of it. Moreover, unlike breast cancer, prostate cancer is still tinged by stigma. Some men are reluctant to get effective treatment until it’s too late, and for many who do undergo treatment, years of distressing side effects await them.

This situation isn’t hopeless, however. Scientists are working hard to predict and detect prostate cancer more accurately, while new DNA testing is helping doctors to offer patients the most effective treatments. These new technologies have the chance to transform the way in which doctors understand prostate cancer, and, by extension, to improve patient well-being.

Prostate cancer: the two types

Prostate cancer takes two main forms. The localised type, which remains inside the prostate, is more common. Although it can be uncomfortable, causing symptoms like poor urine flow, localised prostate cancer is essentially harmless. The tumour often develops so slowly that the patient dies naturally before it has a chance to do any serious harm. But if the cancer develops into the secondary form – as occurs in about 6% of cases – things become more serious. If this happens, the prognosis is dire. Once the prostate cancer has spread to distant lymph nodes and organs, the five-year survival rate is just 29%.

Up to now, a major problem has been discerning which kind of prostate cancer a patient is suffering from, and whether a localised cancer is likely to develop. Many patients end up being put under active surveillance, which involves checking on the cancer’s status via biopsies or prostate specific antigen (PSA) blood tests. But neither test is particularly accurate; 15% of men with normal PSA levels may still have prostate cancer. Biopsies have similar problems and are painfully invasive. Moreover, It doesn’t help that some men judge their state of their health simply based on how they feel. Physical symptoms do not necessarily match with a tumour’s progress, meaning that a seemingly healthy patient might actually be dangerously ill.

Doctors have a more radical option, too: removing the prostate entirely via surgery. In itself, the procedure does its job by stopping the tumour from causing more damage. But prostate removal comes with potentially serious side effects, including erectile dysfunction, incontinence and bowel disease. This leaves patients with an uninviting choice. They can either keep their prostate and gamble that the tumour stays localised, or have pre-emptive surgery and face the consequences, even if they may have lead a healthy life without the operation.

Predicting the prognosis

It is into this frustrating and uncertain world that Dr Sabine Mai and her team at the University of Manitoba first stepped over ten years ago. Working with 3D Signatures, a Toronto-based health company, Dr Mai has developed a system that accurately predicts a patient’s long-term prognosis. This has the chance to ease patients’ suffering and save hospitals money.

At the centre of this work are telomeres; the caps at the end of DNA strands that protect chromosomes in the cell. By examining the telomeres of circulating tumour cells (CTCs), Mai and her team can tell how advanced the cancer is, and whether it’s likely to get worse. Shorter telomeres might suggest that the cancer is malignant, for example. “On top of seeing the length, you are also able to see how they’re distributed,” explains Mai. “Are the telomeres evenly distributed throughout the nucleus, or are they more clustered in one area?”

The telomeres themselves are only one part of this breakthrough, though. To look at them, Mai and her team developed TeloView, a new programme that analyses the CTCs in 3D.

“What’s fascinating about our telomere technology is that you immediately take a photograph of the entire cell’s nucleus and see how that configuration changes,” explains Kevin Little, 3D Signatures’ chief scientific officer. “We can look at how it changes depending on disease progression, how its state is predictive of how a disease is going to respond to a particular therapy, or the aggressiveness of the disease at that moment.”

Because CTCs accurately represent the state of the cancer inside the prostate, it yields far sharper results than unreliable biopsies, especially when combined with TeloView. This is borne out in clinical trials. One recent test found that TeloView correctly predicted the aggressiveness of a patient’s prostate cancer every time, while biopsies only managed a success rate of 42%.

The consequences of this are huge. With TeloView, doctors can confidently tell patients if they’ll need to have their prostate removed and if their localised cancer is likely to spread. Using personalised medicine, doctors can target specific types of cancer with the most effective drugs. “We see a number of opportunities where a very accurate test can play a role, especially as ours is a non-invasive blood test,” adds Little. “I think they can be anywhere from the ongoing monitoring of disease progression, back to predicting responses to treatment, or even all the way back to the diagnostic level.”

