How Genomics is Changing the Face (Again) of Clinical Cancer Care

Cancer is Complicated – It’s Also Very Clever 

Maida Broudo

Maida Broudo, Project Program Manager, Termeer Center for Targeted Cancer Therapies, Massachusetts General Hospital

For half a century, physicians and researchers have devoted their life’s work to figure out ways to outsmart this dreaded disease. For much of that time, they were really shooting in the dark. Conventional chemotherapy and radiation therapy were implemented when surgical removal of the tumour was incomplete or impossible. Physicians knew to target the DNA of the cancer cells, but they did not yet realise that targeting the cancer genes themselves held so much more promise.

Genomics Sheds Light on Cancer Behaviour

Today, a more artisanal approach to treating cancer is not only possible, but necessary to precisely jam cogs and turn off selective switches in particular cancer cells. Owing to the game-changing breakthrough of the Human Genome Project in the 2000s, scientists have learned to sequence the genomes of cancer cells. Human DNA contains an estimated 20,000 to 25,000 genes, which together carry the blueprint for all of our working parts. Some genes encourage our cells to grow and other genes detect excessive growth and shut it down. Some cancers develop from birth (germline) and are heritable, but other genetic mutations occur as cells evolve from a benign to malignant state. Cancer is usually a complex composite of multiple genetic mutations, many of which have been identified by scientists and pathologists as “drivers” of cancer progression and even resistance to treatment. A “genetic biography” for one patient is likely to show a unique story of accumulated mutations and epigenetic changes over a continuum.

Targeted Therapy and Precision Medicine 

cancerWe are now in a new era of targeted cancer therapy, which, in contrast to conventional chemotherapy drugs, matches drugs to a tumour’s specific genetic mutations. These drugs can turn off bad switches and turn on others, sometimes in the form of one’s own immune system, in order to outsmart the growing cancer. Because the drugs are so specifically selective to target mutations and behaviours of cancer cells, there are fewer healthy cells being treated and, in most cases, reduced side effects. Targeted Cancer Therapy requires a biopsy of the tumour, either through surgical excision, or through a core needle aspiration. The sample is then processed and analyzed through genetic sequencing by trained molecular pathologists. This type of genetic testing has revolutionised how we think about cancer. Sequencing a portion of a tumour genome can sometimes tell us what went wrong and how the cancer might be treated more effectively. For instance, testing people with melanomas for mutations in their BRAF genes can influence treatment. But it’s unclear how many people would benefit from sequencing all the genes in a tumour; it, like full germ line sequencing, remains mainly a research tool. Targeted therapy – also known as personalised medicine – is now a standard drug treatment approach nationally for about 30 percent of all cancers, explains Keith Flaherty, MD, director of Massachusetts General’s Henri and Belinda Termeer Center for Targeted Therapies and leader of the breakthrough B-RAF trials. It works on the premise that cancer is not one-size-fits-all. Not only do cancers differ by where they begin in the body — breast cancer, lung cancer or colon cancer — but within each type, there are genetic differences from person to person. One drug won’t help everyone with breast cancer, but a drug targeting women with the same genetic trigger will have a higher likelihood of helping them.

A New Era of Cancer Care 

The targeted therapy approach has advanced the past two years with the realisation that “it’s going to take a village,” says Dr. Flaherty. Single drugs have produced dramatic tumour regressions but, in many cases, resistance to the drug develops as the cancer finds another way to survive. AIDS was rendered a manageable disease by using a cocktail of drugs with different actions, he points out. “For the majority of cancer patients, I think we’re going to need a cocktail of two, three or even more drugs,” he says. He and colleagues made headlines in 2012 when they reported the results of the two-drug B-RAF/MEK cocktail to treat malignant melanoma. This was amongst the first attempts at outsmarting cancer from a different angle. As the cancer became resistant to B-RAF inhibitors, it grew through a new pathway, and the MEK inhibitor caught the cancer “red handed”. One must always be thinking ten steps ahead and many steps across and diagonally at the same time. This year, several three-drug trials for melanoma are planned.

Recruiting the Immune System to the Fight

Similar to targeted cancer therapy, researchers are starting to figure out when it’s more important to take the brakes off the body’s immune responses, when to step on the accelerator to get a sluggish reaction into high gear-and when they can safely do both. Recent breakthroughs have led to FDA approval of two immunotherapy drugs for late-stage melanoma. Immunotherapy is not a silver bullet however. It is not entirely clear which patients will benefit or respond to immunotherapy drugs and which ones will not. “This is something that is very recently being recognised—maybe in the past two years,” says Jedd Wolchok, an oncologist at Memorial Sloan Kettering Cancer Center in New York City. “The same doses of the same medicine may not be tolerated equally in patients who have different cancers. We may have to use less medicine in patients with lung cancer. [Immunotherapy] is not one size fits all.”

Liquid Biopsy and Blood-Based Biomarkers

While biopsies are effective for sequencing and treating tumours, this method of obtaining tissue samples does have certain limitations, predominantly because of their invasive nature – whether performed as a highly invasive surgical or as a fine needle biopsy. And since many biopsies tend to be burdensome and painful for patients, they can’t be used to regularly monitor the progress or recurrence of disease. Getting enough tissue to perform all the necessary diagnostic procedures – including molecular biomarker testing to help guide treatment decisions for targeted therapies – can also prove difficult. And even when there is enough tissue, a traditional biopsy might not capture all of the relevant information because of the inherent heterogeneity of tumour tissue. Perhaps even more important, it is not practical to biopsy tumours repeatedly while patients are undergoing treatment to see if they are responding to a particular regimen. Even if it were feasible, turnaround time for a report to the physician can take weeks. That’s too long for a cancer patient, especially for disease monitoring.

drugsAlternative emerging technologies use blood tests to pick up the DNA that is shed by the cancer cell into the blood. This non-invasive technique shows significant promise in clinical practice; patients could get several liquid biopsies for weeks, months, or even years as their cancer progresses—compared to the one initial tissue biopsy. That would allow doctors to look out for new mutations in the cancer and adjust drug regimens as needed. Patients would no longer need to wait several painful months before having a “scan” to see if their therapy actually worked. Earlier in April, at the (20,000-plus attendee) annual meeting of the American Association for Cancer Research (AACR) meeting in Washington DC, there were no less than 130 presentations, “poster” sessions, and panels on liquid biopsy studies—with research groups revealing their progress in efforts to detect, amplify, decode, and (most importantly) identify meaningful information from liquid biopsies. Much of the progress, it’s worth noting, has been made possible by a remarkable collaboration begun in 1991, christened the International Liquid Biopsy Initiative Team, now led by Luis A. Diaz, at New York’s Memorial Sloan Kettering Cancer Center. “These people stuck together as a team for over 25 years,” said Pat Lorosso, a medical oncologist at the Yale Cancer Center, who presented presenting the AACR’s “Team Science” Award to the group. “And they kept saying, ‘Let’s go one step beyond that”. Clearly, there is reason to be hopeful.

Read more articles like these in issue 13 of Front Line Genomics Magazine, where we talk all things cancer.