This month is Pancreatic Cancer Awareness month, and I would like to begin this post by sharing my story with you. Fifteen years ago, on November 5th (my father’s birthday), my family and I sat down in a small, claustrophobic post-operative consulting room as the surgeon drew a pancreas on the white board and told us that my mother had 3 months to live. It was the second worst day of our lives.
In the 15 years since my mother’s death, despite the advances of the Genomics Revolution, nothing has changed. Every year 35,000 other families receive the same news. Every year the number of families receiving this news, nudges up slightly. And the standard of care remains the same.
Despite all of the bad news about pancreatic cancer, my mother was always an optimist, and to honor her, here are some of the lessons we’ve learned.
Lesson 1: Time and Tide Wait For No Man
By the time a patient is diagnosed with pancreatic cancer, it’s already too late. And although we’ve learned that pancreatic cancer can take 10 years to develop, the disease doesn’t make it’s presence known until it’s in the final stages. Patients may have anywhere from a few months to a year to live. No chemotherapeutic agent, or drug cocktail can undo 10 years worth of damage.
For patients and their families, that means “say what you want to say, do what you want to do”, time is not on your side.
Given the short apparent duration of the disease, families are faced with some tough decisions while trying to cope with going through each of the 5 Stages of Grief. This means that family members may not be willing to accept the impending death of a loved one, and and as a result put the patient through unnecessary heroic measures. Everyone is grieving at different rates and no one wants to give up on a loved one. Hospice care, often seen by family members as a sign of giving up, is often a neglected option, as families fail to realize that it can help alleviate some of the burden of caring for someone with a terminal disease.
Perhaps the hardest lesson for family members, is to simply listen to and accept what the loved one is telling you.
Lesson 2: The Importance of Early Diagnosis
As with most cancers, an early diagnosis can make all the difference. In recent months, two promising approaches have emerged: an oral diagnostic method, and a stool sample method. Either of these methods could lead to an early diagnosis of pancreatic cancer and could potentially be a game changer. However, one has to ask, what would prompt a physician to perform the diagnostic? The disease is virtually asymptomatic until it’s final stages, and unless the physician was aware of a family history of cancer, why would they check?
In my mother’s case, several of her sisters had breast cancer. If a physician was going to monitor something, surely being vigilant for signs of breast cancer would be the extent of it. My mother had regular mammograms which all came back negative. No one thought to look for other types of cancers.
Over the past few years, clinicians have begun to change their view of cancers. Rather than characterizing the disease based on a site of origin, they’re looking at cancer in terms of driver mutations and the pathways affected by those mutations. There is hope that by changing that approach, a more generalized diagnostic panel could be achieved. One in which the diagnostician looks for a pattern of mutations, or a pattern of misregulated genes that point to a specific diagnosis and a treatment regimen.
I imagine that if my mother were examined today by a clinician skilled in genomic medicine, they might find a BRCA2 mutation, in addition to KRAS, MYC, and other common mutations that would point to pancreatic cancer instead of breast cancer. This molecular diagnostic approach might even one day do away with that most elusive of cancers, the “cancer of unknown primary”.
But molecular diagnostics for cancer are very much a work in progress. And most GPs who are at the front lines when it comes to a cancer diagnosis are not well-versed in the latest developments in genomic medicine. Genomic medicine and molecular diagnostics must become part and parcel of a physicians toolbox if more people are to be saved.
Lesson 3: Singing From The Same Sheet
Currently cancers are staged based on the development of the tumor, whether or not the tumor is well defined, whether or not it has spread out of its initial confines, and whether or not there are distal metastases. The problem with this approach is that none of these stages are currently defined based on the pathways and genes that are driving them. Ralph Hruban’s seminal paper (and subsequent followup) on the Pancreatic Intra-epithelial Neoplasia (PAN-IN) model describes the early pre-cancerous stages of the disease, but the model doesn’t describe anything after the development of the adenocarcinoma.
Unfortunately, since most patients present in the final stages of the disease, this model only describes half of the problems that the clinician is faced with treating.
This underscores a basic disconnect between the way in which drugs are developed and the way in which clinicians deal with disease. Since the sequencing of the human genome, drug companies base their development projects on specific gene targets. Clinicians are gradually warming to the idea of cocktail trials, where several chemotherapeutic agents are tried throughout the course of treatment. Each agent is designed to deal with a particular driver mutation in a particular pathway. This approach, first pioneered during the AIDS crisis, shows promise in cancer treatment as well.
There’s also hope that by examining the biomolecular similarities in different types of cancers, researchers may be share lessons learned and treatment regimens. For example, if treatment exists that targets BRCA2 (which plays a role in both breast and pancreatic cancer), then presumably the treatment might work for both types of patients. Again, this is still very much a work in progress.
Real progress will come only when clinicians and drug developers are on the same page and understand the progress of the disease in terms of its pathways and mutations. Clinical trials are still often conducted only by comparing the current standard of care against a regimen that includes both it and a new drug. This approach, at best might show small differences in the effect of the new drug, but it won’t “cure” a patient, because at best the new drug could only deal with one or two additional drug targets.
These conflicting aims, between assessing the relative safety and efficacy of a new drug, and the goal of a patient to be cured, highlight another area where patients and drug developers are not on the same page, and often have different hopes and expectations with regards to the outcome of the trial.
Lesson 4: Sweeping Back The Tide
Even if early diagnosis is able to play a role in changing the statistics for this terrible disease, the fact of the matter is that for a significant number of patients, the diagnosis will come late in the development of the disease. And like Cuchulain’s fight with the tide, clinicians will be faced with the prospect of having to sweep back the progress of a disease that has a 10 year head start on them.
Cocktail treatments will stand the best chance of making a dent in the disease. But ultimately small molecules can only inhibit mutant genes in key pathways. They can’t undo the accumulated damage to the patient’s DNA. Surveys of some of the damage that occurs in pancreatic cancer, have highlighted at least 60 different mutations. No cocktail could cope with that kind of damage. The ultimate form of treatment for this disease, is to undo the damage itself by repairing the damaged genes. Previous attempts at gene therapy have failed in rather dramatic ways. At best, any therapeutic approaches might slow the progress of the disease and buy the patient and their family more time.
More troubling perhaps is the fact that even if a patient were aware of risk factors (both genetic, and behavioral) that predisposes them to pancreatic cancer, it’s not all that clear that they would do anything about it. Risk factors such as a familial history of cancer, smoking, eating barbequed red meats, alcohol use, are all well known. But given the chance to alter behavior and avoid the disease, most patients are unwilling or unable to make the necessary changes.