New Tools In The Battle Against Bile Duct Cancer
Often by the time bile duct cancer is diagnosed, it’s already metastasized. Highly aggressive, bile duct cancer usually comes with limited treatment options and a poor prognosis. Because it’s a relatively rare cancer — only about 8,000 cases are diagnosed each year — additional therapies have not been well-studied.
But a team of nine researchers from across the country, including at Duke, may have just uncovered a new tool in the treatment toolbox; a promising targeted therapy for patients who carry a molecular alteration of human epidermal growth factor receptor 2 (HER2) and whose cancer has metastasized.
It’s a combination therapy — pertuzumab (Perjeta) + trastuzumab (Herceptin) —that’s already been approved by the US Food and Drug Administration (FDA) for breast cancer patients who have the same genetic alteration.
Duke medical oncologist Herbert I. Hurwitz, MD, and some of the researchers presented preliminary data on the efficacy of this combination at the American Society of Clinical Oncology’s 2017 Gastrointestinal Cancers Symposium in late January.
“Four out of the 11 patients in the bile duct cancer cohort of the MyPathway study had their tumors shrink by at least half,” explained Hurwitz, the senior author of the bile duct cancer research and a Duke Cancer Institute (DCI) member. “It’s not only promising, if it holds up, it’s very clinically meaningful.”
My Pathway (NCT02091141) is an ongoing phase IIA multi-center, open-label umbrella study, sponsored by Genentech, Inc. that’s assessing the efficacy and safety of pertuzumab + trastuzumab, vemurafenib, vismodegib, and erlotinib in patients with genetic or molecular alterations in the HER2, BRAF, Hedgehog, or epidermal growth factor receptor (EGFR) pathways. Patients enrolled in the various trials, including for bile duct cancer, have a type of cancer for which these drugs are not yet FDA- approved. Researchers believe these drugs have the potential to work given that they have effectively targeted these mutations (and gotten FDA approval) in patients with other cancers.
By the October 15, 2016 data cut-off, 247 patients had been treated in the MyPathway study, including the 11 with HER2-positive metastatic bile duct cancer who received pertuzumab + trastuzumab.
Most of the HER2 genetic alterations had what is called an amplification or increased copy number of the gene that leads to increased expression of the HER2 protein, Hurwitz explained, and in turn, causes an increase in signals that cause cancer cells to grow and spread. Other patients had a mutation in HER2, which changes how the HER2 protein functions, usually increasing activity.
Hurwitz said that the 35 to 40 percent response rate for bile duct cancer patients who carry the HER2+ alteration is consistent with response rates seen in breast cancer patients with that alteration. About 15 to 20 percent of breast cancer patients, and an estimated 10 to 20 percent of bile duct cancer patients carry the HER2+ alteration. (A large fraction of salivary gland tumors, and a small fraction of non-small cell lung cancers, bladder cancers and stomach cancers carry the HER2+ alteration, with between five and eight percent of colorectal cancer carrying the HER2+ alteration. Trastuzumab is commonly used in the subset of gastric cancers that have a HER2 amplification.)
Hurwitz said that the fact that there was a handful of people with six to 12 months of progression-free survival, “is significant.” While not curative, he said, the therapies at least have the potential to keep the cancer — which at its advanced stage has an average overall survival of three to six months for most patients whose cancers have become resistant to initial therapies — under control.
The two drugs, which are humanized recombinant monoclonal antibodies, target the alteration in complementary ways, explained Hurwitz. They are classically called targeted therapies that block signaling that drives cancer growth and invasion.
“With all the caveats, this HER2+ targeted treatment is promising enough that if someone had a HER2 alteration detected in their tumor, I would strongly suggest they seek out a clinical trial or access these drugs,” said Hurwitz. “They should also make sure their tumor is profiled to look for other alterations that may also potentially be targetable and therefore potentially treatable, including microsatellite instability (MSI).”
MSI is an inherited alteration in mismatch repair that can be related to Lynch syndrome and which has shown response to PD-1 immunotherapy in clinical trials.
"Much of our current basic science understanding of how cells conduct mismatch repair in cells came from the work of Dr. Paul Modrich, a co-recipient of the 2015 Nobel Prize in Chemistry and DCI member," explained Hurwitz. "This fundamental discovery allowed many other researchers to subsequently gain the insights needed to develop treatments that can now help patients whose cancers harbor mismatch repair defects."
Hurwitz noted that knowing whether a patient's cancer has a molecular alteration, whether a mutation or an amplification, is most helpful if there is a targeted therapy or immune treatment that is matched to that alteration.
“A genetic or molecular alteration may or may not be beneficial or harmful per se on its own, but when it has a drug to target it, that’s the game changer,” he said, explaining that of all bile duct cancer patients, there are probably a quarter to a third of patients for which there will be a drug available on a clinical trial that could be matched to their alteration.
Hurwitz said there are standard treatments for bile duct cancer patients, not just those who have a HER2 alteration. If the cancer is caught early, surgery and radiation may be curative. Once the cancer has spread it is not considered curable — but there are a variety of standard chemotherapy treatments that can shrink and control a patient’s cancer.
Localized spread and metastasis both favor involvement of the liver fairly early, which makes surgical resection challenging. Depending upon where the cancer is in the bile ducts, a large amount of the liver may need to be surgically removed, and occasionally a liver transplant is warranted.
“The data we presented is an additional promising avenue of research and potential therapy. It’s too early to tell if the best use of HER2 directed treatment will be before, after, or on top of regular chemotherapy,” he said. “More trials and research are needed to better understand and optimize how to use this promising HER2 directed therapy, but the good news is that we now have the needed tools and forward momentum.”
Milind Javle, MD, was the first author of the research presented (University of Texas MD Anderson Cancer Center) and co-authors also included John Hainsworth, MD (Sarah Cannon Research Institute and Tennessee oncology, PLLC), Charles Swanton, PhD (The Francis Crick Institute), Howard Burris, MD (Sarah Cannon Research Institute and Tennessee oncology, PLLC), Razelle Kurzrock, MD (University of California, San Diego, Moores Cancer Center), Christopher Sweeney, MBBS (Dana-Farber Cancer Institute, Harvard Medical School), Funda Meric-Bernstam, MD (University of Texas, MD Anderson Cancer Center), David R. Spigel, MD (Sarah Cannon Research Institute and Tennessee oncology, PLLC), Ron Bose, MD, PhD (Washington University School of Medicine), Shuangli Guo (Sarah Cannon Research Institute), Bongin Yoo, PhD (Genentech, Inc.), Mary Beattie, MD, MAS (Genentech, Inc.), and Frank Scapaticci MD, PhD (Genentech, Inc.).
The MyPathway study, which is going on at more than 40 centers across the country, including Duke, began in April 2014 and is expected to continue through August 2019, with a target enrollment of 500 patients. In addition to the bile duct cohort of patients, My Pathway has so far yielded signs of activity in several other tumor-specific sub-groups, including cancers of the colon, bladder, lung, and salivary glands.
See the Clinical Trials page on the Duke Cancer Institute web site for more information on getting access to a clinical trial at Duke.