Every 10 years, oncologists have to take a recertification exam in order to ensure that they stay up to speed on the latest advances in their field. This is particularly important in areas where research moves fast; and one hopes that cancer is one of those areas.
In some areas of cancer treatment, much, in fact, has changed in the last 10 years. There has been surprising progress, for instance, in treating melanoma, even though, not long ago, oncologists who dealt with the disease didn’t accrue a large practice because their patients died so quickly.
But other cancers have proven stubborn, especially pancreatic cancer. Pancreatic cancer remains infamous for taking patients’ lives more quickly than any other solid tumor, and it is one of the most deadly forms of the disease. According to the recent Cancer Statistics, 2016 report, there will be 53,070 new cases of pancreatic and 249,260 new cases of breast cancer in the United States this year, but the number of deaths caused by each will be roughly equal—41,780 and 40,890, respectively.
The fact that the number of predicted pancreatic cancer deaths will now (slightly) surpass breast cancer deaths despite the lower rate of diagnosis reflects the dismal survival rate of pancreatic cancer patients, which rests at an abysmal 10% after only five years. This makes pancreatic cancer the third leading cause of cancer-related deaths in the United States behind lung and colon cancer, a large fraction of which can be prevented by not smoking and getting regular colonoscopies.
Pancreatic cancer patients are thus faced with two questions: Has my disease spread from the pancreas to a different organ? And if it hasn’t spread, can my surgeon perform the therapeutic surgery? The surgery, known as the Whipple procedure, removes part of the pancreas, part of the small intestine, and the entire gallbladder. If there’s no evidence the cancer has spread and the surgeon is talented, there’s reason to hope. If the disease has spread, the best thing a patient can do is enroll in a clinical trial in an effort to help future patients. Unfortunately, less than 20 percent of patients are even eligible for surgery.
In 2010, Supreme Court justice Ruth Bader-Ginsburg was one of those “lucky” ones who had both a pancreatic cancer that hadn’t spread and a super-talented surgeon. Today in 2016 Justice Ginsburg is now not only the Notorious RBG but also a rare five-year survivor.
One ray of hope within pancreatic cancer treatment lies in the area of genetics. A better understanding of the genetic causes of the disease may lead to improved prevention and maybe, just maybe, new therapies.
Mutated cancer genes that increase the risk for pancreatic cancer form an alphabet soup -- APC, ATM, BRCA2, CDKN2A, LKB1, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, TP53 and more. Patients who harbor one of these mutations may choose to have frequent MRI and endoscopic ultrasound exams in an effort to locate pre-cancerous clusters of cells or at least catch the cancer early enough to be cured with surgery. These same individuals also know to avoid environmental pancreatic cancer risk factors, mainly alcohol and tobacco. A few of the very high-risk patients—those with these mutations as well as a family history of the disease—are now having their pancreases removed preemptively. Since the pancreas is responsible for the production of insulin, these people choose to live with diabetes in order to avoid the chance of an early death.
We don’t yet know just how likely it is that someone with a mutation in a relevant gene will develop pancreatic cancer, but when mutations are coupled with family history (or lack thereof), it’s easier to make predictions. For instance, if the family has many members but no history of pancreatic cancer, the risk associated with the mutation is reduced.
Recently, Robert Grant and colleagues reported in the journal Gastroenterology that with no known family history of pancreatic cancer, at least 4% of patients have mutations in cancer genes that can put them and their families at risk for additional cancers such as colon, breast, ovarian and melanoma. Knowing this, they can choose additional actions to prevent those cancers (daily aspirins, earlier and more frequent colonoscopies, and even prophylactic surgeries).
Prevention and Treatment
It’s tantalizing to think that with genetic knowledge, more pancreatic cancers will be detected before they spread, and surgeons will be able to cure more patients like Justice Ginsburg. Could we see progress in the early detection or prevention of this horrible disease in the next ten years? Could we increase the rate of survival? Or could we use our new genetic knowledge to better understand pancreatic cancer biology and develop better drugs?