Germline testing

If TeloView is a robust way of diagnosing the type of cancer patients have, its reliance on CTCs means that it can only work if prostate cancer (localised or advanced) is already in the body. Fortunately, other new technology allows doctors to predict patient risk years before tumours even develop.

One of the most exciting advances is genTrue, developed by True Health, a Texan laboratory company. The test works by analysing mutations in germline cells, the egg and sperm cells that provide the rest of the body with its DNA.

“It’s been known for quite a while that men who inherit germline mutations in the BRCA-2 gene have increased lifetime risk for prostate cancer,” explains Ann Jeffers-Brown, True Health’s clinical education manager. “There’s tremendous work going on right now to define what those risks are and what the prevalence of the mutations are. There’s also a push towards finding men who might have inherited these risks for prostate cancer, especially as these prostate cancers tend to be aggressive and metastatic.”

She’s right: inherited germline prostate cancer, which accounts for between 5–10% of all cases, tends to be especially nasty. BRCA-1 and BRCA-2 mutation carriers only have a 50–60% chance of living five years after diagnosis if they develop prostate cancer. To make things worse, this genetic form of prostate cancer is resistant to treatments like taxanes, which slow the tumour down by stopping cell division. Conversely, germline mutation cancers are more effectively attacked by inhibiting the development of the enzyme poly ADPribose polymerase (PARP). This kind of knowledge can help dictate medical decisions, explains Jeffers-Brown.

“First, we need to look at what the person has inherited in general, and then at the DNA and the tumours of people who have prostate cancer to try and predict what the course of that disease is, and how it should be treated,” she notes.

It also helps that genTrue – and other similar systems – can sort through DNA and find various genetic mutations quickly and cheaply. “If a patient had a history that was suggestive of hereditary risk for cancer, they might first be tested for just the BRCA-1 and 2 genes,” adds Jeffers-Brown. “But then, if no mutation was detected in those, they might move out to another gene or two. The technological advances in DNA sequencing allows labs to look at many more genes, or a bigger chunk of the genome, more rapidly and at less cost than [older techniques].”

The availability of genTrue is changing how physicians think about diagnosis. Rather than waiting for prostate cancer to develop in a patient, doctors can send genetically vulnerable men for regular testing from a young age. This way, physicians can tackle a tumour the moment it appears. “Up until now, testing has been primarily focused on patients who were already diagnosed with cancer,” explains Jeffers-Brown. “But now there’s progression into the primary care arena, and the use of technology as a preventative measure. If a man’s father had prostate cancer at 40 years old, and they were found to be carrying one of these BRCA-2 mutations, the unaffected son would start tests at 35 years old.”

Stakeholder engagement

Schemes like this are welcome, but problems remain. Unlike other similar diseases, many men are reluctant to get help fighting prostate cancer. Finding a solution involves engaging with stakeholders directly, says Little.

“I don’t think there’s the stigma attached to breast cancer that there was 20 years ago because of the efforts of advocacy groups,” he explains. “Prostate is moving in the right direction, but it takes a lot of work. It’s important to educate people about the utility of our test.” Not that patients are the only people who matter, he adds. “Does our test satisfy the needs of the clinician experience, and the economics of those who are running a national health system or private care?”

Jeffers-Brown also emphasises the need to raise awareness about prostate cancer in the most vulnerable ethnic groups, like men of African descent and Ashkenazi Jews. “The prevalence of BRCA mutations in the general population is one in 300, but in Ashkenazi Jews it’s one in 40,” she explains. “So guidelines specifically state that if you’re Jewish, that’s adequate [risk] for germline testing. In Canada, there’s a programme of population screening of specific groups for BRCA-1 and 2, which is part of an ongoing effort to make sure that screening is available to people who need it.”

This is all good news. Using new technology like TeloView and genTrue, the medical profession has a real chance to tackle some of the disease’s underlying problems and to fight stigma at the same time. Two decades after our relationship with breast cancer was transformed, prostate cancer now has a chance to start a similar journey.