There’s a lot of research currently underway to help those with this disease, and there’s a real chance the next ten years will be the decade for surviving pancreatic cancer. For example, a recent trial for cancer patients with BRCA mutations, reported last year by Bella Kaufman and colleagues in the Journal of Clinical Oncology, found that a new FDA-approved drug named Olaparib helped pancreatic cancer patients who carry BRCA mutations in ways we rarely see.
Olaparib is the first in the family of drugs approved by the FDA for cancer treatment that inhibit poly(ADP)-ribose polymerase (abbreviated as PARP). PARP enzyme activity was discovered in the 1960s, and in the 1980s the idea that inhibiting PARP could promote the effects of cancer chemotherapy was born. This idea arose because scientists discovered that the PARP enzyme mended broken DNA, like an electric company called out to repair downed wires after a storm. Many types of chemotherapy behave like such storms in the body as they, too, damage DNA. In addition, every day, every human cell experiences DNA breaks that are repaired by PARP. Cells unable to repair enough of these DNA breaks die. Without PARP to repair the DNA, chemotherapy can kill cancer cells more effectively.
Normal cells die less than cancer cells because they have backup repair systems many cancer cells lack. For example, tumors with BRCA mutations are unable to fix certain kinds of complex breaks in both DNA strands. When repairs are needed on only one strand, they are usually easy to fix because the information on the normal DNA strand can be copied. When the PARP enzyme activity is blocked with an inhibitor like Olaparib, single-strand DNA damage can develop into more serious double-stranded damages. The job of BRCA proteins (or other repair proteins) is to fix these double-strand breaks. However, in tumors that have lost BRCA function, the cancer cells can’t fix the double-strand DNA breaks and therefore die. Thus, when treated with a PARP inhibitor, a tumor cell with defective repair systems is unable to repair itself after DNA-damaging chemotherapy and dies while the surrounding normal cells repair their DNA and survive.
Even if a patient with ovarian cancer has no family history of cancer, we now offer her a genetic test for several genes including BRCA1 and BRCA2. With reports such as that from Grant and colleagues, soon we will do the same for pancreatic cancer patients. The more we learn about genetic predisposition, the more we learn about why cancer develops. With that understanding, our chances of improving our ability to prevent and treat pancreatic cancers increase.
So if metastatic melanoma was the old pancreatic cancer, perhaps pancreatic cancer is the new ovarian cancer. Just as we offer to preemptively remove ovaries and fallopian tubes in patients at high risk for ovarian cancer because we can’t catch ovarian cancer in time to treat it, the time is right to offer the same option for those at the highest risk for pancreatic cancer. Our ability to find and fight the cancer before it spreads is just not there. Although living without ovaries, or worse, without a pancreas, is fraught with physical challenges, patients at high risks should be given the option.
Returning to our earlier comparison to breast cancer, removal of the pancreas may have parallels to the ancient radical mastectomy. This old surgery involved the removal of one or both breasts as well as the underlying chest muscle and armpit lymph nodes. Surgeons later moved to the modified radical mastectomy, which still removed lymph nodes but left the muscle alone. And now surgeons simply remove the tumor with margins that are clear of cancer cells and sample the “sentinel” regional lymph nodes rather than removing all they can find. Progress is often learning how little intervention we can get away with to prevent or treat a cancer.
Even though the last ten years have moved many cancer outcomes into realms once unreachable and untouchable, for patients with advanced pancreatic cancer the outlook remains guarded. Better prospects for pancreatic cancer patients will come, but we don’t yet know when or how. After all, ten years ago, oncologists would have said the same for patients with advanced melanoma.
Like good scientists, pancreatic cancer patients are finding ways to thrive while new data are collected and transformed into useful knowledge. Although scientists need the time to learn what we don’t know, and then, with well-designed studies, gain new knowledge, there will be unexpected progress from the most unpredictable places.